Alcohol and phospholipid-free moist heat sterilized nimodipine composition and preparation method thereof

Abstract

The invention relates to a nimodipine composition which does not contain ethanol and phospholipid and is subjected to moist heat sterilization and a preparation method of the nimodipine composition. The composition comprises: (1) nimodipine; (2) a non-phospholipid surfactant selected from a mixture of any two or more of polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, 15-hydroxystearic acid polyethylene glycol ester, vitamin E polyethylene glycol 1000 succinate (TPGS), polysorbate and caprylic / capric acid mono / diglyceride; and (3) a cosolvent which is propylene glycol.

Description

Nimodipine composition sterilized by moist heat without ethanol and phospholipid and preparation method thereof

[0001] This application claims priority to Chinese patent application CN202210734212.7 filed on June 27, 2022, the entire contents of which are incorporated herein by reference. Technical Field

[0002] The present invention belongs to the field of pharmaceutical preparations and more specifically relates to a nimodipine composition sterilized by moist heat without ethanol and phospholipids and a preparation method thereof. Background Art

[0003] Nimodipine, chemical name is (±)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 1-methylethyl ester 2-methoxyethyl ester, is a light yellow crystalline powder, insoluble in water, and its molecular formula is C 21 H 26 N2O7, molecular weight is 418.44, and the structural formula is as follows:

[0004] Nimodipine is a 1,4-dihydropyridine calcium antagonist that is highly selective for brain receptors and readily crosses the blood-brain barrier. Nimodipine effectively blocks calcium ion entry into cells and inhibits smooth muscle contraction, thereby relieving vasospasm. This protects brain neurons and stabilizes their function, enhancing cerebral blood perfusion, improving cerebral blood supply, and increasing tolerance to hypoxia. Studies have shown that nimodipine is effective in preventing and treating ischemic brain damage caused by cerebral vasospasm due to subarachnoid hemorrhage. It can reduce red blood cell fragility and blood viscosity, inhibit platelet aggregation, and prevent thrombosis. At appropriate doses, nimodipine selectively dilates cerebral blood vessels with minimal effect on peripheral vasculature, making it useful for improving circulation during the recovery phase of acute cerebrovascular disease. Nimodipine can also improve memory impairment in patients with elderly brain damage, making it useful for preventing Alzheimer's disease and effectively improving cognitive function after stroke. Nimodipine also has some efficacy in treating sudden deafness. Currently, nimodipine has been approved for a variety of indications, such as for the prevention and treatment of cerebral vasospasm after subarachnoid hemorrhage of various causes and for improving blood circulation during the recovery period of acute cerebrovascular disease, for the treatment of senile brain dysfunction such as memory loss, orientation and attention disorders and mood swings, and for the treatment of sudden deafness, mild and severe hypertension.

[0005] There are many nimodipine dosage forms available on the market both domestically and internationally, including oral dosage forms including regular tablets, sustained-release tablets, hard capsules, and soft capsules; and injectables including small water injections and large infusions. Since solid nimodipine preparations have very low solubility in gastrointestinal fluids and a significant first-pass effect in the liver, they have always had the disadvantage of low bioavailability. Their injectable form has a faster onset and better effect than oral preparations, so injectable forms are more widely used clinically. However, the nimodipine injection currently in clinical use has major drawbacks:

[0006] (1) Contains a large amount of organic solvents. Nimodipine is poorly soluble in water. The commercially available infusion solution (50mL:10mg, ) contains 23.7% (v / v) ethanol (1 mL of solution contains 200 mg of ethanol) and 17% (v / v) polyethylene glycol 400, with the organic solvent accounting for 40% (20 mL). The ethanol content in small water injections is even higher. The presence of large amounts of ethanol causes significant adverse reactions during intravenous injection: it is a strong vascular irritant, easily causing pain at the injection site when injected into a blood vessel, and repeated injections can easily lead to phlebitis in the injection vessel. Furthermore, ethanol affects the nervous system, causing muscle incoordination, slowed reflexes, difficulty concentrating, decreased self-control, memory loss, and decreased intelligence. Alcohol can also damage the liver and irritate the stomach. Alcohol-containing preparations cannot be used by patients with ethanol allergies, limiting their use. Furthermore, when used in combination with cephalosporins or nitroimidazoles, ethanol-containing preparations are highly likely to cause disulfiram-like adverse reactions, potentially leading to chest pain, myocardial infarction, acute heart failure, dyspnea, acute liver damage, convulsions, and even death.

[0007] (2) Nimodipine is a dihydropyridine derivative. In order to control the quality of nimodipine-related preparations, many pharmacopoeias, including the Chinese and 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 ester isopropyl ester). Impurity I is the main impurity in the degradation of nimodipine. This impurity is a structural analogue of a compound with hepatotoxicity and kidney toxicity, and it poses a safety hazard. It is the main quality control impurity. The lower the content of impurity I in the injection, the better. Impurity I is produced by the dehydrogenation of the dihydropyridine ring of nimodipine. Various conditions can promote the formation of this impurity in nimodipine, including strong acid, strong base, high temperature, oxidation, light, etc. Traditional nimodipine injections add citrate buffer as a 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 effectively control the generation of impurities during the production process.

[0008] (3) Nimodipine must be slowly infused at a rate of 1-2 mg / h. The infusion time required for 10 mg of the drug generally takes at least 5 hours, otherwise the patient will not be able to tolerate its side effects. Solubilizing with high-concentration ethanol and then diluting with glucose injection or sodium chloride injection during use reduces the ethanol concentration, causing the drug to crystallize after standing. To address the poor physical stability caused by dilution, a special three-way valve infusion set (see Figure 1) is required for clinical infusion, which is inconvenient to use clinically.

[0009] Therefore, there is a need to develop new ethanol-free nimodipine compositions while ensuring good stability.

