CN116350586B - Nimodipine micelle injection and preparation method thereof - Google Patents

Nimodipine micelle injection and preparation method thereof Download PDF

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CN116350586B
CN116350586B CN202310439077.8A CN202310439077A CN116350586B CN 116350586 B CN116350586 B CN 116350586B CN 202310439077 A CN202310439077 A CN 202310439077A CN 116350586 B CN116350586 B CN 116350586B
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nimodipine
injection
acid
micelle
regulator
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CN116350586A (en
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刘善奎
王静
蒋元勋
宗童欣
耿倩倩
孙孝丽
姜明明
毋立华
孙迎基
李铁军
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Shandong Taihe Pharmaceutical Technology Co ltd
University of Jinan
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Shandong Taihe Pharmaceutical Technology Co ltd
University of Jinan
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention belongs to the field of medicines, and provides nimodipine micelle injection and a preparation method thereof, in particular relates to high-concentration nimodipine micelle injection for intravenous drip, which consists of nimodipine serving as an active ingredient, phospholipid serving as an auxiliary material, cholic acid or salt thereof, a surface modification material, an isotonic regulator, a pH regulator and water for injection. The injection not only greatly improves the solubility of nimodipine, but also adopts a physiologically compatible adjuvant phospholipid, cholic acid and a micelle system with good safety for solubilization, and adopts an innovative film dispersion-hydration process, and ethanol is abandoned as a solubilizer in the prescription, thereby obviously improving the safety of medication. The injection can be directly diluted by injection, the compatibility solution has good stability for 24 hours, special equipment and secondary nursing of an infusion pump are not needed, and the medication safety and compliance are improved.

Description

Nimodipine micelle injection and preparation method thereof
Technical Field
The invention belongs to the field of medicines, and provides nimodipine micelle injection and a preparation method thereof.
Background
Nimodipine is a mixture of optical isomers, and has the chemical name of 2, 6-dimethyl-4- (3-nitrophenyl) -1, 4-dihydro-3, 5-pyridinedicarboxylic acid 2-methoxyethyl- (1-methylethyl) ester, and the formula: c (C) 21 H 26 N 2 O 7 Molecular weight 418.4, structural formula as follows:
nimodipine is a pyridine dicarboxylic acid dimethyl ester, a finely crystallized yellow substance, with a melting point of 125-126 ℃, which is soluble in ethanol, chloroform, ethyl acetate and polyethylene glycol, but insoluble in water. Nimodipine is stable in neutral and acidic media and is sensitive to alkali. It is thermally stable and non-hygroscopic, but moderately sensitive to light, especially in solution; the pH value of the nimodipine 1% (w/v) solution is 6-6.8.
Nimodipine is a second generation 1, 4-dihydropyridine calcium antagonist, has high lipophilicity and is easy to penetrate the blood brain barrier. In animal experiments, nimodipine can be used with L-type Ca 2+ Channel high affinity and high specificity binding, thereby inhibiting Ca 2+ And (3) transmembrane inflow. It is inferred that nimodipine can improve causative nerve cell Ca 2+ The stability and functional capacity of pathological states induced by increased ionic influx, such as cerebral ischemia. Because the medicine is easy to permeate the blood brain barrier, has the functions of selectively expanding cerebral vessels and obviously reversing the spasm of the basilar artery and the anterior spinal artery, is clinically used for treating hypertension, apoplexy, migraine, subarachnoid hemorrhage and other cerebral hemorrhage diseases, is the first choice medicine for treating the current cerebral vascular diseases, and has higher clinical application value particularly for senile dementia. Nimodipine is a first-line therapeutic drug for treating ischemic brain injury.
Original grinding medicineInjection is developed by Bayer GmbH, germany, and is marketed in 4 months of 1985 with a specification of 50ml:10mg. Nimodipine has multiple products entered the 2018 edition of national basic drug catalog (tablets, capsules: 20mg, 30 mg), 2021 edition of national medical insurance catalog (class A: oral normal release dosage form, class B: injection). The present nimodipine is available in various dosage forms, including common tablet, capsule, injection, oral liquid, etc. Although nimodipine has good biological effects, its clinical performance is limited by its low oral bioavailability (as low as10%) and low water solubility (3.86 μg/mL). Intravenous administration is therefore an alternative route to the therapeutic effect of nimodipine. To achieve adequate nimodipine concentrations, commercial formulations are prepared by dissolving nimodipine with a solvent mixture of about 40%, i.e., a solvent mixture consisting of 23.7% (v/v) ethanol and 17% (v/v) polyethylene glycol 400. However, this concentration has a number of significant drawbacks in clinical use: a large amount of ethanol is harmful to alcoholism or to people with impaired alcohol metabolism, pregnant women or lactating women. In addition, high concentrations of ethanol may cause pain and irritation at the injection site. Because nimodipine must drip at a slow speed with the speed of 1-2 mg/h, otherwise, the patient cannot tolerate the side effect, namely the drip time required by 10mg of medicine generally needs at least 5h, when in use, the nimodipine must be mixed with compatible solution (0.9% sodium chloride injection, 5% glucose injection, etc.) for drip or the nimodipine must be drip with special three-way infusion set and injection at the same time, the mixed solution is directly input into the patient; intravenous infusion was continued for up to three weeks. And simultaneously, nimodipine is dissolved in ethanol and is not dissolved in water, and nimodipine transfusion is a water-insoluble preparation containing ethanol, so that crystals can be separated out after the nimodipine transfusion is compatible with other transfusion, the content is reduced, the curative effect of the medicine is reduced, and a certain degree of danger is brought to a patient.
Patent document CN20181146629 discloses a nimodipine injection composition and a preparation method thereof, wherein soybean oil, medium-chain fatty oil or a mixture of soybean oil and medium-chain fatty oil with a high proportion is adopted in the prescription. Therefore, the emulsification level and the technical process are correspondingly improved in commercial production. In addition, unsaturated double bonds in unsaturated fatty acids such as soybean oil are unstable in chemical property, and impurity degradation affects medication safety. Therefore, the quality standard control of indexes such as peroxide value, methoxy aniline value and free fatty acid in the product is required to be correspondingly stricter.
Patent document CN1732936a discloses nimodipine emulsion injection and a preparation method, and a proper amount of benzyl alcohol is added in the preparation process, so that the solubility of nimodipine in the emulsion and the stability of the preparation are improved, and the concentration of nimodipine emulsion is relatively high. Benzyl alcohol has disinfectant, antiseptic, and local anesthetic effects, and can be used as antibacterial agent and analgesic in injection, and has hemolysis effect. The injection for intramuscular injection of children may cause contracture of gluteus muscles when benzyl alcohol is contained therein. The intravenous injection is strictly limited by adding bacteriostatic agent under the annex injection item of the 2020 edition of Chinese pharmacopoeia.
Patent document CN112137956a discloses a preparation method of nimodipine sustained-release emulsion injection, wherein tween 80 is used in the prescription. The existing intravenous injection containing Tween 80 has many clinical adverse reactions, and can cause hemolytic reaction, acute hypersensitivity reaction, peripheral neurotoxicity, P-glycoprotein activity inhibition, intrinsic anti-tumor effect, hepatotoxicity, etc. Accordingly, intravenous injection containing tween 80 should be used with care.
Patent document CN101485632a discloses nimodipine lipid microsphere injection and a preparation method thereof, but lipid microsphere preparation has complex process and high cost, and the package of lipid microsphere is easy to damage and leak after long-term storage, so that clinical risk is brought, and the particle size is larger, and intravenous injection risk is high.
