WO2024001964A1 - 不含乙醇和磷脂的湿热灭菌的尼莫地平组合物及其制备方法 - Google Patents

不含乙醇和磷脂的湿热灭菌的尼莫地平组合物及其制备方法 Download PDF

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WO2024001964A1
WO2024001964A1 PCT/CN2023/102147 CN2023102147W WO2024001964A1 WO 2024001964 A1 WO2024001964 A1 WO 2024001964A1 CN 2023102147 W CN2023102147 W CN 2023102147W WO 2024001964 A1 WO2024001964 A1 WO 2024001964A1
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nimodipine
composition
solution
polysorbate
injection
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PCT/CN2023/102147
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English (en)
French (fr)
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吴翠栓
张丹
孙亚美
娄双月
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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
    • 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
    • A61K47/08—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
    • 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
    • A61K47/08—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
    • 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
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic 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
    • A61P9/12—Antihypertensives

Definitions

  • the invention belongs to the field of pharmaceutical preparations. More specifically, the present invention relates to an ethanol- and phospholipid-free moist heat sterilizable nimodipine composition and a preparation method thereof.
  • Nimodipine chemical name is ( ⁇ )-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 1-methylethyl
  • the ester 2-methoxyethyl ester is a light yellow crystalline powder, insoluble in water, the molecular formula is C 21 H 26 N 2 O 7 , the molecular weight is 418.44, and the structural formula is as follows:
  • Nimodipine is a 1,4-dihydropyridine calcium antagonist that is highly selective for brain tissue receptors and easily penetrates the blood-brain barrier. Nimodipine achieves the purpose of relieving vasospasm by effectively preventing calcium ions from entering cells and inhibiting smooth muscle contraction, thereby protecting brain neurons and stabilizing their functions, increasing cerebral blood perfusion, improving cerebral blood supply, and improving tolerance to hypoxia. force. Research shows that nimodipine can effectively prevent and treat ischemic damage to brain tissue caused by cerebral vasospasm caused by subarachnoid hemorrhage. It can reduce red blood cell fragility and blood viscosity, inhibit platelet aggregation, and resist thrombosis.
  • Nimodipine selectively dilates cerebral blood vessels at an appropriate dose and hardly affects peripheral blood vessels, and can be used to improve blood circulation during the recovery period of acute cerebrovascular disease; Nimodipine can also improve memory impairment in patients with senile brain injury, so it can be used It can prevent Alzheimer's disease and effectively improve cognitive function after stroke; nimodipine also has certain effects on sudden deafness.
  • nimodipine has been approved for a variety of indications, e.g., for the prevention and treatment of various Cerebral vasospasm after various causes of subarachnoid hemorrhage and blood circulation improvement during the recovery period of acute cerebrovascular disease, used to treat senile brain dysfunction, such as memory loss, orientation and attention disorders, and mood swings, used Treats sudden deafness, mild and severe hypertension.
  • nimodipine injection currently in clinical application has major shortcomings:
  • Nimodipine is poorly soluble in water and is commercially available for infusion (50mL:10mg, ) contains 23.7% (v/v) ethanol (1mL liquid medicine contains 200mg ethanol) and 17% (v/v) polyethylene glycol 400, with organic solvents accounting for 40% (20ml); while the ethanol ratio of the small water injection is more high.
  • the presence of a large amount of ethanol causes intravenous injection to have great adverse reactions: it has strong vascular irritation and can easily cause pain at the injection site when injected into the blood vessel, and repeated injections can easily cause phlebitis in the injected blood vessel; in addition, ethanol is harmful to the injection vessel.
  • ethanol can also damage the liver and cause irritation to the stomach.
  • Prescriptions containing ethanol cannot be used by patients allergic to ethanol, resulting in limited medication use for these patients.
  • preparations containing ethanol are combined with cephalosporins or nitroimidazole drugs, 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. .
  • Nimodipine is a dihydropyridine derivative.
  • many pharmacopoeias including China and the European Pharmacopoeia require the control of impurities in nimodipine preparations, especially impurity I ( 2,6-Dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid-2-methoxyethyl isopropyl ester).
  • Impurity I is the most important impurity in the degradation of nimodipine. This impurity is a structural analog of a compound with liver and kidney toxicity, which poses safety risks and is the main quality control impurity.
  • Impurity I is produced by dehydrogenation of the dihydropyridine ring of nimodipine.
  • Various conditions can cause nimodipine to generate this impurity, including strong acid, strong alkali, high temperature, oxidation, light, etc.
  • Traditional nimodipine injection adds citrate buffer salt as the pH regulator of the system. Although it can buffer the pH fluctuation of the injection, relying solely on the stability of the pH value cannot control production well. Generation of impurities during the process.
  • Nimodipine must be infused slowly at a rate of 1-2 mg/h.
  • the infusion time required for 10 mg of the drug generally requires at least 5 hours, otherwise the patient will not be able to tolerate its side effects.
  • Original preparation Solubilize it with high-concentration ethanol, and dilute it with glucose injection or sodium chloride injection during use, which will cause the ethanol concentration to decrease and the drug will precipitate and crystallize after being left alone.
  • a special three-way valve infusion set (see Figure 1) needs to be used for clinical infusion, which is inconvenient to use clinically.
  • nimodipine can be prepared into a more stable non-containing solution by using non-phospholipid surfactants and specific co-solvents to prepare concentrated solutions and subjecting them to moist heat sterilization.
  • the composition of ethanol can achieve good dissolution of nimodipine and is a uniform transparent solution, and the preparation process is extremely simple.
  • the composition of the present invention can be diluted with an aqueous solvent into a solution before use, and the resulting solution is directly used for administration to patients. It is convenient to administer, has excellent stability, and does not have the problem of precipitation and crystallization.
  • the aqueous vehicle can be an aqueous vehicle for injection (for example, water for injection, 5% glucose injection, 0.9% sodium chloride injection, sodium lactate Ringer's solution, dextran 40 solution, hydroxyethyl starch 130/0.4 sodium chloride injection, hydroxyethyl starch 200/0.5 sodium chloride injection, etc.) or a vehicle suitable for oral administration (for example, purified water, etc.).
  • a vehicle suitable for oral administration for example, purified water, etc.
  • the composition of the present invention fully meets the requirements for intravenous injection, and can be infused through an ordinary infusion set due to its excellent stability after dilution. Therefore, the composition of the present invention not only has excellent stability, but also can smoothly realize the administration of nimodipine, especially injection administration, which meets the currently unmet clinical needs.
  • the object of the present invention is to provide a moist heat sterilized nimodipine composition that does not contain ethanol and phospholipids, and to provide a simple, environmentally friendly, and easy industrialization method for preparing the composition.
  • the present invention provides a moist heat sterilized nimodipine composition free of ethanol and phospholipids, characterized in that the composition contains:
  • Non-phospholipid surfactant which is selected from polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, 15-hydroxystearic acid polyethylene glycol ester, vitamin E polyethylene glycol 1000 succinate (TPGS) , polysorbate, octanoic acid mono- and diglycerides, and mixtures of any two or more thereof;
  • Co-solvent which is propylene glycol
  • the content of nimodipine is ⁇ 1.1% w/w, preferably 0.5%-1.1% w/w, more preferably 0.8-1.1% w/ w; the amount of non-phospholipid surfactant is 42-50% w/w, preferably 44-46% w/w; the balance is co-solvent,
  • the composition is terminally sterilized by moist heat sterilization.
  • compositions of the present invention may also contain pH adjusters and antioxidants.
  • the pH adjuster 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 ⁇ -tocopherol succinate, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene ( butylated hydroxytoluene (BHT) one or more.
  • the composition of the invention consists of nimodipine, a non-phospholipid emulsifier and a co-solvent.
  • the invention provides a method for preparing the composition of the invention, characterized in that the method includes the following steps: (1) Mixing nimodipine, non-phospholipid surfactants and co-solvents to form a solution , heat to dissolve if necessary, (2) fill the resulting solution into a container, (3) perform moist heat sterilization of the filled solution,
  • the method is performed in the dark;
  • step (2) the solution obtained in step (1) is filled with nitrogen;
  • the moist heat sterilization is performed at 115°C for 30 minutes or at 121°C for 15 minutes.
  • composition of the present invention can be diluted into a solution using an aqueous solvent.
  • the resulting solution has a uniform and transparent appearance, good stability, and can be intravenously infused through an ordinary infusion set.
  • the ethanol- and phospholipid-free composition of the present invention has the following advantages: (1) It can dissolve nimodipine well, while avoiding the irritation caused by ethanol, and meets the needs of patients allergic to ethanol; avoiding combination It is very likely to cause disulfiram-like adverse reactions when taking the drug; (2) It can be sterilized by moist heat, which better guarantees the sterility level and ensures low impurity levels, especially the level of impurity I with liver and kidney toxicity. Greatly reduced; (3) After dilution with aqueous solvent, the resulting solution has good stability and can be used for ordinary infusion device infusion. Therefore, the composition of the present invention has good safety and stability, is convenient for clinical use, and provides a better choice for the clinical application of nimodipine.
  • Embodiment 1 A phospholipid- and ethanol-free nimodipine composition, characterized in that the composition contains:
  • Non-phospholipid surfactant which is selected from polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, 15-hydroxystearic acid polyethylene glycol ester, vitamin E polyethylene glycol 1000 succinate (TPGS) , polysorbate, octanoic acid mono- and diglycerides, and mixtures of any two or more thereof;
  • Co-solvent which is propylene glycol
  • the content of nimodipine is ⁇ 1.1% w/w, preferably 0.5%-1.1% w/w, more preferably 0.8-1.1% w/ w; the amount of non-phospholipid surfactant is 42-50% w/w, preferably 44-46% w/w; the balance is co-solvent,
  • the composition is terminally sterilized by moist heat sterilization.
  • Embodiment 2 The composition of embodiment 1, wherein the non-phospholipid surfactant is selected from the group consisting of polyoxyethylene 35 castor oil, pure polyoxyethylene 35 castor oil, polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 40 hydrogenated castor oil, Ethylene 60 hydrogenated castor oil, polyethylene glycol 15-hydroxystearate, vitamin E polyethylene glycol 1000 succinate (TPGS), polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60.
  • Embodiment 3 The composition of embodiment 2, wherein the non-phospholipid surfactant is polyethylene glycol 15-hydroxystearate.
  • Embodiment 4 The composition according to one of embodiments 1 to 3, wherein the composition further comprises a pH adjuster and an antioxidant, the pH adjuster being preferably selected from the group consisting of citric acid, citrate (such as sodium citrate), maleic acid, tartaric acid, hydrochloric acid, sodium hydroxide, acetic acid, acetates (such as sodium acetate), phosphoric acid, phosphates (such as sodium monohydrogen phosphate, sodium dihydrogen phosphate or sodium phosphate)
