WO2022160970A1 - Concentrated solution of insoluble drug not containing ethanol, and micellar solution prepared therefrom - Google Patents

Concentrated solution of insoluble drug not containing ethanol, and micellar solution prepared therefrom 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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French (fr)
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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    • 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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    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
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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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
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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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    • 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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    • 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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    • A61K47/08—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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    • A61K9/107—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.

Abstract

A concentrated solution of an insoluble drug not containing ethanol, the concentrated solution comprising an insoluble drug and a carrier, which helps to form a micelle, wherein the carrier is composed of a composite emulsifier and a co-solvent. The composite emulsifier is composed of a phospholipid and a non-phospholipid emulsifier, the phospholipid being selected from soybean phospholipid, egg yolk lecithin and a mixture thereof. The co-solvent is selected from propylene glycol, glycerol, PEG200, PEG300, PEG400 and a mixture thereof. In addition, the concentrated solution does not contain oil. The concentrated solution can be used to prepare a micellar solution for intravenous injection.

Description

一种不含乙醇的难溶性药物浓缩液以及由其制备的胶束溶液A kind of ethanol-free insoluble drug concentrate and micellar solution prepared therefrom 技术领域technical field
本发明属于药物制剂领域。具体而言，本发明涉及一种不含乙醇的难溶性药物浓缩液及其制备方法，还涉及由所述浓缩液制备得到的胶束溶液。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.
背景技术Background technique
据统计，目前市场上销售的药物有40％以上属于难溶性药物，处于开发阶段的药物中难溶药物占70％。难溶性药物给药、特别是难溶性药物注射给药一直是药物制剂领域研究的难点和热点之一。主要原因是很多难溶性药物由于溶解度问题不能制备成注射剂，而注射剂在临床上又具有不可替代的作用，因此，增加难溶性药物的溶解度，进而实现难溶性药物注射给药，已经成为药剂学领域最活跃的研究方向之一。According to statistics, more than 40% of the drugs currently on the market are insoluble drugs, and 70% of the drugs in the development stage are insoluble drugs. The administration of poorly soluble drugs, especially the injection administration of poorly soluble drugs, has always been one of the difficulties and hotspots in the field of pharmaceutical preparations. The main reason is that many poorly soluble drugs cannot be prepared into injections due to solubility problems, and injections have an irreplaceable role in clinical practice. Therefore, increasing the solubility of poorly soluble drugs, and then realizing injection administration of poorly soluble drugs, has become the field of pharmacy. One of the most active research directions.
近年来，科研工作者已经开发出了很多增加难溶性药物溶解度的方法，包括制成前药、调节pH值、采用共溶剂、使用助溶物、制成乳剂或脂质体、包合技术、胶束增溶、纳米悬浮技术等。其中，应用较为广泛的是使用助溶剂，其中作为助溶剂应用较多的是乙醇。In recent years, researchers have developed many methods to increase the solubility of poorly soluble drugs, including making prodrugs, adjusting pH, using co-solvents, using solubilizers, making emulsions or liposomes, inclusion technology, Micellar solubilization, nano-suspension technology, etc. Among them, the most widely used is the use of co-solvents, among which ethanol is used more as a co-solvent.
乙醇作为重要的助溶剂，被广泛应用于注射剂中。例如，作为抗肿瘤药物，多西他赛注射液含13％无水乙醇；作为肾上腺皮质激素类药物，氢化可的松注射液含50％乙醇，醋酸氢化可的松注射液(醇型)含50％乙醇；作为心脑血管药物，去乙酰毛花苷注射液含10％乙醇，洋地黄毒苷注射液含10％(V/V)乙醇，尼莫地平注射液含20％(V/V)乙醇，硝酸甘油注射液、地西泮注射液、盐酸吡硫醇注射液、舒血宁注射液也均使用95％乙醇作为辅料；作为抗菌药物，阿奇霉素注射液、阿奇霉素氯化钠注射液、注射用两性霉素B脂质体、注射用伏立康唑也均含乙醇；作为免疫抑制药物，他克莫司注射液每毫升含有638mg乙醇，环孢素注射液的辅料也包括乙醇；作为呼吸系统用药，穿琥宁注射液含乙醇；作为妇产科用药，前列腺素E2注射液也含有乙醇。As an important cosolvent, ethanol is widely used in injections. For example, as an antitumor drug, docetaxel injection contains 13% absolute ethanol; as adrenocortical hormone drug, hydrocortisone injection contains 50% ethanol, and hydrocortisone acetate injection (alcohol type) contains 50% ethanol; as 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; as antibacterial drugs, azithromycin injection, azithromycin sodium chloride injection, Amphotericin B liposome for injection and voriconazole for injection also contain ethanol; as an immunosuppressive drug, tacrolimus injection contains 638 mg of ethanol per milliliter, and the excipients of cyclosporine injection also include ethanol; as a respiratory system drug , Chuanhuning injection contains ethanol; as a medicine for obstetrics and gynecology, prostaglandin E2 injection also contains ethanol.
另外，在难溶性药物的口服给药制剂中，乙醇也被广泛应用。例如，藿香正气水含乙醇40％-50％；十滴水的乙醇含量为60％-70％；复方甘草口服溶液含甘草流浸膏和复方樟脑酊；感冒止咳糖浆含甘草流浸膏和橙皮酊；环孢素口服溶液、左卡尼汀口服溶液均含少量乙醇；地高辛口服溶液含乙醇9％-11％；麦角 隐亭咖啡因口服液含5.8％(v/v)的乙醇。此外，以下药物也均含有乙醇：酮咯酸氨丁三醇片/胶囊、硝酸甘油气雾剂、沙丁胺醇气雾剂、盐酸克仑特罗气雾剂、麝香祛痛气雾剂(乙醇量为47％-57％)、宽胸气雾剂(乙醇量为27％(ml/g)-42％(ml/g))、硝酸异山梨酯喷雾剂(含90％乙醇)、骨痛灵酊(乙醇量为45％-55％)、消肿止痛酊(乙醇量为47％-57％)、祛伤消肿酊(乙醇量为50％-60％)、烧伤灵酊(乙醇量为70％-75％)、筋痛消酊(乙醇量为50％-60％)、复方樟脑酊(乙醇量为52％-60％)、颠茄酊(乙醇量为60％-70％)、姜酊(乙醇量为80％-88％)、远志酊(乙醇量为50％-58％)、碘酊(含乙醇45％-55％(ml/ml)、颠茄流浸膏(乙醇量为52％-66％)、浙贝流浸膏(乙醇量为50％-70％)、姜流浸膏(乙醇量为72％-80％)、远志流浸膏(乙醇量为38％-48％)、当归流浸膏(乙醇量为45％-50％)、甘草流浸膏(乙醇量为20％-25％)、大黄流浸膏(乙醇量为40％-50％)、益母草流浸膏(乙醇量为16％-20％)、姜黄消痤搽剂(乙醇量为35％-60％)、骨友灵搽剂(乙醇量为20％-25％)、麝香舒活搽剂(乙醇量为50％-58％)、麝香祛痛搽剂(乙醇量为47％-57％)、癣宁搽剂(乙醇量不低于60％)、酮洛芬搽剂(乙醇量为65％-75％)、疏痛安涂膜剂(乙醇量为42％-52％)、正骨水(乙醇量为56％-66％)、甘油醇溶液(含2％(V/V)乙醇)、复方醋酸氯己定喷剂等。In addition, ethanol is also widely used in preparations for oral administration of poorly soluble drugs. For example, 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 . In addition, 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 (50%-58% ethanol), iodine tincture (45%-55% ethanol (ml/ml), belladonna extract (52% ethanol) %-66%), Zhebei flow extract (ethanol content is 50%-70%), ginger flow extract (ethanol content is 72%-80%), Yuanzhi flow extract (ethanol content is 38%-48%) ), Angelica sinensis (45%-50% ethanol), Licorice (20%-25% ethanol), Rhubarb (40%-50% ethanol), Motherwort Cream (the amount of ethanol is 16%-20%), turmeric anti-acne liniment (the amount of ethanol is 35%-60%), Guyouling liniment (the amount of ethanol is 20%-25%), musk Shuhuo liniment ( Ethanol content is 50%-58%), musk pain-relieving liniment (ethanol content is 47%-57%), Xuexuanning liniment (ethanol content is not less than 60%), ketoprofen liniment (ethanol content is 65%) %-75%), Shutong'an coating agent (42%-52% ethanol), Zhenggu water (56%-66% ethanol), glycerol solution (containing 2% (V/V) ethanol) , Compound chlorhexidine acetate spray, etc.
然而，处方中含乙醇的制剂、特别是注射液在给药后经常产生不良作用，例如，具有强烈的血管刺激性，注入血管时易引起注射部位的疼痛，且反复多次的注射还易造成静脉炎；另外，乙醇对神经系统有影响，导致肌肉不协调、反应迟钝、注意力不集中、自控能力下降、记忆力减退、智力下降等；乙醇还对肝脏会有损伤，对胃也会产生刺激。处方中含乙醇的制剂，对于乙醇过敏的患者则无法使用，导致该部分患者用药受限。此外，含有乙醇的制剂与头孢类或硝基咪唑类药物合用时，极可能导致双硫仑样不良反应，甚至可能诱发胸痛、心肌梗塞、急性心衰、呼吸困难、急性肝损伤、惊厥乃至死亡。因此，从难溶性药物的处方中去掉乙醇意义重大。However, 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. In addition, when ethanol-containing preparations are combined with cephalosporins or nitroimidazoles, it is very likely to cause disulfiram-like adverse reactions, and may even induce chest pain, myocardial infarction, acute heart failure, dyspnea, acute liver injury, convulsions and even death . Therefore, removing ethanol from the formulation of poorly soluble drugs is significant.
目前仍然非常需要具有良好稳定性的不含乙醇的难溶性药物组合物、特别是注射用药物组合物。There is still a great need for a poorly soluble ethanol-free pharmaceutical composition with good stability, especially a pharmaceutical composition for injection.
本发明的目的之一是提供一种不含乙醇的难溶性药物浓缩液，避免乙醇带来的上述副作用，为难溶性药物的临床应用提供一个更安全的选择。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.
发明人经过大量的实验研究，惊喜地发现，采用特定的复合乳化剂和助乳化剂可以将临床适用剂量的难溶性药物制备成稳定的组合物，所述组合物能实 现对难溶性药物的良好溶解，其是一种浓缩物，为均一透明的溶液，并且制备工艺极其简单。本发明的组合物可在临用前用水性溶媒稀释成胶束溶液，所形成的胶束溶液直接用于对患者进行给药，用药方便，具有优良的稳定性。所述水性溶媒可以是适合注射的水性溶媒(例如，注射用水、5％葡萄糖注射液、0.9％氯化钠注射液等)或适合口服施用的水性溶媒(例如，纯净水等)。而且，由本发明的组合物经稀释获得的胶束溶液完全满足静脉内注射的要求，可通过静脉内注射给药。After a lot of experimental research, the inventor surprisingly found that 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.). Moreover, 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.
因此，本发明的浓缩液不仅具有优良的稳定性，而且包含较少种类的赋形剂、制备工艺简单、适用于多种难溶性药物。由本发明的浓缩液经稀释获得的胶束溶液可顺利实现难溶性药物的给药、特别是注射给药，满足了目前未被满足的临床需求。Therefore, 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.
发明简述Brief description of the invention
本发明的目的在于提供一种不含乙醇的难溶性药物浓缩液，并且提供一种制备所述浓缩液的简单、环保、易产业化的方法。此外，本发明的目的还在于提供一种胶束溶液，其可顺利实现难溶性药物的给药、特别是注射给药。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. In addition, 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.
在第一个方面，本发明提供了一种不含乙醇的难溶性药物浓缩液，其特征在于，所述浓缩液包含难溶性药物和有助于形成胶束的载体，所述载体由复合乳化剂和助溶剂组成，其中所述复合乳化剂由磷脂与非磷脂乳化剂组成，所述助溶剂选自丙二醇、甘油、PEG200、PEG300、PEG400及它们的混合物，更优选选自丙二醇、PEG200、PEG300、PEG400及它们的混合物，并且所述浓缩液不含油。In a first aspect, 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.
所述的磷脂优选选自大豆磷脂、蛋黄卵磷脂及它们的混合物，更优选为蛋黄卵磷脂。The phospholipid is preferably selected from soybean lecithin, egg yolk lecithin and mixtures thereof, more preferably egg yolk lecithin.
所述的非磷脂乳化剂优选选自聚氧乙烯蓖麻油(例如聚氧乙烯35蓖麻油、纯的聚氧乙烯35蓖麻油)、聚氧乙烯氢化蓖麻油(例如，聚氧乙烯40氢化蓖麻油、聚氧乙烯60氢化蓖麻油)、15-羟基硬脂酸聚乙二醇酯、维生素E聚乙二醇1000琥珀酸酯(TPGS)、聚山梨酯(例如聚山梨酯20、21、40、60、61、65、80、81、85、120，特别是聚山梨酯80)及它们的混合物。更优选地，所述的非磷脂乳化剂选自聚氧乙烯40氢化蓖麻油、聚氧乙烯35蓖麻油、纯的聚氧乙烯35蓖麻油、15-羟基硬脂酸聚乙二醇酯、聚山梨酯80及它们的混合物。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. More preferably, 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.
在该方面的一个实施方案中，在本发明的浓缩液中，当将难溶性药物、复合乳化剂、助溶剂的重量总计为100重量％时，所述难溶性药物的重量百分比为0.1％～20％，优选0.5％～15％，例如0.5％、1％、1.5％、2％、5％、6％、10％、15％；所述磷脂的重量百分比为0.1％～20％，优选0.5％～10％，例如0.5％、1％、1.5％、2％、3％、4％、5％、10％；所述非磷脂乳化剂的重量百分比为20％～80％，优选30％～70％，例如30％、35％、40％、43％、46％、48％、50％、70％；余量为助溶剂。In one embodiment of this aspect, in the concentrated solution of the present invention, when the total weight of the poorly soluble drug, the compound emulsifier and the cosolvent is 100% by weight, 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.
本发明的浓缩液可以仅由难溶性药物和有助于形成胶束的载体组成，所述载体由复合乳化剂和助溶剂组成，其中所述复合乳化剂由磷脂与非磷脂乳化剂组成，所述助溶剂选自丙二醇、甘油、PEG200、PEG300、PEG400及它们的混合物，优选选自丙二醇、PEG200、PEG300、PEG400及它们的混合物，并且所述浓缩液不含油。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.
或者，本发明的浓缩液还可以含有pH调节剂和/或抗氧化剂。所述的pH调节剂可以选自枸橼酸、枸橼酸盐(如枸橼酸钠)、马来酸、酒石酸、盐酸、氢氧化钠、醋酸、醋酸盐(如醋酸钠)、磷酸、磷酸盐(如磷酸一氢钠、磷酸二氢钠或磷酸钠)中的一种或多种。所述的抗氧化剂可以选自α-生育酚琥珀酸酯(α-tocopherol succinate)、棕榈酸抗坏血酸酯(ascorbyl palmitate)、丁基化羟基苯甲醚(butylated hydroxyanisole,BHA)、丁化羟基甲苯(butylated hydroxytoluene,BHT)中的一种或多种。Alternatively, the concentrates of the present invention may further contain pH adjusters and/or antioxidants. Described pH adjusting agent 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 α-tocopherol succinate (α-tocopherol succinate), ascorbyl palmitate (ascorbyl palmitate), butylated hydroxyanisole (BHA), butylated hydroxytoluene ( one or more of butylated hydroxytoluene, BHT).
当本发明的浓缩液含油时，经放置浓缩液发生分层。因此，本发明的浓缩液不含油。所述“油”例如是：植物油，如大豆油、玉米油、椰子油、红花油、紫苏油、橄榄油、蓖麻油、葵花籽油、棉籽油、茶油等；动物油，如鱼油、蛋黄油、羊毛脂等；矿物油，如液体石蜡等；天然或合成的甘油三酯，如中链甘油三酸酯(MCT)、长链甘油三酸酯(LCT)、结构油等；以及其它公知的油脂。When the concentrate of the present invention contains oil, separation of the concentrate occurs upon standing. Therefore, the concentrates of the present invention are free of oil. 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.