[0010] Summary of the Invention

[0011] After a large number of experimental studies, the inventors were surprised to find that by using a non-phospholipid surfactant and a specific cosolvent to prepare a concentrate and sterilizing it with moist heat, a clinically applicable dose of nimodipine can be prepared into a more stable ethanol-free composition. The composition can achieve good dissolution of nimodipine, is a uniform transparent solution, and has an extremely simple preparation process. The composition of the present invention can be diluted into a solution with an aqueous solvent before use, and the formed solution is directly used to administer the drug to the patient, which is convenient for use and has excellent stability without the problem of crystallization. The aqueous solvent can be an aqueous solvent 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 solvent suitable for oral administration (for example, purified water, etc.). Moreover, the composition of the present invention fully meets the requirements of intravenous injection, and because it has excellent stability after dilution, it can be infused through a common infusion set. Therefore, the composition of the present invention not only has excellent stability, but also can smoothly achieve the administration of nimodipine, especially injection administration, meeting the currently unmet clinical needs.

[0012] The purpose of the present invention is to provide a nimodipine composition sterilized by moist heat without ethanol and phospholipids, and to provide a simple, environmentally friendly and easily industrialized method for preparing the composition.

[0013] In a first aspect, the present invention provides a nimodipine composition sterilized by moist heat without ethanol and phospholipid, characterized in that the composition comprises:

[0014] (1) Nimodipine;

[0015] (2) a non-phospholipid surfactant selected from polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, 15-hydroxystearate polyethylene glycol, vitamin E polyethylene glycol 1000 succinate (TPGS), polysorbate, caprylic and capric monoglycerides, and a mixture of any two or more thereof;

[0016] (3) a cosolvent, which is propylene glycol,

[0017] Wherein, based on the total weight of nimodipine, non-phospholipid surfactant and cosolvent, 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 cosolvent,

[0018] The composition is terminally sterilized by moist heat sterilization.

[0019] The composition of the present invention may further contain a pH adjuster and an antioxidant. The pH adjuster may be selected from one or more of citric acid, citrates (such as sodium citrate), maleic acid, tartaric acid, hydrochloric acid, sodium hydroxide, acetic acid, acetates (such as sodium acetate), phosphoric acid, and phosphates (such as sodium monohydrogen phosphate, sodium dihydrogen phosphate, or sodium phosphate). The antioxidant may be selected from one or more of α-tocopherol succinate, ascorbyl palmitate, butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT).

[0020] In a preferred embodiment of this aspect, the composition of the present invention consists of nimodipine, a non-phospholipid emulsifier and a cosolvent.

[0021] In a second aspect, the present invention provides a method for preparing the composition of the present invention, characterized in that the method comprises the following steps: (1) mixing nimodipine, a non-phospholipid surfactant, and a cosolvent to form a solution, and heating to dissolve the solution if necessary; (2) filling the resulting solution into a container; (3) sterilizing the filled solution with moist heat;

[0022] Optionally, the method is carried out in the absence of light;

[0023] Optionally, before step (2), the solution obtained in step (1) is filled with nitrogen;

[0024] Preferably, the moist heat sterilization is performed at 115°C for 30 minutes or at 121°C for 15 minutes.

[0025] The composition of the present invention can be diluted into a solution using an aqueous solvent. The obtained solution has a uniform and transparent appearance and good stability and can be intravenously infused through a common infusion device.

[0026] In summary, 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, meeting the needs of patients allergic to ethanol; it avoids the occurrence of disulfiram-like adverse reactions that are likely to occur when combined with other drugs; (2) it can be sterilized by moist heat, better ensuring the sterility level while ensuring low impurity levels, especially the level of impurity I with hepatotoxicity and kidney toxicity is greatly reduced; (3) after dilution with an aqueous solvent, the resulting solution is stable and can be infused using a common infusion set. 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.

[0027] Detailed Description of the Invention Specific implementation plan

[0028] Embodiment 1. A nimodipine composition free of phospholipids and ethanol, characterized in that the composition comprises:

[0029] (1) Nimodipine;

[0030] (2) a non-phospholipid surfactant selected from polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, 15-hydroxystearate polyethylene glycol, vitamin E polyethylene glycol 1000 succinate (TPGS), polysorbate, caprylic and capric monoglycerides, and a mixture of any two or more thereof;

[0031] (3) a cosolvent, which is propylene glycol,

[0032] Wherein, based on the total weight of nimodipine, non-phospholipid surfactant and cosolvent, 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 cosolvent,

[0033] The composition is terminally sterilized by moist heat sterilization.

[0034] Embodiment 2. The composition of embodiment 1, wherein the non-phospholipid surfactant is selected from polyoxyl 35 castor oil, pure polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 60 hydrogenated castor oil, polyethylene glycol 15-hydroxystearate, vitamin E polyethylene glycol 1000 succinate (TPGS), polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85, polysorbate 120, caprylic and capric mono- and diglycerides, and mixtures of any two or more thereof.

[0035] Embodiment 3. The composition of embodiment 2, wherein the non-phospholipid surfactant is polyethylene glycol 15-hydroxystearate.

[0036] Embodiment 4. The composition according to one of embodiments 1 to 3, wherein the composition further comprises a pH adjuster and an antioxidant, wherein the pH adjuster is preferably selected from one or more of citric acid, citrate (such as sodium citrate), maleic acid, tartaric acid, hydrochloric acid, sodium hydroxide, acetic acid, acetate (such as sodium acetate), phosphoric acid, phosphate (such as sodium monohydrogen phosphate, sodium dihydrogen phosphate or sodium phosphate), and the antioxidant is preferably selected from one or more of α-tocopheryl succinate, ascorbyl palmitate, butylated hydroxyanisole, and butylated hydroxytoluene.

[0037] Embodiment 5. The composition according to any one of embodiments 1 to 3, wherein the composition consists of nimodipine, a non-phospholipid surfactant and a cosolvent.

[0038] Embodiment 6. The composition according to embodiment 5, wherein the composition consists of nimodipine, 15-hydroxystearate polyethylene glycol and propylene glycol, and based on the total weight of the composition, 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 15-hydroxystearate polyethylene glycol is 42-50% w / w, preferably 44-46% w / w; the balance is propylene glycol,

[0039] The composition is terminally sterilized by moist heat sterilization.