  • the antioxidants are preferably selected from one or more of ⁇ -tocopherol succinate, ascorbyl palmitate, butylated hydroxyanisole, and butylated hydroxytoluene.
  • Embodiment 5 The composition according to any one of embodiments 1 to 3, wherein said combination
  • the product consists of nimodipine, non-phospholipid surfactant and co-solvent.
  • Embodiment 6 The composition of embodiment 5, wherein the composition consists of nimodipine, polyethylene glycol 15-hydroxystearate, and propylene glycol, and based on the total weight of the composition, nimodipine
  • the content of dipine is ⁇ 1.1% w/w, preferably 0.5%-1.1% w/w, more preferably 0.8-1.1% w/w; the amount of 15-hydroxystearate polyethylene glycol ester is 42-50% w/ w, preferably 44-46% w/w; the balance is propylene glycol,
  • the composition is terminally sterilized by moist heat sterilization.
  • Embodiment 7 The composition of any one of embodiments 1 to 6, wherein the composition is prepared protected from light.
  • Embodiment 9 A method for preparing the composition of any one of embodiments 1 to 5, the method comprising the following steps: (1) mixing nimodipine, non-phospholipid surfactant and co-solvent to form a solution, If necessary, heat to dissolve, (2) fill the resulting solution into a container, (3) perform moist heat sterilization of the filled solution,
  • the method is performed in the dark;
  • step (2) the solution obtained in step (1) is filled with nitrogen;
  • the moist heat sterilization is performed at 115°C for 30 minutes or at 121°C for 15 minutes.
  • Embodiment 10 Use of a composition according to any one of embodiments 1 to 8 for the preparation of a solution for intravenous injection, in particular intravenous infusion.
  • Embodiment 11 A solution, which is obtained by diluting the composition according to any one of embodiments 1 to 8 with an aqueous vehicle.
  • the aqueous vehicle is preferably a vehicle suitable for injection, such as water for injection, 5% glucose Injection, 0.9% sodium chloride injection, sodium lactate Ringer's solution, dextran 40 solution, hydroxyethyl starch 130/0.4 sodium chloride injection, or hydroxyethyl starch 200/0.5 sodium chloride injection.
  • composition of the present invention and preparation method thereof
  • nimodipine As an active ingredient, if phospholipids are present in the prepared concentrate, it can only be sterilized by filtration and cannot be sterilized by moist heat, because moist heat Sterilization can cause the concentrate to discolor, resulting in a failure in the stability check of the concentrate.
  • the inventor further studied and optimized the composition of the composition, and obtained a better composition of the present invention.
  • the nimodipine composition of the present invention is a concentrated solution that does not contain ethanol and phospholipids, and is terminally sterilized by moist heat sterilization.
  • the concentrated solution is mixed with an aqueous solvent (such as water for injection, 5% glucose injection, 0.9% sodium chloride injection, sodium lactate Ringer's solution, dextran 40 solution, hydroxyethyl starch 130/0.4 chloride Sodium Chloride Injection, or Hydroxyethyl Starch 200/0.5 Sodium Chloride Injection) is diluted to form a solution.
  • the solution has good physical and chemical stability and can be administered directly to the patient, such as by oral administration or injection such as intravenous injection. Administer to patient.
  • the formed diluent has good stability, there is no need to use a three-way valve infusion set during intravenous infusion.
  • the present invention provides an ethanol- and phospholipid-free nimodipine composition, characterized in that the composition contains:
  • the composition is terminally sterilized by moist heat sterilization.
  • the non-phospholipid surfactant may be selected from polyoxyethylene castor oil (e.g., polyoxyethylene 35 castor oil, especially pure polyoxyethylene 35 castor oil), polyoxyethylene hydrogenated castor oil (e.g., polyoxyethylene 40 hydrogenated Castor oil, polyoxyethylene 60 hydrogenated castor oil), polyethylene glycol 15-hydroxystearate, vitamin E polyethylene glycol 1000 succinate (TPGS), polysorbates (such as polysorbate 20, 21, 40, 60, 61, 65, 80, 81, 85, 120, especially polysorbate 80), glyceryl caprylate and mixtures of any two or more thereof.
  • polyoxyethylene castor oil e.g., polyoxyethylene 35 castor oil, especially pure polyoxyethylene 35 castor oil
  • polyoxyethylene hydrogenated castor oil e.g., polyoxyethylene 40 hydrogenated Castor oil, polyoxyethylene 60 hydrogenated castor oil
  • polyethylene glycol 15-hydroxystearate e.g., vitamin E polyethylene glycol 1000 succinate (TPGS)
  • the non-phospholipid surfactant is selected from polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 35 castor oil, pure polyoxyethylene 35 castor oil, 15-hydroxystearate polyethylene glycol ester, Polysorbate 80 and mixtures of any two or more thereof. More preferably, the non-phospholipid surfactant is polyethylene glycol 15-hydroxystearate.
  • the composition of the present invention is a concentrate that can be diluted with an aqueous vehicle to form a solution.
  • the aqueous vehicle can be an injectable vehicle (for example, water for injection, 5% glucose injection, 0.9% sodium chloride injection, sodium lactate Ringer's solution, dextran 40 solution, hydroxyethyl starch 130/0.4 sodium chloride injection, or hydroxyethyl starch 200/0.5 sodium chloride injection, etc.) or a vehicle that can be orally administered (for example, purified water, etc.).
  • an injectable vehicle such as 5% glucose injection
  • the diluted solution formed by the composition of the present invention meets the requirements for intravenous injections and even intravenous drip injections. Therefore, the The diluted solution can be directly used for injection, such as subcutaneous injection, intradermal injection, intraperitoneal injection, or intravenous injection, including intravenous bolus injection and intravenous drip.
  • the composition of the present invention is a uniform and transparent solution with good physical and chemical stability.
  • the composition of the present invention is packed in a colored bottle and tested for influencing factors under the conditions of 60°C and a light test of 5000 Lux. All indicators are consistent. Meet the requirements.
  • the solution obtained by diluting the composition of the present invention also has good physical and chemical stability. For example, when the composition of the present invention is diluted with an aqueous solvent such as 5% glucose injection or 0.9% sodium chloride injection, the solution is left at room temperature for 48 hours, and no drug is precipitated.
  • composition of the invention described above may consist solely of the following components: nimodipine; a non-phospholipid surfactant; and a co-solvent, which is propylene glycol.
  • the concentrated liquid and the diluted liquid formed by the present invention can be used to prevent and treat cerebral vasospasm after various causes of subarachnoid hemorrhage, improve blood circulation in the recovery period of acute cerebrovascular disease, and treat senile brain dysfunction. , such as memory loss, disorientation and attention disorders, and mood swings, used to treat sudden deafness, mild and severe hypertension.
  • the method is preferably carried out in the dark, which can further reduce related substances.
  • step (1) is filled with nitrogen before step (2).
  • the moist heat sterilization described herein can be performed under known conditions, such as 115°C for 30 minutes or 121°C for 15 minutes.
  • the preparation method of the invention is simple and easy to implement and is suitable for industrial production.
  • nimodipine composition containing nimodipine, a non-phospholipid surfactant and a co-solvent, unless the context indicates otherwise.
  • polyoxyethylene castor oil refers to substances obtained by reacting varying amounts of ethylene oxide and 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 glyceryl ricinoleate and 35 mol of ethylene oxide, which in addition to polyoxyethylene glycerol triricinoleate, also contains a small amount of Polyethylene glycol ricinoleate and free ethylene glycol.
  • Polyoxyethylene 35 castor oil is commercially available, for example, under the trade names kolliphor EL and kolliphor ELP from BASF and others.
  • pure polyoxyethylene 35 castor oil refers to purified polyoxyethylene glycerol triricinoleate.
  • polyoxyethylene hydrogenated castor oil refers to substances obtained by reacting varying amounts of ethylene oxide and hydrogenated castor oil.
  • examples of polyoxyethylene hydrogenated castor oil include, but are not limited to, polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 60 hydrogenated castor oil.
  • polyoxyethylene 40 hydrogenated castor oil refers to a substance obtained by reacting 1 mol of glyceryl trihydroxystearic acid with 40-45 mol of ethylene oxide, except for polyoxyethylene glyceryl trihydroxystearate. , 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 trade name kolliphor RH40 from BASF and others.
  • polyoxyethylene 60 hydrogenated castor oil refers to a substance obtained by reacting 1 mol of glyceryl trihydroxystearate with 60 mol of ethylene oxide, in which, in addition to polyoxyethylene glyceryl trihydroxystearate, Also contains a small amount of polyethylene glycol trihydroxystearic acid and free polyethylene glycol.
  • the "15-hydroxystearic acid polyethylene glycol ester" described in this article is the monoester and diester of 12-hydroxystearic acid polyethylene glycol formed by the ethoxylation of 12-hydroxystearic acid, as well as the free polyester.
  • a mixture of ethylene glycol as the main component has a freezing point of 22°C-30°C. It is a light yellow to white viscous semi-solid at room temperature and becomes a liquid at about 30°C.
  • Polyethylene glycol 15-hydroxystearate has been included in the German Pharmacopoeia, British Pharmacopoeia, United States Pharmacopeia and European Pharmacopoeia.
  • the chemical names in the United States Pharmacopoeia and European Pharmacopoeia are polyoxyl 15 hydroxystearate and macrogol 15 hydroxystearate respectively.
  • TPGS titamin E polyethylene glycol succinate
  • Polysorbate refers to a series of partial fatty acid esters of polyoxyethylene sorbitan, which are copolymerized in a ratio of approximately 20.5 mol or 4 mol of ethylene oxide per mole of sorbitol.
  • polysorbates include, but are not limited to, polysorbates 20, 21, 40, 60, 61, 65, 80, 81, 85, 120, especially polysorbate 80.
  • Polysorbates are commercially available, for example, under the trade names of Tween 20, Tween 40, Tween 80, etc. from Nanjing Well Pharmaceutical Co., Ltd.
  • Example 1 Effect of phospholipids on the quality of nimodipine injection before and after sterilization
  • Free fatty acids Precisely measure 5g of the test solution, place it in a 25ml measuring bottle, dilute to the mark with isopropanol, shake well, accurately transfer 5ml, place it in a 20ml test tube with a stopper, add isopropanol-n-heptane- Mix 5.0 ml of 0.5 mol/L sulfuric acid solution (40:10:1), shake for 1 minute, and leave for 10 minutes. Precisely add 3 ml each of n-heptane and water, seal tightly, turn up and down 10 times, and let stand for at least 15 minutes to separate the layers.
  • Peroxide value Precisely measure 5g of this product and add 30ml of glacial acetic acid-chloroform (3:2). Precisely add 0.5ml of saturated potassium iodide solution, seal tightly immediately, shake accurately for 1 minute, add 30ml of water and 5ml of starch indicator solution, and immediately titrate with sodium thiosulfate titrant (0.01mol/L) until the purple-blue color of the upper water phase disappears. , and correct the titration results with the blank test.
  • Nimodipine injection in prescriptions 1-3 is a light yellow clear and transparent oil solution.
  • the color of the solution gradually becomes darker. Compared with before sterilization, the color of the solution after sterilization was significantly darker, causing the color inspection to fail. As the EPC concentration increased, the color deepened more obviously.
  • Diluent Dilute the nimodipine concentrate obtained in prescriptions 1-3 with 5% glucose injection to the same concentration (nimodipine is 0.1mg/mL). Both are colorless and transparent solutions. The diluent should be allowed to stand for 24 hours. No precipitate precipitated, and there was no significant difference in the diluents prepared by the three prescriptions.