Patent document CN105796490B discloses an nimodipine injection composition containing amino acid and a preparation method thereof, and ethanol and polyethylene glycol are adopted for solubilization to prepare injection.
Patent document CN114886850a discloses nimodipine formulations and methods of treating disorders, using the surfactant polysorbate 80 and an organic solvent ethanol solubiliser in the formulation.
Both of the above prior art techniques have the following disadvantages: a large amount of ethanol is harmful to alcoholism or to people with impaired alcohol metabolism, pregnant women or lactating women. In addition, high concentrations of ethanol may cause pain and irritation at the injection site.
Patent document CN101088503a discloses nimodipine freeze-dried powder injection and a preparation method thereof, wherein tween 80, polyethylene glycol 400, propylene glycol, ethanol and the like are used in the formula. The clinical adverse reaction of propylene glycol has a plurality of clinical reports, which limit the clinical application of the propylene glycol.
The nimodipine micelle injection disclosed in patent document CN102525917B and a preparation method thereof adopt active carbon in a formula, the content of the nimodipine micelle injection after hot press sterilization is obviously reduced, and the nimodipine micelle injection does not accord with the standards of Chinese pharmacopoeia and import registration. The active carbon is used as a common adsorbent in injection and plays a role in corresponding adsorption pyrogen. However, the diversity of the raw materials and production processes of activated carbon, uncertainty of the activation mechanism, limitation of quality control, and the possibility of introducing impurities and insoluble particles caused thereby, all pose risks for the application of activated carbon in injection. Because of the source of the active carbon raw material and the various production processes, the active carbon may contain different element impurities; some elemental impurities are toxic, including neurotoxicity, nephrotoxicity, and the like. The injection has various pyrogen control modes, and the imported injection variety basically does not use active carbon. Therefore, it is a necessary trend to maximally reduce the risks introduced by activated carbon in the production of injections.
Patent CN114796110a discloses a insoluble drug concentrate without ethanol and micelle solution prepared therefrom, aiming at insoluble drug nimodipine, egg yolk lecithin, 15-hydroxy stearic acid polyethylene glycol ester and propylene glycol are adopted in the prescription, wherein the weight percentage of 15-hydroxy stearic acid polyethylene glycol ester is up to 46%, and the weight percentage of propylene glycol is up to 51%. 15-hydroxy stearic acid polyethylene glycol ester is an artificial synthesis auxiliary material, and has large dosage and low safety; high concentrations of propylene glycol can cause pain and irritation, and higher concentrations can cause hemolysis in humans. Ethanol is abandoned in the prescription, but an organic solvent is still used, and the organic solvent has toxic and side effects, so that the use of the organic solvent in injection is more strict.
Therefore, whether to provide an injection with higher nimodipine concentration, which is safer, is a technical problem to be solved in the field.
Disclosure of Invention
Aiming at the defects of the technology, the inventor provides a high-concentration nimodipine micelle injection for intravenous drip and a preparation method thereof, wherein the injection consists of nimodipine serving as an active ingredient, phospholipid serving as an auxiliary material, cholic acid or salt thereof, a surface modification material, an isotonic regulator, a pH regulator and water for injection. The injection not only greatly improves the solubility of nimodipine, but also adopts a physiologically compatible adjuvant phospholipid, cholic acid and a micelle system with good safety for solubilization, and adopts an innovative film dispersion-hydration process, and ethanol is abandoned as a solubilizer in the prescription, thereby obviously improving the safety of medication. The injection can be directly diluted by injection, the compatibility solution has good stability for 24 hours, special equipment and secondary nursing of an infusion pump are not needed, and the medication safety and compliance are improved.
The main inventive concept of the present invention is to provide a more ideal carrier for nimodipine, and Phosphatidylcholine (PC) -Bile Salt (BS) Mixed Micelle (MM) formulation is an attractive candidate for intravenous administration of poorly soluble drugs based on the physiological compatibility and dissolution ability of nimodipine, and this simple method of combining a water-soluble surfactant with a water-insoluble phospholipid can give an isotropically clear solution. The bile salt existing in the high-concentration bile can dissolve phosphatidylcholine to a great extent to form a transparent mixed micelle solution, and further can dissolve substances with poor water solubility. By dissolving phospholipids, the hemolysis of phosphatidylcholine can be neutralized and most importantly Phosphatidylcholine (PC) -Bile Salt (BS) Mixed Micelle (MM) formulations have been shown to be well tolerated locally and systemically without embryotoxicity, teratogenicity or mutagenicity after administration. In the absence of a toxicological solvent mixture, phosphatidylcholine (PC) -Bile Salt (BS) Mixed Micelle (MM) formulations can reduce irritation and improve patient compliance. Thus, phosphatidylcholine (PC) -Bile Salt (BS) Mixed Micelle (MM) formulations are ideal drug carriers for intravenous administration of nimodipine. Based on the thought, the application is finally based on a phospholipid-bile salt mixed micelle system, abandons an organic solvent solubilization scheme, develops an innovative formula design of phospholipid, bile salt and surface modification materials, constructs a novel nano micelle solubilization system, realizes effective solubilization of nimodipine, and breaks through the technical problem of 'neck' improvement of nimodipine injection.
Specifically, the technical scheme of the application is as follows:
a nimodipine micelle injection comprises nimodipine, phospholipid, cholic acid or salt thereof, a surface modification material, an isotonic regulator, a pH regulator and water for injection as active ingredients; the proportions of the components are as follows:
the concentration of nimodipine as the active component in the injection is 0.1 mg/ml-4 mg/ml, more preferably 0.5 mg/ml-2.5 mg/ml; in addition, the weight ratio of nimodipine to phospholipid is 0.5-20: 100, the weight ratio of cholic acid or salt thereof to phospholipid is 0.1-10: 1, the weight ratio of the surface modification material to nimodipine is 0-10: 1, the weight ratio of the isotonic regulator to the phospholipid is 0.1-5: 1, a step of; the dosage of the pH regulator is determined according to the pH of the final injection;
the nimodipine micelle injection has a volume specification of 1ml to 10ml, preferably 5ml, and is contained in an ampoule bottle.
Preferably, the phospholipid comprises, but is not limited to, one of soybean phospholipid, egg yolk phospholipid, hydrogenated Soybean Phospholipid (HSPC), hydrogenated egg yolk phospholipid (HEPC), dipalmitoyl phosphatidylcholine (DPPC), dipalmitoyl phosphatidylethanolamine (DPPE), distearoyl phosphatidylcholine (DSPC), dilauroyl phosphatidylcholine (DLPC), dioleoyl phosphatidylethanolamine (DOPE), distearoyl phosphatidylethanolamine (DSPE), dioleoyl phosphatidylcholine (DOPC); among them, soybean phospholipids are preferred.
Preferably, the cholic acid is one or a mixture of more of glycocholic acid, deoxycholic acid, glycochenodeoxycholic acid, taurocholic acid and taurochenodeoxycholic acid or salts thereof; among them, glycocholic acid or sodium glycocholate is preferable.
The surface modification material is preferably one or more of 15-hydroxystearic acid polyethylene glycol ester, polyoxyethylene polyoxypropylene copolymer, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, polyethylene glycol vitamin E succinate and polyethylene glycol-distearoyl phosphatidylcholine according to any proportion; among them, 15-hydroxystearic acid polyethylene glycol ester is preferableHS 15 or->HS 15), polyoxyethylene polyoxypropylene copolymer (poloxamer 188), polyoxyethylene sorbitan fatty acid esters (polysorbate 80).
Preferably, the isotonic regulator is any one or more of sucrose, trehalose, glucose, lactose, fructose, mannitol, dextran, sorbitol, dextran, glycine, hydroxyethyl starch, polyvinylpyrrolidone and the like which are combined according to any proportion; among them, sucrose is preferable.