在第二个方面，本发明提供了制备所述的不含乙醇的难溶性药物浓缩液的方法，其特征在于，所述方法包括以下步骤：将难溶性药物、磷脂、非磷脂乳化剂和助溶剂以任何顺序混合，搅拌均匀，过滤，分装压盖密封。In a second aspect, 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.
在第三个方面，本发明提供了一种胶束溶液，其是通过将上文所述的不含乙醇的难溶性药物浓缩液用水性溶媒稀释获得的。所得胶束溶液外观均一透明，可用于注射给药。In a third aspect, 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.
在第四个方面，本发明提供了上文所述的不含乙醇的难溶性药物浓缩液在 制备胶束溶液中的用途。所述胶束溶液尤其可用于静脉注射。In a fourth aspect, 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.
附图简要说明Brief Description of Drawings
图1是给予5％葡萄糖注射液的家兔的兔耳的代表性HE染色切片的显微镜下观察结果。FIG. 1 is a microscopic observation of a representative HE-stained section of a rabbit ear of a rabbit administered 5% glucose injection.
图2是给予市售尼莫地平注射液的家兔的兔耳代表性HE染色切片的显微镜下观察结果。Figure 2 shows the results of microscope observation of representative HE-stained sections of rabbit ears of rabbits administered with commercially available nimodipine injection.
图3是给予本发明的尼莫地平注射液的家兔的兔耳的代表性HE染色切片的显微镜下观察结果。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.
发明详述Detailed description of the invention
具体实施方案specific implementation
实施方案1.一种不含乙醇的难溶性药物浓缩液，其特征在于，所述浓缩液包含难溶性药物和有助于形成胶束的载体，其中：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:
所述载体由复合乳化剂和助溶剂组成，The carrier is composed of a composite emulsifier and a cosolvent,
所述复合乳化剂由磷脂与非磷脂乳化剂组成，且所述磷脂选自大豆磷脂、蛋黄卵磷脂及它们的混合物，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,
所述助溶剂选自丙二醇、甘油、PEG200、PEG300、PEG400及它们的混合物，优选选自丙二醇、PEG200、PEG300、PEG400及它们的混合物，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,
并且所述浓缩液不含油。And the concentrate is oil-free.
实施方案2.根据实施方案1所述的浓缩液，其中所述非磷脂乳化剂选自聚氧乙烯蓖麻油(例如，聚氧乙烯35蓖麻油、纯的聚氧乙烯35蓖麻油)、聚氧乙烯氢化蓖麻油(例如聚氧乙烯40氢化蓖麻油、聚氧乙烯60氢化蓖麻油)、15-羟基硬脂酸聚乙二醇酯、维生素E聚乙二醇1000琥珀酸酯(TPGS)、聚山梨酯(例如聚山梨酯20、21、40、60、61、65、80、81、85、120，特别是聚山梨酯80)以及它们的混合物。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.
实施方案3.根据实施方案2所述的浓缩液，其中所述的非磷脂乳化剂选自聚氧乙烯40氢化蓖麻油、聚氧乙烯35蓖麻油、纯的聚氧乙烯35蓖麻油、15-羟基硬脂酸聚乙二醇酯、聚山梨酯80及它们的混合物。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.
实施方案4.根据实施方案1至3中任意一项所述的浓缩液，其中所述助溶剂选自丙二醇、PEG300、PEG400及它们的混合物。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.
实施方案5.根据实施方案1至4中任意一项所述的浓缩液，其中当将难溶性药物、复合乳化剂、助溶剂的重量总计为100重量％时，所述难溶性药物的重量百分比为0.1％～20％，优选0.5％～15％；所述磷脂的重量百分比为0.1％～20％，优选0.5％～10％；所述非磷脂乳化剂的重量百分比为20％～80％，优选30％～70％；余量为助溶剂。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.
实施方案6.根据实施方案1至5中任意一项所述的组合物，其中所述难溶性药物选自塞来昔布(celecoxib)、伐地昔布(valdecoxib)、依托考昔(Etocoxib)、布洛芬(ibuprofen)、右旋布洛芬(dexibuprofen)、丙泊酚(propofol)、氟比洛芬酯(flurbiprofen axetil)、前列地尔(alprostadil)、丁酸氯维地平(clevidipine butyrate)、地塞米松棕榈酸酯(dexamethasone palmitate)、非洛地平(felodipine)、尼莫地平(nimodipine)、硝苯地平(nifedipine)、尼群地平(nitrendipine)、环孢素(cyclosporin)、他克莫司(tacrolimus)、左西孟旦(levosimendan)、阿德福韦酯(adefovir dipivoxil)、红霉素(erythromycin)、罗红霉素(roxithromycin)、泊沙康唑(posaconazole)、伊曲康唑(itraconazole)、伏立康唑(voriconazole)、咪康唑(miconazole)、酮康唑(ketoconazole)、黄体酮(progesterone)、辅酶Q10(Coenzyme Q10)、氯吡格雷(clopidogrel)、紫杉醇(paclitaxel)、多西他赛(docetaxel)、卡巴他赛(cabazitaxel)、依托泊苷(etoposide)、替尼泊苷(teniposide)、羟基喜树碱(hydroxycamptothecin)、伊立替康(irinotecan)、乌苯美司(ubenimex)、顺铂(cisplatin)、卡铂(carboplatin)、卡培他滨(capecitabine)、奥沙利铂(oxaliplatin)、吉非替尼(gefitinib)、多柔比星(doxorubicin)、长春碱(vinblastine)、长春新碱(vincristine)、长春西汀(vinpocetine)、长春地辛(vindesine)、吡罗昔康(piroxicam)、螺内酯(spironolactone)、丙戊酸(valproic acid)、他莫昔芬(tamoxifen)、阿奇霉素(azithromycin)、维生素A、维生素D、维生素E、维生素K、非诺贝特(fenofibrate)、吲哚美辛(indomethacin)、瑞德西韦(remdesivir)；优选地，所述难溶性药物选自塞来昔布、布洛芬、右旋布洛芬、丙泊酚、氟比洛芬酯、前列地尔、丁酸氯维地平、地塞米松棕榈酸酯、非洛地平、尼莫地平、硝苯地平、尼群地平、环孢素、他克莫司、左西孟旦、阿德福韦酯、红霉素、罗红霉素、泊沙康唑、伊曲康唑、伏立康唑、黄体酮、辅酶Q10、氯吡格雷、紫杉醇、多西他赛、卡巴他赛、依托泊苷、替尼泊苷和依托考昔；最优选地，所述难溶性药物选自尼莫地平、泊沙康唑、多西他赛、氯吡格雷、左西孟旦、他克莫司、环孢素、紫杉醇、布洛芬、辅酶Q10、卡巴他赛、塞来昔布和依托考昔。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, cabazitaxel, etoposide, teniposide, hydroxycamptothecin, irinotecan, ubenimex , cisplatin, carboplatin, capecitabine, oxaliplatin, gefitinib, doxorubicin, vinblastine , vincristine, vinpocetine, vindesine, piroxicam, spironolactone, valproic acid, tamoxifen, azithromycin (azithromycin), vitamin A, vitamin D, vitamin E, vitamin K, non- Norfibrate (fenofibrate), indomethacin (indomethacin), remdesivir (remdesivir); preferably, the insoluble drug is selected from celecoxib, ibuprofen, dextroibuprofen, propor Phenol, flurbiprofen axetil, alprostadil, clevidipine butyrate, dexamethasone palmitate, felodipine, nimodipine, nifedipine, nitrendipine, cyclosporine, tacrolimus, Levosimendan, adefovir dipivoxil, erythromycin, roxithromycin, posaconazole, itraconazole, voriconazole, progesterone, coenzyme Q10, clopidogrel, paclitaxel, docetaxel, carbachol Taxel, etoposide, teniposide and etoricoxib; most preferably, the poorly soluble drug is selected from nimodipine, posaconazole, docetaxel, clopidogrel, levosimendan, Tacrolimus, cyclosporine, paclitaxel, ibuprofen, coenzyme Q10, cabazitaxel, celecoxib, and etoricoxib.
实施方案7.根据实施方案1至6中任意一项所述的浓缩液，其还含有pH调节剂、抗氧化剂或这二者。Embodiment 7. The concentrate of any one of Embodiments 1 to 6, further comprising a pH adjuster, an antioxidant, or both.
实施方案8.根据实施方案1至6中任意一项所述的组合物，其中：Embodiment 8. The composition of any one of Embodiments 1 to 6, wherein:
所述的难溶性药物是尼莫地平，所述的磷脂是蛋黄卵磷脂，所述的非磷脂乳化剂是15-羟基硬脂酸聚乙二醇酯，所述的助溶剂是丙二醇，并且当将难溶性药物、复合乳化剂、助溶剂的重量总计为100重量％时，尼莫地平的重量百分比为1％，蛋黄卵磷脂的重量百分比为2％，15-羟基硬脂酸聚乙二醇酯的重量百分比为46％，丙二醇重量百分比为51％；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, and when When the total weight of the poorly soluble drug, compound emulsifier and cosolvent is 100% by weight, the weight percentage of nimodipine is 1%, the weight percentage of egg yolk lecithin is 2%, and the 15-hydroxystearic acid polyethylene glycol is The weight percentage of ester is 46%, and the weight percentage of propylene glycol is 51%;
或者or
所述的难溶性药物是泊沙康唑，所述的磷脂是蛋黄卵磷脂，所述的非磷脂乳化剂是15-羟基硬脂酸聚乙二醇酯，所述的助溶剂是PEG300，并且当将难溶性药物、复合乳化剂、助溶剂的重量总计为100重量％时，其中泊沙康唑的重量百分比为1％，蛋黄卵磷脂的重量百分比为3％，15-羟基硬脂酸聚乙二醇酯的重量百分比为50％，PEG300的重量百分比为46％；The insoluble drug is posaconazole, the phospholipid is egg yolk lecithin, the non-phospholipid emulsifier is polyethylene glycol 15-hydroxystearate, the cosolvent is PEG300, and When the total weight of the poorly soluble drug, compound emulsifier and cosolvent is 100% by weight, the weight percentage of posaconazole is 1%, the weight percentage of egg yolk lecithin is 3%, and the 15-hydroxystearic acid polymer The weight percent of ethylene glycol ester is 50%, and the weight percent of PEG300 is 46%;
或者or
所述的难溶性药物是多西他赛，所述的磷脂是蛋黄卵磷脂，所述的非磷脂乳化剂是15-羟基硬脂酸聚乙二醇酯，所述的助溶剂是丙二醇，并且当将难溶性药物、复合乳化剂、助溶剂的重量总计为100重量％时，其中多西他赛的重量百分比为1％，蛋黄卵磷脂的重量百分比为3％，15-羟基硬脂酸聚乙二醇酯的重量百分比为48％，丙二醇的重量百分比为48％；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, and When the total weight of the poorly soluble drug, compound emulsifier and cosolvent is 100% by weight, the weight percentage of docetaxel is 1%, the weight percentage of egg yolk lecithin is 3%, and the 15-hydroxystearic acid poly The weight percent of ethylene glycol ester is 48%, and the weight percent of propylene glycol is 48%;
或者or
所述的难溶性药物是氯吡格雷，所述的磷脂是蛋黄卵磷脂，所述的非磷脂乳化剂是15-羟基硬脂酸聚乙二醇酯，所述的助溶剂是丙二醇，并且当将难溶性药物、复合乳化剂、助溶剂的重量总计为100重量％时，其中氯吡格雷的重量百分比为15％，蛋黄卵磷脂的重量百分比为2％，15-羟基硬脂酸聚乙二醇酯的重量百分比为43％，丙二醇的重量百分比为40％；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, and when When the total weight of the poorly soluble drug, compound emulsifier and cosolvent is 100% by weight, the weight percentage of clopidogrel is 15%, the weight percentage of egg yolk lecithin is 2%, and the weight percentage of 15-hydroxystearic acid polyethylene glycol The weight percentage of alcohol ester is 43%, and the weight percentage of propylene glycol is 40%;
或者or
所述的难溶性药物是左西孟旦，所述的磷脂是蛋黄卵磷脂，所述的非磷脂乳化剂是15-羟基硬脂酸聚乙二醇酯，所述的助溶剂是丙二醇，并且当将难溶性药物、复合乳化剂、助溶剂的重量总计为100重量％时，其中左西孟旦的重量百分比为0.5％，蛋黄卵磷脂的重量百分比为2％，15-羟基硬脂酸聚乙二醇酯的 重量百分比为50％，丙二醇的重量百分比为47.5％；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, and When the total weight of the poorly soluble drug, compound emulsifier and cosolvent is 100% by weight, the weight percentage of levosimendan is 0.5%, the weight percentage of egg yolk lecithin is 2%, and the 15-hydroxystearic acid poly The weight percentage of ethylene glycol ester is 50%, and the weight percentage of propylene glycol is 47.5%;
或者or
所述的难溶性药物是他克莫司，所述的磷脂是蛋黄卵磷脂，所述的非磷脂乳化剂是15-羟基硬脂酸聚乙二醇酯，所述的助溶剂是丙二醇，并且当将难溶性药物、复合乳化剂、助溶剂的重量总计为100重量％时，其中他克莫司的重量百分比为1.5％，蛋黄卵磷脂的重量百分比为2％，15-羟基硬脂酸聚乙二醇酯的重量百分比为46％，丙二醇的重量百分比为50.5％；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, and When the total weight of the poorly soluble drug, compound emulsifier and cosolvent is 100% by weight, the weight percentage of tacrolimus is 1.5%, the weight percentage of egg yolk lecithin is 2%, and the weight percentage of 15-hydroxystearic acid poly The weight percentage of ethylene glycol ester is 46%, and the weight percentage of propylene glycol is 50.5%;
或者or
所述的难溶性药物是环孢素，所述的磷脂是蛋黄卵磷脂，所述的非磷脂乳化剂是15-羟基硬脂酸聚乙二醇酯，所述的助溶剂是丙二醇，并且当将难溶性药物、复合乳化剂、助溶剂的重量总计为100重量％时，其中环孢素的重量百分比为10％，蛋黄卵磷脂的重量百分比为2％，15-羟基硬脂酸聚乙二醇酯的重量百分比为43％，丙二醇的重量百分比为45％；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, and when When the total weight of the poorly soluble drug, compound emulsifier and cosolvent is 100% by weight, the weight percentage of cyclosporine is 10%, the weight percentage of egg yolk lecithin is 2%, and the weight percentage of 15-hydroxystearic acid polyethylene glycol is 100%. The weight percentage of alcohol ester is 43%, and the weight percentage of propylene glycol is 45%;
或者or
所述的难溶性药物是紫杉醇，所述的磷脂是蛋黄卵磷脂，所述的非磷脂乳化剂是15-羟基硬脂酸聚乙二醇酯，所述的助溶剂是丙二醇，并且当将难溶性药物、复合乳化剂、助溶剂的重量总计为100重量％时，其中紫杉醇的重量百分比为1％，蛋黄卵磷脂的重量百分比为2％，15-羟基硬脂酸聚乙二醇酯的重量百分比为46％，丙二醇的重量百分比为51％；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, and when the insoluble drug is When the total weight of the soluble drug, compound emulsifier and cosolvent is 100% by weight, the weight percentage of paclitaxel is 1%, the weight percentage of egg yolk lecithin is 2%, and the weight of 15-hydroxystearic acid polyethylene glycol ester The percentage is 46%, and the weight percentage of propylene glycol is 51%;
或者or
所述的难溶性药物是布洛芬，所述的磷脂是蛋黄卵磷脂，所述的非磷脂乳化剂是15-羟基硬脂酸聚乙二醇酯，所述的助溶剂是PEG300，并且当将难溶性药物、复合乳化剂、助溶剂的重量总计为100重量％时，其中布洛芬的重量百分比为10％，蛋黄卵磷脂的重量百分比为2％，15-羟基硬脂酸聚乙二醇酯的重量百分比为40％，PEG300的重量百分比为48％；The insoluble drug is ibuprofen, the phospholipid is egg yolk lecithin, the non-phospholipid emulsifier is polyethylene glycol 15-hydroxystearate, the cosolvent is PEG300, and when When the total weight of the poorly soluble drug, compound emulsifier and cosolvent is 100% by weight, the weight percentage of ibuprofen is 10%, the weight percentage of egg yolk lecithin is 2%, and the weight percentage of 15-hydroxystearic acid polyethylene glycol is 100%. The weight percentage of alcohol ester is 40%, and the weight percentage of PEG300 is 48%;
或者or
所述的难溶性药物是辅酶Q10，所述的磷脂是蛋黄卵磷脂，所述的非磷脂乳化剂是15-羟基硬脂酸聚乙二醇酯，所述的助溶剂是丙二醇，并且当将难溶性药物、复合乳化剂、助溶剂的重量总计为100重量％时，其中辅酶Q10的重量百分比为5％，蛋黄卵磷脂的重量百分比为10％，15-羟基硬脂酸聚乙二醇酯的重量百分比为30％，丙二醇的重量百分比为55％；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, and when the When the total weight of the poorly soluble drug, compound emulsifier and cosolvent is 100% by weight, the weight percentage of coenzyme Q10 is 5%, the weight percentage of egg yolk lecithin is 10%, and 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%;
所述的难溶性药物是卡巴他赛，所述的磷脂是蛋黄卵磷脂，所述的非磷脂乳化剂是吐温80，所述的助溶剂是丙二醇，并且当将难溶性药物、复合乳化剂、助溶剂的重量总计为100重量％时，其中卡巴他赛的重量百分比为1％，蛋黄卵磷脂的重量百分比为2％，吐温80的重量百分比为46％，丙二醇的重量百分比为51％；The insoluble drug is cabazitaxel, the phospholipid is egg yolk lecithin, the non-phospholipid emulsifier is Tween 80, the cosolvent is propylene glycol, and when 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% ;
所述的难溶性药物是塞来昔布，所述的磷脂是蛋黄卵磷脂，所述的非磷脂乳化剂是15-羟基硬脂酸聚乙二醇酯，所述的助溶剂是丙二醇，并且当将难溶性药物、复合乳化剂、助溶剂的重量总计为100重量％时，其中塞来昔布的重量百分比为6％，蛋黄卵磷脂的重量百分比为0.5％，15-羟基硬脂酸聚乙二醇酯的重量百分比为70％，丙二醇的重量百分比为23.5％；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, and When the total weight of the poorly soluble drug, compound emulsifier and cosolvent is 100% by weight, the weight percentage of celecoxib is 6%, the weight percentage of egg yolk lecithin is 0.5%, and the 15-hydroxystearic acid poly The weight percentage of ethylene glycol ester is 70%, and the weight percentage of propylene glycol is 23.5%;
或者or
所述的难溶性药物是依托考昔，所述的磷脂是蛋黄卵磷脂，所述的非磷脂乳化剂是15-羟基硬脂酸聚乙二醇酯，所述的助溶剂是丙二醇，并且当将难溶性药物、复合乳化剂、助溶剂的重量总计为100重量％时，其中依托考昔的重量百分比为5％，蛋黄卵磷脂的重量百分比为5％，15-羟基硬脂酸聚乙二醇酯的重量百分比为35％，丙二醇的重量百分比为55％。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, and when When the total weight of the poorly soluble drug, compound emulsifier and cosolvent is 100% by weight, the weight percentage of etoricoxib is 5%, the weight percentage of egg yolk lecithin is 5%, and the weight percentage of 15-hydroxystearic acid polyethylene glycol is 5%. The weight percent of alcohol ester is 35%, and the weight percent of propylene glycol is 55%.