  • nimodipine can form a clear and transparent concentrated solution in the co-solvent propylene glycol. After moist heat sterilization, the concentrated solution becomes a clear and transparent light yellow solution. Dilute the concentrate with water-based solvent After release, the formed dilute solution was left for 8 hours without drug precipitation; however, when glycerin was used as a cosolvent, the prepared concentrated solution separated into layers after sterilization, and the solubilization effect was not ideal. This shows that not all cosolvents are suitable for nimodipine.
  • nimodipine can form a clear and transparent concentrated solution in the non-phospholipid surfactants HS15, Tween 80, RH40 and ELP. After moist heat sterilization, the concentrated solution becomes a clear and transparent light yellow solution. After diluting the concentrated solution with an aqueous solvent, the resulting diluted solution was left standing for 8 hours without drug precipitation.
  • Example 5 Screening of drug loading capacity of nimodipine injection
  • step 3 Fill the concentrate obtained in step 2) into a vial (7mL) (filling volume: 2mL), and sterilize at 121°C for 15 minutes;
  • the concentrated solution formed by prescriptions 15-29 with a drug loading amount of 0%-10% is a uniform and transparent solution, and the raw and auxiliary materials are evenly mixed without insoluble foreign matter.
  • the color of the concentrated solution changes from The colorless and transparent gradually turned into light yellow; however, prescriptions 30 and 31 with drug loading contents of 15% and 20% respectively still had nimodipine that could not be dissolved after sufficient stirring.
  • the concentrates of prescriptions 15-29 were left to stand at 25°C for 1 hour. It was found that the concentrate of prescription 29 with a drug loading content of 10% precipitated crystals after standing for 1 hour, while no crystals precipitated from other prescriptions.
  • Low drug loading will result in low drug concentration in the diluent, making clinical use inconvenient.
  • the preferred drug loading is 0.5%-1.1%.
  • Example 6 Screening of the dosage of HS15 in nimodipine injection
  • the specific experiments are as follows:
  • Dilute the sterilized concentrated solution with 5% glucose injection (the concentration of nimodipine in the diluent is 0.1 mg/mL), shake well, and observe the stability of the diluted solution within 24 hours, including visual inspection and microscopic observation.
  • HS15 Concentrated solution: Preparations with HS15 accounting for less than 40% (weight ratio) are light yellow turbid liquids, and nimodipine is not completely dissolved; preparations with HS15 accounting for between 40% and 60% are light yellow clear and transparent solutions, and nimodipine is not completely dissolved. Modipine dissolves completely. Therefore, the content of HS15 should be greater than 40%.
  • Diluent Dilute the sterilized concentrates from Prescription 35 to Prescription 37 with 0.5% glucose injection to the same concentration (the concentration of nimodipine in the diluent is 0.1 mg/mL). They are all colorless and transparent solutions. There is no obvious difference in the appearance of these dilutions, and no crystals precipitate when observed under a microscope after all dilutions were left standing at 25°C for 24 hours.
  • Dilute the sterilized concentrated solution with 5% glucose injection the concentration of nimodipine in the diluent is 0.1 mg/mL
  • the nimodipine concentrates in Prescriptions 38 to 48 are all light yellow, clear and transparent solutions, and the raw and auxiliary materials are mixed evenly without insoluble foreign matter; when left to cool to 25°C, the nimodipine concentrates in Prescriptions 39 to 48 are all clear and transparent solutions.
  • the concentrated solution of Prescription 48 remains unchanged and is a clear and transparent solution; while the concentrated solution of Prescription 38 becomes turbid and turns back to a light yellow clear and transparent solution after being heated again, and then cooled to 25°C, the turbidity still appears. The inventor speculates that this may be due to the low dosage of HS15 resulting in poor solubilization effect.
  • HS15 has a low freezing point (22°C-30°C)
  • the greater the content the higher the freezing temperature, which is not conducive to quality assurance and clinical administration. Therefore, the inventor further studied the effect of temperature on the concentration of prescriptions 39 to 48 The influence of the physical state of the liquid.
  • the experimental results show that the concentrate of prescription 46-48 (HS15 percentage is 56-60%) starts to solidify at 18°C; the concentrate of prescription 42-45 (HS15 percentage is 48-54%) starts to solidify at 12°C. Solidification; the concentrate of formulation 39-41 (HS15 percentage 42-46%) remains unchanged at temperatures as low as 10°C.
  • Diluent Dilute the sterilized concentrates from Prescription 38 to Prescription 48 with 0.5% glucose injection to the same concentration (0.1mg/ml). They are all colorless and transparent solutions. There is no obvious difference in the appearance of these diluted solutions, and All dilutions were left standing at 25°C for 24 hours and no crystals precipitated when observed under a microscope.
  • nimodipine concentrates from Prescription 38 to Prescription 48 high-heat sterilization has no effect on the content, related substances, and pH value of nimodipine.
  • HS15 has a certain degree of hemolysis, but the hemolysis is lower than polysorbate 80, and the serum histamine release level and the possibility of causing biological allergies are also much lower than the latter (Lu H, Li J, Li M, et al. Systemic delivery of alpha-asarone with Kolliphor HS 15improves its safety and therapeutic effect on asthma[J]. Drug Deliv, 2015, 22(3):266-275). Yi Hong et al. (Yi Hong, Gao Jin, Yang Hua et al., Overview of the quality standards and safety of several injectable surfactants [J]. Chinese Journal of Experimental Prescriptions, 2010, 16(1):115-119) found After intravenous injection of HS15 into mice, the LD50 was measured to be 3.16g/kg.
  • the results of the guinea pig allergy test showed that compared with the polysorbate 80 group, the plasma histamine release in the HS15 group was lower (the serum histamine level in the HS15 group after 60 minutes of intravenous injection was 8 nmol ⁇ L-1, and the polysorbate 80 group was 247 nmol ⁇ L-1), the hemolytic property is also low (after intravenous injection with a solubilizer mass concentration of 1%, 1% of red blood cells were dissolved in the HS15 group, and 4% in the polysorbate 80 group); and due to the low viscosity of HS15 itself, it is The viscosity of the drug solution has almost no effect, greatly reducing the irritation of injection administration. Nonetheless, excessive dosage of HS15 can easily cause hemolysis and allergic reactions.
  • the content of HS15 in the present invention is preferably 42%-50% (weight ratio), more preferably 44%-46% (weight ratio).
  • Example 7 Screening of terminal sterilization methods in the preparation process of nimodipine concentrate
  • Example 11 According to the method in Example 11, the nimodipine content and related substances of each group of concentrated solutions were determined.
  • nimodipine in diluent 1 is 0.1mg/mL
  • concentration of nimodipine in diluent 2 is 0.04mg/mL. Determine the pH value of the diluted solution and observe the stability of the diluted solution.
  • Impurity I is the most important impurity in the degradation of nimodipine. This impurity is a structural analog of a compound with liver and kidney toxicity, which poses safety risks and is the main quality control impurity. Therefore, the fewer impurities the better.
  • the nimodipine concentrated solution of the present invention is sterilized by moist heat at 115°C for 30 minutes or sterilized by moist heat at 121°C for 15 minutes, the content of nimodipine in the concentrated solution, related substances, and the pH of the diluent all meet the limits. requirements, and the contents of impurity I and total impurities in the concentrated solution are significantly less than
  • Example 8 Screening of whether the preparation process of nimodipine concentrate is protected from light
  • Preparation process 1) Heat HS15 at 60°C until HS15 in the bottle is completely dissolved, mix it upside down and set aside; 2) Weigh the prescribed amount of propylene glycol into a conical flask, and add the prescribed amount of HS15 and nimodipine raw materials in sequence. , seal, stir magnetically in a water bath at 60°C until dissolved into a uniform solution, and obtain nimodipine concentrated solution; 3) Fill the concentrated solution into a vial (7mL) (filling volume: 2mL), and sterilize at 121°C bacteria for 15 minutes. The preparation process was divided into two conditions: natural light and light protection.
  • Example 9 Screening of whether the preparation process of nimodipine concentrate is filled with nitrogen
  • Example 10 The inventor investigated the effect of nitrogen on nimodipine injection.
  • the nitrogen gas was used to study the related substances of nimodipine injection on the 2022012201 batch.
  • the specific experimental results are shown in the table below.
  • Example 10 Small-scale process verification of the composition of the present invention
  • the inventor prepared two batches of nimodipine injection (batch numbers 2022012201 and 2022012202), each batch of 600 injections, and conducted small-scale prescription process verification.
  • Preparation process 1) Heat HS15 at 60°C until HS15 in the bottle is completely dissolved, mix it upside down and set aside; 2) Weigh the prescribed amount of propylene glycol into a conical flask, and add the prescribed amount of HS15 and nimodipine raw materials in sequence. , seal, stir magnetically in a 60°C water bath until dissolved into a uniform solution, and obtain nimodipine concentrated solution; 3) Fill the obtained concentrated solution with nitrogen, and fill it into a 7ml brown and colorless vial; 4) In Moist heat sterilization at 121°C for 15 minutes. Avoid light during the preparation process.
  • Example 10 In accordance with the guiding principles for stability testing of raw materials and pharmaceutical preparations in the 2020 edition of the Four General Chapters 9001 of the "Chinese Pharmacopoeia", the concentrate prepared in Example 10 was placed under the conditions of light (5000Lux) at a temperature of 60°C, and placed on the 5th and 10th , take samples at the end of 30 days and inspect the corresponding indicators.
  • Sample information Nimodipine injection (self-made sample), batch number 2022012201 (two types, brown and transparent); original research ( It is brown packaging; transparent packaging is packed in colorless vials), batch number: BXJC7A1
  • Inspection method visual inspection.
  • Chromatographic column C18 column (model: Ultinate XB-C18, XDB-C18, 125cm, inner diameter 4.6mm, filler particle size 5.0 ⁇ m)
  • UV detector detection wavelength 235nm
  • Chromatographic column C18 column (model: Ultinate XB-C18, XDB-C18, 125cm, inner diameter 4.6mm, filler particle size 5.0 ⁇ m)
  • UV detector detection wavelength 235nm
  • the chromatographic peak tailing factor of the reference solution is not greater than 2.0.
  • Transparent packaging concentrate and original product of the invention After being placed under the light test condition of 5000 Lux for 30 days, there was no obvious change in the properties and pH, but the related substances increased significantly and the content decreased significantly. This is due to the degradation of nimodipine when placed under light. It can be seen from the investigation under these extreme conditions that after being placed under 5000 Lux light for 30 days, the content of nimodipine in the concentrated solution of the present invention is 76.25%, while The content of nimodipine dropped to 3.06% and was almost completely degraded.
  • Inspection method visual inspection.
  • Inspection methods visual inspection and electron microscopy.
  • the nimodipine concentrated solution of the present invention overcomes the shortcomings of the commercially available nimodipine injection, has good stability after dilution, and can be infused with an ordinary infusion set.
  • Figure 1 is clinically used for intravenous infusion
  • a photo of the three-way valve in which the port marked with the number "1" is the "venous end”, which is connected to the patient's vein, and the port marked with the number "2" is the “liquid end with pump”, which is connected to the aqueous solvent controlled by the pump.
  • the port marked with the number “3” is the "nimodipine port” and is the same as the nimodipine injection connect.
  • the purpose of using this three-way valve is to make nimodipine injection and water-based The solvent is infused into the patient's vein immediately after mixing to avoid the problem of nimodipine crystallization caused by the diluent being placed.