[0040] Embodiment 7. The composition of any one of embodiments 1 to 6, wherein the composition is prepared in the absence of light.

[0041] Embodiment 8. The composition according to any one of embodiments 1 to 7, wherein the composition is prepared by a method comprising a nitrogen filling step.

[0042] Embodiment 9. A method for preparing the composition of any one of embodiments 1 to 5, comprising the steps of: (1) mixing nimodipine, a non-phospholipid surfactant, and a cosolvent to form a solution, and heating to dissolve the solution if necessary; (2) filling the resulting solution into a container; (3) sterilizing the filled solution by moist heat;

[0043] Optionally, the method is carried out in the absence of light;

[0044] Optionally, before step (2), the solution obtained in step (1) is filled with nitrogen;

[0045] Preferably, the moist heat sterilization is performed at 115°C for 30 minutes or at 121°C for 15 minutes.

[0046] Embodiment 10. Use of the composition according to any one of embodiments 1 to 8 for preparing a solution for intravenous injection, especially intravenous drip.

[0047] Embodiment 11. A solution obtained by diluting the composition of any one of embodiments 1 to 8 with an aqueous vehicle, wherein the aqueous vehicle is preferably a vehicle suitable for injection, such as water for injection, 5% glucose injection, 0.9% sodium chloride injection, lactated Ringer's solution, dextran 40 solution, hydroxyethyl starch 130 / 0.4 sodium chloride injection, or hydroxyethyl starch 200 / 0.5 sodium chloride injection.

[0048] Embodiment 12. The solution according to embodiment 11, which is for intravenous injection, especially intravenous drip.

[0049] Composition of the present invention and preparation method thereof

[0050] Through further research into the basic physical and chemical properties of nimodipine, the inventors discovered that when nimodipine is used as the active ingredient, if phospholipids are present in the prepared concentrate, filtration sterilization is the only option, not wet heat sterilization, as wet heat sterilization can cause the concentrate to discolor, resulting in a failure in stability testing. To address this issue, the inventors further studied and optimized the composition of the composition, resulting in the present invention's superior composition.

[0051] 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. Before use, the concentrated solution is diluted with an aqueous solvent (e.g., 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) to form a solution. The solution has good physical and chemical stability and can be directly administered to the patient, for example, by oral administration or injection, such as intravenous injection. In addition, since the formed dilution has good stability, there is no need to use a three-way valve infusion set during intravenous infusion.

[0052] Therefore, in a first aspect, the present invention provides a nimodipine composition free of ethanol and phospholipids, characterized in that the composition comprises:

[0053] (1) Nimodipine;

[0054] (2) non-phospholipid surfactants;

[0055] (3) a cosolvent, which is propylene glycol,

[0056] Wherein, based on the total weight of nimodipine, non-phospholipid surfactant and cosolvent, 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 cosolvent,

[0057] The composition is terminally sterilized by moist heat sterilization.

[0058] The non-phospholipid surfactant can be selected from polyoxyethylene castor oil (e.g., polyoxyethylene 35 castor oil, in particular, 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 (e.g., polysorbate 20, 21, 40, 60, 61, 65, 80, 81, 85, 120, in particular, polysorbate 80), caprylic / capric glyceride, and mixtures of any two or more thereof. More preferably, the non-phospholipid surfactant is selected from polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 35 castor oil, pure polyoxyethylene 35 castor oil, polyethylene glycol 15-hydroxystearate, polysorbate 80, and mixtures of any two or more thereof. More preferably, the non-phospholipid surfactant is polyethylene glycol 15-hydroxystearate.

[0059] The composition of the present invention is a concentrated solution that can be diluted with an aqueous solvent to form a solution. The aqueous solvent can be an injectable solvent (e.g., 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 an orally administrable solvent (e.g., purified water, etc.). After dilution with an injectable solvent such as 5% glucose injection, the solution formed by the dilution of the composition of the present invention meets the requirements of an intravenous injection or even an intravenous drip injection. Therefore, the diluted solution can be directly used for injection, such as subcutaneous injection, intradermal injection, intraperitoneal injection, and can also be used for intravenous injection, including intravenous push injection and intravenous drip.

[0060] The composition of the present invention is a homogeneous, transparent solution with excellent physical and chemical stability. When the composition of the present invention was packaged in a colored bottle and subjected to an influencing factor test at 60°C and 5000 Lux, all indicators met the requirements. Furthermore, the solution obtained by dilution of the composition of the present invention also exhibits excellent physical and chemical stability. For example, when the solution formed by diluting the composition of the present invention with an aqueous solvent such as 5% glucose injection or 0.9% sodium chloride injection was left at room temperature for 48 hours, no drug precipitation was observed.

[0061] The inventors also screened non-phospholipid surfactants for use in the compositions of the present invention, examining polyoxyethylene 40 hydrogenated castor oil (e.g., Kolliphor RH40), polyethylene glycol 15-hydroxystearate (e.g., Kolliphor HS15), vitamin E polyethylene glycol succinate (TPGS), and polysorbate 80 (e.g., Tween 80). The experimental results showed that all of these surfactants were able to solubilize nimodipine.

[0062] The inventors screened cosolvents, including propylene glycol and glycerol. The results showed that using propylene glycol as a cosolvent allowed nimodipine to form a uniform and transparent solution, but using glycerol as a cosolvent caused the prepared concentrate to separate into layers upon standing.

[0063] The composition of the present invention described above may consist solely of the following components: nimodipine; a non-phospholipid surfactant; and a cosolvent, which is propylene glycol.

[0064] Alternatively, the nimodipine composition of the present invention described above may further contain other components, such as a pH regulator and / or an antioxidant. The pH regulator may be selected from one or more of citric acid, citrate (such as sodium citrate), maleic acid, tartaric acid, hydrochloric acid, sodium hydroxide, acetic acid, acetate (such as sodium acetate), phosphoric acid, and phosphate (such as sodium monohydrogen phosphate, sodium dihydrogen phosphate, or sodium phosphate). The antioxidant may be selected from one or more of α-tocopheryl succinate, ascorbyl palmitate, butylated hydroxyanisole (BHA), and butylated hydroxytoluene (BHT).