Preferably, the acid in the physiologically and pharmaceutically acceptable pH regulator is selected from any one or more of glacial acetic acid, formic acid, trifluoroacetic acid, phosphoric acid, citric acid, tartaric acid, oxalic acid, malic acid, alanine, hydrochloric acid, leucine, isoleucine, malic acid, valine, tryptophan, maleic acid, fumaric acid, lactic acid, phenylalanine, methionine and succinic acid according to any proportion, wherein citric acid is preferred; the alkali in the pH regulator is one or more of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, choline hydroxide, arginine, lysine, histidine, diethylamine, triethylamine, meglumine, sodium citrate, sodium tartrate, sodium lactate, sodium phosphate and disodium hydrogen phosphate, wherein sodium hydroxide is preferred.
In addition, the inventor also provides a preparation method of the nimodipine micelle injection, which is a film dispersion method, and the specific process is as follows:
step (1): weighing nimodipine, phospholipid, cholic acid or salt thereof and surface modification material in the formula, and dissolving in a proper amount of organic solvent;
step (2): transferring the solution obtained in the step (1) to a rotary evaporator, and opening vacuum to remove the organic solvent at the water bath temperature of 30-70 ℃ to obtain a loose film;
step (3): weighing the isotonic regulator in the formula, and diluting the regulator in water for injection; if the auxiliary material in the step (1) is cholic acid, adding alkali in a pH regulator with the molar ratio of the alkali to the cholic acid being 1:1, and filling a protective gas to obtain a stabilizer solution; completely transferring the nimodipine micelle solution into the loose film obtained in the step (2), stirring to enable the loose film to be hydrated completely, adjusting the pH of the solution by a pH regulator, performing heat treatment, and cooling to obtain nimodipine micelle solution;
step (4): and (3) fixing the volume of the solution obtained in the step (3) by using water for injection, filling protective gas, sterilizing, filtering, sub-packaging into ampoule bottles for sealing, and performing hot-pressing sterilization to obtain nimodipine micelle injection.
In certain preferred embodiments, the present invention relates in part to nimodipine micelle injection having a ratio of cholic acid or salt thereof to phospholipid of 0.5 to 2:1; the weight ratio of the surface modification material to nimodipine is 0-10: 1, and as one of the preferred embodiments, preferably 0.1:1.
The organic solvent is one or more of methanol, ethanol, ethyl acetate and isopropanol in any proportion, the dosage of the organic solvent is 2-8% of the volume of the prepared injection, and the protective gas is one of nitrogen, helium, carbon dioxide and argon.
The organic solvent is preferably a mixed solvent of methanol and ethanol, and the preferable ratio of the methanol to the ethanol is 4:1.
the heat treatment in the step (3) is carried out at the temperature of 90-100 ℃ for 20-30 min; the protective gas in the step (3) and the step (4) is nitrogen, and the time for introducing the protective gas is 0.5-2 hours, wherein the residual range of dissolved oxygen in the step (4) is controlled to be 5-10 ppm.
The nano micelle injection obtained in the step (4) has a specification of 0.1mg/ml to 4mg/ml, and more preferably 0.5mg/ml to 2.5mg/ml.
The pH value of the micelle injection finally obtained in the step (4) is 5.0-8.5, and the preferable pH value is 5.5-7.5; Z-Average of the micelle injection is 2-10 nm; the Zeta potential of the micelle injection is-20 mV to-50 mV; the transmittance of the micelle injection is more than 90%.
In specific application, the compatible dilution injection of nimodipine micelle injection provided by the invention comprises but is not limited to 0.9% sodium chloride injection, 5% glucose, sodium lactate ringer's solution, magnesium-containing sodium lactate ringer's solution, dextran 40 solution, 6% polyoxy-2-hydroxyethyl starch, 5% human serum albumin or blood, and as one of preferred embodiments, 0.9% sodium chloride injection or 5% glucose is preferred. When the nimodipine is diluted to a concentration of 0.02mg/ml to 0.04mg/ml, the nimodipine is still a clear and transparent solution and no precipitated crystals of nimodipine are found.
The nimodipine micelle injection provided by the invention can be used for treating cerebral vasospasm after subarachnoid hemorrhage and blood circulation improvement in the recovery period of acute cerebrovascular diseases such as various reasons, treating diffuse brain injury together with hyperbaric oxygen treatment, assisting recovery after cranial nerve injury, treating frequent migraine and migraine prophylaxis, peripheral dizziness and meniere disease, and reducing occurrence of delirium, drug-resistant epilepsy, orgasmic headache and bath-related headache of old patients under general anesthesia.
Compared with the prior art, the invention has the following beneficial effects:
(1) The nimodipine micelle injection prepared by the invention can be selectively added with auxiliary materials containing polyethylene glycol chains as micelle surface modification materials, and can be specifically 15-hydroxystearic acid polyethylene glycol ester (Solutol HS 15 or KolliphorHS 15), polyoxyethylene polyoxypropylene copolymer (poloxamer 188), polyoxyethylene sorbitan fatty acid esters (polysorbate 80) or polyethylene glycol 2000-distearate phosphatidylethanolamine (PEG 2000-DSPE), polyoxyethylene castor oil (Cremophor ELP or Kolliphor ELP), polyethylene glycol vitamin E succinate (TPGS 1000); when the nano micelle solubilizing system is selected and added, the dosage is small, the weight percentage can be as low as 0.02 percent of the whole system, the novel nano micelle solubilizing system is constructed, the physical and chemical stability of the mixed micelle can be obviously improved, the drug loading capacity is improved, the water solubility and stability of nimodipine are greatly improved, and no crystal is separated out through a low-temperature circulation test, a freeze thawing test and a compatibility stability test. The stability of electrolyte solution such as sodium chloride injection with concentration of 0.9% is obviously improved, so that the electrolyte injection can be used for transfusion, and clinical application is facilitated.
(2) The nimodipine micelle injection prepared by the invention has the concentration of nimodipine injection concentration up to 4mg/ml, solves the problem of poor solubility of nimodipine injection in the neck, and has higher clinical value compared with the commercial injection of 0.2 mg/ml.
(3) The nimodipine micelle injection prepared by the invention has the advantages that the heat treatment step is added in the preparation process, the physical and chemical stability of the injection is obviously improved, the filtered liquid medicine is placed at 25 ℃ for 48 hours, the appearance, the content, related substances, the particle size and the like are not obviously changed, and sufficient time is provided for the next filling, sealing and other steps, so that the amplified production is facilitated.
(4) The nimodipine micelle injection prepared by the invention can resist hot press sterilization, has no obvious change in indexes such as properties, pH, particle size, content, related substances and the like of the injection before and after sterilization, meets the pharmacopoeia requirements of 2020 edition, and greatly improves sterility assurance.
(5) The nimodipine micelle injection prepared by the invention abandons ethanol solubilizer in the prescription, does not contain organic solvent, reduces anaphylaxis, alcoholism or alcohol metabolism damage, pain, inflammation and the like, and obviously improves the safety of clinical medication
(6) The preparation process is easy to amplify, and the innovative film dispersion-hydration process is adopted, so that the consumption of organic solvents such as absolute ethyl alcohol and the like is obviously reduced, and the use of active carbon is abandoned in the process, thereby being beneficial to the amplified production. In the prior art, absolute ethyl alcohol or propylene glycol is adopted in micelle patents, so that the safety is low, the use amount is large, and the difficulty of amplified production is increased; other complex injection formulations such as fat emulsion, liposome and the like have complex prescription process, are unfavorable for process amplification, have large quality control difficulty and have poor stability.