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Abstract

一种不含乙醇和磷脂的湿热灭菌的尼莫地平组合物及其制备方法。所述组合物包含：(1)尼莫地平；(2)非磷脂表面活性剂，其选自聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油、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、辛癸酸单双甘油酯其任意两种或更多种的混合物；(3)助溶剂，其为丙二醇。

Description

不含乙醇和磷脂的湿热灭菌的尼莫地平组合物及其制备方法
本申请要求了于2022年6月27日提交的中国专利申请CN202210734212.7的优先权，通过引用将其全部内容合并入本文。
技术领域
本发明属于药物制剂领域。更具体而言，本发明涉及一种不含乙醇和磷脂的湿热灭菌的尼莫地平组合物及其制备方法。
背景技术
尼莫地平，化学名称为(±)-2,6-二甲基-4-(3-硝基苯基)-1,4-二氢吡啶-3,5-二羧酸1-甲基乙基酯2-甲氧基乙基酯，为淡黄色结晶性粉末，不溶于水，分子式为C21H26N2O7，分子量为418.44，结构式如下：
尼莫地平为1,4-二氢吡啶类钙离子拮抗剂，对脑组织受体有高度选择性，容易透过血脑屏障。尼莫地平通过有效地阻止钙离子进入细胞内、抑制平滑肌收缩，达到解除血管痉挛之目的，从而保护脑神经元并稳定其功能、增进脑血灌流、改善脑供血、提高对缺氧的耐受力。研究显示，尼莫地平能有效地预防和治疗因蛛网膜下腔出血引起的脑血管痉挛所造成的脑组织缺血性损伤，能降低红细胞脆性及血液粘稠度，抑制血小板聚集，抗血栓形成；在适宜剂量下尼莫地平选择性扩张脑血管且几乎不影响外周血管，可用于急性脑血管病恢复期的血液循环改善；尼莫地平还可以改善老年性脑损伤患者的记忆障碍，因此可用于预防老年痴呆、有效改善卒中后认知功能；尼莫地平还对突发性耳聋有一定疗效。目前，尼莫地平已经被批准用于多种适应症，例如，用于预防和治疗各 种原因的蛛网膜下腔出血后的脑血管痉挛和急性脑血管病恢复期的血液循环改善、用于治疗老年性脑功能障碍，例如记忆力减退、定向力和注意力障碍和情绪波动、用于治疗突发性耳聋、轻度和重度高血压。
国内外上市的尼莫地平剂型很多，其中口服剂型包括普通片剂、缓释片剂、硬胶囊剂、软胶囊剂；注射剂包括小水针和大输液。由于尼莫地平固体制剂在胃肠液中溶解度很小，肝首过效应明显，一直存在着生物利用度低的缺点。其注射剂型比口服制剂起效快、效果更好，所以注射剂型在临床上的应用更为广泛。但目前在临床应用的尼莫地平注射液存在很大缺陷：
(1)含有大量的有机溶剂。尼莫地平难溶于水，市售输液(50mL:10mg， )中含有23.7％(v/v)乙醇(1mL药液含200mg乙醇)和17％(v/v)聚乙二醇400，有机溶剂占40％(20ml)；而小水针的乙醇比例更高。大量乙醇的存在导致静脉注射具有很大的不良反应：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注射血管的静脉炎；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、记忆力衰退、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。
(2)尼莫地平属于二氢吡啶类衍生物，为了控制尼莫地平相关制剂产品的质量，包括中国和欧洲药典在内的多国药典均要求控制尼莫地平制剂的杂质，特别是杂质I(2,6-二甲基-4-(3-硝基苯基)-3,5-吡啶二甲酸-2-甲氧乙酯异丙酯)。杂质I为尼莫地平降解最主要杂质，该杂质是具有肝肾毒性化合物的结构类似物，存在安全隐患，是主要的质控杂质。在注射剂中杂质I的含量越低越好。杂质I是尼莫地平二氢吡啶环脱氢产生，多种条件均可促使尼莫地平生成此杂质，包括强酸、强碱、高温、氧化、光照等。传统的尼莫地平注射液中加入了枸橼酸缓冲盐作为体系的pH值调节剂，虽然可以对注射液的pH值波动产生缓冲作用，但单纯依靠pH值的稳定并不能较好地控制生产过程中杂质的产生。
(3)尼莫地平必须以1-2mg/h的速度慢速滴注，10mg药物所需滴注时间一般需要至少5小时，否则病人无法耐受其副作用。原研制剂用高浓度的乙醇增溶，使用时用葡萄糖注射液或氯化钠注射液稀释，导致乙醇浓度降低，经放置药物会析出结晶。为了解决稀释造成的物理稳定性差的问题，临床上需采用特殊的三通阀输液器(参见图1)输注，在临床上使用不方便。
因此，需要开发新的不含乙醇的尼莫地平组合物，同时确保良好的稳定性。
发明简述
发明人经过大量的实验研究，惊喜地发现，通过采用非磷脂表面活性剂和特定的助溶剂制备浓缩液并且将其进行湿热灭菌可以将临床适用剂量的尼莫地平制备成更稳定的不含乙醇的组合物，所述组合物能实现对尼莫地平良好溶解，为均一透明溶液，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溶液，所形成的溶液直接用于对患者进行给药，用药方便，并且具有优良的稳定性，不存在析出结晶的问题。所述水性溶媒可以是注射用水性溶媒(例如，注射用水、5％葡萄糖注射液、0.9％氯化钠注射液、乳酸钠林格氏液、右旋糖酐40溶液、羟乙基淀粉130/0.4氯化钠注射液、羟乙基淀粉200/0.5氯化钠注射液等)或适合口服施用的溶媒(例如，纯净水等)。而且，本发明的组合物完全满足静脉内注射的要求，并且由于在稀释后具有优良的稳定性使得其可通过普通输液器进行输注。因此，本发明的组合物不仅具有优良的稳定性，而且可顺利实现尼莫地平的给药、特别是注射给药，满足了目前未被满足的临床需求。
本发明的目的在于提供一种不含乙醇和磷脂的湿热灭菌的尼莫地平组合物，并且提供一种制备所述组合物的简单、环保、易产业化的方法。
在第一个方面，本发明提供了一种不含乙醇和磷脂的湿热灭菌的尼莫地平组合物，其特征在于，所述组合物包含：
(1)尼莫地平；
(2)非磷脂表面活性剂，其选自聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油、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、辛癸酸单双甘油酯其任意两种或更多种的混合物；
(3)助溶剂，其为丙二醇，
其中，以尼莫地平、非磷脂表面活性剂和助溶剂的总重量计，尼莫地平的含量≤1.1％w/w，优选0.5％-1.1％w/w，更优选0.8-1.1％w/w；非磷脂表面活性剂的量为42-50％w/w，优选44-46％w/w；余量为助溶剂，
所述组合物是通过湿热灭菌进行终端灭菌的。
本发明的组合物还可以含有pH调节剂和抗氧化剂。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。
在该方面的一个优选的实施方案中，本发明的组合物由尼莫地平、非磷脂乳化剂和助溶剂组成。
在第二个方面，本发明提供了制备本发明的组合物的方法，其特征在于，所述方法包括以下步骤：(1)将尼莫地平、非磷脂表面活性剂和助溶剂混合，形成溶液，在需要的情况下酌情加热以溶解，(2)将所得溶液灌装入容器中，(3)将灌装后的溶液进行湿热灭菌，
任选地，所述方法在避光下进行；
任选地，在步骤(2)之前，将步骤(1)所获得的溶液充氮气；
优选地，所述湿热灭菌在115℃下进行30min或在121℃进行15min。
本发明的组合物可以使用水性溶媒稀释成溶液，所得溶液外观均一透明，具有良好的稳定性，可通过普通输液器静脉内输注。
概括而言，本发明的不含乙醇和磷脂的组合物具有如下优点：(1)能良好溶解尼莫地平，同时避免了乙醇带来的刺激性，满足对乙醇过敏的患者的需求；避免联合用药时极可能导致双硫仑样不良反应的发生；(2)可以湿热灭菌，更好地保障了无菌水平，同时确保了低的杂质水平，尤其是具有肝肾毒性的杂质I的水平大大降低；(3)用水性溶媒稀释后，所得溶液稳定性好，可使用普通输液 器输注。因此，本发明的组合物具有良好的安全性和稳定性，临床用药方便，为尼莫地平的临床应用提供一个更优的选择。
发明详述
具体实施方案
实施方案1.一种不含磷脂和乙醇的尼莫地平组合物，其特征在于，所述组合物包含：
(1)尼莫地平；
(2)非磷脂表面活性剂，其选自聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油、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、辛癸酸单双甘油酯其任意两种或更多种的混合物；
(3)助溶剂，其为丙二醇，
其中，以尼莫地平、非磷脂表面活性剂和助溶剂的总重量计，尼莫地平的含量≤1.1％w/w，优选0.5％-1.1％w/w，更优选0.8-1.1％w/w；非磷脂表面活性剂的量为42-50％w/w，优选44-46％w/w；余量为助溶剂，
所述组合物是通过湿热灭菌进行终端灭菌的。
实施方案2.根据实施方案1所述的组合物，其中所述非磷脂表面活性剂选自聚氧乙烯35蓖麻油、纯的聚氧乙烯35蓖麻油、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20、聚山梨酯21、聚山梨酯40、聚山梨酯60、聚山梨酯61、聚山梨酯65、聚山梨酯80、聚山梨酯81、聚山梨酯85、聚山梨酯120、辛癸酸单双甘油酯及其任意两种或更多种的混合物。
实施方案3.根据实施方案2所述的组合物，其中所述的非磷脂表面活性剂是15-羟基硬脂酸聚乙二醇酯。