[0065] The concentrated solution of the present invention and the diluted solution formed therefrom can be used to prevent and treat cerebral vasospasm after subarachnoid hemorrhage of various causes and improve blood circulation in the recovery period of acute cerebrovascular disease, to treat senile brain dysfunction, such as memory loss, orientation and attention disorders and mood swings, and to treat sudden deafness and mild and severe hypertension.

[0066] In a second aspect, the present invention provides a method for preparing the composition of the present invention, characterized in that the preparation method comprises: (1) mixing nimodipine, a non-phospholipid surfactant and a cosolvent to form a solution, and heating to dissolve the solution as needed, (2) filling the resulting solution into a container, and (3) sterilizing the filled solution by moist heat.

[0067] Since light can cause nimodipine to degrade, the method is preferably carried out in the dark to further reduce related substances.

[0068] In addition, nitrogen protection is also helpful to reduce the related substances in the concentrated solution of the present invention. Therefore, preferably, before step (2), the solution obtained in step (1) is filled with nitrogen.

[0069] The moist heat sterilization described herein can be performed under known conditions, for example, at 115° C. for 30 min or at 121° C. for 15 min.

[0070] The preparation method of the present invention is simple and easy to implement and is suitable for industrial production.

[0071] definition

[0072] In the context of this application, the terms "nimodipine composition sterilized by moist heat without ethanol and phospholipids", "the composition of the present invention", "the concentrate of the present invention", "the nimodipine composition of the present invention" and the like are used interchangeably to refer to a composition comprising nimodipine, a non-phospholipid surfactant and a cosolvent, unless the context indicates otherwise.

[0073] The term "polyoxyethylene castor oil" as used herein refers to a substance obtained by reacting different amounts of ethylene oxide with castor oil. Examples of polyoxyethylene castor oil include, but are not limited to, polyoxyethylene 35 castor oil and pure polyoxyethylene 35 castor oil.

[0074] As used herein, the term "polyoxyl 35 castor oil" refers to a material obtained by reacting 1 mol of glyceryl ricinoleate with 35 mol of ethylene oxide. In addition to polyoxyl triricinoleate, the material also contains a small amount of polyethylene glycol ricinoleate and free ethylene glycol. Polyoxyl 35 castor oil is commercially available, for example, from BASF under the trade names Kolliphor EL and Kolliphor ELP.

[0075] As used herein, the term "purified polyoxyl 35 castor oil" refers to purified polyoxyethylene triricinoleate.

[0076] The term "polyoxyethylene hydrogenated castor oil" as used herein refers to a substance obtained by reacting different amounts of ethylene oxide with hydrogenated castor oil. Examples of polyoxyethylene hydrogenated castor oil include, but are not limited to, polyoxyethylene 40 hydrogenated castor oil and polyoxyethylene 60 hydrogenated castor oil.

[0077] As used herein, the term "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. In addition to polyoxyethylene glyceryl trihydroxystearate, the substance 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.

[0078] The term "polyoxyethylene 60 hydrogenated castor oil" used herein refers to a substance obtained by the reaction of 1 mol of glyceryl trihydroxystearic acid with 60 mol of ethylene oxide, which, in addition to polyoxyethylene glyceryl trihydroxystearate, also contains a small amount of polyethylene glycol trihydroxystearic acid and free polyethylene glycol.

[0079] The "15-hydroxystearate polyethylene glycol ester" described herein is a mixture of monoesters and diesters of 12-hydroxystearate polyethylene glycol formed by ethoxylation of 12-hydroxystearate and free polyethylene glycol as the main components. It has a freezing point of 22°C-30°C and is a light yellow to white viscous semisolid at room temperature, becoming liquid at about 30°C. It is a new non-ionic solubilizer and emulsifier that can be commercially obtained, for example, from BASF or Sigma-Aldrich under the trade names kolliphor HS15 or Solutol HS-15. 15-hydroxystearate polyethylene glycol ester has been included in the German Pharmacopoeia, the British Pharmacopoeia, the United States Pharmacopoeia, and the European Pharmacopoeia. Its chemical names in the US Pharmacopoeia and the European Pharmacopoeia are polyoxyl 15 hydroxystearate and macrogol 15 hydroxystearate, respectively.

[0080] The "Vitamin E polyethylene glycol succinate (TPGS)" described herein is a water-soluble derivative of vitamin E, which is formed by the reaction of the carboxyl group of vitamin E succinate with the hydroxyl group of polyethylene glycol. It can be commercially obtained, for example, from BASF under the trade name Tocofersolan (TPGS).

[0081] As used herein, "polysorbate" refers to a series of partial fatty acid esters of polyoxyethylene sorbitan, copolymerized with approximately 20.5 mol or 4 mol of ethylene oxide per mol of sorbitol. Examples of polysorbates include, but are not limited to, polysorbates 20, 21, 40, 60, 61, 65, 80, 81, 85, and 120, particularly polysorbate 80. Polysorbates are commercially available, for example, from Nanjing Well Pharmaceutical Co., Ltd. under the trade names Tween 20, Tween 40, and Tween 80.

[0082] The "caprylic and dicapric acid glycerides" described herein refer to mixed triesters of glycerol and medium-chain fatty acids in vegetable oils, typically prepared from coconut oil and glycerol. They are commercially available, for example, under the trade name IMWITOR742 from IOI Oleo GmbH in Germany.

[0083] Unless otherwise stated, percentages given herein are by weight (w / w).

[0084] Example

[0085] The following examples are provided to illustrate the present invention but are not intended to limit the scope of the invention as defined by the appended claims in any way.

[0086] The meanings of the abbreviations used in the examples are shown in Table 1.