Drawings
Fig. 1 shows an external appearance pattern of nimodipine mixed micelle injection prepared by a film dispersion method in example 1.
Fig. 2 shows a high performance liquid chromatogram of the nimodipine micelle injection prepared by the thin film dispersion method in example 5 for determining related substances.
Fig. 3 and 4 show particle size distribution diagrams of nimodipine micelle injection prepared by a thin film dispersion method in example 7.
FIG. 5 shows the content change curves (0.02 mg/ml and 0.04 mg/ml) measured when the compatibility stability of nimodipine micelle injection prepared by the film dispersion method of example 7 of experimental example 8 was examined (0.9% sodium chloride injection).
FIG. 6 shows the content change curves (0.02 mg/ml and 0.04 mg/ml) measured when the compatibility stability of nimodipine micelle injection prepared by the film dispersion method of example 7 of experimental example 8 was examined (5% glucose injection).
FIG. 7 is a graph showing the content change (0.02 mg/ml and 0.04 mg/ml) of the raw injection (Nimotop, same as Nimembrane) in Experimental example 8 when the compatibility stability of the raw injection was examined (0.9% sodium chloride injection).
FIG. 8 is a graph showing the content change (0.02 mg/ml and 0.04 mg/ml) of the original ground injection (Nimotop) in Experimental example 8 when the compatibility stability of the injection (5% glucose injection) was examined.
Detailed Description
The above-described aspects of the present invention will be described in further detail by way of the following embodiments, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to the following embodiments. All techniques realized based on the above description of the present invention are within the scope of the present invention, and the following examples are accomplished by conventional techniques unless otherwise specified.
EXAMPLE 1 preparation of nimodipine micelle injection
Each nimodipine-containing 10mg,25 nimodipine micelle injection comprises the following components:
the preparation process comprises the following steps:
(1) Weighing nimodipine, soybean lecithin and glycine to dissolve in methanol and ethanol according to the prescription amount, and stirring and dispersing uniformly to obtain clear liquid;
(2) Removing methanol and ethanol from the clear solution obtained in the step (1) by rotary evaporation by using a rotary evaporator to form a film;
(3) Weighing sucrose, sodium hydroxide, citric acid and sodium citrate according to the prescription, dissolving in 100ml of water for injection to obtain a clear solution, charging nitrogen as a protective gas, adding the clear solution into the film for hydration to obtain a clear liquid, carrying out heat treatment at 100 ℃ for 30min in an oil bath, cooling to room temperature, regulating the pH value to 6.5 by 0.1mol/L sodium hydroxide solution, and fixing the volume of the water for injection to 125ml to obtain nimodipine mixed micelle solution;
(4) Sterilizing, filtering, packaging into ampoule bottles, sealing, and performing hot press sterilization at 121 ℃ for 15min to obtain nimodipine mixed micelle injection.
The same batch of injection is clear and transparent and light yellow green as shown in figure 1. The mixed micelle solution Z-Average was 2.577nm, PDI was 0.239, and zeta potential was-30.0 mV.
Example 2
Each nimodipine-containing 10mg,25 nimodipine micelle injection comprises the following components:
the preparation process comprises the following steps:
steps (1) and (2) are the same as in example 1.
(3) Weighing sucrose and sodium hydroxide according to the prescription, dissolving in 100ml of water for injection to obtain a clear solution, charging nitrogen as a protective gas, adding the clear solution into the film, hydrating to obtain a clear liquid completely, adjusting the pH value to 6.5 by using 0.1mol/L sodium hydroxide solution, and fixing the volume of the water for injection to 125ml to obtain nimodipine mixed micelle solution;
(4) Sterilizing, filtering, packaging into ampoule bottles, sealing, and hot-pressing at 121deg.C for 12min for sterilization to obtain nimodipine mixed micelle injection.
The injection is clear and transparent, and has light yellow green color. The mixed micelle solution Z-Average was 5.105nm, PDI was 0.350, and zeta potential was-43.9 mV.
Example 3
Each nimodipine-containing 10mg,20 nimodipine micelle injection comprises the following components:
the preparation process comprises the following steps:
steps (1) and (2) are the same as in example 1.
(3) The sucrose is weighed according to the prescription and dissolved in 80ml of water for injection to obtain a clear solution, the clear solution is filled with nitrogen gas as a protective gas, the protective gas is added into the film, the clear solution is obtained after hydration, the oil bath is subjected to heat treatment at 80 ℃ for 30min, and the solution is cooled to room temperature. And regulating the pH value to 6.0 by using 0.1mol/L sodium hydroxide solution, and fixing the volume to 100ml by using water for injection to obtain the nimodipine mixed micelle solution.
(4) Sterilizing, filtering, packaging into ampoule bottles, sealing, and hot-pressing at 121deg.C for 12min to obtain nimodipine mixed micelle injection.
The injection is clear and transparent, and has light yellow green color. The mixed micelle solution Z-Average was 2.639nm, PDI was 0.301, and zeta potential was-30.5 mV.
Example 4
Each nimodipine-containing 10mg,20 nimodipine micelle injection comprises the following components:
the preparation process comprises the following steps:
steps (1) and (2) are the same as in example 1.
(3) Weighing sucrose and sodium hydroxide according to the prescription, dissolving in 80ml of water for injection to obtain clear solution, charging nitrogen as protective gas, adding into the film, hydrating completely, heat treating in oil bath at 100deg.C for 60min, and cooling to room temperature. And regulating the pH value to 6.0 by using 0.1mol/L citric acid solution, and fixing the volume to 100ml by using water for injection to obtain the nimodipine mixed micelle solution.
(4) Sterilizing, filtering, packaging into ampoule bottles, sealing, and hot-pressing at 121deg.C for 12min to obtain nimodipine mixed micelle injection.
The injection is clear and transparent, and has light yellow green color. The mixed micelle solution Z-Average was 5.698nm, PDI was 0.310, and zeta potential was-29.7 mV.
Example 5
Each nimodipine-containing 10mg,20 nimodipine micelle injection comprises the following components:
the preparation process comprises the following steps:
(1) Weighing nimodipine, soybean lecithin, glycocholic acid and poloxamer 188 according to the proportion, dissolving in methanol and ethanol, and stirring and dispersing uniformly to obtain clear liquid;
(2) Removing methanol and ethanol from the clear solution obtained in the step (1) by rotary evaporation by using a rotary evaporator to form a film;
(3) Weighing sucrose, sodium hydroxide and citric acid according to the prescription, dissolving in 80ml of water for injection, adding into the film, hydrating to obtain clear solution, heat treating in oil bath at 100deg.C for 30min, and cooling to room temperature. And regulating the pH value to 6.5 by 0.1mol/L citric acid solution, and fixing the volume to 100ml by water for injection to obtain the nimodipine mixed micelle solution.
(4) Sterilizing, filtering, packaging into ampoule bottles, sealing, and hot-pressing at 121deg.C for 12min to obtain nimodipine mixed micelle injection.
The injection is clear and transparent, and has light yellow green color. As shown in FIGS. 3 and 4, the mixed micelle solution Z-Average was 2.734nm, PDI was 0.255, and zeta potential was-28.8 mV.