实施方案4.根据实施方案1至3中一项所述的组合物，其中所述组合物还包含pH调节剂和抗氧化剂，所述pH调节剂优选选自枸橼酸、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，所述抗氧化剂优选选自α-生育酚琥珀酸酯、棕榈酸抗坏血酸酯、丁基化羟基苯甲醚、丁化羟基甲苯中的一种或多种。
实施方案5.根据实施方案1至3中任意一项所述的组合物，其中所述组合 物由尼莫地平、非磷脂表面活性剂和助溶剂组成。
实施方案6.根据实施方案5所述的组合物，其中所述组合物由尼莫地平、15-羟基硬脂酸聚乙二醇酯和丙二醇组成，并且以组合物的总重量计，尼莫地平的含量≤1.1％w/w，优选0.5％-1.1％w/w，更优选0.8-1.1％w/w；15-羟基硬脂酸聚乙二醇酯的量为42-50％w/w，优选44-46％w/w；余量为丙二醇，
所述组合物是通过湿热灭菌进行终端灭菌的。
实施方案7.根据实施方案1至6中任意一项所述的组合物，其中所述组合物是避光制备的。
实施方案8.根据实施方案1至7中任意一项所述的组合物，其中所述组合物是通过包括充氮气的步骤的方法制备的。
实施方案9.制备实施方案1至5中任意一项所述的组合物的方法，所述方法包括以下步骤：(1)将尼莫地平、非磷脂表面活性剂和助溶剂混合，形成溶液，在需要的情况下酌情加热以溶解，(2)将所得溶液灌装入容器中，(3)将灌装后的溶液进行湿热灭菌，
任选地，所述方法在避光下进行；
任选地，在步骤(2)之前，将步骤(1)所获得的溶液充氮气；
优选地，所述湿热灭菌在115℃下进行30min或在121℃进行15min。
实施方案10.根据实施方案1至8中任意一项所述的组合物在制备用于静脉内注射、特别是静脉内滴注的溶液剂中的用途。
实施方案11.一种溶液剂，其通过将实施方案1至8中任意一项所述的组合物用水性溶媒稀释获得，所述水性溶媒优选是适合注射的溶媒，例如注射用水、5％葡萄糖注射液、0.9％氯化钠注射液、乳酸钠林格氏液、右旋糖酐40溶液、羟乙基淀粉130/0.4氯化钠注射液、或羟乙基淀粉200/0.5氯化钠注射液。
实施方案12.根据实施方案11所述的溶液剂，其用于静脉内注射，特别是静脉内滴注。
本发明的组合物及其制备方法
发明人通过对尼莫地平的基本理化性质进一步的研究发现，包含尼莫地平作为活性成分时，所制备的浓缩液中如果存在磷脂，就只能进行过滤灭菌，不能湿热灭菌，因为湿热灭菌会导致所述浓缩液发生变色，从而导致在浓缩液的稳定性检查中被判定为不合格。为了解决这一问题，发明人进一步对组合物的组成进行了研究和优化，得到了本发明的更优的组合物。
本发明的尼莫地平组合物是一种不包含乙醇和磷脂浓缩液，并且通过湿热灭菌进行终端灭菌。在临用前，将所述浓缩液用水性溶媒(例如注射用水、5％葡萄糖注射液、0.9％氯化钠注射液、乳酸钠林格氏液、右旋糖酐40溶液、羟乙基淀粉130/0.4氯化钠注射液、或羟乙基淀粉200/0.5氯化钠注射液)稀释后形成溶液，该溶液具有良好的物理和化学稳定性，可直接施用于患者，例如通过口服或注射例如静脉内注射施用于患者。并且，由于所形成的稀释液具有良好的稳定性，在静脉内输注时，无需再使用三通阀输液器。
因此，在第一个方面，本发明提供了一种不含乙醇和磷脂的尼莫地平组合物，其特征在于，该组合物包含：
(1)尼莫地平；
(2)非磷脂表面活性剂；
(3)助溶剂，其为丙二醇，
其中，以尼莫地平、非磷脂表面活性剂和助溶剂的总重量计，尼莫地平的含量≤1.1％w/w，优选0.5％-1.1％w/w，更优选0.8-1.1％w/w；非磷脂表面活性剂的量为42-50％w/w，优选44-46％w/w；余量为助溶剂，
所述组合物是通过湿热灭菌进行终端灭菌的。
所述非磷脂表面活性剂可以选自聚氧乙烯蓖麻油(例如聚氧乙烯35蓖麻油，特别是纯的聚氧乙烯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)、辛癸酸甘油酯及其任意两种或更多种的混合物。更优选地，所述的非磷脂表面活性剂选自聚氧乙烯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及其任意两种或更多种的混合物。更优选地，所述非磷脂表面活性剂是15-羟基硬脂酸聚乙二醇酯。
本发明的组合物是一种浓缩液，其可以用水性溶媒稀释，从而形成溶液。所述水性溶媒可以是可注射的溶媒(例如，注射用水、5％葡萄糖注射液、0.9％氯化钠注射液、乳酸钠林格氏液、右旋糖酐40溶液、羟乙基淀粉130/0.4氯化钠注射液、或羟乙基淀粉200/0.5氯化钠注射液等)或可口服施用的溶媒(例如，纯净水等)。用可注射的溶媒例如5％葡萄糖注射液稀释后，本发明的组合物经稀释所形成的溶液符合静脉内注射剂、甚至静脉内滴注的注射剂的要求，因此，所 述稀释的溶液可以直接用于注射，例如用于皮下注射、皮内注射、腹膜内注射，也可用于静脉内注射，包括静脉内推注和静脉内滴注。
本发明的组合物是均一透明的溶液，具有良好的物理和化学稳定性，将本发明的组合物装在有色瓶中，在60℃和光照试验5000Lux条件下进行影响因素试验，各项指标均符合要求。而且，本发明的组合物经稀释获得的溶液也具有良好的物理和化学稳定性。例如，将本发明的组合物用水性溶媒例如5％葡萄糖注射液或0.9％氯化钠注射液等稀释后形成的溶液于室温条件下放置48小时，未见药物析出。
发明人还对本发明的组合物中所用的非磷脂表面活性剂进行了筛选，考察了聚氧乙烯40氢化蓖麻油(例如kolliphor RH40)、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)。实验结果显示这些表面活性剂均能增溶尼莫地平。
发明人对助溶剂进行了筛选，包括丙二醇和甘油，结果显示，用丙二醇作为助溶剂使尼莫地平形成均一透明的溶液，但用甘油作为助溶剂导致配制的浓缩液经放置分层。
上文所述的本发明的组合物可以仅由以下组分组成：尼莫地平；非磷脂表面活性剂；和助溶剂，其为丙二醇。
或者，上文所述的本发明的尼莫地平组合物还可以含有其他组分，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。
本发明的浓缩液及其形成的稀释液可用于预防和治疗各种原因的蛛网膜下腔出血后的脑血管痉挛和急性脑血管病恢复期的血液循环改善、用于治疗老年性脑功能障碍，例如记忆力减退、定向力和注意力障碍和情绪波动、用于治疗突发性耳聋、轻度和重度高血压。
在第二个方面，本发明提供了制备本发明的组合物的方法，其特征在于，该制备方法为：(1)将尼莫地平、非磷脂表面活性剂和助溶剂混合，形成溶液，在需要的情况下酌情加热以溶解，(2)将所得溶液灌装入容器中，(3)将灌装后的溶液进行湿热灭菌。
由于光可导致尼莫地平降解，因此所述方法优选在避光下进行，可以进一步减少有关物质。
此外，氮气的保护也有助于减少本发明的浓缩液的有关物质，因此，优选地，在步骤(2)之前，将步骤(1)所获得的溶液充氮气。
本文所述的湿热灭菌可以在已知条件下进行，例如在115℃下进行30min或在121℃进行15min。
本发明的制备方法简单易行，适合工业生产。
定义
在本申请的上下文中，“不含乙醇和磷脂的湿热灭菌的尼莫地平组合物”、“本发明的组合物”、“本发明的浓缩液”、“本发明的尼莫地平组合物”等术语可以互换使用，均指包含尼莫地平、非磷脂表面活性剂和助溶剂的组合物，上下文显示含义并非如此的除外。
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。
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。
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。
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。
本文所用的术语“聚氧乙烯40氢化蓖麻油”是指由lmol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。
本文所用的术语“聚氧乙烯60氢化蓖麻油”是指由lmol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。
本文所述的“15-羟基硬脂酸聚乙二醇酯”是由12-羟基硬脂酸乙氧基化形成的12-羟基硬脂酸聚乙二醇的单酯和双酯以及游离聚乙二醇为主要成分的混合物，凝点为22℃-30℃，在室温时呈浅黄色至白色粘稠状半固体，约30℃时变为液体。其是一种新型非离子型增溶剂和乳化剂，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。15-羟基硬脂酸聚乙二醇酯已被德国药典、英国药典、美国药典和欧洲药典收录，在美国药典和欧洲药典中的化学名分别为polyoxyl 15 hydroxystearate和macrogol 15 hydroxystearate。
本文所述的“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。
本文所述的“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。
本文所述的“辛癸酸单双甘油酯”是指甘油和植物油中的中碳链脂肪酸的混合三酯，通常用椰子油与甘油制得，其可以商购获得，例如以商品名IMWITOR742从德国IOI Oleo GmbH等商购获得。
除非另有说明，本文所给出的百分比是重量百分比(w/w)。
实施例
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。
实施例中所用的缩略语的含义如表1所示。
表1—缩略语含义