[0087] Table 1 - Meaning of Abbreviations

[0088] Example 1: Effect of phospholipids on the quality of nimodipine injection before and after sterilization

[0089] Prescriptions 1-4: Effects of phospholipids on the quality of nimodipine injection before and after sterilization

[0090] Table 2—Effects of phospholipids on the quality of nimodipine injection before and after sterilization

[0091] Process:

[0092] 1) Place the prescribed amount of HS15 in a conical flask, heat at 60°C until the HS15 is completely dissolved, and mix thoroughly by inverting.

[0093] 2) Weigh the prescribed amount of EPC and place it in another conical flask. Add the prescribed amount of nimodipine API, propylene glycol, and melted HS15 in sequence. Seal the flask and stir in a 60°C water bath until dissolved into a uniform oil solution. Fill the solution into vials to obtain nimodipine concentrates with different percentages of EPC.

[0094] 3) The concentrates of prescriptions 1-3 were divided into two groups, one group was sterilized at 121°C for 15 minutes, and the other group was not sterilized.

[0095] The preparations before and after sterilization were tested for properties, pH, peroxide value, free fatty acids, content, and related substances. The testing methods for properties, pH, content, and related substances are shown in Example 11. Testing methods for peroxide value and free fatty acids:

[0096] Free fatty acids: Accurately measure 5 g of the test solution into a 25 ml volumetric flask. Dilute to the mark with isopropanol and shake well. Accurately pipette 5 ml into a 20 ml stoppered test tube. Add 5.0 ml of a mixture of isopropanol, n-heptane, and 0.5 mol / L sulfuric acid solution (40:10:1). Shake for 1 minute and let stand for 10 minutes. Accurately add 3 ml each of n-heptane and water, stopper tightly, invert up and down 10 times, and let stand for at least 15 minutes to allow layers to separate. Accurately measure 3 ml of the upper solution and place it in a 10 ml centrifuge tube. Add 1 ml of Nile blue indicator solution (dissolve 0.04 g of Nile blue in 200 ml of water, add 100 ml of n-heptane, shake, discard the upper n-heptane layer, and repeat this process four times. Take 20 ml of the lower aqueous solution, add 180 ml of anhydrous ethanol, mix well, place in a brown bottle, and use within 1 month at room temperature). Titrate with sodium hydroxide solution (0.01 mol / L) until the solution turns light purple. Compare the milliliters of titrant consumed by each batch of test sample.

[0097] Peroxide value: Accurately measure 5g of this product and add 30ml of glacial acetic acid-chloroform (3:2). Accurately add 0.5ml of saturated potassium iodide solution, immediately seal the tube, and shake accurately for 1 minute. Add 30ml of water and 5ml of starch indicator solution, and immediately titrate with sodium thiosulfate solution (0.01mol / L) until the purple-blue color of the upper aqueous phase disappears. Correct the titration result with a blank test.

[0098] Dilute with 5% glucose injection containing 0.1 mg / mL nimodipine. Shake well and observe the stability of the dilution.

[0099] Here are the results:

[0100] Concentrate: Nimodipine injections in prescriptions 1-3 are light yellow, clear, and transparent oil solutions. The color of the solutions gradually darkens with increasing EPC dosage. The color of the solutions after sterilization is significantly darker than before sterilization, resulting in a color inspection failure. The color deepening becomes more pronounced with increasing EPC concentration.

[0101] Dilution: The nimodipine concentrates obtained from prescriptions 1-3 were diluted with 5% glucose injection to the same concentration (nimodipine: 0.1 mg / mL). All of them were colorless and transparent solutions. No precipitate was formed after the dilutions were allowed to stand for 24 hours. There was no significant difference in the dilutions prepared from the three prescriptions.

[0102] Effect of EPC on the concentrate and dilution of nimodipine injection before and after sterilization: The effect of the sterilization process of 121℃ for 15 minutes on the nimodipine content and related substances in the nimodipine concentrate and the pH value of the dilution was investigated. The results are shown in Table 3.

[0103] Table 3—Effects of sterilization on nimodipine injection

[0104] The above experimental data show that the amount of EPC used has no significant effect on the pH, nimodipine content, and related substances of the preparation before and after sterilization. However, the color of the nimodipine concentrate containing EPC becomes significantly darker after sterilization, and the color deepens more significantly after sterilization as the EPC concentration increases. In other words, moist heat sterilization causes a significant change in the properties of the nimodipine concentrate. This indicates that the color change is caused by the inclusion of phospholipids in the composition. Therefore, in order to perform moist heat sterilization on the nimodipine concentrate, the use of phospholipids in the concentrate should be avoided.

[0105] Example 2: Solubilization effect of cosolvent on nimodipine

[0106] Prescriptions 4-5: Solubilization effect of cosolvent on nimodipine

[0107] Table 4—Solubilization effect of cosolvent on nimodipine

[0108] Process:

[0109] 1) First, add HS15 and RH40 to different conical flasks, heat at 60°C until completely dissolved, and mix by inverting.

[0110] 2) Weigh the prescribed amount of nimodipine API into a beaker, add cosolvents propylene glycol and glycerol, respectively, and stir in a 60°C water bath to obtain a concentrate;

[0111] 3) Fill the concentrate into a 7 mL vial (filling volume: 2 mL) and sterilize at 121°C for 15 minutes;

[0112] 4) The appearance of the concentrate was examined, and the solution formed by dilution with 5% glucose injection and the stability of the diluted solution (nimodipine concentration was 0.1 mg / mL) were examined.

[0113] The experimental results are shown in the table below:

[0114] Table 5 - Solubilization effect of cosolvent on nimodipine

[0115] Experimental results showed that nimodipine formed a clear, transparent concentrate in the cosolvent propylene glycol. After wet heat sterilization, the concentrate was a clear, transparent, pale yellow solution. When the concentrate was diluted with an aqueous solvent, the resulting diluted solution remained for 8 hours without drug precipitation. However, when glycerol was used as the cosolvent, the prepared concentrate separated after sterilization, indicating unsatisfactory solubilization. This suggests that not all cosolvents are suitable for nimodipine.