Example 6
Each nimodipine-containing 10mg,20 nimodipine micelle injection comprises the following components:
the preparation process comprises the following steps:
(1) Weighing nimodipine, soybean lecithin, glycocholic acid and Solutol HS 15 according to the proportion, dissolving in methanol and ethanol, and stirring and dispersing uniformly to obtain clear liquid;
(2) Removing methanol and ethanol from the clear solution obtained in the step (1) by rotary evaporation by using a rotary evaporator to form a film;
(3) And weighing sucrose, sodium hydroxide, citric acid and sodium citrate according to the prescription, dissolving in 80ml of water for injection to obtain a clear solution, charging protective gas nitrogen for 10min, adding the clear solution into the film, and adjusting the pH value to 6.5 by using 0.1mol/L sodium hydroxide solution after hydration is completed, wherein the volume of the water for injection is fixed to 100ml to obtain nimodipine mixed micelle solution.
(4) Sterilizing, filtering, packaging into ampoule bottles, sealing, and hot-pressing at 121deg.C for 15min to obtain nimodipine mixed micelle injection.
The injection is clear and transparent, and has light yellow green color. The mixed micelle solution Z-Average was 9.860nm, PDI was 0.357, and zeta potential was-26.9 mV.
Example 7
Each nimodipine-containing 10mg,20 nimodipine micelle injection comprises the following components:
the preparation process comprises the following steps:
(1) Weighing nimodipine, soybean lecithin, glycocholic acid and Solutol HS 15 according to the proportion, dissolving in methanol and ethanol, and stirring and dispersing uniformly to obtain clear liquid;
(2) Removing methanol and ethanol from the clear solution obtained in the step (1) by rotary evaporation by using a rotary evaporator to form a film;
(3) Weighing sucrose, sodium hydroxide and citric acid according to the prescription, dissolving in 80ml of water for injection to obtain clear solution, charging protective gas nitrogen for 30min, adding into the film, heating in oil bath at 100deg.C for 30min after hydration, and cooling to room temperature. And regulating the pH value to 6.5 by using 0.1mol/L sodium hydroxide solution, and fixing the volume to 100ml by using water for injection to obtain the nimodipine mixed micelle solution.
(4) Sterilizing, filtering, packaging into ampoule bottles, sealing, and hot-pressing at 121deg.C for 15min to obtain nimodipine mixed micelle injection.
The injection is clear and transparent, and has light yellow green color. The mixed micelle solution Z-Average was 2.834nm, PDI was 0.201, and zeta potential was-34.7 mV.
Example 8
Each nimodipine-containing 10mg,20 nimodipine micelle injection comprises the following components:
the preparation process comprises the following steps:
(1) Weighing nimodipine, soybean lecithin, glycocholic acid and Solutol HS 15 according to the proportion, dissolving in methanol and ethanol, and stirring and dispersing uniformly to obtain clear liquid;
(2) Removing methanol and ethanol from the clear solution obtained in the step (1) by rotary evaporation by using a rotary evaporator to form a film;
(3) Weighing sucrose, sodium hydroxide and citric acid according to the prescription, dissolving in 80ml of water for injection to obtain clear solution, charging protective gas nitrogen for 60min, adding into the film, heating in oil bath at 100deg.C for 30min after hydration, and cooling to room temperature. And regulating the pH value to 6.5 by 0.1mol/L citric acid solution, and fixing the volume to 100ml by water for injection to obtain the nimodipine mixed micelle solution.
(4) Sterilizing, filtering, packaging into ampoule bottles, sealing, and hot-pressing at 121deg.C for 15min to obtain nimodipine mixed micelle injection.
The injection is clear and transparent, and has light yellow green color. The mixed micelle solution Z-Average was 3.325nm, PDI was 0.315, and zeta potential was-37.6 mV.
Example 9
Each nimodipine-containing 10mg,20 nimodipine micelle injection comprises the following components:
the preparation process comprises the following steps:
(1) Weighing nimodipine, egg yolk lecithin, taurocholate and Solutol HS 15 according to the proportion, dissolving in methanol and ethanol, and stirring and dispersing uniformly to obtain clear liquid;
(2) Removing methanol and ethanol from the clear solution obtained in the step (1) by rotary evaporation by using a rotary evaporator until the removal is completed and a film is formed;
(3) Weighing sucrose and sodium hydroxide according to the prescription, dissolving in 80ml of water for injection to obtain clear solution, charging protective gas nitrogen for 60min, adding into the film, heating in oil bath at 100deg.C for 30min after hydration, and cooling to room temperature. And regulating the pH value to 5.5 by 0.1mol/L citric acid solution, and fixing the volume to 100ml by using water for injection to obtain the nimodipine mixed micelle solution.
(4) Sterilizing, filtering, packaging into ampoule bottles, sealing, and hot-pressing at 121deg.C for 15min to obtain nimodipine mixed micelle injection.
The injection is clear and transparent, and has light yellow green color. The mixed micelle solution Z-Average was 3.325nm, PDI was 0.315, and zeta potential was-37.6 mV.
Example 10
Each nimodipine-containing 10mg,20 nimodipine micelle injection comprises the following components:
the preparation process comprises the following steps:
(1) Weighing nimodipine, hydrogenated soybean phospholipid, glycocholic acid and poloxamer 188 according to the proportion, dissolving in methanol and ethanol, and stirring and dispersing uniformly to obtain clear liquid;
(2) Placing the clear solution obtained in the step (1) in a rotary evaporator to remove methanol and ethanol by rotary evaporation until the removal is completed and a film is formed;
(3) Weighing sucrose and sodium hydroxide according to the prescription, dissolving in 60ml of water for injection to obtain clear solution, charging protective gas nitrogen for 30min, adding into the film, heating in oil bath at 100deg.C for 30min after hydration, and cooling to room temperature. And regulating the pH value to 6.5 by using 0.1mol/L sodium hydroxide solution, and fixing the volume to 80ml by using water for injection to obtain the nimodipine mixed micelle solution.
(4) Sterilizing, filtering, packaging into ampoule bottles, sealing, and hot-pressing at 121deg.C for 15min to obtain nimodipine mixed micelle injection.
The injection is clear and transparent, and has light yellow green color. The mixed micelle solution Z-Average was 2.679nm, PDI was 0.371, and zeta potential was-29.1 mV.
Example 11
Each nimodipine-containing 10mg,20 nimodipine micelle injection comprises the following components:
the preparation process comprises the following steps:
(1) Weighing nimodipine, soybean lecithin, glycocholic acid and Solutol HS 15 according to the proportion, dissolving in methanol and ethanol, and stirring and dispersing uniformly to obtain clear liquid;
(2) Placing the clear solution obtained in the step (1) in a rotary evaporator to remove methanol and ethanol by rotary evaporation until the removal is completed and a film is formed;
(3) Weighing sucrose and sodium hydroxide according to the prescription, dissolving in 80ml of water for injection to obtain clear solution, charging protective gas nitrogen for 30min, adding into the film, heating in oil bath at 100deg.C for 30min after hydration, and cooling to room temperature. And regulating the pH value to 7.0 by using 0.1mol/L sodium hydroxide solution, and fixing the volume to 100ml by using water for injection to obtain the nimodipine mixed micelle solution.
(4) Sterilizing, filtering, packaging into ampoule bottles, sealing, and hot-pressing at 121deg.C for 15min to obtain nimodipine mixed micelle injection.
The injection is clear and transparent, and has light yellow green color. The mixed micelle solution Z-Average was 3.517nm, PDI was 0.392 and zeta potential was-34.2 mV.