实施例1：磷脂对尼莫地平注射液灭菌前后质量的影响
处方1～4:磷脂对尼莫地平注射液灭菌前后质量的影响
表2—磷脂对尼莫地平注射液灭菌前后质量的影响
工艺：
1)将处方量的HS15置于锥形瓶中，于60℃下加热至瓶内HS15完全溶解，上下颠倒混匀备用；
2)称取处方量的EPC置于另一个锥形瓶中，依次加入处方量的尼莫地平原料药、丙二醇、加热熔化的HS15，密封，60℃水浴搅拌至溶解成均一油溶液，将溶液灌装在西林瓶中，即得不同百分比的EPC的尼莫地平浓缩液；
3)将处方1-3的浓缩液分别分为两组，一组在121℃灭菌15分钟，另外一组不做灭菌处理。
将灭菌前后制剂检测性状、pH、过氧化值、游离脂肪酸、含量及有关物质。性状、pH、含量及有关物质的检测方法见实施例11。过氧化值和游离脂肪酸的检测方法：
游离脂肪酸：精密量取供试品溶液5g，置25ml量瓶中，用异丙醇稀释至刻度，摇匀，精密移取5ml，置20ml具塞试管中，加异丙醇-正庚烷-0.5mol/L硫酸溶液(40:10:1)的混合溶液5.0ml，振摇1分钟，放置10分钟。精密加入正庚烷与水各3ml，密塞，上下翻动10次，静置至少15分钟使分层。精密量取上层溶液3ml，置10ml离心管中，加尼罗蓝指示液(取尼罗蓝0.04g，加水200ml使溶解，加正庚烷100ml，振摇，弃去上层正庚烷，反复操作4次。取下层水溶液20ml，加无水乙醇180ml，混匀，置棕色瓶中，室温1个月内使用)1ml，用氢氧 化钠滴定液(0.01mol/L)滴定至溶液显淡紫色。比较各个批次供试品消耗的滴定液的毫升数有无差别。
过氧化值：精密量取本品5g，加冰醋酸-三氯甲烷(3:2)30ml。精密加饱和碘化钾溶液0.5ml，立即密塞，准确振摇萃取1分钟，加水30ml与淀粉指示液5ml，立即用硫代硫酸钠滴定液(0.01mol/L)滴定至上层水相紫蓝色消失，并将滴定的结果用空白试验校正。
用5％葡萄糖注射液稀释，稀释液含尼莫地平0.1mg/mL。摇匀，观察稀释液的稳定性。
结果如下：
浓缩液：处方1-3的尼莫地平注射液为淡黄色澄清透明的油溶液，随着EPC用量的增加，溶液颜色逐渐变深。与灭菌前相比，灭菌后的溶液颜色显著加深，导致颜色检查不合格，且随着EPC浓度的增加，颜色加深越明显。
稀释液：将处方1-3所得的尼莫地平浓缩液用5％葡萄糖注射液稀释至相同的浓度(尼莫地平为0.1mg/mL)，均为无色透明溶液，稀释液静置24小时没有沉淀物析出，三种处方所配制的稀释液无明显差别。
EPC对尼莫地平注射液灭菌前后浓缩液和稀释液的影响：考察了121℃灭菌15分钟的灭菌过程对尼莫地平浓缩液中的尼莫地平含量和有关物质及稀释液的pH值的影响，结果见表3。
表3—灭菌对尼莫地平注射液的影响
上述实验数据表明，EPC的用量对灭菌前后制剂的pH、尼莫地平含量和有 关物质没有显著影响。但是，含有EPC的尼莫地平浓缩液在灭菌后颜色明显变深，并且随着EPC浓度的增加，灭菌后颜色加深越明显。换言之，湿热灭菌导致尼莫地平浓缩液的性状有明显改变。这说明颜色的改变是由于组合物中包含磷脂造成的。因此，为了对尼莫地平浓缩液进行湿热灭菌，在所述浓缩液中应当避免使用磷脂。
实施例2：助溶剂对尼莫地平的增溶效果
处方4～5:助溶剂对尼莫地平的增溶效果
表4—助溶剂对尼莫地平的增溶效果
工艺：
1)首先将HS15和RH40分别加入不同的锥形瓶中，60℃下加热至完全溶解，上下颠倒混匀备用；
2)称取处方量的尼莫地平原料药于烧杯中，分别加入助溶剂丙二醇和甘油，在60℃的水浴中搅拌，得到浓缩液；
3)将浓缩液灌装在西林瓶(7mL)中(灌装量：2mL)，在121℃灭菌15分钟；
4)考察浓缩液的外观，并且考察用5％葡萄糖注射液稀释形成溶液的情况和稀释后的溶液(尼莫地平浓度为0.1mg/mL)的稳定性。
实验结果见下表：
表5—助溶剂对尼莫地平的增溶效果
实验结果表明，尼莫地平在助溶剂丙二醇中能够形成澄清透明的浓缩液，在经过湿热灭菌后，浓缩液为澄清透明的淡黄色溶液。将浓缩液用水性溶媒稀 释后，所形成的稀释溶液放置8小时没有药物析出；但是，当使用甘油为助溶剂时，配制的浓缩液灭菌后分层，增溶效果不理想。这说明，并非任何助溶剂都适用于尼莫地平。
实施例3：非磷脂表面活性剂对尼莫地平的增溶效果
处方6-9:非磷脂表面活性剂对尼莫地平的增溶效果
表6—非磷脂表面活性剂对尼莫地平的增溶效果的筛选
工艺：
1)首先将HS15和RH40分别加入不同的锥形瓶中，60℃下加热至完全溶解，上下颠倒混匀备用；
2)称取处方量的尼莫地平原料药于烧杯中，加入处方量的丙二醇。分别加入HS15、吐温80、RH40和ELP，在60℃的水浴中搅拌，得到浓缩液；
3)将浓缩液灌装在西林瓶(7mL)中(灌装量：2mL)，在121℃灭菌15分钟；
4)考察浓缩液的外观，并且考察用5％葡萄糖注射液稀释形成溶液的情况和稀释后的溶液(尼莫地平浓度为0.1mg/mL)的稳定性。
实验结果见下表：
表7—非磷脂表面活性剂对尼莫地平的增溶效果
实验结果表明，尼莫地平在非磷脂表面活性剂HS15、吐温80、RH40和ELP中能够形成澄清透明的浓缩液，在经过湿热灭菌后，浓缩液为澄清透明的淡黄色溶液。将浓缩液用水性溶媒稀释后，所形成的稀释溶液放置8小时没有药物析出。
实施例4：对不同活性成分的增溶效果
处方10-14:对不同活性成分的增溶效果
表8—对不同活性成分增溶效果研究
工艺：
1)将处方量的HS15置于锥形瓶中，于60℃下加热至瓶内HS15完全溶解，上下颠倒混匀备用；
2)称取处方量的不同活性成分置于锥形瓶中，依次加入处方量的丙二醇、HS15，密封，在60℃水浴中搅拌；
3)将步骤2)所得的浓缩液灌装在西林瓶(7mL)中(灌装量：2mL)，在121℃灭菌15分钟；
4)考察浓缩液的外观。
实验结果见下表：
表9—对不同活性成分增溶效果研究结果
结果显示，本发明所使用的非磷脂表面活性剂和助溶剂体系对不同的活性分子增溶效果不同。与尼莫地平不同，穿心莲内酯、泊沙康唑、人参皂苷和替尼泊苷在该体系中不能形成澄清透明的溶液。这说明，HS15和丙二醇的组合并不适用于增溶所有难溶性药物。
实施例5：尼莫地平注射液载药量的筛选
处方15-31:尼莫地平注射液载药量的筛选
表10—尼莫地平注射液载药量的筛选