[0116] Example 3: Solubilization effect of non-phospholipid surfactant on nimodipine

[0117] Prescription 6-9: Solubilization effect of non-phospholipid surfactant on nimodipine

[0118] Table 6 - Screening of non-phospholipid surfactants for solubilization of nimodipine

[0119] Process:

[0120] 1) First, add HS15 and RH40 to different conical flasks, heat at 60°C until completely dissolved, and mix by inverting.

[0121] 2) Weigh the prescribed amount of nimodipine API into a beaker and add the prescribed amount of propylene glycol. Separately add HS15, Tween 80, RH40, and ELP, and stir in a 60°C water bath to obtain a concentrate.

[0122] 3) Fill the concentrate into a 7 mL vial (filling volume: 2 mL) and sterilize at 121°C for 15 minutes;

[0123] 4) The appearance of the concentrate was examined, and the solution formed by dilution with 5% glucose injection and the stability of the diluted solution (nimodipine concentration was 0.1 mg / mL) were examined.

[0124] The experimental results are shown in the table below:

[0125] Table 7 - Solubilization effect of non-phospholipid surfactants on nimodipine

[0126] Experimental results showed that nimodipine formed a clear, transparent concentrate in the non-phospholipid surfactants HS15, Tween 80, RH40, and ELP. After moist heat sterilization, the concentrate was a clear, transparent, pale yellow solution. When the concentrate was diluted with an aqueous solvent, the resulting diluted solution showed no drug precipitation after 8 hours.

[0127] Example 4: Solubilization effect on different active ingredients

[0128] Prescriptions 10-14: Solubilization effect on different active ingredients

[0129] Table 8 - Study on the solubilization effect of different active ingredients

[0130] Process:

[0131] 1) Place the prescribed amount of HS15 in a conical flask, heat at 60°C until the HS15 is completely dissolved, and mix thoroughly by inverting.

[0132] 2) Weigh the prescribed amount of different active ingredients into a conical flask, add the prescribed amount of propylene glycol and HS15 in sequence, seal the flask, and stir in a 60°C water bath;

[0133] 3) Filling the concentrated solution obtained in step 2) into a vial (7 mL) (filling volume: 2 mL) and sterilizing at 121° C. for 15 minutes;

[0134] 4) Inspect the appearance of the concentrate.

[0135] The experimental results are shown in the table below:

[0136] Table 9 - Results of studies on the solubilization effect of different active ingredients

[0137] The results showed that the non-phospholipid surfactant and cosolvent system used in this study had varying solubilization effects on different active molecules. Unlike nimodipine, andrographolide, posaconazole, ginsenosides, and teniposide failed to form clear, transparent solutions in this system. This suggests that the HS15 and propylene glycol combination is not suitable for solubilizing all poorly soluble drugs.

[0138] Example 5: Screening of drug loading of nimodipine injection

[0139] Prescription 15-31: Screening of drug loading of nimodipine injection

[0140] Table 10—Screening of drug loading of nimodipine injection

[0141] Process:

[0142] 1) Place the prescribed amount of HS15 in a conical flask and heat at 60°C until the HS15 is completely dissolved. Invert the flask to mix thoroughly and set aside.

[0143] 2) Weigh the prescribed amount of nimodipine into a conical flask, add the prescribed amount of propylene glycol and HS15 in sequence, seal the flask, and stir in a 60°C water bath.

[0144] 3) Filling the concentrated solution obtained in step 2) into a vial (7 mL) (filling volume: 2 mL) and sterilizing at 121° C. for 15 minutes;

[0145] 4) Inspect the appearance and stability of the concentrate.

[0146] The results showed that the concentrated solutions formed by formulations 15-29 with drug loadings of 0%-10% were uniform and transparent solutions, with the raw and excipient materials mixed evenly and no insoluble foreign matter. As the drug loading increased, the color of the concentrated solution gradually changed from colorless and transparent to light yellow; however, formulations 30 and 31 with drug loadings of 15% and 20%, respectively, still had nimodipine that was not dissolved after thorough stirring.

[0147] The concentrated solutions of prescriptions 15-29 were allowed to stand at 25°C for 1 hour. It was found that the concentrated solution of prescription 29 with a drug loading of 10% precipitated crystals after standing for 1 hour, while no crystals were precipitated in the other prescriptions.

[0148] Formulas 15-29 with drug loadings of 0%-10% were diluted with 5% glucose injection to a nimodipine concentration of 0.1 mg / ml. The color of the resulting dilutions gradually changed from colorless and transparent to pale yellow as the drug loading increased. The dilutions were allowed to stand at 25°C. Results showed that dilutions prepared from nimodipine concentrates with drug loadings of 3%, 5%, and 10% all precipitated crystals within approximately 30 minutes, while dilutions prepared from nimodipine concentrates with drug loadings of 1.2%, 1.5%, and 2.0% all precipitated crystals within 24 hours. Furthermore, as the drug loading increased, the stability time of the dilutions became shorter and the amount of crystals precipitated increased. Dilutions prepared from nimodipine concentrates with drug loadings of 0%-1.1% showed no crystal precipitation after 96 hours of standing, with no significant differences between the groups, indicating that all met the requirements for intravenous administration. Therefore, the concentration of nimodipine in the concentrate should be ≤1.1%.

[0149] Low drug loading will result in low drug concentration in the diluent, which is inconvenient for clinical use. The preferred drug loading is 0.5%-1.1%.

[0150] Example 6: Screening of HS15 Dosage in Nimodipine Injection

[0151] The inventors screened the dosage of HS15 twice: the first screening was a large-scale screening (10%-60%), and the second screening was a small-scale screening (40%-60%). The specific experiments are as follows:

[0152] Table 11 - Screening of HS15 dosage (wide range screening: 10%-60%)

[0153] Process:

[0154] 1) Place the prescribed amount of HS15 in a conical flask and heat at 60°C until the HS15 is completely dissolved. Invert the flask to mix thoroughly and set aside.

[0155] 2) Weigh the prescribed amount of nimodipine into another conical flask, add the prescribed amount of propylene glycol and melted HS15 in sequence, seal the flask, and stir in a 60°C water bath until dissolved to form a uniform oil solution to obtain a concentrate.