实施方案9.实施方案1至8中任意一项所述的浓缩液在制备用于静脉内注射、特别是静脉内滴注的胶束溶液中的用途。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.
实施方案10.制备实施方案1至8中任意所述的浓缩液的方法，所述方法包括以下步骤：将难溶性药物、磷脂、非磷脂乳化剂和助溶剂以任意顺序混合，搅拌均匀，过滤，分装压盖密封。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.
实施方案11.一种胶束溶液，其是通过将实施方案1至8中任意一项所述的浓缩液用水性溶媒稀释获得的。Embodiment 11. A micellar solution obtained by diluting the concentrate of any one of Embodiments 1 to 8 with an aqueous vehicle.
实施方案12.根据实施方案11所述的胶束溶液，其中所述水性溶媒是注射用水、5％葡萄糖注射液或0.9％氯化钠注射液。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.
实施方案13.根据实施方案12所述的胶束溶液，其用于静脉内注射，特别是静脉内滴注。Embodiment 13. The micellar solution according to Embodiment 12 for intravenous injection, in particular intravenous drip.
本发明的组合物及其制备方法The composition of the present invention and its preparation method
发明人令人惊奇地发现可以将难溶性药物例如尼莫地平等用由磷脂和非磷脂乳化剂组成的复合乳化剂以及特定的助溶剂制备成不含乙醇的稳定的组合物，其是一种浓缩液，在临用前用水性溶媒稀释，形成胶束溶液。当用适合注 射的水性溶媒例如注射用水、5％葡萄糖注射液或0.9％氯化钠注射液稀释时，所形成的胶束溶液可直接用于注射给药，例如静脉内注射给药。The inventors have surprisingly found that poorly soluble drugs such as nimodipine can be prepared into ethanol-free stable compositions with a complex emulsifier consisting of a phospholipid and a non-phospholipid emulsifier and a specific cosolvent. The concentrate is diluted with an aqueous vehicle just before use to form a micellar solution. When diluted with an aqueous vehicle suitable for injection, such as water for injection, 5% dextrose injection or 0.9% sodium chloride injection, the resulting micellar solution can be used directly for administration by injection, such as intravenous administration.
因此，在第一个方面，本发明提供了一种不含乙醇的难溶性药物浓缩液，其特征在于，所述浓缩液包含难溶性药物和有助于形成胶束的载体，其中所述载体由复合乳化剂与助溶剂组成，所述复合乳化剂由磷脂与非磷脂乳化剂组成，所述助溶剂选自丙二醇、甘油、PEG200、PEG300、PEG400及它们的混合物，优选选自丙二醇、PEG200、PEG300或PEG400，并且所述浓缩物不含油。Therefore, in a first aspect, 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.
所述的磷脂优选选自大豆磷脂、蛋黄卵磷脂及它们的混合物，更优选是蛋黄卵磷脂。The phospholipid is preferably selected from soybean lecithin, egg yolk lecithin and mixtures thereof, more preferably egg yolk lecithin.
所述的非磷脂乳化剂选自聚氧乙烯蓖麻油(例如聚氧乙烯35蓖麻油、纯的聚氧乙烯35蓖麻油)、聚氧乙烯氢化蓖麻油(例如聚氧乙烯40氢化蓖麻油、聚氧乙烯60氢化蓖麻油)、15-羟基硬脂酸聚乙二醇酯、维生素E聚乙二醇1000琥珀酸酯(TPGS)、聚山梨酯(例如聚山梨酯20、21、40、60、61、65、80、81、85、120，特别是聚山梨酯80)及它们的混合物。优选地，所述的非磷脂乳化剂选自聚氧乙烯40氢化蓖麻油、聚氧乙烯35蓖麻油、纯的聚氧乙烯35蓖麻油、15-羟基硬脂酸聚乙二醇酯、聚山梨酯80及它们的混合物。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. Preferably, 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.
当本发明的浓缩液含油时，浓缩液经放置发生分层。因此，本发明的组合物不含油。所述“油”例如是：植物油，如大豆油、玉米油、椰子油、红花油、紫苏油、橄榄油、蓖麻油、葵花籽油、棉籽油、茶油等；动物油，如鱼油、蛋黄油、羊毛脂等；矿物油，如液体石蜡等；天然或合成的甘油三酯，如中链甘油三酸酯(MCT)、长链甘油三酸酯(LCT)、结构油等；以及其它公知的油脂。When the concentrate of the present invention contains oil, the concentrate is left to separate into layers. Thus, the 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.
在该方面的一个优选的实施方案中，在本发明的浓缩液中，当将难溶性药物、复合乳化剂、助溶剂的重量总计为100重量％时，所述难溶性药物的重量百分比为0.1％～20％，优选0.5％～15％，例如0.5％、1％、1.5％、2％、5％、6％、10％、15％；所述磷脂的重量百分比为0.1％～20％，优选0.5％～10％，例如0.5％、1％、1.5％、2％、3％、4％、5％、10％；所述非磷脂乳化剂的重量百分比为20％～80％，优选30％～70％，例如30％、35％、40％、43％、46％、48％、50％、70％；余量为助溶剂。In a preferred embodiment of this aspect, in the concentrated solution of the present invention, when the total weight of the poorly soluble drug, the compound emulsifier and the cosolvent is 100 wt %, 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.
本发明的浓缩液是均一透明的溶液，具有良好的物理和化学稳定性。例如，在室温下放置12个月或者在40℃放置30天，本发明的实施例5中的浓缩液的一直是透明均一的溶液，未见分层，也未见药物析出，难溶性药物的含量和有 关物质等均未发生明显变化，符合药品质控标准要求。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.
本发明的浓缩液可以用水性溶媒稀释，从而形成胶束溶液。所述水性溶媒可以是适合注射的水性溶媒(例如，注射用水、5％葡萄糖注射液、0.9％氯化钠注射液等)或适合口服施用的水性溶媒(例如，纯净水等)。用适合注射的水性溶媒例如5％葡萄糖注射液稀释后，本发明的浓缩液所形成的胶束溶液符合静脉内注射剂、甚至是静脉内滴注的注射剂的要求，因此，所述胶束溶液可以直接用于皮下注射、皮内注射、腹膜内注射、静脉内注射，包括静脉内推注和静脉内滴注。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.). After being diluted with 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.
在将本发明的浓缩液用水性溶媒稀释后，产生了透明的溶液，其既不浑浊，也不存在任何沉淀物。经过初步检测，估计在该溶液中形成了粒度约10nm或更小的胶束，因此将所形成的溶液称为“胶束溶液”。After dilution of the concentrate of the present invention with an aqueous vehicle, a clear solution was produced which was neither cloudy nor present any precipitate. After preliminary inspection, it was estimated that micelles with a particle size of about 10 nm or less were formed in this solution, so the formed solution was called "micellar solution".
本发明的浓缩液不仅自身具有良好的稳定性，而且由其稀释获得的胶束溶液也具有良好的稳定性。例如，将本发明的浓缩液用5％葡萄糖注射液稀释后形成的溶液于室温条件下放置24小时，未见药物析出或分层。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. For example, 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.
本发明所述的“难溶性药物”是指已知的在医药领域中可以应用的药物，且相对其有效给药量而言，其在水中的溶解度较低。更具体地，本发明所述的“难溶性药物”是指属于中国药典“凡例”中记载的溶解度为“微溶”(溶质1g(ml)能在溶剂100～不到1000ml中溶解)、“极微溶解”(溶质1g(ml)能在溶剂1000～不到10000ml中溶解)或“几乎不溶或不溶”(溶质1g(ml)在溶剂10000ml中不能完全溶解)的药物。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.
本发明所述的难溶性药物的实例包括、但不限于：塞来昔布、伐地昔布、依托考昔、布洛芬、右旋布洛芬、丙泊酚、氟比洛芬酯、前列地尔、丁酸氯维地平、地塞米松棕榈酸酯、非洛地平、尼莫地平、硝苯地平、尼群地平、环孢素、他克莫司、左西孟旦、阿德福韦酯、红霉素、罗红霉素、泊沙康唑、伊曲康唑、伏立康唑、咪康唑、酮康唑、黄体酮、辅酶Q10、氯吡格雷、紫杉醇、多西他赛、卡巴他赛、依托泊苷、替尼泊苷、羟基喜树碱、伊立替康、乌苯美司、顺铂、卡铂、卡培他滨、奥沙利铂、吉非替尼、多柔比星、长春碱、长春新碱、长春西汀、长春地辛、吡罗昔康、螺内酯、丙戊酸、他莫昔芬、阿奇霉素、维生素A、维生素D、维生素E、维生素K、非诺贝特、吲哚美辛、瑞德西韦。优选地，所述难溶性药物选自塞来昔布、布洛芬、右旋布洛芬、丙泊酚、氟比洛芬酯、前列地尔、丁酸氯维地平、地塞米松棕榈酸酯、非洛地平、尼莫 地平、硝苯地平、尼群地平、环孢素、他克莫司、左西孟旦、阿德福韦酯、红霉素、罗红霉素、泊沙康唑、伊曲康唑、伏立康唑、黄体酮、辅酶Q10、氯吡格雷、紫杉醇、多西他赛、卡巴他赛、依托泊苷、替尼泊苷和依托考昔。最优选地，所述难溶性药物选自尼莫地平、泊沙康唑、多西他赛、氯吡格雷、左西孟旦、他克莫司、环孢素、紫杉醇、布洛芬、辅酶Q10、卡巴他赛、塞来昔布和依托考昔。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, irinotecan, ubenimex, cisplatin, carboplatin, capecitabine, oxaliplatin, gefitinib, doxorubicin Star, vinblastine, vincristine, vinpocetine, vindesine, piroxicam, spironolactone, valproic acid, tamoxifen, azithromycin, vitamin A, vitamin D, vitamin E, vitamin K, fenofibrate, Indomethacin, Remdesivir. Preferably, 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. Most preferably, the insoluble drug is selected from nimodipine, posaconazole, docetaxel, clopidogrel, levosimendan, tacrolimus, cyclosporine, paclitaxel, ibuprofen, coenzyme Q10, cabazitaxel, celecoxib, and etoricoxib.
发明人对本发明的浓缩液中所用的乳化剂进行了筛选，磷脂乳化剂考察了大豆磷脂、蛋黄卵磷脂、氢化大豆卵磷脂；非磷脂乳化剂考察了聚氧乙烯40氢化蓖麻油(例如kolliphor RH40)、聚氧乙烯35蓖麻油(例如kolliphor EL)、15-羟基硬脂酸聚乙二醇酯(例如kolliphor HS15)、维生素E聚乙二醇琥珀酸酯(TPGS)、聚山梨酯80(例如吐温80)。实验结果显示，使用单独的磷脂乳化剂或非磷脂乳化剂制备得到的浓缩液在稀释后所得的溶液稳定性均较差，在形成溶液后1小时左右便会分层；只有将磷脂和非磷脂乳化剂这二者组合使用时，所得的浓缩液才稳定、均一，并且在稀释成后所得溶液具有良好的稳定性，满足静脉注射给药制剂的所有要求。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). 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.
发明人还对助溶剂进行了筛选，包括丙二醇、甘油、PEG200、PEG300、PEG400等，均能形成均一透明的溶液形式的浓缩液，且浓缩液的物理及化学稳定性良好。但是，与其它几种助溶剂相比，用甘油制备的浓缩液较粘稠。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. However, the concentrates prepared with glycerol were more viscous than several other co-solvents.
本发明最优选的浓缩液是具有本申请的实施例5中所给出的组分和比例的那些。The most preferred concentrates of the present invention are those having the components and proportions given in Example 5 of this application.
上文所述的本发明的不含乙醇的难溶性药物浓缩液可以仅由难溶性药物和有助于形成胶束的载体组成，所述载体由复合乳化剂和助溶剂组成，其中所述复合乳化剂由磷脂与非磷脂乳化剂组成，所述助溶剂选自丙二醇、甘油、PEG200、PEG300、PEG400及它们的混合物，优选选自丙二醇、PEG200、PEG300、PEG400及它们的混合物，并且所述浓缩液不含油。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, and the concentrated Fluid does not contain oil.