Example 12
Each nimodipine-containing 10mg,20 nimodipine micelle injection comprises the following components:
the preparation process comprises the following steps:
(1) Weighing nimodipine, soybean lecithin, glycocholic acid and polysorbate 80 according to the proportion, dissolving in methanol and ethanol, and stirring and dispersing uniformly to obtain clear liquid;
(2) Removing methanol and ethanol from the clear solution obtained in the step (1) by rotary evaporation by using a rotary evaporator until the removal is completed and a film is formed;
(3) Weighing mannitol and sodium hydroxide according to the prescription, dissolving in 80ml of water for injection to obtain clear solution, charging nitrogen as protective gas, adding into the film, hydrating completely, heat treating in oil bath at 100deg.C for 30min, and cooling to room temperature. And regulating the pH value to 6.5 by 0.1mol/L citric acid solution, and fixing the volume to 100ml by water for injection to obtain the nimodipine mixed micelle solution.
(4) Sterilizing, filtering, packaging into ampoule bottles, sealing, and hot-pressing at 121deg.C for 12min to obtain nimodipine mixed micelle injection.
The injection is clear and transparent, and has light yellow green color. The mixed micelle solution Z-Average was 2.267nm, PDI was 0.321, and zeta potential was-31.5 mV.
Example 13
Each nimodipine-containing 10mg,20 nimodipine micelle injection comprises the following components:
the preparation process comprises the following steps:
(1) Weighing nimodipine, soybean lecithin, glycocholic acid and polyethylene glycol 1000 vitamin E succinate (TPGS 1000) according to the prescription, dissolving in methanol and ethanol, and stirring and dispersing uniformly to obtain clear liquid;
(2) Removing methanol and ethanol from the clear solution obtained in the step (1) by rotary evaporation by using a rotary evaporator until the removal is completed and a film is formed;
(3) Weighing trehalose and sodium hydroxide according to the prescription, dissolving in 80ml of water for injection to obtain a clear solution, charging nitrogen as a protective gas, adding into the film, performing heat treatment at 100 ℃ for 30min in an oil bath after hydration is completed, and cooling to room temperature. And regulating the pH value to 6.0 by using 0.1mol/L citric acid solution, and fixing the volume to 100ml by using water for injection to obtain the nimodipine mixed micelle solution.
(4) Sterilizing, filtering, packaging into ampoule bottles, sealing, and hot-pressing at 121deg.C for 12min to obtain nimodipine mixed micelle injection.
The injection is clear and transparent, and has light yellow green color. The mixed micelle solution Z-Average was 2.627nm, PDI was 0.291, and zeta potential was-35.1 mV.
The above examples were experimentally verified to apply examples 5 to 13, most preferably examples 5 to 8.
Comparative example 1
According to example 1 of patent CN 102525917B, nimodipine micelle injection was prepared as follows:
50mg of egg yolk lecithin, 50mg of sodium glycocholate and 1.25mg of nimodipine are weighed into a 50ml round bottom flask, 10ml of ethanol is added for dissolution and ultrasonic dispersion is uniform. Removing ethanol by rotary evaporation at water bath temperature of 40deg.C until no ethanol smell is present, forming a transparent film, and dispersing with 2.5ml injectable water to obtain dispersion solution of mixed micelle containing medicine. Adding 0.05% injection-grade active carbon, stirring for 15min, centrifuging at 12000rpm/min for 5min, filtering with 0.22 μm microporous membrane, collecting filtrate, packaging, and sterilizing at 121deg.C for 15min to obtain nimodipine mixed micelle injection.
Comparative example 2
According to example 2 of patent CN 102525917B, nimodipine micelle injection was prepared as follows:
50mg of egg yolk lecithin, 50mg of sodium glycocholate and 1mg of nimodipine are weighed into a 50ml round bottom flask, 10ml of ethanol is added for dissolution and ultrasonic dispersion is uniform. And removing ethanol by rotary evaporation, rotating the water bath temperature to 35 ℃ until no alcohol smell exists, forming a layer of transparent film, and dispersing with 2.5ml of water for injection to obtain a dispersion solution of the drug-containing mixed micelle. Adding 0.05% injection-grade active carbon, stirring for 15min, centrifuging at 12000rpm/min for 5min, filtering with 0.22 μm microporous membrane, collecting filtrate, packaging, and sterilizing at 121deg.C for 15min to obtain nimodipine mixed micelle injection.
Experimental example 1 method for measuring drug-loading amount, content, related substances and residual solvent
1. Drug loading= (amount of nimodipine dissolved in the formulation)/{ amount of total excipients added (phospholipid+bile salts+nimodipine) }.
2. Content determination method
Chromatographic conditions: octadecylsilane chemically bonded silica is used as a filler; methanol-acetonitrile-water (35:38:27) as mobile phase; the detection wavelength is 235nm; the sample volume was 10. Mu.l and the column temperature was 40 ℃.
Control solution: weighing nimodipine 20mg, placing into a 20ml volumetric flask, adding methanol for dissolving and diluting to scale, shaking, diluting with solvent (methanol-acetonitrile-water, 35:38:27) for 10 times, and shaking.
Test solution: 2ml of the sample solution under the relevant substance item is precisely measured, placed in a 20ml measuring flask, diluted to a scale with a solvent (methanol-acetonitrile-water, 35:38:27) and shaken well.
3. Method for testing related substances
Chromatographic conditions: octadecylsilane chemically bonded silica is used as a filler; methanol-water (40:60) is used as a mobile phase A, and acetonitrile-water (90:10) is used as a mobile phase B; the detection wavelength is 235nm; the sample volume was 10. Mu.l and the column temperature was 40 ℃. Gradient elution was performed as in table 1.
TABLE 1 gradient elution Table for nimodipine micelle injection related substances method
Test solution: precisely weighing 1ml of the product, placing into a 10ml measuring flask, diluting to scale with methanol, and shaking.
4. Residual solvent measurement method:
(1) Chromatographic conditions: capillary columns with 6% cyanopropylphenyl-94% dimethylpolysiloxane (or similar polarity) as the fixative (Agilent DB-624,0.53 mm. Times.30 m,3 μm or equivalent performance columns are recommended); the initial temperature is 40 ℃, the temperature is maintained for 8 minutes, the temperature is increased to 180 ℃ at the rate of 10 ℃ per minute, and the temperature is maintained for 5 minutes; the temperature of the sample inlet is 200 ℃; the detector is a flame ionization detector, and the temperature of the detector is 300 ℃; the column flow was 2ml per minute; the split ratio was 10:1, a step of; the headspace equilibrium temperature is 80 ℃; the quantitative ring temperature is 90 ℃; the equilibration time was 30 minutes.
System applicability requirements: in the chromatogram of the reference substance solution, methanol and ethanol sequentially form peaks, and the separation degree among the color spectrum peaks meets the requirements.
(2) Preparation of the solution
Test solution: about 100mg of the product is taken, precisely weighed, placed in a 20ml headspace bottle, precisely added with 2ml of ultrapure water, shaken and sealed.
Control solution: respectively weighing appropriate amounts of methanol and ethanol, accurately weighing, quantitatively diluting with ultrapure water to obtain mixed solution containing about 150 μg and 250 μg per 1ml, accurately weighing 2ml of the solution, placing into a 20ml headspace bottle, and sealing.
Examples 1-13 and comparative examples 1-2 were tested according to the above-mentioned drug loading, content, related substances, residual solvent measurement methods, and the results are shown in Table 2; the chromatogram of the micelle injection prepared in example 5 after sterilization is shown in FIG. 2. As can be seen from the results in table 2, the micelle injection prepared in the examples has a significantly higher drug loading than the comparative examples; the micelle injection prepared in the embodiment has no obvious change of contents before and after hot press sterilization, and related substances accord with pharmacopoeia and import registration standards; the injection prepared in comparative examples 1-2 has significant content reduction before and after sterilization, and related substances exceed standards, so that examples 1-13 have significant advantages.