工艺：
1)将处方量的HS15至于锥形瓶中，于60℃下加热至瓶内HS15完全溶解，上下颠倒混匀备用；
2)称取处方量的尼莫地平置于锥形瓶中，依次加入处方量的丙二醇、HS15，密封，在60℃水浴中搅拌。
3)将步骤2)所得的浓缩液灌装在西林瓶(7mL)中(灌装量：2mL)，在121℃灭菌15分钟；
4)考察浓缩液的外观和稳定性。
结果显示，载药量为0％-10％的处方15-29所形成的浓缩液为均一透明的溶液，原辅料混合均匀，无不溶性异物，随着载药量的增加，浓缩液的颜色从无色透明逐渐变为淡黄色；但是，载药量分别为15％和20％的处方30和31在充分搅拌后仍有尼莫地平不能溶解。
将处方15-29的浓缩液在25℃下静置1小时，发现载药量为10％的处方29的浓缩液在静置1h后析出晶体，其他处方没有晶体析出。
将载药量为0％-10％的处方15-29用5％葡萄糖注射液稀释，使稀释液中尼莫地平的浓度为0.1mg/ml，所形成的稀释液的颜色随着载药量的增加从无色透明逐渐变为淡黄色。将稀释液在25℃下静置，结果显示，由载药量为3％、5％、10％的尼莫地平浓缩液制备的稀释液约30分钟均析出晶体，由载药量为1.2％、1.5％、2.0％的尼莫地平浓缩液所制备的稀释液均在24小时内析出晶体，并且随着载药量的增加，稀释液的稳定时间依次变短，析出量也依次增加。由载药量为0％-1.1％的尼莫地平浓缩液制备的稀释液在静置96小时后仍然没有结晶析出，且各组之间无显著差异，均满足静脉注射给药的需求。由此可将，尼莫地平在浓缩液中的浓度应≤1.1％。
低的载药量会导致稀释液中的药物浓度较低，临床使用不便。优选的载药量为0.5％-1.1％。
实施例6：尼莫地平注射液中HS15用量的筛选
发明人对HS15的用量进行了两次筛选：第一次筛选为大范围筛选(10％-60％)，第二次筛选为小范围筛选(40％-60％)，具体实验如下：
表11—HS15用量的筛选(大范围筛选：10％-60％)

工艺：
1)将处方量的HS15至于锥形瓶中，于60℃下加热至瓶内HS15完全溶解，上下颠倒混匀备用；
2)称取处方量的尼莫地平置于另一个锥形瓶中，依次加入处方量的丙二醇、加热熔化的HS15，密封，在60℃水浴中搅拌至溶解，形成成均一油溶液，得到浓缩液。
3)将浓缩液充氮气，然后灌装在西林瓶(7mL)中(灌装量：2mL)，在121℃灭菌15min。
检测灭菌后的浓缩液中尼莫地平的含量和有关物质。
取灭菌后的浓缩液1ml用25ml注射用水(pH为5.9-6.1)稀释，测定pH值。
将灭菌后的浓缩液用5％葡萄糖注射液稀释(稀释液中尼莫地平的浓度为0.1mg/mL)，摇匀，观察稀释液24小时内的稳定性，包括目测和显微镜观察。
浓缩液：HS15占比低于40％(重量比)的制剂为淡黄色浑浊液，尼莫地平没有完全溶解；HS15占比在40％-60％之间的制剂为淡黄色澄清透明溶液，尼莫地平完全溶解。因此，HS15的含量应该大于40％。
稀释液：将处方35至处方37的灭菌后的浓缩液用0.5％葡萄糖注射液稀释相同的浓度(稀释液中尼莫地平的浓度为0.1mg/mL)，均为无色透明的溶液，这些稀释液的外观无明显差别，并且所有稀释液在25℃静置24小时后在显微镜下观察也没有晶体析出。
表12—HS15用量的筛选(小范围筛选：40％-60％)
工艺：
1)将处方量的HS15至于锥形瓶中，于60℃下加热至瓶内HS15完全溶解， 上下颠倒混匀备用；
2)称取处方量的尼莫地平置于另一个锥形瓶中，依次加入处方量的丙二醇、加热熔化的HS15，密封，在60℃水浴中搅拌至溶解成均一油溶液，得到浓缩液；
3)将浓缩液充氮气，然后灌装在西林瓶(7mL)中(灌装量：2mL)，在121℃灭菌15min。
检测尼莫地平的含量和有关物质。
取灭菌后的浓缩液1ml用25ml注射用水(pH为5.9-6.1)稀释后，测定pH值。
将灭菌后的浓缩液用5％葡萄糖注射液稀释(稀释液中尼莫地平的浓度为0.1mg/mL)，观察稀释液24小时内的稳定性，包括目测和显微镜观察。
浓缩液：
在高于25℃的温度下，处方38至处方48的尼莫地平浓缩液均为淡黄色澄清透明的溶液，原辅料混合均匀，无不溶性异物；当静置冷却至25℃后，处方39至处方48的浓缩液状态不变，均为澄清透明的溶液；而处方38的浓缩液变浑浊，再次加热后变回淡黄色澄清透明的溶液，再冷却到25℃，仍然会出现浑浊。发明人推测，这可能是由于HS15的用量低导致增溶效果不佳。
另外，由于HS15的凝点较低(22℃-30℃)，含量越大，凝固温度越高，不利于保证质量和临床给药，因此，发明人进一步研究了温度对处方39至48的浓缩液的物理状态的影响。实验结果显示，处方46-48(HS15百分比为56-60％)的浓缩液在18℃条件下开始凝固；处方42-45(HS15百分比为48-54％)的浓缩液在12℃条件下开始凝固；处方39-41(HS15百分比为42-46％)的浓缩液在低至10℃的温度状态保持不变。
稀释液：将处方38至处方48的灭菌后的浓缩液用0.5％葡萄糖注射液稀释相同的浓度(0.1mg/ml)，均为无色透明溶液，这些稀释液的外观无明显差别，并且所有稀释液在25℃静置24小时后在显微镜下观察也没有晶体析出。
表13—HS15的用量对灭菌前后尼莫地平浓缩液的影响：
对于处方38至处方48的尼莫地平浓缩液而言，高热灭菌对尼莫地平的含量、有关物质、pH值没有影响。
上述实验结果显示，HS15在本发明中的用量优选为42％-60％。
HS15具有一定的溶血性，但是溶血性低于聚山梨酯80，并且血清组胺释放水平和引起生物过敏的可能性也远低于后者(Lu H,Li J,Li M,et al.Systemic delivery of alpha-asarone with Kolliphor HS 15improves its safety and therapeutic effect on asthma[J].Drug Deliv,2015,22(3):266-275)。易红等(易红,高进,杨华等，几种注射用表面活性剂的质量标准及安全性概述[J].中国实验方剂学杂志,2010,16(1):115-119)发现给小鼠静脉注射HS15后测得其LD50为3.16g/kg。豚鼠过敏性实验结果显示，与聚山梨酯80组相比，HS15组血浆的组胺释放更低(60min静脉注射后HS15组血清组胺水平为8nmol·L-1，聚山梨酯80组为247nmol·L-1)，溶血性也较低(以增溶剂质量浓度为1％静脉注射后，HS15组有1％红细胞溶解，聚山梨酯80组为4％)；且由于HS15本身粘度低，对药物溶液的粘度几乎无影响，大大降低了注射给药刺激性。尽管如此，HS15用量过大也容易引起溶血和过敏反应。
因此，优选地，HS15在本发明的含量优选为42％-50％(重量比)，更优选44％-46％(重量比)。
实施例7：尼莫地平浓缩液制备过程终端灭菌方式的筛选
发明人考察了灭菌条件对尼莫地平注射液质量的影响。
处方(2022011901)：尼莫地平1.00g(1％)，HS15 45.00g(45％)，丙二醇54.00g(54％)，总计100.00g。
制备工艺：1)将HS15于60℃下加热至瓶内HS15完全溶解，上下颠倒混匀 备用；2)称取处方量的丙二醇于锥形瓶中，依次加入处方量的HS15、尼莫地平原料，密封，在60℃的水浴中磁力搅拌至溶解成均一溶液，即得尼莫地平浓缩液；3)将浓缩液灌装在西林瓶(7mL)中(灌装量：2mL)，分为三组，第一组在121℃灭菌15分钟，第二组在115℃灭菌30分钟，第三组过滤除菌。
按照实施例11中的方法，测定各组浓缩液的尼莫地平含量和有关物质。
将上述三组样品和分别用5％葡萄糖注射液稀释，稀释液1中尼莫地平的浓度为0.1mg/mL，稀释液2中尼莫地平的浓度为0.04mg/mL。测定稀释液的pH值并观察稀释液的稳定性。
表14—终端灭菌方式对尼莫地平浓缩液和稀释液的影响
申请者惊奇的发现，湿热灭菌能够显著改善稀释液的稳定性。不受理论的束缚，发明人推测，造成这一现象的原因可能是，湿热灭菌导致浓缩液中各种物质的分子之间结合更紧密。
国家药品监督管理局药审中心颁布的《化学药物杂质研究的技术指导原则》明确指出由于药品在临床使用中产生的不良反应除了与药品本身的药理活性有关外，有时与药品中存在的杂质也有很大关系。杂质I为尼莫地平降解最主要杂 质，该杂质是具有肝肾毒性化合物的结构类似物，存在安全隐患，是主要的质控杂质。因此，杂质越少越好。由上表可知，本发明的尼莫地平浓缩液无论在115℃湿热灭菌30min，还是在121℃湿热灭菌15min，浓缩液中尼莫地平的含量和有关物质以及稀释液的pH均符合限度要求，且浓缩液中杂质I和总杂质的含量均明显小于
实施例8：尼莫地平浓缩液的制备过程是否避光的筛选
处方(2022011901-2)：尼莫地平1.00g(1％)，HS15 45.00g(45％)，丙二醇54.00g(54％)，总计100.00g。
制备工艺：1)将HS15于60℃下加热至瓶内HS15完全溶解，上下颠倒混匀备用；2)称取处方量的丙二醇于锥形瓶中，依次加入处方量的HS15、尼莫地平原料，密封，在60℃的水浴中磁力搅拌至溶解成均一溶液，得到尼莫地平浓缩液；3)将浓缩液灌装在西林瓶(7mL)中(灌装量：2mL)，在121℃灭菌15min。制备过程中分自然光和避光两种条件。
按照实施例11中的方法测定浓缩液的pH值、尼莫地平含量和有关物质。表15-光对尼莫地平浓缩液的影响
N/A：未检测到
实验数据表明，避光和不避光的工艺所制备的浓缩液杂质均符合要求，但是避光使得杂质I的含量更低。因此，避光工艺是更优选的。
实施例9：尼莫地平浓缩液的制备过程是否充氮的筛选
发明人考察了氮气对尼莫地平注射液的影响。在实施例10中2022012201批次上进行氮气对尼莫地平注射液有关物质的研究，具体实验结果见下表。
表16-氮气对尼莫地平浓缩液有关物质的影响
实验数据表明，充氮气和不充氮气制备的本发明的浓缩液的总杂质和杂质I均符合要求，但是在制备过程中充氮气总杂质和杂质I的含量更低。因此，充氮的制备方法是更优选的。
实施例10：本发明的组合物的小试工艺验证
发明者制备两批尼莫地平注射液(批号为2022012201和2022012202)，每批600支，进行小试处方工艺验证。
处方：尼莫地平1.00g(1％)，HS15 45.00g(45％)，丙二醇54.00g(54％)，总计100.00g。
制备工艺：1)将HS15于60℃下加热至瓶内HS15完全溶解，上下颠倒混匀备用；2)称取处方量的丙二醇于锥形瓶中，依次加入处方量的HS15、尼莫地平原料，密封，在60℃的水浴中磁力搅拌至溶解成均一溶液，即得尼莫地平浓缩液；3)将所得浓缩液充氮气，灌装于7ml的棕色和无色西林瓶中；4)在121℃湿热灭菌15min。配制过程避光操作。
制备了两批样品，理论批量：600支，合格样品支数：560支，收率：93.3％。
实施例11：本发明的组合物的稳定性考察
浓缩液稳定性考察：
按照《中国药典》2020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，对实施例10中制备的浓缩液，在温度60℃光照(5000Lux)条件下放置，于第5、10、30天末取样，对相应指标进行考察。
1、样品信息：尼莫地平注射液(自制样品)，批号2022012201(两种，棕色和透明)；原研(为棕色包装；透明包装用无色西林瓶分装)，批号：BXJC7A1
2、稳定性试验放样条件：
表17-稳定性试验放样条件
3、分析方法
(1)性状
检查方法：目测。
(2)pH值
将浓缩液1ml用新沸的冷水以1:25的体积比稀释，测定其pH值；pH值应为4.0～7.0之间
(3)有关物质
检测方法：HPLC法
实验条件：
色谱柱：C18柱(型号：Ultinate XB-C18，XDB-C18，125cm，内径4.6mm，填料粒径5.0μm)
柱温：40℃
检测器：UV检测器(检测波长235nm)
流动相：甲醇-四氢呋喃-水(20:20:60)
流速：2.0mL/min
进样体积：20μL
运行时间：40min
系统适应性：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。
具体实验操作：
在各个规定的时间点取放置的浓缩液，精密称定，加流动相溶解并定量稀释制成每1mL中约含1.6mg的溶液，作为供试品溶液；精密称取尼莫地平对照品适量，用流动相稀释成每1mL中约含3.2μg尼莫地平的溶液，作为对照溶液A，另取尼莫地平对照品与杂质Ⅰ对照品适量，加流动相溶解并稀释制成每1mL中约含 1.6μg尼莫地平与1.6μg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。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。
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。供试品溶液色谱图中，如出现与杂质Ⅰ保留时间一致的色谱峰，按外标法以峰面积计算，含杂质Ⅰ不得过尼莫地平标示量的0.5％，其他杂质以对照品溶液A色谱图中主峰面积为对照，按外标法以峰面积计算，其他单个杂质不得过尼莫地平标示量的0.2％，杂质总量不得过1.0％。
(4)尼莫地平含量
检测方法：HPLC法
实验条件：
色谱柱：C18柱(型号：Ultinate XB-C18，XDB-C18,125cm，内径4.6mm，填料粒径5.0μm)
柱温：室温
检测器：UV检测器(检测波长235nm)
流动相：甲醇-四氢呋喃-水(20:20:60)
流速：2.0mL/min
进样体积：20μL
运行时间：40min
系统适应性：对照品溶液色谱峰拖尾因子不大于2.0.
具体实验操作：
取浓缩液，精密称定，用流动相溶解并稀释成每1mL中约含0.2mg尼莫地平的溶液，作为供试品溶液；取尼莫地平对照品，精密称定，加流动相溶解并稀释成每1mL中约含0.2mg尼莫地平的溶液，作为对照品溶液。精密量取20μL供试品溶液和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。
4、实验结果