[0156] 3) The concentrated solution was filled with nitrogen and then filled into a vial (7 mL) (filling volume: 2 mL), and sterilized at 121°C for 15 min.

[0157] The content of nimodipine and related substances in the sterilized concentrate was detected.

[0158] Take 1 ml of the sterilized concentrate and dilute it with 25 ml of water for injection (pH 5.9-6.1) and measure the pH value.

[0159] The sterilized concentrate was diluted with 5% glucose injection (the concentration of nimodipine in the dilution was 0.1 mg / mL), shaken well, and the stability of the dilution was observed within 24 hours, including visual inspection and microscopic observation.

[0160] Concentrate: Preparations containing less than 40% HS15 (by weight) are pale yellow, turbid solutions with incomplete dissolution of nimodipine. Preparations containing between 40% and 60% HS15 are pale yellow, clear, and transparent solutions with complete dissolution of nimodipine. Therefore, the HS15 content should be greater than 40%.

[0161] Dilutions: The sterilized concentrates of Prescriptions 35 to 37 were diluted with 0.5% glucose injection to the same concentration (the concentration of nimodipine in the dilutions was 0.1 mg / mL). All of the dilutions were colorless and transparent solutions. There was no significant difference in the appearance of these dilutions, and no crystals were precipitated when all the dilutions were left to stand at 25°C for 24 hours under a microscope.

[0162] Table 12 - Screening of HS15 dosage (small range screening: 40%-60%)

[0163] Process:

[0164] 1) Place the prescribed amount of HS15 in a conical flask and heat at 60°C until the HS15 is completely dissolved. Invert the flask to mix thoroughly and set aside.

[0165] 2) Weigh the prescribed amount of nimodipine into another conical flask, add the prescribed amount of propylene glycol and melted HS15 in sequence, seal the flask, and stir in a 60°C water bath until dissolved into a uniform oil solution to obtain a concentrate;

[0166] 3) The concentrated solution was filled with nitrogen and then filled into a vial (7 mL) (filling volume: 2 mL), and sterilized at 121°C for 15 min.

[0167] Detect the content of nimodipine and related substances.

[0168] Take 1 ml of the sterilized concentrate and dilute it with 25 ml of water for injection (pH 5.9-6.1), and then measure the pH value.

[0169] The sterilized concentrate was diluted with 5% glucose injection (the concentration of nimodipine in the dilution was 0.1 mg / mL), and the stability of the dilution was observed within 24 hours, including visual inspection and microscopic observation.

[0170] Concentrate:

[0171] At temperatures above 25°C, the nimodipine concentrates in formulations 38 to 48 were all pale yellow, clear, and transparent solutions. The raw materials and excipients were uniformly mixed, and free of insoluble foreign matter. After cooling to 25°C, the concentrates in formulations 39 to 48 remained clear and transparent. However, the concentrate in formulation 38 became turbid, but returned to a pale yellow, clear, and transparent solution upon reheating. However, it remained turbid upon further cooling to 25°C. The inventors speculate that this may be due to the low dosage of HS15, which resulted in poor solubilization.

[0172] In addition, since HS15 has a low freezing point (22°C-30°C), a higher HS15 content results in a higher freezing temperature, which is detrimental to quality assurance and clinical administration. Therefore, the inventors further investigated the effect of temperature on the physical state of the concentrates of formulations 39 to 48. The experimental results showed that the concentrates of formulations 46-48 (56-60% HS15) began to solidify at 18°C; the concentrates of formulations 42-45 (48-54% HS15) began to solidify at 12°C; and the concentrates of formulations 39-41 (42-46% HS15) remained unchanged at temperatures as low as 10°C.

[0173] Dilutions: The sterilized concentrates of Prescriptions 38 to 48 were diluted with 0.5% glucose injection to the same concentration (0.1 mg / ml). All of the dilutions were colorless and transparent solutions. There was no significant difference in the appearance of these dilutions, and no crystals were precipitated when all the dilutions were left to stand at 25°C for 24 hours under a microscope.

[0174] Table 13 - Effect of HS15 dosage on nimodipine concentrate before and after sterilization:

[0175] For the nimodipine concentrates of prescriptions 38 to 48, high-temperature sterilization has no effect on the content, related substances, and pH value of nimodipine.

[0176] The above experimental results show that the usage of HS15 in the present invention is preferably 42%-60%.

[0177] HS15 has a certain degree of hemolysis, but its hemolysis is lower than that of polysorbate 80, and its 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 15 improves 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 quality standards and safety of several surfactants for injection [J]. Chinese Journal of Experimental Traditional Chinese Medicine, 2010, 16 (1): 115-119) found that the LD50 of HS15 was 3.16 g / kg after intravenous injection into mice. Guinea pig allergy testing showed that compared with the polysorbate 80 group, the HS15 group released less plasma histamine (60 minutes after intravenous injection, the serum histamine level in the HS15 group was 8 nmol·L-1, while that in the polysorbate 80 group was 247 nmol·L-1). Hemolysis was also lower (after intravenous injection at a solubilizer concentration of 1%, 1% of red blood cells were lysed in the HS15 group, while that in the polysorbate 80 group was 4%). Furthermore, due to the low viscosity of HS15 itself, it had little effect on the viscosity of the drug solution, significantly reducing the irritation of the injection. Nevertheless, excessive HS15 dosage can easily cause hemolysis and allergic reactions.

[0178] Therefore, preferably, the content of HS15 in the present invention is preferably 42%-50% (weight ratio), more preferably 44%-46% (weight ratio).

[0179] Example 7: Screening of terminal sterilization methods during the preparation of nimodipine concentrate

[0180] The inventors investigated the effect of sterilization conditions on the quality of nimodipine injection.

[0181] Prescription (2022011901): Nimodipine 1.00g (1%), HS15 45.00g (45%), propylene glycol 54.00g (54%), total 100.00g.