Table 2 detection results of nimodipine micelle injection drug loading, content, related substances, etc
Experimental example 2 investigating the Effect of adding surface finishing Material
The nimodipine micelle injection prepared by the invention is prepared by adding the surface modification material into the prescription, so that a novel nano micelle solubilization system is constructed, the physical and chemical stability of the mixed micelle can be obviously improved, the drug loading capacity is improved, and the water solubility and stability of nimodipine are greatly improved.
As can be seen from the drug-loading results of experimental example 1, the formulations of examples 1 to 4 are not added with surface modification materials, the drug-loading is larger than that of comparative examples, and the formulations of examples 5 to 11 are added with surface modification materials with different formulations, the drug-loading is larger than that of examples 1 to 4, and the addition of the surface modification materials can improve the drug-loading.
By comparing example 2 (not added) with example 6 (added), both of which were not heat treated, the filtered sample was left at 25℃for 48 hours, and physical stability was judged by observing the behavior (presence or absence of crystal precipitation). The results are shown in the following table, the injection prepared in example 2 is placed for 6 hours to precipitate, the injection prepared in example 6 is placed for 12 hours at 25 ℃ to not precipitate, and the physical stability of the micelle injection can be remarkably improved.
TABLE 3 physical stability investigation results
Experimental example 3 investigation of the effect of Heat treatment on stability
The nimodipine micelle injection prepared by the invention is characterized in that a heat treatment step is added in the preparation process, design examples 2, 3, 4, 5 and 7 are examined and compared with a comparative example, a filtered sample is placed at 25 ℃ for 48 hours, and the physical stability is judged by observing the properties (whether crystals are precipitated or not).
As can be seen from the results in Table 4, the samples of comparative examples 1-2 were subjected to filtration and left at 25℃for 4 hours, and crystals were precipitated; example 2 shows that crystals are precipitated after being placed for 6 hours, which is superior to the comparative example; example 3, the mixture was left for 8 hours and crystals were precipitated; examples 4, 5 and 7 were left unchanged in the 36h trait at 25℃and examples 5 and 7 were left unchanged for 48 h;
as is apparent from the results shown in Table 5 below, the pH, the content, the related substances, etc. were not significantly changed as measured by the content and the related substances in Experimental example 1.
In the experimental results, the nimodipine micelle injection prepared by the invention has the advantages that the physical stability of the injection is obviously improved by adding a heat treatment step in the preparation process, and the filtered solution is placed at 25 ℃ for 48 hours without obvious changes in appearance, content, related substances, granularity and the like.
Table 4 results of heat treatment investigation
TABLE 5 detection results of nimodipine micelle injection content, related substances, particle size, etc
Experimental example 4 investigation of the Effect of the protective gas filling on the micelle injection
In comparative examples 5 to 8, the necessity of charging the protective gas was confirmed from the results of Table 6, and the charging time of the protective gas was maintained for 0.5 to 1 hour, and the hydration solution of nimodipine mixed micelle injection was used as the protective gas by using nitrogen gas, so that the level of the related substances (key impurity I) was reduced, and the physical and chemical stability of nimodipine injection was improved.
TABLE 6 test results of related substances
Experimental example 5 investigation of sterilization conditions
The influence of the selection of the hot-press sterilization conditions on the content of nimodipine micelle injection is examined, 121 ℃/12min or 121 ℃/15min is selected for hot-press sterilization on the prepared micelle injection, and the content detection method in the example 6 is adopted, so that the results are shown in Table 7. As can be seen from Table 7, the content results before and after sterilization have no significant change, and factors such as stability of auxiliary materials are comprehensively considered, so that the hot press sterilization is selected to be 121 ℃/12min.
TABLE 7 self-made sample content test results under different sterilization conditions
Experimental example 6 Low temperature cycle test
The nimodipine micelle injection prepared in example 5 is taken for a low-temperature cycle test, the test comprises 3 cycles, each cycle is placed at 2-8 ℃ for 2 days, then at 40 ℃ for 2 days, sampling and detection are carried out after each cycle is finished, and the content and related substances in the test are detected according to the method of the content and related substances in the test example 1, and the results are shown in Table 8.
As can be seen from the results in Table 8, after the 3 rounds are completed, no precipitation phenomenon occurs; the pH value, clarity, color, grain diameter, potential, content, related substances and the like have no obvious change compared with 0 day, and the self-made micelle injection can withstand a low-temperature circulation test.
TABLE 8 Low temperature cycle test results
Experimental example 7 Freeze thawing test
The nimodipine micelle injection prepared in example 4 was subjected to freeze thawing test, which comprises 3 cycles, each cycle was allowed to stand at-10- -20deg.C for 2 days, then at 40deg.C for 2 days, and after each cycle was completed, the samples were taken and tested, and the content and related substances in experimental example 1 were measured, and the results are shown in Table 9.
As is clear from the results in Table 9, after the 3-cycle was completed, the properties were observed and no precipitation phenomenon was observed; the pH value, clarity, color, granularity, potential, content, related substances and the like have no obvious change compared with 0 day, and the self-made micelle injection can withstand a freeze thawing test.
TABLE 9 freeze thawing test results
Experimental example 8 compatibility stability
Taking nimodipine micelle injection prepared in example 7 and original injectionDiluting with 0.9% sodium chloride injection and 5% glucose injection to give a concentration0.04mg/ml or 0.02mg/ml, and the mixture was left at room temperature (25 ℃) for 24 hours to examine the stability under clinical use conditions. The dilution stability was examined in combination with the content and related substance analysis and detection method in experimental example 1, the results are shown in Table 10, table 11, and the content change curves are shown in FIGS. 5 to 8.
As is clear from the results shown in Table 10 and Table 11, the product (example 7) showed no precipitation during 24 hours, no significant change in the content and the related substances (impurity I and total impurities), and no significant increase in insoluble fine particles.
TABLE 10 example 7 determination of the content of the compatible solutions
TABLE 11 determination of the content of the solutions of the crude injection formulations
Conclusion: original grinding injectionThe content fluctuation is obvious when the sodium chloride injection or the glucose injection is diluted to 0.9%, particularly when the sodium chloride injection is diluted to 0.9% and is placed for 1h, the fluctuation is abnormal, the analysis reasons are that the compatible solution is crystallized and separated out, and the content test is abnormal when the separated out crystals are collected by sample injection, so that the follow-up stability is not required to be inspected. Compared with the original ground product injection, the prepared mixed solution of the self-made sample is placed for 24 hours without precipitation phenomenon, the content is not obviously changed, and the stability is good.
Experimental example 9 influence factor test
Nimodipine micelle injection prepared in example 8 was taken and placed under high temperature 40℃and light conditions (light intensity 4500lx, UV 200 W.h/m, respectively 2 ) The influence factors were examined, sampled at 30 days, and tested according to the content and related substances in experimental example 1, and the results are shown in Table 12. As can be seen from the results of Table 12, the self-prepared injections were respectively placed under light conditions at a high temperature of 40℃for 30The characteristics, pH value, clarity, color, granularity, potential, content and related substances of the composition are not obviously changed, and all meet pharmacopoeia standards.
TABLE 12 influence factor test results
Experimental example 10 accelerated test and long-term test
The nimodipine mixed micelle injection in examples 11, 12 and 13 was subjected to stability study under the following conditions, and changes in appearance, properties, pH and Zeta potential were recorded, and the nimodipine content, related substances were measured according to example 6 above, and the results are shown in table 13.
Wherein, the content of the sterilized comparative example is reduced by about 6%, and the total impurities exceed the standards in pharmacopoeia, so the stability is not examined.