实验结果表明：
棕色包装：本发明的浓缩液和原研产品在高温试验60℃条件下放置30天，各项指标无显著变化，均符合要求。本发明的浓缩液和原研产品 无明显差别；在光照试验5000Lux(10天)条件下放置30天，尼膜同的有关物质含量超出可接受的限度，而本发明的浓缩液各项指标均符合要求。
透明包装：本发明的浓缩液和原研产品在光照试验5000Lux条件下30天放置，性状和pH无明显变化，但有关物质显著增加，含量显著降低，这是由于尼莫地平在光照下放置会降解所导致的。由该极端条件下的考察可见，在5000Lux光照下放置30天，本发明的浓缩液中尼莫地平的含量为76.25％，而中尼莫地平的含量下降到3.06％，几乎全部降解。
因此，本发明的浓缩液的稳定性显著优于原研产品
稀释液稳定性考察：
考察本品和原研稀释液的稳定性。
1、样品信息：尼莫地平注射液，批号2022012201
2、稀释液稳定性考察条件：
表19-稀释液稳定性试验放样条件
3、分析方法
(1)性状
检查方法：目测。
(2)pH值
测定稀释液的pH值。
(3)结晶状态
检查方法：目测和电子显微镜。
4、实验结果
表20-稀释液稳定性试验结果
由上表中的实验结果可见，无论是用5％葡萄糖注射液稀释，还是用0.9％氯化钠稀释，在稀释后均快速析出尼莫地平结晶。在临床上，尼莫地平必须以1-2mg/h的速度慢速滴注，否则病人无法耐受其副作用，导致10mg药物所需滴注时间一般需要至少5小时。原研制剂用高浓度的有机溶剂增溶，用葡萄糖和氯化钠注射液稀释后由于有机溶剂浓度的降低，导致药物结晶，这会增加不良反应、降低疗效。为了解决该问题，在临床上需采用特殊的三通阀输液器(图1)输注，使用不方便。
相比之下，本发明的尼莫地平浓缩液在用5％葡萄糖注射液或0.9％氯化钠注射液稀释后，稀释液在25℃下放置48小时，性状和pH值无显著性变化，无药物结晶出现。因此，本发明的尼莫地平浓缩液克服了市售的尼莫地平注射液的缺点，在稀释后稳定性良好，可用普通输液器输注。
附图说明
图1是临床上用于静脉输注的三通阀照片，其中标记数字“1”的端口为“静脉端”，与患者的静脉连接，标记数字“2”的端口为“带泵液端”，与由泵控制的水性溶媒连接，标记数字“3”的端口为“尼莫地平端”，与尼莫地平注射液连接。使用这个三通阀的目的在于，使尼莫地平注射液与水性 溶媒在混合后立即输注到患者静脉内，避免稀释液经放置导致尼莫地平析出结晶的问题。
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。
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。

Claims (10)

  1. 一种不含磷脂和乙醇的尼莫地平组合物，其特征在于，所述组合物包含：
    (1)尼莫地平；
    (2)非磷脂表面活性剂，其选自聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油、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、辛癸酸单双甘油酯其任意两种或更多种的混合物；
    (3)助溶剂，其为丙二醇，
    其中，以尼莫地平、非磷脂表面活性剂和助溶剂的总重量计，尼莫地平的含量≤1.1％w/w，优选0.5％-1.1％w/w，更优选0.8-1.1％w/w；非磷脂表面活性剂的量为42-50％w/w，优选44-46％w/w；余量为助溶剂，
    所述组合物是通过湿热灭菌进行终端灭菌的。
  2. 根据权利要求1所述的组合物，其中所述非磷脂表面活性剂选自聚氧乙烯35蓖麻油、纯的聚氧乙烯35蓖麻油、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20、聚山梨酯21、聚山梨酯40、聚山梨酯60、聚山梨酯61、聚山梨酯65、聚山梨酯80、聚山梨酯81、聚山梨酯85、聚山梨酯120、辛癸酸单双甘油酯及其任意两种或更多种的混合物。
  3. 根据权利要求2所述的组合物，其中所述的非磷脂表面活性剂是15-羟基硬脂酸聚乙二醇酯。
  4. 根据权利要求1至3中一项所述的组合物，其中所述组合物还包含pH调节剂和抗氧化剂，所述pH调节剂优选选自枸橼酸、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，所述抗氧化剂优选选自α-生育酚琥珀酸酯、棕榈酸抗坏血酸酯、丁基化羟基苯甲醚、丁化羟基甲苯中的一种或多种。
  5. 根据权利要求1至3中任意一项所述的组合物，其中所述组合物由尼莫地平、非磷脂表面活性剂、助溶剂组成。
  6. 根据权利要求5所述的组合物，其中所述组合物由尼莫地平、15-羟基硬脂酸聚乙二醇酯和丙二醇组成，并且以组合物的总重量计，尼莫地平的含量≤1.1％w/w，优选0.5％-1.1％w/w，更优选0.8-1.1％w/w；15-羟基硬脂酸聚乙二醇 酯的量为42-50％w/w，优选44-46％w/w；余量为丙二醇，
    所述组合物是通过湿热灭菌进行终端灭菌的。
  7. 根据权利要求案1至6中任意一项所述的组合物，其中所述组合物是避光制备的。
  8. 根据权利要求1至7中任意一项所述的组合物，其中所述组合物是通过包括充氮气的步骤的方法制备的。
  9. 制备权利要求1至5中任意一项所述的组合物的方法，所述方法包括以下步骤：(1)将尼莫地平、非磷脂表面活性剂和助溶剂混合，形成溶液，在需要的情况下酌情加热以溶解，(2)将所得溶液灌装入容器中，(3)将灌装后的溶液进行湿热灭菌，
    任选地，所述方法在避光下进行；
    任选地，在步骤(2)之前，将步骤(1)所获得的溶液充氮气；
    优选地，所述湿热灭菌在115℃下进行30min或在121℃进行15min。
  10. 一种溶液剂，其通过将实施方案1至7中任意一项所述的组合物用水性溶媒稀释获得，所述水性溶媒优选是适合注射的溶媒，例如注射用水、5％葡萄糖注射液、0.9％氯化钠注射液、乳酸钠林格氏液、右旋糖酐40溶液、羟乙基淀粉130/0.4氯化钠注射液、或羟乙基淀粉200/0.5氯化钠注射液。
PCT/CN2023/102147 2022-06-27 2023-06-25 不含乙醇和磷脂的湿热灭菌的尼莫地平组合物及其制备方法 WO2024001964A1 (zh)

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