或者，上文所述的本发明的不含乙醇的难溶性药物浓缩液还可以含有其它组分，例如pH调节剂和/或抗氧化剂。所述的pH调节剂可以选自枸橼酸、枸橼酸盐(如枸橼酸钠)、马来酸、酒石酸、盐酸、氢氧化钠、醋酸、醋酸盐(如醋酸钠)、磷酸、磷酸盐(如磷酸一氢钠、磷酸二氢钠或磷酸钠)中的一种或多种。所述的抗氧化剂可以选自α-生育酚琥珀酸酯、棕榈酸抗坏血酸酯、丁基化羟基苯甲醚(BHA)、丁化羟基甲苯(BHT)中的一种或多种。Alternatively, 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. Described pH adjusting agent 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 α-tocopheryl succinate, ascorbyl palmitate, butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT).
在第二个方面，本发明提供了制备所述的不含乙醇的难溶性药物浓缩物的方法，其特征在于，所述方法包括以下步骤：将难溶性药物、磷脂、非磷脂乳化剂和助溶剂以任意顺序混合，搅拌均匀，过滤，分装压盖密封。In a second aspect, 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.
发明人发现，制备本发明的浓缩液的方法非常简单，各个组分的加入顺序、搅拌时间等对浓缩液的品质没有影响，只要确保难溶性药物溶解即可。The inventors found that the method for preparing the concentrated solution of the present invention is very simple, and the order of adding each component, stirring time, etc. have no effect on the quality of the concentrated solution, as long as the insoluble drugs are dissolved.
本发明采用极其简单的处方工艺，制备出了具有良好稳定性的不含乙醇的难溶性药物浓缩液，其经水性溶媒稀释即可获得直接可用于静脉注射给药的胶束溶液。相比于现有技术，本发明的浓缩液配方简化，制备工艺简单，只需简单的混合、搅拌、过滤、封装即可获得。无需均质机、微射流仪及复杂的配液系统；一般企业都可以实现该工艺。而且，本发明的浓缩液物理、化学稳定性显著提高；储存和运输无需冷链，极大地降低了生产、运输、储存及使用的成本，为临床用药提供巨大方便。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. Compared with the prior art, 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. Moreover, 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.
在第三个方面，本发明提供了一种胶束溶液，其是通过将上文所述的不含乙醇的难溶性药物浓缩液用水性溶媒稀释获得的。所得胶束溶液外观均一透明，可用于注射给药。In a third aspect, 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.
所述胶束溶液均一透明，既不浑浊，也不存在任何沉淀物。经初步检测，估计在该溶液中形成了粒度约10nm或更小的胶束，因此将所形成的溶液称为“胶束溶液”，该胶束溶液接近于真溶液。所述胶束溶液在室温下可以稳定至少24小时。The 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.
所述胶束溶液由于不含有乙醇而避免了与乙醇相关的副作用，例如，与含有乙醇的相应注射液相比，具有大幅度降低的血管刺激性。The 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.
所述胶束溶液可以施用于患者，以治疗其中所包含的难溶性药物所能治疗的疾病。例如，包含尼莫地平的浓缩液和胶束溶液可用于改善急性脑血管病恢复期的血液循环、治疗各种原因的蛛网膜下腔出血后的脑血管痉挛以及其所导致的缺血性神经障碍高血压、偏头痛等、治疗血管性痴呆和突发性耳聋等；包含塞来昔布的浓缩液和胶束溶液可用于治疗急性疼痛和炎性疾病例如骨关节炎和类风湿性关节炎；包含紫杉醇或多西他赛的浓缩液和胶束溶液可用于治疗癌症，例如实体瘤，如乳腺癌、卵巢癌、头颈癌、肺癌(包括非小细胞肺癌和小细胞肺癌)、胰腺癌、胃癌、黑色素瘤、软组织肉瘤；包含布洛芬或右旋布洛芬的浓缩液和胶束溶液可用于治疗疼痛，例如头痛、关节痛、偏头痛、牙痛、肌肉痛、神经痛、痛经。本文所述的难溶性药物及其用途均是本领域已知的，描述 这些难溶性药物的用途的现有技术文献均视为本申请的一部分。The micellar solution can be administered to a patient to treat a disease that the poorly soluble drug contained therein can treat. For example, 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. Disorders hypertension, migraine, etc., treatment of vascular dementia and sudden deafness, etc.; 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.
在第四个方面，本发明提供了上文所述的不含乙醇的难溶性药物浓缩液在制备胶束溶液中的用途。所述胶束溶液尤其可用于静脉注射，例如静脉推注和静脉滴注。In a fourth aspect, 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.
在本公开内容中，发明人以尼莫地平等多种药物作为难溶性药物的模型，详细考察了影响不含乙醇的难溶性药物浓缩液的形成、物理和化学稳定性、稀释后所得胶束溶液的物理稳定性的主要因素，获得了本发明的浓缩液。该浓缩液可广泛应用于难溶性药物，实现难溶性药物的注射给药，为临床应用提供新的治疗可能。In the present disclosure, 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.
定义definition
在本申请的上下文中，“不含乙醇的难溶性药物浓缩液”、“本发明的组合物”、“本发明的浓缩液”等术语可以互换使用，均指本文所述的包含所述难溶性药物和所述有助于形成胶束的载体的组合物，上下文显示含义并非如此的除外。In the context of this application, terms such as "ethanol-free poorly soluble drug concentrate", "composition of the present invention", "concentrate of the present invention" and the like can be used interchangeably, and all refer to the Composition of a poorly soluble drug and said carrier that facilitates the formation of micelles, unless the context indicates otherwise.
本文所用的术语“有助于形成胶束的载体”是指在将本发明的浓缩液用水性溶媒稀释时有助于形成胶束溶液的药学上可接受的载体。The term "carrier that aids in micelle formation" as used herein 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.
本文所用的术语“由……组成”是指除了所列明的组份外不包含显著量的其它物质。例如，在本发明的浓缩液中，有助于形成胶束的载体由复合乳化剂和助溶剂组成，这意味着除了本文所定义的复合乳化剂和助溶剂之外，不包含显著量的其它有助于形成胶束的物质。The term "consisting of" as used herein means that it does not contain significant amounts of other materials in addition to the listed components. For example, in the concentrates of the present invention, 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.
本文所用的术语“乙醇”是指式CH 3CH 2OH的物质。 The term "ethanol" as used herein refers to a substance of formula CH3CH2OH .
本文所用的术语“中链甘油三酸酯”是指从椰子坚硬干燥的内胚乳或者油椰干燥的内胚乳中提取的非挥发性植物油，是由饱和脂肪酸甘油三酸酯组成的混合物。中链甘油三酸酯可以商购获得，例如从辽宁新兴药业、德国IOI Oleo GmbH等商购获得。As used herein, the term "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.
本文所用的术语“聚氧乙烯蓖麻油”是指由不同量环氧乙烷和蓖麻油反应得到的物质。聚氧乙烯蓖麻油的实例包括、但不限于聚氧乙烯35蓖麻油、纯的聚氧乙烯35蓖麻油。The term "polyoxyethylene castor oil" as used herein 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.
本文所用的术语“聚氧乙烯35蓖麻油”是指由1mol甘油蓖麻酸酯与35mol环氧乙烷反应得到的物质，其中除了聚氧乙烯甘油三蓖麻酸酯之外，还含有少量的聚乙二醇蓖麻酸酯和游离乙二醇。聚氧乙烯35蓖麻油可以商购获得，例如以商品名kolliphor EL和kolliphor ELP从巴斯夫公司(BASF)等商购获得。The term "polyoxyethylene 35 castor oil" as used herein 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.
本文所用的术语“纯的聚氧乙烯35蓖麻油”是指纯化的聚氧乙烯甘油三蓖麻酸酯，基本上不含聚乙二醇蓖麻酸酯和游离乙二醇。The term "pure polyoxyethylene 35 castor oil" as used herein refers to purified polyoxyethylene glycerol triricinoleate substantially free of polyethylene glycol ricinoleate and free glycol.
本文所用的术语“聚氧乙烯氢化蓖麻油”是指由不同量环氧乙烷和氢化蓖麻油反应得到的物质。聚氧乙烯氢化蓖麻油的实例包括、但不限于聚氧乙烯40氢化蓖麻油、聚氧乙烯60氢化蓖麻油。The term "polyoxyethylene hydrogenated castor oil" as used herein 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.
本文所用的术语“聚氧乙烯40氢化蓖麻油”是指由l mol甘油三羟基硬脂酸与40-45mol环氧乙烷反应得到的物质，其中除了聚氧乙烯甘油三羟基硬脂酸酯之外，还含有少量聚乙二醇三羟基硬脂酸、游离的聚乙二醇。聚氧乙烯40氢化蓖麻油可以商购获得，例如以商品名kolliphor RH40从巴斯夫公司(BASF)等商购获得。As used herein, the term "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.
本文所用的术语“聚氧乙烯60氢化蓖麻油”是指由l mol甘油三羟基硬脂酸与60mol环氧乙烷反应得到的物质，其中除了聚氧乙烯甘油三羟基硬脂酸酯之外，还含有少量聚乙二醇三羟基硬脂酸、游离的聚乙二醇。The term "polyoxyethylene 60 hydrogenated castor oil" as used herein 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.
本文所用的术语“15-羟基硬脂酸聚乙二醇酯”可以商购获得，例如以商品名kolliphor HS15或Solutol HS-15从巴斯夫公司(BASF)或Sigma-Aldrich商购获得。The term "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.
本文所用的术语“维生素E聚乙二醇琥珀酸酯(TPGS)”是一种维生素E的水溶性衍生物，由维生素E琥珀酸酯的羧基与聚乙二醇的羟基反应而成，其可以商购获得，例如以商品名Tocofersolan(TPGS)从巴斯夫公司(BASF)商购获得。The term "vitamin E polyethylene glycol succinate (TPGS)" as used herein is a water-soluble derivative of vitamin E formed by the reaction of the carboxyl group of vitamin E succinate with the hydroxyl group of polyethylene glycol, which can Commercially available, eg from BASF under the tradename Tocofersolan (TPGS).
本文所用的术语“聚山梨酯”是指一系列聚氧乙烯去水山梨醇的部分脂肪酸酯，按其每摩尔山梨醇与大约20.5mol或4mol环氧乙烷的比例共聚而成。聚山梨酯的实例包括、但不限于例如聚山梨酯20、21、40、60、61、65、80、81、85、120，特别是聚山梨酯80。聚山梨酯可以商购获得，例如以商品名吐温20、吐温40、吐温80等从南京威尔药业股份有限公司商购获得。The term "polysorbate" as used herein 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. Examples of 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.
本文所用的术语“约”、“大约”、“左右”表示其后所给出的数值可以上下扩展20％。例如，“约100”表示80％至120％。As used herein, the terms "about", "approximately" and "around" mean that the numerical value given thereafter may be extended up or down by 20%. For example, "about 100" means 80% to 120%.
实施例Example
以下实施例用于对本发明进行举例说明，但不以任何方式限制所附的权利要求所定义的范围。The following examples serve to illustrate the invention, but in no way limit the scope defined by the appended claims.
除非另有说明，高效液相色谱法是使用岛津LC-20AT进行的，所给出的温度单位是摄氏度，未说明温度的操作是在环境温度下进行的。实施例中所用的 缩略语的含义如表1所示。Unless otherwise stated, high performance liquid chromatography was performed using a Shimadzu LC-20AT, temperatures are given in degrees Celsius, and operations where temperatures were not stated were performed at ambient temperature. The meanings of the abbreviations used in the examples are shown in Table 1.
表1—缩略语含义Table 1—The meaning of abbreviations
缩略语abbreviation 含义meaning 来源source
ELPELP 聚氧乙烯35蓖麻油kolliphor ELPolyoxyethylene 35 Castor Oil kolliphor EL BASFBASF
EPCEPC 蛋黄卵磷脂EPC 80Egg yolk lecithin EPC 80 LipoidLipoid
SPCSPC 大豆磷脂Soy lecithin 江苏曼氏生物Jiangsu Man Bio
HSPCHSPC 氢化大豆卵磷脂Hydrogenated Soy Lecithin LipoidLipoid
RH40RH40 聚氧乙烯40氢化蓖麻油kolliphor RH40Polyoxyethylene 40 Hydrogenated Castor Oil kolliphor RH40 BASFBASF
HS15HS15 15-羟基硬脂酸聚乙二醇酯kolliphor HS15Polyethylene glycol 15-hydroxystearate kolliphor HS15 BASFBASF
Tween 80Tween 80 吐温80Tween 80 南京威尔药业Nanjing Weir Pharmaceutical
TPGSTPGS 聚乙二醇1000维生素E琥珀酸酯Macrogol 1000 Vitamin E Succinate BASFBASF
MCTMCT 中链甘油三酸酯medium chain triglycerides 辽宁新兴药业Liaoning Xinxing Pharmaceutical
LCTLCT 大豆油Soybean oil 辽宁新兴药业Liaoning Xinxing Pharmaceutical
实施例1：单一乳化剂的筛选Example 1: Screening of Single Emulsifiers
表2—包含单一乳化剂的处方Table 2 - Formulations Containing a Single Emulsifier
组分component 处方1prescription 1 处方2prescription 2 处方3prescription 3 处方4prescription 4 处方5prescription 5 处方6prescription 6 处方7prescription 7 处方8prescription 8
尼莫地平Nimodipine 0.1g0.1g 0.1g0.1g 0.1g0.1g 0.1g0.1g 0.1g0.1g 0.1g0.1g 0.1g0.1g 0.1g0.1g
HS15HS15 4.6g4.6g ---- ---- ---- ---- ---- ---- ----
Tween80Tween80 ---- 4.6g4.6g ---- ---- ---- ---- ---- ----
ELPELP ---- ---- 4.6g4.6g ---- ---- ---- ---- ----
TPGSTPGS ---- ---- ---- 4.6g4.6g ---- ---- ---- ----
RH40RH40 ---- ---- ---- ---- 4.6g4.6g ---- ---- ----
EPCEPC ---- ---- ---- ---- ---- 4.6g4.6g ---- ----
SPCSPC ---- ---- ---- ---- ---- ---- 4.6g4.6g ----
HSPCHSPC ---- ---- ---- ---- ---- ---- ---- 4.6g4.6g
丙二醇Propylene Glycol 5.3g5.3g 5.3g5.3g 5.3g5.3g 5.3g5.3g 5.3g5.3g 5.3g5.3g 5.3g5.3g 5.3g5.3g
总计total 10g10g 10g10g 10g10g 10g10g 10g10g 10g10g 10g10g 10g10g
工艺：将处方量的各组分加入20ml的小瓶中，磁力搅拌，直至所有组分完全溶解。Process: Add the prescribed amount of each component into a 20ml vial and stir magnetically until all components are completely dissolved.
处方1-5所得的尼莫地平浓缩液均为淡黄色澄清透明的溶液，处方6-8所得 的尼莫地平浓缩液为浑浊液，EPC、SPC及HSPC在体系中不溶，无法获得溶液，故不再做稀释后的考察。The nimodipine concentrates obtained from prescriptions 1-5 are light yellow clear and transparent solutions, and 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.
将按照处方1-5制备的浓缩液取1ml，用100ml 5％葡萄糖注射液稀释。在25℃下放置，观察形成溶液的情况并考察所得溶液的稳定性。Take 1ml of the concentrate prepared according to prescriptions 1-5 and dilute it with 100ml of 5% glucose injection. After standing at 25°C, the formation of a solution was observed and the stability of the resulting solution was examined.
实验结果如表3所示。The experimental results are shown in Table 3.