Long-term test: 25 ℃ +/-2 ℃/60%RH+/-5%RH; acceleration test: 40 ℃ + -2 ℃/75% RH+ -5% RH.
Table 13 nimodipine micelle injection stability investigation results
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Conclusion: as is clear from the above table, the nimodipine micelle injection of examples 11-13 is placed for 6 months under the conditions of long-term stability and accelerated stability, and the indexes of appearance, pH, potential, content, related substances (impurity I, total impurities) and the like are not changed significantly. The results show that the nimodipine micelle injection of examples 11-13 has good stability. The nimodipine micelle injection is stored at 2-8 ℃ under the designed storage condition, and the validity period of the nimodipine micelle injection is tentatively set for 2 years according to the accelerated stability test result.
It will be apparent to those skilled in the art that the present invention has been described in detail by way of illustration only, and it is not intended to be limited by the above-described embodiments, as long as various insubstantial modifications of the method concepts and aspects of the invention are employed or the inventive concepts and aspects of the invention are directly applied to other applications without modification, all within the scope of the invention.

Claims (8)

1. A nimodipine micelle injection is characterized in that: comprises nimodipine, phospholipid, cholic acid or salt thereof, surface modification material, isotonic regulator, pH regulator and water for injection; wherein the proportion of each component is as follows:
The concentration of nimodipine as the active component in the injection is 0.1 mg/ml-4 mg/ml; in addition, the weight ratio of nimodipine to phospholipid is 0.5-20: 100, the weight ratio of cholic acid or salt thereof to phospholipid is 0.1-10: 1, the weight ratio of the surface modification material to nimodipine is 0.1-10: 1, the weight ratio of the isotonic regulator to the phospholipid is 0.1-5: 1, a step of;
the preparation method is a film dispersion method, and the specific process is as follows:
step (1): weighing nimodipine, phospholipid, cholic acid or salt thereof and surface modification material in the formula, and dissolving in a proper amount of organic solvent;
step (2): transferring the solution obtained in the step (1) to a rotary evaporator, and opening vacuum to remove the organic solvent at the water bath temperature of 30-70 ℃ to obtain a loose film;
step (3): weighing the isotonic regulator in the formula, and diluting the regulator in water for injection; if the auxiliary material in the step (1) is cholic acid, adding alkali in a pH regulator with the molar ratio of the alkali to the cholic acid being 1:1, and filling a protective gas to obtain a stabilizer solution; completely transferring the nimodipine micelle solution into the loose film obtained in the step (2), stirring to enable the loose film to be hydrated completely, adjusting the pH of the solution by a pH regulator, performing heat treatment, and cooling to obtain nimodipine micelle solution;
the heat treatment is carried out at 90-100 ℃ for 20-30 min;
Step (4): fixing the volume of the solution obtained in the step (3) by using water for injection, filling protective gas, sterilizing, filtering, sub-packaging into ampoule bottles for sealing, and performing hot-press sterilization to obtain nimodipine micelle injection;
the surface modification material is composed of any one or more of 15-hydroxystearic acid polyethylene glycol ester, polyoxyethylene polyoxypropylene copolymer, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, polyethylene glycol vitamin E succinate and polyethylene glycol-distearoyl phosphatidylcholine according to any proportion.
2. Nimodipine micelle injection according to claim 1, wherein: the phospholipid is selected from one of soybean phospholipid, yolk phospholipid, hydrogenated soybean phospholipid, hydrogenated yolk phospholipid, dipalmitoyl phosphatidylcholine, dipalmitoyl phosphatidylethanolamine, distearoyl phosphatidylcholine, dilauroyl phosphatidylcholine, dioleoyl phosphatidylethanolamine, distearoyl phosphatidylethanolamine and dioleoyl phosphatidylcholine.
3. Nimodipine micelle injection according to claim 1, wherein: the cholic acid or its salt is one or more of glycocholic acid, deoxycholic acid, glycochenodeoxycholic acid, taurocholic acid and taurochenodeoxycholic acid or its salt.
4. Nimodipine micelle injection according to claim 1, wherein: the isotonic regulator is one or more of sucrose, trehalose, glucose, lactose, fructose, mannitol, dextran, sorbitol, dextran, glycine, hydroxyethyl starch, polyvinylpyrrolidone and polyvinylpyrrolidone according to any proportion;
the acid in the physiologically and pharmaceutically acceptable pH regulator is selected from any one or more of glacial acetic acid, formic acid, trifluoroacetic acid, phosphoric acid, citric acid, tartaric acid, oxalic acid, malic acid, alanine, hydrochloric acid, leucine, isoleucine, malic acid, valine, tryptophan, maleic acid, fumaric acid, lactic acid, phenylalanine, methionine and succinic acid according to any proportion; the alkali in the pH regulator is one or more of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, choline hydroxide, arginine, lysine, histidine, diethylamine, triethylamine, meglumine, sodium citrate, sodium tartrate, sodium lactate, sodium phosphate and disodium hydrogen phosphate according to any proportion.
5. Nimodipine micelle injection according to any one of claims 1-4, wherein:
The phospholipid is selected from soybean phospholipid, and the cholic acid or salt thereof is selected from glycocholic acid or sodium glycocholate; the surface modification material is one of 15-hydroxystearic acid polyethylene glycol ester, polyoxyethylene polyoxypropylene copolymer and polyoxyethylene sorbitan fatty acid ester, the isotonic regulator is sucrose, the acid in the pH regulator is selected from citric acid, and the alkali in the pH regulator is sodium hydroxide.
6. The method for preparing nimodipine micelle injection as claimed in claim 1, which is characterized in that: the preparation method is a film dispersion method, and the specific process is as follows:
step (1): weighing nimodipine, phospholipid, cholic acid or salt thereof and surface modification material in the formula, and dissolving in a proper amount of organic solvent;
step (2): transferring the solution obtained in the step (1) to a rotary evaporator, and opening vacuum to remove the organic solvent at the water bath temperature of 30-70 ℃ to obtain a loose film;
step (3): weighing the isotonic regulator in the formula, and diluting the regulator in water for injection; if the auxiliary material in the step (1) is cholic acid, adding alkali in a pH regulator with the molar ratio of the alkali to the cholic acid being 1:1, and filling a protective gas to obtain a stabilizer solution; completely transferring the nimodipine micelle solution into the loose film obtained in the step (2), stirring to enable the loose film to be hydrated completely, adjusting the pH of the solution by a pH regulator, performing heat treatment, and cooling to obtain nimodipine micelle solution;
The heat treatment is carried out at 90-100 ℃ for 20-30 min;
step (4): and (3) fixing the volume of the solution obtained in the step (3) by using water for injection, filling protective gas, sterilizing, filtering, sub-packaging into ampoule bottles for sealing, and performing hot-pressing sterilization to obtain nimodipine micelle injection.
7. The method for preparing nimodipine micelle injection according to claim 6, wherein:
the organic solvent in the film dispersion method is one or a plurality of compositions of methanol, ethanol, ethyl acetate and isopropanol according to any proportion, the dosage of the organic solvent is 2-8% of the volume of the prepared injection, and the protective gas is one of nitrogen, helium, carbon dioxide and argon; the protective gas in the step (3) and the step (4) is nitrogen, the time of introducing the protective gas is 0.5-2 hours, and the residual range of dissolved oxygen in the step (4) is controlled to be 5-10 ppm; the concentration of nimodipine in the nano micelle injection obtained in the step (4) is 0.1 mg/ml-4 mg/ml.
8. The use of nimodipine micelle injection according to claim 1 in the preparation of a medicament for preventing and treating ischemic nerve injury caused by cerebral vasospasm after aneurysmal subarachnoid hemorrhage.
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