表3—用单一乳化剂制备的尼莫地平浓缩液的外观、经稀释形成溶液的情况以及稀释后形成的溶液的稳定性Table 3 - Appearance of Nimodipine Concentrates Prepared with a Single Emulsifier, Solution Formation upon Dilution, and Stability of the Formed Solution After Dilution
Figure PCTCN2021137169-appb-000001
Figure PCTCN2021137169-appb-000001
上述实验数据表明，单独使用磷脂乳化剂EPC、SPC或HSPC无法制备得到透明溶液形式的浓缩液。虽然单独使用非磷脂乳化剂HS15、Tween80、ELP、TPGS或RH40制备的尼莫地平浓缩液都是透明的溶液，并且用5％葡萄糖注射液按照1:100的体积比稀释后均形成澄清透明的溶液，但是稀释后所获得的溶液在25℃下放置1h左右会出现药物析出的现象，这说明稀释后的溶液不稳定，无法满足临床给药、尤其是注射给药的需求。The above experimental data show that the use of the phospholipid emulsifier EPC, SPC or HSPC alone cannot prepare a concentrate in the form of a clear solution. Although the nimodipine concentrates prepared with the non-phospholipid emulsifiers HS15, Tween80, ELP, TPGS or RH40 alone were clear solutions and were diluted 1:100 by volume with 5% Dextrose Injection all formed clear and transparent solutions However, the solution obtained after dilution will cause drug precipitation when placed at 25°C for about 1 hour, which indicates that the diluted solution is unstable and cannot meet the needs of clinical administration, especially injection administration.
实施例2：复合乳化剂的筛选Example 2: Screening of composite emulsifiers
表4—包含复合乳化剂的处方Table 4—Formulations Containing Compound Emulsifiers
组分component 处方9prescription 9 处方10prescription 10 处方11Prescription 11
尼莫地平Nimodipine 0.1g0.1g 0.1g0.1g 0.1g0.1g
HS15HS15 4.6g4.6g 4.6g4.6g 4.6g4.6g
EPCEPC 0.20.2      
SPCSPC    0.2g0.2g   
HSPCHSPC       0.2g0.2g
丙二醇Propylene Glycol 5.1g5.1g 5.1g5.1g 5.1g5.1g
总计total 10g10g 10g10g 10g10g
工艺：将处方量的各组分加入20ml的小瓶中，磁力搅拌，直至所有组分完全溶解。Process: Add the prescribed amount of each component into a 20ml vial and stir magnetically until all components are completely dissolved.
处方9-10所得的尼莫地平浓缩液均为澄清透明的淡黄色溶液，并且观察到这些浓缩液在25℃下放置12月后均不发生分层。The 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.
处方11所得的尼莫地平浓缩液为浑浊液，HSPC在体系中不溶，无法形成溶液，故不再做稀释后的考察。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.
将处方9-10所得浓缩液取1ml，用100ml 5％葡萄糖注射液稀释，形成澄清透明的溶液。将其在25℃下放置，观察稀释后所得的溶液的稳定性。结果显示，在25℃下放置24h，未见有沉淀物析出。Take 1ml of the concentrated solution obtained from prescriptions 9-10 and dilute it with 100ml of 5% glucose injection to form a clear and transparent solution. This was left at 25°C, and the stability of the solution obtained after dilution was observed. The results showed that no precipitate was found after being placed at 25°C for 24 hours.
实验结果如表5所示。The experimental results are shown in Table 5.
表5—用复合乳化剂制备的尼莫地平浓缩液稀释后形成的溶液的稳定性Table 5—Stability of solutions formed after dilution of nimodipine concentrate prepared with complex emulsifier
Figure PCTCN2021137169-appb-000002
Figure PCTCN2021137169-appb-000002
上述实验结果表明，用HS15与HSPC组成的复合乳化剂无法制备得到透明 溶液形式的尼莫地平浓缩液，但是用HS15分别与EPC和SPC组成的复合乳化剂制备的尼莫地平浓缩液均为均一透明的溶液，并且观察到这些浓缩液在25℃下放置12个月后均不发生分层。将处方9和10的浓缩液用5％葡萄糖注射液以1:100的体积比稀释，均形成澄清透明的溶液。如表5所示，将这些溶液在25℃下放置24小时，未见有沉淀物析出，满足静脉注射给药的需求。The above experimental results show that the 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.
由此说明，应当使用包含磷脂和非磷脂复合乳化剂的处方，且其中的磷脂不应当是HSPC，因为并非所有磷脂乳化剂均能制备得到澄清透明的溶液。Thus, 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.
实施例3：油的筛选Example 3: Screening of oils
发明人对多种可药用的油进行了考察，具体实验设计如下：The inventor has investigated a variety of medicinal oils, and the specific experimental design is as follows:
表6—包含不同油的处方Table 6 - Formulations containing different oils
Figure PCTCN2021137169-appb-000003
Figure PCTCN2021137169-appb-000003
工艺：将处方量的各组分加入20ml的小瓶中，磁力搅拌，直至所有组分完 全溶解。Process: add each component of the recipe amount into a 20ml vial and stir magnetically until all components are completely dissolved.
观察按照处方12-21制备的尼莫地平浓缩液的外观。实验结果如表7所示。Observe the appearance of the nimodipine concentrate prepared according to formulations 12-21. The experimental results are shown in Table 7.
表7—用处方12-21制备的尼莫地平浓缩液的稳定性Table 7—Stability of Nimodipine Concentrate Prepared with Recipe 12-21
Figure PCTCN2021137169-appb-000004
Figure PCTCN2021137169-appb-000004
由表7的实验结果可见，处方12-21的浓缩液均是浑浊的液体，在室温放置约1h即分层，不是稳定的体系，因此不再考察其稀释液的稳定性。From the experimental results in Table 7, it can be seen that the concentrated solutions of prescriptions 12-21 are all turbid liquids, which are layered after being placed at room temperature for about 1 hour, and are not stable systems, so the stability of their diluents is no longer investigated.
上述实验结果说明，浓缩液中不能含有油，除了处方12-21中考察的MCT、LCT、橄榄油、鱼油、玉米油、结构油、蓖麻油、葵花籽油、棉籽油、茶油之外，其它性质类似的油脂也均不应包括在本发明的处方中。Above-mentioned experimental result shows, can not contain oil in concentrated solution, except MCT, LCT, olive oil, fish oil, corn oil, structure oil, castor oil, sunflower oil, cottonseed oil, camellia oil investigated in prescription 12-21, Other oils and fats with similar properties should not be included in the formulation of the present invention.
实施例4：助溶剂的筛选Example 4: Screening of cosolvents
发明人对多种可药用的非乙醇助溶剂进行了考察，具体实验设计如下：The inventor has investigated a variety of pharmaceutically acceptable non-ethanol cosolvents, and the specific experimental design is as follows:
表8—包含不同助溶剂的处方Table 8 - Formulations Including Different Cosolvents
组分component 处方22prescription 22 处方23prescription 23 处方24prescription 24 处方25prescription 25 处方26prescription 26
尼莫地平Nimodipine 0.1g0.1g 0.1g0.1g 0.1g0.1g 0.1g0.1g 0.1g0.1g
HS15HS15 4.6g4.6g 4.6g4.6g 4.6g4.6g 4.6g4.6g 4.6g4.6g
EPCEPC 0.3g0.3g 0.3g0.3g 0.3g0.3g 0.3g0.3g 0.3g0.3g
丙二醇Propylene Glycol 1.6g1.6g ---- ---- ---- ----
PEG200PEG200 ---- 1.6g1.6g ---- ---- ----
PEG300PEG300 ---- ---- 1.6g1.6g ---- ----
PEG400PEG400 ---- ---- ---- 1.6g1.6g ----
甘油glycerin             1.6g1.6g
总计total 10g10g 10g10g 10g10g 10g10g 10g10g
工艺：将处方量的各组分加入20ml的小瓶中，磁力搅拌，直至所有组分完 全溶解。Process: add each component of the recipe amount into a 20ml vial and stir magnetically until all components are completely dissolved.
观察按照处方22-26制备的尼莫地平浓缩液的外观。Observe the appearance of the nimodipine concentrate prepared according to formulations 22-26.
将按照处方22-26制备的尼莫地平浓缩液以1:100的体积比用5％葡萄糖注射液稀释100倍。在25℃下放置24小时，观察形成溶液的情况并考察所得溶液的稳定性。实验结果如表9所示。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.
表9—用处方22-26制备的尼莫地平浓缩液的外观、经稀释形成溶液的情况以及稀释产生的溶液的稳定性Table 9 - Appearance of Nimodipine Concentrates Prepared with Formulations 22-26, Formation of Solutions upon Dilution, and Stability of Solutions Produced by Dilution
Figure PCTCN2021137169-appb-000005
Figure PCTCN2021137169-appb-000005
由表9的实验结果可见，用所考察的助溶剂制备的浓缩液均为淡黄色澄清透明溶液，处方22-25的浓缩液流动性很好，相比之下，处方26的浓缩液较为粘稠，流动性比处方22-25的浓缩液差。用这些浓缩液稀释后所得的溶液均具有良好的稳定性，在25℃下静置24小时未见有沉淀物析出。As can be seen from the experimental results of 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.
实施例5：不含乙醇的难溶性药物组合物的制备(*将难溶性药物、复合乳化剂、助溶剂的总量视为100％)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%)
浓缩液1Concentrate 1
组分component 重量百分比*Weight percent* 用量Dosage
尼莫地平Nimodipine 1％1% 0.1g0.1g
HS15HS15 46％46% 4.6g4.6g
EPCEPC 2％2% 0.2g0.2g
丙二醇Propylene Glycol 51％51% 5.1g5.1g
共计total 100％100% 10g10g
工艺：Craft:
称取处方量的EPC与尼莫地平，放入20ml小瓶中，加入处方量的丙二醇，在60℃的水浴中以2000rpm搅拌1min。再向其中加入处方量的HS15，在60℃的水浴中以2000rpm搅拌5min，获得均一透明的溶液。Weigh the prescription amount of EPC and nimodipine, put it into a 20ml vial, add the prescription amount of propylene glycol, and stir at 2000rpm for 1min 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.
浓缩液2Concentrate 2
组分component 重量百分比*Weight percent* 用量Dosage
泊沙康唑posaconazole 1％1% 0.1g0.1g
HS15HS15 50％50% 5.0g5.0g
EPCEPC 3％3% 0.3g0.3g
PEG300PEG300 46％46% 4.6g4.6g
共计total 100％100% 10g10g
工艺：Craft:
称取处方量的EPC、泊沙康唑、PEG300、HS15，放入20ml小瓶中，在60℃的水浴中以2000rpm搅拌15min，获得均一透明的溶液。Weigh the EPC, posaconazole, PEG300, HS15 in the recipe amount, put it into a 20ml vial, and stir at 2000rpm for 15min in a 60°C water bath to obtain a uniform and transparent solution.
浓缩液3Concentrate 3
组分component 重量百分比*Weight percent* 用量Dosage
多西他赛Docetaxel 1％1% 0.1g0.1g
HS15HS15 48％48% 4.8g4.8g
EPCEPC 3％3% 0.3g0.3g
丙二醇Propylene Glycol 48％48% 4.8g4.8g
共计total 100％100% 10g10g
工艺：Craft:
称取处方量的EPC与多西他赛，放入20ml小瓶中，加入处方量的丙二醇，在60℃的水浴中以2000rpm搅拌10min。再向其中加入处方量的HS15，在60℃的水浴中以2000rpm搅拌5min，获得均一透明的溶液。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.
浓缩液4Concentrate 4
组分component 重量百分比*Weight percent* 用量Dosage
氯吡格雷Clopidogrel 15％15% 1.5g1.5g
HS15HS15 43％43% 4.3g4.3g
EPCEPC 2％2% 0.2g0.2g
丙二醇Propylene Glycol 40％40% 4.0g4.0g
共计total 100％100% 10g10g
工艺：Craft:
称取处方量的EPC、氯吡格雷、丙二醇、HS15，放入20ml小瓶中，在60℃的水浴中以2000rpm搅拌15min，获得均一透明的溶液。Weigh the prescribed amounts of EPC, clopidogrel, propylene glycol, and HS15, put them into a 20 ml vial, and stir at 2000 rpm for 15 min in a 60° C. water bath to obtain a uniform and transparent solution.
浓缩液5Concentrate 5
组分component 重量百分比*Weight percent* 用量Dosage
左西孟旦Levosimendan 0.5％0.5% 0.05g0.05g
HS15HS15 50％50% 5.0g5.0g
EPCEPC 2％2% 0.2g0.2g
丙二醇Propylene Glycol 47.5％47.5% 4.75g4.75g
共计total 100％100% 10g10g
工艺：Craft:
称取处方量的EPC、左西孟旦、丙二醇、HS15，放入20ml小瓶中，在60℃的水浴中以2000rpm搅拌15min，获得均一透明的溶液。Weigh the EPC, levosimendan, propylene glycol, and HS15 in the recipe amount, put them into a 20ml vial, and stir at 2000rpm for 15min in a 60°C water bath to obtain a uniform and transparent solution.
浓缩液6Concentrate 6
组分component 重量百分比*Weight percent* 用量Dosage
他克莫司Tacrolimus 1.5％1.5% 0.15g0.15g
HS15HS15 46％46% 4.6g4.6g
EPCEPC 2％2% 0.2g0.2g
丙二醇Propylene Glycol 50.5％50.5% 5.05g5.05g
共计total 100％100% 10g10g
工艺：Craft:
称取处方量的EPC、他克莫司、丙二醇、HS15，放入20ml小瓶中，在60℃的水浴中以2000rpm搅拌15min，获得均一透明的溶液。Weigh the EPC, tacrolimus, propylene glycol, and HS15 in the prescribed amounts, put them into a 20 ml vial, and stir at 2000 rpm for 15 min in a water bath at 60° C. to obtain a uniform and transparent solution.
浓缩液7Concentrate 7
组分component 重量百分比*Weight percent* 用量Dosage
环孢素cyclosporine 10％10% 1.0g1.0g
HS15HS15 43％43% 4.3g4.3g
EPCEPC 2％2% 0.2g0.2g
丙二醇Propylene Glycol 45％45% 4.5g4.5g
共计total 100％100% 10g10g
工艺：Craft:
称取处方量的EPC、环孢素、丙二醇、HS15，放入20ml小瓶中，在60℃ 的水浴中以2000rpm搅拌15min，获得均一透明的溶液。Weigh the recipe amounts of EPC, cyclosporine, propylene glycol, and HS15, put them into a 20ml vial, and stir at 2000rpm for 15min in a 60°C water bath to obtain a uniform and transparent solution.
浓缩液8Concentrate 8
组分component 重量百分比*Weight percent* 用量Dosage
紫杉醇paclitaxel 1％1% 0.1g0.1g
HS15HS15 46％46% 4.6g4.6g
EPCEPC 2％2% 0.2g0.2g
丙二醇Propylene Glycol 51％51% 5.1g5.1g
共计total 100％100% 10g10g
工艺：Craft:
称取处方量的EPC、紫杉醇、丙二醇、HS15，放入20ml小瓶中，在60℃的水浴中以2000rpm搅拌15min，获得均一透明的溶液。Weigh the recipe amounts of EPC, paclitaxel, propylene glycol, and HS15, put them into a 20ml vial, and stir at 2000rpm for 15min in a 60°C water bath to obtain a uniform and transparent solution.
浓缩液9concentrate 9
组分component 重量百分比*Weight percent* 用量Dosage
布洛芬ibuprofen 10％10% 1.0g1.0g
HS15HS15 40％40% 4.0g4.0g
EPCEPC 2％2% 0.2g0.2g
PEG300PEG300 48％48% 4.8g4.8g
共计total 100％100% 10g10g
工艺：Craft:
称取处方量的EPC、布洛芬、PEG300、HS15，放入20ml小瓶中，在60℃的水浴中以2000rpm搅拌15min，获得均一透明的溶液。Weigh the EPC, ibuprofen, PEG300, HS15 of the recipe amount, put it into a 20ml vial, and stir at 2000rpm for 15min in a 60°C water bath to obtain a uniform and transparent solution.
浓缩液10Concentrate 10
组分component 重量百分比*Weight percent* 用量Dosage
辅酶Q10Coenzyme Q10 5％5% 0.5g0.5g
HS15HS15 30％30% 3.0g3.0g
EPCEPC 10％10% 1.0g1.0g
丙二醇Propylene Glycol 55％55% 5.5g5.5g
共计total 100％100% 10g10g
工艺：Craft:
称取处方量的EPC、辅酶Q10、丙二醇、HS15，放入20ml小瓶中，在60℃的水浴中以2000rpm搅拌15min，获得均一透明的溶液。Weigh the recipe amounts of EPC, coenzyme Q10, propylene glycol, and HS15, put them in a 20ml vial, and stir at 2000rpm for 15min in a 60°C water bath to obtain a uniform and transparent solution.
浓缩液11Concentrate 11
组分component 重量百分比*Weight percent* 用量Dosage
卡巴他赛Cabazitaxel 1％1% 0.1g0.1g
Tween80Tween80 46％46% 4.6g4.6g
EPCEPC 2％2% 0.2g0.2g
丙二醇Propylene Glycol 51％51% 5.1g5.1g
共计total 100％100% 10g10g
工艺：Craft:
称取处方量的EPC、卡巴他赛、丙二醇、Tween80，放入20ml小瓶中，在60℃的水浴中以2000rpm搅拌15min，获得均一透明的溶液。Weigh the prescribed amounts of EPC, cabazitaxel, propylene glycol, and Tween80, put them into a 20ml vial, and stir at 2000rpm for 15min in a 60°C water bath to obtain a uniform and transparent solution.
浓缩液12Concentrate 12
组分component 重量百分比*Weight percent* 用量Dosage
塞来昔布Celecoxib 6％6% 0.6g0.6g
HS15HS15 70％70% 7.0g7.0g
EPCEPC 0.5％0.5% 0.05g0.05g
丙二醇Propylene Glycol 23.5％23.5% 2.35g2.35g
共计total 100％100% 10g10g
工艺：Craft:
称取处方量的EPC、塞来昔布、丙二醇、HS15，放入20ml小瓶中，在60℃的水浴中以2000rpm搅拌15min，获得均一透明的溶液。Weigh the EPC, celecoxib, propylene glycol, and HS15 in the prescribed amounts, put them into a 20 ml vial, and stir at 2000 rpm for 15 min in a water bath at 60° C. to obtain a uniform and transparent solution.
浓缩液13Concentrate 13
组分component 重量百分比*Weight percent* 用量Dosage
依托考昔etoricoxib 5％5% 0.5g0.5g
HS15HS15 35％35% 3.5g3.5g
EPCEPC 5％5% 0.5g0.5g
丙二醇Propylene Glycol 55％55% 5.5g5.5g
共计total 100％100% 10g10g
工艺：Craft:
称取处方量的EPC、依托考昔、丙二醇、HS15，放入20ml小瓶中，在60℃的水浴中以2000rpm搅拌15min，获得均一透明的溶液。Weigh the EPC, etoricoxib, propylene glycol, and HS15 in the prescribed amounts, put them into a 20 ml vial, and stir at 2000 rpm for 15 min in a water bath at 60° C. to obtain a uniform and transparent solution.
浓缩液14Concentrate 14
组分component 重量百分比*Weight percent* 用量Dosage
尼莫地平Nimodipine 1％1% 0.1g0.1g
ELPELP 46％46% 4.6g4.6g
EPCEPC 2％2% 0.2g0.2g
丙二醇Propylene Glycol 51％51% 5.1g5.1g
共计total 100％100% 10g10g
工艺：Craft:
称取处方量的EPC与尼莫地平，放入20ml小瓶中，加入处方量的丙二醇，在60℃的水浴中以2000rpm搅拌1min。再向其中加入处方量的ELP，在60℃的水浴中以2000rpm搅拌5min，获得均一透明的溶液。Weigh the prescription amount of EPC and nimodipine, put it into a 20ml vial, add the prescription amount of propylene glycol, and stir for 1min at 2000rpm in a water bath at 60°C. Then, the prescribed amount of ELP was added to it, and the solution was stirred at 2000 rpm for 5 min in a water bath at 60° C. to obtain a uniform and transparent solution.
浓缩液15Concentrate 15
组分component 重量百分比*Weight percent* 用量Dosage
泊沙康唑posaconazole 1％1% 0.1g0.1g
RH40RH40 50％50% 5.0g5.0g
EPCEPC 3％3% 0.3g0.3g
PEG300PEG300 46％46% 4.6g4.6g
共计total 100％100% 10g10g
工艺：Craft:
称取处方量的EPC、泊沙康唑、PEG300、RH40，放入20ml小瓶中，在60℃的水浴中以2000rpm搅拌15min，获得均一透明的溶液。Weigh the EPC, posaconazole, PEG300, RH40 of the recipe amount, put it into a 20ml vial, and stir at 2000rpm for 15min in a 60°C water bath to obtain a uniform and transparent solution.
浓缩液16Concentrate 16
组分component 重量百分比*Weight percent* 用量Dosage
多西他赛Docetaxel 1％1% 0.1g0.1g
Tween80Tween80 48％48% 4.8g4.8g
EPCEPC 3％3% 0.3g0.3g
丙二醇Propylene Glycol 48％48% 4.8g4.8g
共计total 100％100% 10g10g
工艺：Craft:
称取处方量的EPC与多西他赛，放入20ml小瓶中，加入处方量的丙二醇，在60℃的水浴中以2000rpm搅拌10min。再向其中加入处方量的Tween80，在 60℃的水浴中以2000rpm搅拌5min，获得均一透明的溶液。Weigh the prescription amount of EPC and docetaxel, put it into a 20ml vial, add the prescription amount of propylene glycol, and stir at 2000rpm for 10min in a water bath at 60°C. Then add the prescribed amount of Tween80 to it, and stir at 2000rpm for 5min in a 60°C water bath to obtain a uniform and transparent solution.
浓缩液17Concentrate 17
组分component 重量百分比*Weight percent* 用量Dosage
氯吡格雷Clopidogrel 15％15% 1.5g1.5g
ELPELP 43％43% 4.3g4.3g
EPCEPC 2％2% 0.2g0.2g
丙二醇Propylene Glycol 40％40% 4.0g4.0g
共计total 100％100% 10g10g
工艺：Craft:
称取处方量的EPC、氯吡格雷、丙二醇、ELP，放入20ml小瓶中，在60℃的水浴中以2000rpm搅拌15min，获得均一透明的溶液。Weigh the prescribed amounts of EPC, clopidogrel, propylene glycol, and ELP, put them into a 20 ml vial, and stir at 2000 rpm for 15 min in a 60° C. water bath to obtain a uniform and transparent solution.
浓缩液18Concentrate 18
组分component 重量百分比*Weight percent* 用量Dosage
左西孟旦Levosimendan 0.5％0.5% 0.05g0.05g
HS15HS15 25％25% 2.5g2.5g
Tween80Tween80 25％25% 2.5g2.5g
EPCEPC 2％2% 0.2g0.2g
丙二醇Propylene Glycol 47.5％47.5% 4.75g4.75g
共计total 100％100% 10g10g
工艺：Craft:
称取处方量的EPC、左西孟旦、丙二醇、HS15、Tween80，放入20ml小瓶中，在60℃的水浴中以2000rpm搅拌15min，获得均一透明的溶液。Weigh the EPC, Levosimendan, Propylene Glycol, HS15, Tween80 in the recipe amount, put it into a 20ml vial, and stir at 2000rpm for 15min in a 60°C water bath to obtain a uniform and transparent solution.
浓缩液19Concentrate 19
组分component 重量百分比*Weight percent* 用量Dosage
他克莫司Tacrolimus 1.5％1.5% 0.15g0.15g
ELPELP 46％46% 4.6g4.6g
EPCEPC 2％2% 0.2g0.2g
丙二醇Propylene Glycol 50.5％50.5% 5.05g5.05g
共计total 100％100% 10g10g
工艺：Craft:
称取处方量的EPC、他克莫司、丙二醇、ELP，放入20ml小瓶中，在60℃ 的水浴中以2000rpm搅拌15min，获得均一透明的溶液。Weigh the prescribed amounts of EPC, tacrolimus, propylene glycol, and ELP, put them into a 20 ml vial, and stir at 2000 rpm for 15 min in a 60° C. water bath to obtain a uniform and transparent solution.
浓缩液20Concentrate 20
组分component 重量百分比*Weight percent* 用量Dosage
左西孟旦Levosimendan 0.5％0.5% 0.05g0.05g
Tween80Tween80 50％50% 5.0g5.0g
EPCEPC 2％2% 0.2g0.2g
丙二醇Propylene Glycol 47.5％47.5% 4.75g4.75g
共计total 100％100% 10g10g
工艺：Craft:
称取处方量的EPC、左西孟旦、丙二醇、Tween80，放入20ml小瓶中，在60℃的水浴中以2000rpm搅拌15min，获得均一透明的溶液。Weigh the EPC, levosimendan, propylene glycol, and Tween80 in the recipe amount, put it into a 20ml vial, and stir at 2000rpm for 15min in a 60°C water bath to obtain a uniform and transparent solution.
实施例6：本发明的浓缩液的稳定性考察Example 6: Investigation of the stability of the concentrated solution of the present invention
按照《中国药典》2015版四部通则9001中关于原料药与药物制剂稳定性试验指导原则，将实施例5中的浓缩液1在温度25℃±2℃、相对湿度60％±5％下放置，于第0、3、6、12个月末取样，对相应指标进行考察。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.
1.样品信息：实施例5的浓缩液1，批号201906151. Sample information: Concentrate 1 of Example 5, batch number 20190615
2.稳定性试验条件：2. Stability test conditions:
Figure PCTCN2021137169-appb-000006
Figure PCTCN2021137169-appb-000006
3.分析方法3. Analysis method
(1)性状(1) Characters
检查方法：目测。Inspection method: Visual inspection.
(2)有关物质(2) Related substances
检测方法：HPLC法Detection method: HPLC method
实验条件：Experimental conditions:
色谱柱：C18柱(型号：AgiLent EcLipse XDB-C18，长25cm，内径4.6mm，填料粒径5.0μm)Chromatographic column: C18 column (Model: AgiLent EcLipse XDB-C18, length 25cm, inner diameter 4.6mm, particle size 5.0μm)
柱温：室温Column temperature: room temperature
检测器：UV检测器(检测波长235nm)Detector: UV detector (detection wavelength 235nm)
流动相：甲醇-乙腈-水(35:38:27)Mobile phase: methanol-acetonitrile-water (35:38:27)
流速：1.0mL/minFlow rate: 1.0mL/min
进样体积：20μLInjection volume: 20 μL
运行时间：25minRunning time: 25min
系统适应性：系统适应性溶液色谱中，尼莫地平峰与杂质I(2,6-二甲基-4-(3-硝基苯基)-3,5-吡啶二甲酸2-甲氧基乙酯异丙酯)峰的分离度应大于3.0。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.
具体实验操作：Specific experimental operations:
在各个规定的时间点取放置的浓缩液1，精密称定，加甲醇溶解并定量稀释制成每1mL中约含0.2mg尼莫地平的溶液，作为供试品溶液；精密量取尼莫地平标准品适量，用甲醇稀释成每1mL中约含2μg尼莫地平的溶液，作为对照品溶液。另取尼莫地平标准品与杂质I标准品适量，加甲醇溶解并稀释制成每1mL中约含200μg尼莫地平与1μg杂质I的混合溶液，作为系统适应性溶液。在如上所述的条件下用高效液相色谱法测定。避光操作。记录色谱图至主成分峰保留时间的3倍。系统适应性溶液色谱中，尼莫地平峰与杂质I峰的分离度应大于3.0。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 μg 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 μg of nimodipine and 1 μg of impurity I per 1 mL, as a system adaptability solution. Determined by high performance liquid chromatography under the conditions described above. Avoid light operation. Record the chromatogram to 3 times the retention time of the principal component peak. In the system adaptability solution chromatography, the resolution of nimodipine peak and impurity I peak should be greater than 3.0.
精密量取供试品溶液与对照品溶液各20μL，分别注入液相色谱仪，记录色谱图。在供试品溶液色谱图中，除空白溶剂峰外如有杂质峰(最小峰面积3000Counts)，按加校正因子的1％自身对照法计算杂质含量，其杂质限度见下表。Precisely measure 20 μL each of the test solution and the reference solution, inject them into the liquid chromatograph, and record the chromatogram. In the chromatogram of the test solution, if there is any impurity peak (minimum peak area 3000Counts) except for the blank solvent peak, calculate the impurity content according to the 1% self-control method with the correction factor added, and its impurity limit is shown in the following table.
Figure PCTCN2021137169-appb-000007
Figure PCTCN2021137169-appb-000007
(3)含量及有关物质(3) Content and related substances
检测方法：HPLC法Detection method: HPLC method
实验条件：Experimental conditions:
色谱柱：C18柱(型号：AgiLent EcLipse XDB-C18，长25cm，内径4.6mm，填料粒径5.0μm)Chromatographic column: C18 column (Model: AgiLent EcLipse XDB-C18, length 25cm, inner diameter 4.6mm, particle size 5.0μm)
柱温：室温Column temperature: room temperature
检测器：UV检测器(检测波长235nm)Detector: UV detector (detection wavelength 235nm)
流动相：甲醇-乙腈-水(35:38:27)Mobile phase: methanol-acetonitrile-water (35:38:27)
流速：1.0mL/minFlow rate: 1.0mL/min
进样体积：10μLInjection volume: 10 μL
运行时间：10minRunning time: 10min
系统适应性：理论板数按尼莫地平主峰计算不低于8000，尼莫地平与相邻杂质峰的分离度应符合要求，重复进样的相对标准偏差不超过2.0％。System adaptability: 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%.
具体实验操作：Specific experimental operations:
在上述色谱条件下，重复进样的主峰保留时间的相对标准偏差不超过2.0％。Under the above chromatographic conditions, the relative standard deviation of the retention time of the main peak of repeated injections did not exceed 2.0%.
取有关物质项下系统适用性溶液10μL注入液相色谱仪，尼莫地平与杂质I峰的分离度应大于3.0。取浓缩液1一支，精密称定，用甲醇溶解并稀释成每1mL中约含2mg尼莫地平的溶液，作为供试品溶液；取尼莫地平标准品，精密称定，加甲醇溶解并稀释成每1mL中约含20μg尼莫地平的溶液，作为对照品溶液。精密量取10μL供试品溶液或对照品溶液注入液相色谱仪，记录色谱图。按外标法以峰面积计算。Take 10 μL of the system suitability solution under the item of related substances and inject it into the liquid chromatograph. The separation degree of nimodipine and impurity I peak should be greater than 3.0. Take 1 concentrated solution, accurately weigh it, dissolve it with methanol and dilute it into a solution containing about 2 mg of nimodipine per 1 mL, as the test solution; take the nimodipine standard, accurately weigh it, add methanol to dissolve it Dilute into a solution containing about 20 μg of nimodipine per 1 mL as a reference solution. Precisely measure 10 μL of the test solution or reference solution and inject it into the liquid chromatograph, and record the chromatogram. Calculate the peak area by the external standard method.
4.实验结果4. Experimental results
表10—实施例5中的浓缩液1的长期稳定性试验(25℃±2℃,RH60％±5％)考察结果(批号：20190615)Table 10—Long-term stability test (25°C ± 2°C, RH60% ± 5%) of concentrated solution 1 in Example 5 The results of the investigation (lot number: 20190615)
Figure PCTCN2021137169-appb-000008
Figure PCTCN2021137169-appb-000008
“-”表示未检测到该物质，RRT表示相对保留时间"-" means that the substance is not detected, RRT means relative retention time
以上实验结果显示，实施例5中的浓缩液1在温度25℃±2℃、相对湿度60％±5％的条件下放置12个月，各项指标均符合要求，物理稳定性和化学稳定性良好。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.
发明人还将实施例5的浓缩液2-13在温度40℃±2℃、相对湿度60％±5％的条件下进行了稳定性考察，取样时间为0、5、10、30天，考察指标为难溶性药物的含量，结果如表11所示。The inventor also carried out the stability investigation of the concentrated solution 2-13 of Example 5 under the conditions of temperature 40 ℃ ± 2 ℃, 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.
表11—实施例5的浓缩液2-13的稳定性考察结果The stability investigation result of the concentrated solution 2-13 of table 11—embodiment 5
制剂preparation 0天0 days 5天5 days 10天10 days 30天30 days
浓缩液2Concentrate 2 100％100% 98.2％98.2% 99.1％99.1% 96.8％96.8%
浓缩液3Concentrate 3 100％100% 98.2％98.2% 97.6％97.6% 96.7％96.7%
浓缩液4Concentrate 4 100％100% 99.5％99.5% 97.3％97.3% 98.1％98.1%
浓缩液5Concentrate 5 100％100% 99.6％99.6% 98.1％98.1% 96.2％96.2%
浓缩液6Concentrate 6 100％100% 100.1％100.1% 98.9.7％98.9.7% 97.7％97.7%
浓缩液7Concentrate 7 100％100% 100.1％100.1% 99.7％99.7% 98.5％98.5%
浓缩液8Concentrate 8 100％100% 100.1％100.1% 98.4％98.4% 96.9％96.9%
浓缩液9concentrate 9 100％100% 99.8％99.8% 98.5％98.5% 98.1％98.1%
浓缩液10Concentrate 10 100％100% 99.5％99.5% 97.6％97.6% 97.0％97.0%
浓缩液11Concentrate 11 100％100% 100.2％100.2% 98.5％98.5% 97.3％97.3%
浓缩液12Concentrate 12 100％100% 100.2％100.2% 101.7％101.7% 99.5％99.5%
浓缩液13Concentrate 13 100％100% 98.6％98.6% 98.7％98.7% 97.2％97.2%
由上述结果可见，实施例5的浓缩液2-13在40℃±2℃、RH 60％±5％的条件下放置30天，难溶性药物的含量均保持在90％-110％范围内，具有良好的化学稳定性。It can be seen from the above results that the concentrates 2-13 of Example 5 were placed for 30 days under the conditions of 40°C ± 2°C and RH 60% ± 5%, and the content of the poorly soluble drugs was kept in the range of 90%-110%, Has good chemical stability.
此外，将在0、5、10、30天取样的浓缩液2-13用5％葡萄糖注射液以1:100的体积比稀释后，均形成稳定至少24小时的胶束溶液。In addition, after diluting the concentrates 2-13 sampled at 0, 5, 10, and 30 days with 5% glucose injection at a volume ratio of 1:100, all formed micellar solutions that were stable for at least 24 hours.
实施例7：本发明的胶束溶液的刺激性考察Example 7: Investigation of irritation of the micellar solution of the present invention
1、实验方法1. Experimental method
1.1给药方案和考察指标1.1 Dosing schedule and inspection indicators
市售尼莫地平注射液的用于人给药的日剂量为10mg，按照人的平均体重为60kg，折算成家兔的日剂量为0.47mg/kg。将本发明的尼莫地平注射液、市售尼莫地平注射液、5％葡萄糖注射液分别通过耳缘静脉滴注对家兔给药，每天给药 1次，连续给药7天。每天给药前和最后一次给药后48小时，目测观察。在最后一次目测察后将动物安乐死，剪取注射部位及附近处兔耳，进行苏木精-伊红染色(hematoxylin-eosin staining,简称为HE染色)，用光学显微镜下观察切片以确定有无血管扩张、充血、出血、血栓形成、管壁增生、炎症细胞浸润、内皮细胞变性坏死、周围组织水肿等病理改变，并且按表12中所示的“血管剖检评分标准”对每只动物进行评分。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. After the last visual inspection, 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.
表12—血管剖检评分标准Table 12—Vascular Necropsy Scoring Criteria
血管刺激反应Vascular stimulation response 评分score
无明显反应No obvious reaction 00
轻度充血mild congestion 11
轻.中度充血、肿胀Mild to moderate congestion, swelling 22
中.重度充血、肿胀、耳下垂Moderate to severe congestion, swelling, ear droop 33
轻.中度充血、肿胀，且有轻-中度坏死Mild to moderate hyperemia, swelling, and mild to moderate necrosis 44
轻.中度充血、肿胀，且有中-重度广泛坏死Mild to moderate hyperemia, swelling, and moderate to severe extensive necrosis 55
将同组中的动物的评分求平均值，按照如下标准确定刺激等级。The scores of animals in the same group were averaged, and the stimulation level was determined according to the following criteria.
组平均分值group mean 刺激等级stimulus level
0～0.40～0.4 无none
0.5～1.40.5～1.4 极轻微very slight
1.5～2.41.5～2.4 轻度mild
2.5～3.42.5～3.4 中度Moderate
3.5～4.43.5～4.4 重度severe
4.5及以上4.5 and above 极重度very severe
1.2实验材料1.2 Experimental materials
1.2.1供试品1.2.1 Test article
名称：本发明的尼莫地平浓缩液(将批号为DME-009 2020121701的实施例5的浓缩液1用5％葡萄糖注射液稀释至尼莫地平浓度为0.2mg/ml)Name: 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)
浓度：0.2mg/mlConcentration: 0.2mg/ml
性状：澄清透明淡黄色油溶液Appearance: Clear and transparent pale yellow oil solution
生产厂家：北京德立福瑞医药科技有限公司Manufacturer: Beijing Deli Furui Pharmaceutical Technology Co., Ltd.
1.2.2市售对照1.2.2 Commercially available controls
名称：尼莫地平注射液(商品名：尼膜同，含有23.7％(v/v)乙醇)，规格：50ml:10mg。给药前将其用5％葡萄糖注射液稀释至尼莫地平浓度为0.2mg/mlName: 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
批号：BXJC7A1Lot number: BXJC7A1
性状：微黄色澄明液体Appearance: Light yellow clear liquid
有效期至：2024.01.28Valid until: 2024.01.28
厂家：拜耳医药保健有限公司Manufacturer: Bayer Healthcare Co., Ltd.
1.2.3阴性对照1.2.3 Negative control
名称：5％葡萄糖注射液Name: 5% glucose injection
批号：SD20091515Batch number: SD20091515
厂家：山东华鲁制药有限公司Manufacturer: Shandong Hualu Pharmaceutical Co., Ltd.
1.3实验动物1.3 Experimental animals
品种：家兔Breed: Rabbit
级别：SPF级Level: SPF level
数量：18只Quantity: 18
体重：2～3kgWeight: 2～3kg
来源：北京金牧阳实验动物养殖有限责任公司Source: Beijing Jinmuyang Experimental Animal Breeding Co., Ltd.
1.4剂量和分组1.4 Dosage and grouping
给药剂量：0.47mg尼莫地平/kgDosage: 0.47mg nimodipine/kg
分组：将家兔随机分为3组，每组6只。将三个组分别给予市售尼莫地平注射液(A组)、本发明的尼莫地平注射液(B组)和5％葡萄糖注射液(C组)。具体见表13。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.
表13—家兔血管刺激性试验设计Table 13—Rabbit Vascular Irritation Test Design
Figure PCTCN2021137169-appb-000009
Figure PCTCN2021137169-appb-000009
给药方式：采用注射泵进行的耳缘静脉滴注。Mode of administration: Instillation in the marginal ear vein using a syringe pump.
2.实验结果2. Experimental results
2.1目测观察结果2.1 Visual observation results
实验期间，各组家兔饮食饮水、行为活动、体温、呼吸、被毛、口、鼻、眼和粪便等一般状况良好，均未见异常。所有动物耳部于给药前未见明显异常。During the experiment, the general conditions of the rabbits in each group, such as diet and drinking water, behavior, body temperature, respiration, coat, mouth, nose, eyes and feces, were good, and no abnormality was found. There was no obvious abnormality in the ears of all animals before administration.
2.2注射部位观察及评分结果2.2 Injection site observation and scoring results
将如1.1节所述用HE染色制备的切片用光学显微镜进行观察。结果如下：Sections prepared with HE staining as described in Section 1.1 were observed with a light microscope. The result is as follows:
C组动物的给药侧耳朵均未见充血、红肿、变性、坏死等局部刺激性反应。在低倍镜下，表皮完整，可见完好的毛囊及皮脂腺结构；在高倍镜下，间质主要由胶原纤维及成纤维细胞组成，其间可见小的毛细血管。结果证明，5％葡萄糖注射液滴注给药对兔耳基本没有刺激性。C组家兔的代表性HE染色(100×和400×)结果见图1。There were no local irritant reactions such as congestion, redness, degeneration and necrosis in the ears of animals in group C. Under low magnification, the epidermis is intact, and intact hair follicles and sebaceous glands can be seen; under high magnification, the interstitium is mainly composed of collagen fibers and fibroblasts, with small capillaries in between. The results showed that the administration of 5% glucose injection droplets did not irritate rabbit ears. Representative HE staining (100× and 400×) results of rabbits in group C are shown in Figure 1.
A组动物给药侧兔耳出现充血、肿胀及大面积坏死、变黑。在低倍镜下，观察到全耳严重水肿，血管扩张，局部出血严重，表皮可见一处明显的化脓坏死灶。在高倍镜下，观察到局部结缔组织成纤维细胞增生，其间散在分布少量炎性细胞；表皮区坏死灶可见大量嗜中性粒细胞、淋巴细胞、巨噬细胞等炎性细胞浸润；间质出血严重，散在大量红细胞弥漫性分布。结果证明，含乙醇的市售尼莫地平注射液滴注给药对兔耳产生了严重的刺激性，导致严重的水肿、诱发了炎症并导致大面积皮肤坏死。A组家兔的代表性HE染色(20×和400×)结果见图2。Congestion, swelling and large area of necrosis and blackening appeared in the rabbit ears of the animals in group A on the administration side. Under the low magnification microscope, severe edema, vasodilation, and local hemorrhage were observed in the whole ear, and an obvious foci of suppurative necrosis was seen on the epidermis. Under the high magnification microscope, local connective tissue fibroblast proliferation was observed, with a small amount of inflammatory cells scattered among them; a large number of neutrophils, lymphocytes, macrophages and other inflammatory cells were infiltrated in the necrotic foci of the epidermis; interstitial hemorrhage Severe, diffuse distribution of scattered large numbers of red blood cells. The results demonstrated that the administration of commercially available nimodipine injections containing ethanol produced severe irritation to rabbit ears, resulting in severe edema, induced inflammation, and resulted in extensive skin necrosis. Representative HE staining (20× and 400×) results of group A rabbits are shown in Figure 2.
B组动物给药侧兔耳整体完好，只有少量的轻度充血和肿胀。光镜下观察，可见兔耳轻度疏松水肿，未见其他明显异常。结果证明，本发明的尼莫地平注射液刺激性很小，与市售尼莫地平注射液相比刺激性显著改善。B组家兔的代表性HE染色(20×和200×)结果见图3。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 .
根据1.1详细的评分标准，各组刺激性评分结果见表14。According to the detailed scoring criteria in 1.1, the irritation scoring results of each group are shown in Table 14.
表14 血管刺激性评分Table 14 Vascular irritation score
组别group 平均分值average score 刺激等级stimulus level
AA 5±0.25±0.2 严重serious
BB 2±0.32±0.3 轻度mild
CC 00 无none
由以上实验结果可知，本发明的尼莫地平注射液对血管的刺激性显著小于市售尼莫地平注射液，具有极为明显的优势。It can be seen from the above experimental results that 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.
通过引用将本文所列出的所有专利和非专利文献的全部内容合并入本文， 就如同将它们各自的全部内容逐一列出一样。All patent and non-patent literature listed herein are incorporated by reference in their entirety, as if each were individually listed in their entirety.
尽管本文提供了具体实施方案和实施例以对本发明进行举例说明，但是这并不是对本发明范围的限制。基于本公开内容，本领域技术人员能在不背离本发明的精神实质的情况下显而易见地获得其它变型或等同方案，这些变型和等同方案均在本发明的范围内。While specific embodiments and examples are provided herein to illustrate the invention, they are not intended to limit the scope of the invention. Based on the present disclosure, other modifications or equivalents will be apparent to those skilled in the art without departing from the spirit of the present invention, which are within the scope of the present invention.

Claims (13)

  1. 一种不含乙醇的难溶性药物浓缩液，其特征在于，所述浓缩液包含难溶性药物和有助于形成胶束的载体，其中：An ethanol-free insoluble drug concentrate, characterized in that the concentrate contains insoluble drugs and a carrier that helps to form micelles, wherein:
    所述载体由复合乳化剂和助溶剂组成，The carrier is composed of a composite emulsifier and a cosolvent,
    所述复合乳化剂由磷脂与非磷脂乳化剂组成，且所述磷脂选自大豆磷脂、蛋黄卵磷脂及它们的混合物，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,
    所述助溶剂选自丙二醇、甘油、PEG200、PEG300、PEG400及它们的混合物，优选选自丙二醇、PEG200、PEG300、PEG400及它们的混合物，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,
    并且所述浓缩液不含油。And the concentrate is oil-free.
  2. 根据权利要求1所述的浓缩液，其中所述非磷脂乳化剂选自聚氧乙烯蓖麻油(例如，聚氧乙烯35蓖麻油、纯的聚氧乙烯35蓖麻油)、聚氧乙烯氢化蓖麻油(例如聚氧乙烯40氢化蓖麻油、聚氧乙烯60氢化蓖麻油)、15-羟基硬脂酸聚乙二醇酯、维生素E聚乙二醇1000琥珀酸酯(TPGS)、聚山梨酯(例如聚山梨酯20、21、40、60、61、65、80、81、85、120，特别是聚山梨酯80)以及它们的混合物。The concentrate of claim 1, wherein the non-phospholipid emulsifier is selected from the group consisting of polyoxyethylene castor oil (eg, polyoxyethylene 35 castor oil, pure polyoxyethylene 35 castor oil), polyoxyethylene 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), polysorbate (eg Polysorbate 20, 21, 40, 60, 61, 65, 80, 81, 85, 120, especially polysorbate 80) and mixtures thereof.
  3. 根据权利要求2所述的浓缩液，其中所述的非磷脂乳化剂选自聚氧乙烯40氢化蓖麻油、聚氧乙烯35蓖麻油、纯的聚氧乙烯35蓖麻油、15-羟基硬脂酸聚乙二醇酯、聚山梨酯80及它们的混合物。The concentrate according to claim 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-hydroxystearic acid Polyethylene glycol esters, polysorbate 80 and mixtures thereof.
  4. 根据权利要求1至3中任意一项所述的浓缩液，其中所述助溶剂选自丙二醇、PEG300、PEG400及它们的混合物。The concentrate according to any one of claims 1 to 3, wherein the co-solvent is selected from the group consisting of propylene glycol, PEG300, PEG400 and mixtures thereof.
  5. 根据权利要求1至4中任意一项所述的浓缩液，其中当将难溶性药物、复合乳化剂、助溶剂的重量总计为100重量％时，所述难溶性药物的重量百分比为0.1％～20％，优选0.5％～15％；所述磷脂的重量百分比为0.1％～20％，优选0.5％～10％；所述非磷脂乳化剂的重量百分比为20％～80％，优选30％～70％；余量为助溶剂。The concentrated solution according to any one of claims 1 to 4, wherein when the total weight of the poorly soluble drug, the complex emulsifier and the cosolvent is 100% by weight, the weight percentage of the poorly soluble drug is 0.1% to 100% by weight. 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%, preferably 30% to 10%. 70%; the balance is cosolvent.
  6. 根据权利要求1至5中任意一项所述的组合物，其中所述难溶性药物选自塞来昔布、伐地昔布、依托考昔、布洛芬、右旋布洛芬、丙泊酚、氟比洛芬酯、前列地尔、丁酸氯维地平、地塞米松棕榈酸酯、非洛地平、尼莫地平、硝苯地平、尼群地平、环孢素、他克莫司、左西孟旦、阿德福韦酯、红霉素、罗红霉素、泊沙康唑、伊曲康唑、伏立康唑、咪康唑、酮康唑、黄体酮、辅酶Q10、 氯吡格雷、紫杉醇、多西他赛、卡巴他赛、依托泊苷、替尼泊苷、羟基喜树碱、伊立替康、乌苯美司、顺铂、卡铂、卡培他滨、奥沙利铂、吉非替尼、多柔比星、长春碱、长春新碱、长春西汀、长春地辛、吡罗昔康、螺内酯、丙戊酸、他莫昔芬、阿奇霉素、维生素A、维生素D、维生素E、维生素K、非诺贝特、吲哚美辛、瑞德西韦；优选地，所述难溶性药物选自塞来昔布、布洛芬、右旋布洛芬、丙泊酚、氟比洛芬酯、前列地尔、丁酸氯维地平、地塞米松棕榈酸酯、非洛地平、尼莫地平、硝苯地平、尼群地平、环孢素、他克莫司、左西孟旦、阿德福韦酯、红霉素、罗红霉素、泊沙康唑、伊曲康唑、伏立康唑、黄体酮、辅酶Q10、氯吡格雷、紫杉醇、多西他赛、卡巴他赛、依托泊苷、替尼泊苷和依托考昔；最优选地，所述难溶性药物选自尼莫地平、泊沙康唑、多西他赛、氯吡格雷、左西孟旦、他克莫司、环孢素、紫杉醇、布洛芬、辅酶Q10、卡巴他赛、塞来昔布和依托考昔。The composition according to any one of claims 1 to 5, wherein the poorly soluble drug is selected from the group consisting of celecoxib, valdecoxib, etoricoxib, ibuprofen, dextroibuprofen, propor Phenol, flurbiprofen axetil, alprostadil, clevidipine butyrate, dexamethasone palmitate, felodipine, nimodipine, nifedipine, nitrendipine, cyclosporine, tacrolimus, Levosimendan, adefovir dipivoxil, erythromycin, roxithromycin, posaconazole, itraconazole, voriconazole, miconazole, ketoconazole, progesterone, coenzyme Q10, clopidogrel, Paclitaxel, Docetaxel, Cabazitaxel, Etoposide, Teniposide, Hydroxycamptothecin, Irinotecan, Ubenemex, Cisplatin, Carboplatin, Capecitabine, Oxaliplatin, Gefitinib, doxorubicin, vinblastine, vincristine, vinpocetine, vindesine, piroxicam, spironolactone, valproic acid, tamoxifen, azithromycin, vitamin A, vitamin D, vitamin E, Vitamin K, fenofibrate, indomethacin, remdesivir; preferably, the poorly soluble drug is selected from celecoxib, ibuprofen, dextroibuprofen, propofol, flurbirol Fendexate, alprostadil, clevidipine butyrate, dexamethasone palmitate, felodipine, nimodipine, nifedipine, nitrendipine, cyclosporine, tacrolimus, levosimendan, Adefovir dipivoxil, erythromycin, roxithromycin, posaconazole, itraconazole, voriconazole, progesterone, coenzyme Q10, clopidogrel, paclitaxel, docetaxel, cabazitaxel, etopo glycosides, teniposide and etoricoxib; most preferably, the poorly soluble drug is selected from nimodipine, posaconazole, docetaxel, clopidogrel, levosimendan, tacrolimus, Cyclosporine, paclitaxel, ibuprofen, coenzyme Q10, cabazitaxel, celecoxib, and etoricoxib.
  7. 根据权利要求1至6中任意一项所述的浓缩液，其还含有pH调节剂、抗氧化剂或这二者。The concentrate of any one of claims 1 to 6, further comprising a pH adjuster, an antioxidant, or both.
  8. 根据权利要求1至6中任意一项所述的组合物，其中：The composition of any one of claims 1 to 6, wherein:
    所述的难溶性药物是尼莫地平，所述的磷脂是蛋黄卵磷脂，所述的非磷脂乳化剂是15-羟基硬脂酸聚乙二醇酯，所述的助溶剂是丙二醇，并且当将难溶性药物、复合乳化剂、助溶剂的重量总计为100重量％时，尼莫地平的重量百分比为1％，蛋黄卵磷脂的重量百分比为2％，15-羟基硬脂酸聚乙二醇酯的重量百分比为46％，丙二醇重量百分比为51％；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, and when When the total weight of the poorly soluble drug, compound emulsifier and cosolvent is 100% by weight, the weight percentage of nimodipine is 1%, the weight percentage of egg yolk lecithin is 2%, and the 15-hydroxystearic acid polyethylene glycol is The weight percentage of ester is 46%, and the weight percentage of propylene glycol is 51%;
    或者or
    所述的难溶性药物是泊沙康唑，所述的磷脂是蛋黄卵磷脂，所述的非磷脂乳化剂是15-羟基硬脂酸聚乙二醇酯，所述的助溶剂是PEG300，并且当将难溶性药物、复合乳化剂、助溶剂的重量总计为100重量％时，其中泊沙康唑的重量百分比为1％，蛋黄卵磷脂的重量百分比为3％，15-羟基硬脂酸聚乙二醇酯的重量百分比为50％，PEG300的重量百分比为46％；The insoluble drug is posaconazole, the phospholipid is egg yolk lecithin, the non-phospholipid emulsifier is polyethylene glycol 15-hydroxystearate, the cosolvent is PEG300, and When the total weight of the poorly soluble drug, compound emulsifier and cosolvent is 100% by weight, the weight percentage of posaconazole is 1%, the weight percentage of egg yolk lecithin is 3%, and the 15-hydroxystearic acid polymer The weight percent of ethylene glycol ester is 50%, and the weight percent of PEG300 is 46%;
    或者or
    所述的难溶性药物是多西他赛，所述的磷脂是蛋黄卵磷脂，所述的非磷脂乳化剂是15-羟基硬脂酸聚乙二醇酯，所述的助溶剂是丙二醇，并且当将难溶性药物、复合乳化剂、助溶剂的重量总计为100重量％时，其中多西他赛的重量百分比为1％，蛋黄卵磷脂的重量百分比为3％，15-羟基硬脂酸聚乙二醇酯的重 量百分比为48％，丙二醇的重量百分比为48％；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, and When the total weight of the poorly soluble drug, compound emulsifier and cosolvent is 100% by weight, the weight percentage of docetaxel is 1%, the weight percentage of egg yolk lecithin is 3%, and the 15-hydroxystearic acid poly The weight percent of ethylene glycol ester is 48%, and the weight percent of propylene glycol is 48%;
    或者or
    所述的难溶性药物是氯吡格雷，所述的磷脂是蛋黄卵磷脂，所述的非磷脂乳化剂是15-羟基硬脂酸聚乙二醇酯，所述的助溶剂是丙二醇，并且当将难溶性药物、复合乳化剂、助溶剂的重量总计为100重量％时，其中氯吡格雷的重量百分比为15％，蛋黄卵磷脂的重量百分比为2％，15-羟基硬脂酸聚乙二醇酯的重量百分比为43％，丙二醇的重量百分比为40％；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, and when When the total weight of the poorly soluble drug, compound emulsifier and cosolvent is 100% by weight, the weight percentage of clopidogrel is 15%, the weight percentage of egg yolk lecithin is 2%, and the weight percentage of 15-hydroxystearic acid polyethylene glycol The weight percentage of alcohol ester is 43%, and the weight percentage of propylene glycol is 40%;
    或者or
    所述的难溶性药物是左西孟旦，所述的磷脂是蛋黄卵磷脂，所述的非磷脂乳化剂是15-羟基硬脂酸聚乙二醇酯，所述的助溶剂是丙二醇，并且当将难溶性药物、复合乳化剂、助溶剂的重量总计为100重量％时，其中左西孟旦的重量百分比为0.5％，蛋黄卵磷脂的重量百分比为2％，15-羟基硬脂酸聚乙二醇酯的重量百分比为50％，丙二醇的重量百分比为47.5％；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, and When the total weight of the poorly soluble drug, compound emulsifier and cosolvent is 100% by weight, the weight percentage of levosimendan is 0.5%, the weight percentage of egg yolk lecithin is 2%, and the 15-hydroxystearic acid poly The weight percentage of ethylene glycol ester is 50%, and the weight percentage of propylene glycol is 47.5%;
    或者or
    所述的难溶性药物是他克莫司，所述的磷脂是蛋黄卵磷脂，所述的非磷脂乳化剂是15-羟基硬脂酸聚乙二醇酯，所述的助溶剂是丙二醇，并且当将难溶性药物、复合乳化剂、助溶剂的重量总计为100重量％时，其中他克莫司的重量百分比为1.5％，蛋黄卵磷脂的重量百分比为2％，15-羟基硬脂酸聚乙二醇酯的重量百分比为46％，丙二醇的重量百分比为50.5％；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, and When the total weight of the poorly soluble drug, compound emulsifier and cosolvent is 100% by weight, the weight percentage of tacrolimus is 1.5%, the weight percentage of egg yolk lecithin is 2%, and the 15-hydroxystearic acid poly The weight percentage of ethylene glycol ester is 46%, and the weight percentage of propylene glycol is 50.5%;
    或者or
    所述的难溶性药物是环孢素，所述的磷脂是蛋黄卵磷脂，所述的非磷脂乳化剂是15-羟基硬脂酸聚乙二醇酯，所述的助溶剂是丙二醇，并且当将难溶性药物、复合乳化剂、助溶剂的重量总计为100重量％时，其中环孢素的重量百分比为10％，蛋黄卵磷脂的重量百分比为2％，15-羟基硬脂酸聚乙二醇酯的重量百分比为43％，丙二醇的重量百分比为45％；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, and when When the total weight of the poorly soluble drug, compound emulsifier and cosolvent is 100% by weight, the weight percentage of cyclosporine is 10%, the weight percentage of egg yolk lecithin is 2%, and the weight percentage of 15-hydroxystearic acid polyethylene glycol is 100%. The weight percentage of alcohol ester is 43%, and the weight percentage of propylene glycol is 45%;
    或者or
    所述的难溶性药物是紫杉醇，所述的磷脂是蛋黄卵磷脂，所述的非磷脂乳化剂是15-羟基硬脂酸聚乙二醇酯，所述的助溶剂是丙二醇，并且当将难溶性药物、复合乳化剂、助溶剂的重量总计为100重量％时，其中紫杉醇的重量百分比为1％，蛋黄卵磷脂的重量百分比为2％，15-羟基硬脂酸聚乙二醇酯的重量百分比为46％，丙二醇的重量百分比为51％；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, and when the insoluble drug is When the total weight of the soluble drug, compound emulsifier and cosolvent is 100% by weight, the weight percentage of paclitaxel is 1%, the weight percentage of egg yolk lecithin is 2%, and the weight of 15-hydroxystearic acid polyethylene glycol ester The percentage is 46%, and the weight percentage of propylene glycol is 51%;
    或者or
    所述的难溶性药物是布洛芬，所述的磷脂是蛋黄卵磷脂，所述的非磷脂乳化剂是15-羟基硬脂酸聚乙二醇酯，所述的助溶剂是PEG300，并且当将难溶性药物、复合乳化剂、助溶剂的重量总计为100重量％时，其中布洛芬的重量百分比为10％，蛋黄卵磷脂的重量百分比为2％，15-羟基硬脂酸聚乙二醇酯的重量百分比为40％，PEG300的重量百分比为48％；The insoluble drug is ibuprofen, the phospholipid is egg yolk lecithin, the non-phospholipid emulsifier is polyethylene glycol 15-hydroxystearate, the cosolvent is PEG300, and when When the total weight of the poorly soluble drug, compound emulsifier and cosolvent is 100% by weight, the weight percentage of ibuprofen is 10%, the weight percentage of egg yolk lecithin is 2%, and the weight percentage of 15-hydroxystearic acid polyethylene glycol is 100%. The weight percentage of alcohol ester is 40%, and the weight percentage of PEG300 is 48%;
    或者or
    所述的难溶性药物是辅酶Q10，所述的磷脂是蛋黄卵磷脂，所述的非磷脂乳化剂是15-羟基硬脂酸聚乙二醇酯，所述的助溶剂是丙二醇，并且当将难溶性药物、复合乳化剂、助溶剂的重量总计为100重量％时，其中辅酶Q10的重量百分比为5％，蛋黄卵磷脂的重量百分比为10％，15-羟基硬脂酸聚乙二醇酯的重量百分比为30％，丙二醇的重量百分比为55％；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, and when the When the total weight of the poorly soluble drug, compound emulsifier and cosolvent is 100% by weight, the weight percentage of coenzyme Q10 is 5%, the weight percentage of egg yolk lecithin is 10%, and 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%;
    所述的难溶性药物是卡巴他赛，所述的磷脂是蛋黄卵磷脂，所述的非磷脂乳化剂是吐温80，所述的助溶剂是丙二醇，并且当将难溶性药物、复合乳化剂、助溶剂的重量总计为100重量％时，其中卡巴他赛的重量百分比为1％，蛋黄卵磷脂的重量百分比为2％，吐温80的重量百分比为46％，丙二醇的重量百分比为51％；The insoluble drug is cabazitaxel, the phospholipid is egg yolk lecithin, the non-phospholipid emulsifier is Tween 80, the cosolvent is propylene glycol, and when 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% ;
    所述的难溶性药物是塞来昔布，所述的磷脂是蛋黄卵磷脂，所述的非磷脂乳化剂是15-羟基硬脂酸聚乙二醇酯，所述的助溶剂是丙二醇，并且当将难溶性药物、复合乳化剂、助溶剂的重量总计为100重量％时，其中塞来昔布的重量百分比为6％，蛋黄卵磷脂的重量百分比为0.5％，15-羟基硬脂酸聚乙二醇酯的重量百分比为70％，丙二醇的重量百分比为23.5％；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, and When the total weight of the poorly soluble drug, compound emulsifier and cosolvent is 100% by weight, the weight percentage of celecoxib is 6%, the weight percentage of egg yolk lecithin is 0.5%, and the 15-hydroxystearic acid poly The weight percentage of ethylene glycol ester is 70%, and the weight percentage of propylene glycol is 23.5%;
    或者or
    所述的难溶性药物是依托考昔，所述的磷脂是蛋黄卵磷脂，所述的非磷脂乳化剂是15-羟基硬脂酸聚乙二醇酯，所述的助溶剂是丙二醇，并且当将难溶性药物、复合乳化剂、助溶剂的重量总计为100重量％时，其中依托考昔的重量百分比为5％，蛋黄卵磷脂的重量百分比为5％，15-羟基硬脂酸聚乙二醇酯的重量百分比为35％，丙二醇的重量百分比为55％。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, and when When the total weight of the poorly soluble drug, compound emulsifier and cosolvent is 100% by weight, the weight percentage of etoricoxib is 5%, the weight percentage of egg yolk lecithin is 5%, and the weight percentage of 15-hydroxystearic acid polyethylene glycol is 5%. The weight percent of alcohol ester is 35%, and the weight percent of propylene glycol is 55%.
  9. 权利要求1至8中任意一项所述的浓缩液在制备用于静脉内注射、特别是静脉内滴注的胶束溶液中的用途。Use of a concentrate according to any one of claims 1 to 8 in the preparation of a micellar solution for intravenous injection, in particular intravenous drip.
  10. 制备权利要求1至8中任意所述的浓缩液的方法，所述方法包括以下步 骤：将难溶性药物、磷脂、非磷脂乳化剂和助溶剂以任意顺序混合，搅拌均匀，过滤，分装压盖密封。A method for preparing the concentrated solution described in any of claims 1 to 8, the method comprising the steps of: mixing insoluble drugs, phospholipids, non-phospholipid emulsifiers and cosolvents in any order, stirring evenly, filtering, sub-packing and pressing The lid is sealed.
  11. 一种胶束溶液，其是通过将权利要求1至8中任意一项所述的浓缩液用水性溶媒稀释获得的。A micellar solution obtained by diluting the concentrated solution of any one of claims 1 to 8 with an aqueous vehicle.
  12. 根据权利要求11所述的胶束溶液，其中所述水性溶媒是注射用水、5％葡萄糖注射液或0.9％氯化钠注射液。The micellar solution according to claim 11, wherein the aqueous vehicle is water for injection, 5% dextrose injection or 0.9% sodium chloride injection.
  13. 根据权利要求12所述的胶束溶液，其用于静脉内注射，特别是静脉内滴注。Micellar solution according to claim 12 for intravenous injection, in particular intravenous drip.
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