[0182] Preparation process: 1) Heat HS15 at 60°C until HS15 in the bottle is completely dissolved, and mix thoroughly by inverting for later use; 2) Weigh the prescribed amount of propylene glycol into a conical flask, add the prescribed amount of HS15 and nimodipine raw materials in sequence, seal the flask, and stir magnetically in a 60°C water bath until dissolved into a uniform solution, thereby obtaining nimodipine concentrate; 3) Fill the concentrate into 7 mL vials (filling volume: 2 mL) and divide the vials into three groups: sterilize the first group at 121°C for 15 minutes, the second group at 115°C for 30 minutes, and the third group by filtration sterilization.

[0183] According to the method in Example 11, the nimodipine content and related substances of each group of concentrated solutions were determined.

[0184] The above three groups of samples and Each of the dilutions was diluted with 5% glucose injection, with the concentration of nimodipine being 0.1 mg / mL in dilution 1 and 0.04 mg / mL in dilution 2. The pH values ​​of the dilutions were measured and the stability of the dilutions was observed.

[0185] Table 14—Effect of terminal sterilization method on nimodipine concentrate and dilution

[0186] The applicants were surprised to find that moist heat sterilization significantly improved the stability of the dilution. Without being bound by theory, the inventors speculate that this phenomenon may be due to moist heat sterilization causing the molecules of various substances in the concentrate to bind more tightly.

[0187] The "Technical Guiding Principles for the Study of Impurities in Chemical Drugs" issued by the Drug Review Center of the State Food and Drug Administration clearly points out that the adverse reactions caused by drugs during clinical use are not only related to the pharmacological activity of the drugs themselves, but sometimes also have a lot to do with the impurities present in the drugs. Impurity I is the most important impurity in the degradation of nimodipine. This impurity is a structural analogue of a compound with hepatotoxicity and kidney toxicity, which poses a safety hazard and is the main quality control impurity. Therefore, the fewer impurities, the better. As can be seen from the above table, whether the nimodipine concentrate of the present invention is sterilized at 115°C for 30 minutes or at 121°C for 15 minutes, the content of nimodipine and related substances in the concentrate and the pH of the diluent all meet the limit requirements, and the content of impurity I and total impurities in the concentrate are significantly less than

[0188] Example 8: Screening of whether the preparation process of nimodipine concentrate is protected from light

[0189] Prescription (2022011901-2): Nimodipine 1.00g (1%), HS15 45.00g (45%), propylene glycol 54.00g (54%), total 100.00g.

[0190] Preparation process: 1) Heat HS15 at 60°C until completely dissolved in the bottle, invert and mix thoroughly; 2) Weigh the prescribed amount of propylene glycol into a conical flask, add the prescribed amount of HS15 and nimodipine raw material in sequence, seal, and magnetically stir in a 60°C water bath until a uniform solution is obtained to obtain a nimodipine concentrate; 3) Fill the concentrate into 7 mL vials (fill volume: 2 mL) and sterilize at 121°C for 15 minutes. The preparation process is carried out under both natural light and dark conditions.

[0191] The pH value, nimodipine content and related substances of the concentrate were determined according to the method in Example 11. Table 15 - Effect of light on nimodipine concentrate

[0192] N / A: Not detected

[0193] Experimental data show that the impurities in the concentrate prepared by the light-shielding and non-light-shielding processes meet the requirements, but light-shielding results in a lower content of impurity I. Therefore, the light-shielding process is more preferred.

[0194] Example 9: Screening of whether nitrogen is charged during the preparation of nimodipine concentrate

[0195] The inventors investigated the effect of nitrogen on nimodipine injection. The effects of nitrogen on the related substances of nimodipine injection were studied on batches 2022012201 in Example 10. The specific experimental results are shown in the table below.

[0196] Table 16 - Effects of nitrogen on related substances in nimodipine concentrate

[0197] Experimental data show that the total impurities and impurity I content of the concentrate of the present invention prepared with and without nitrogen filling meet the requirements, but the content of total impurities and impurity I is lower during the preparation process of nitrogen filling. Therefore, the preparation method with nitrogen filling is more preferred.

[0198] Example 10: Small-scale process verification of the composition of the present invention

[0199] The inventors prepared two batches of nimodipine injection (batch numbers 2022012201 and 2022012202), 600 vials each, for pilot-scale formulation process verification.

[0200] Prescription: Nimodipine 1.00g (1%), HS15 45.00g (45%), propylene glycol 54.00g (54%), total 100.00g.

[0201] Preparation process: 1) Heat HS15 at 60°C until completely dissolved in the bottle, invert and mix thoroughly; 2) Weigh the prescribed amount of propylene glycol into a conical flask, add the prescribed amount of HS15 and nimodipine, seal the flask, and stir magnetically in a 60°C water bath until a uniform solution is obtained to obtain the nimodipine concentrate; 3) Nitrogen is added to the resulting concentrate and filled into 7ml brown and colorless vials; 4) Stir in a 121°C sterilizer for 15 minutes. Protect from light during the preparation process.

[0202] Two batches of samples were prepared, with a theoretical batch size of 600 pieces, 560 qualified samples, and a yield of 93.3%.

[0203] Example 11: Stability study of the composition of the present invention

[0204] Study on the stability of concentrated solution:

[0205] In accordance with the guidelines for stability testing of raw materials and pharmaceutical preparations in Part IV General Chapter 9001 of the 2020 edition of the Chinese Pharmacopoeia, the concentrate prepared in Example 10 was placed at a temperature of 60°C and light (5000 Lux), and samples were taken at the end of the 5th, 10th, and 30th days to examine the corresponding indicators.

[0206] 1. Sample information: Nimodipine injection (self-made sample), batch number 2022012201 (two types, brown and transparent); original research ( Brown packaging; transparent packaging is packaged in colorless vials), batch number: BXJC7A1

[0207] 2. Stability test setting-out conditions:

[0208] Table 17 - Stability test conditions

[0209] 3. Analysis methods

[0210] (1) Properties

[0211] Inspection method: visual inspection.

[0212] (2) pH value

[0213] Dilute 1 ml of the concentrate with freshly boiled cold water at a volume ratio of 1:25 and measure its pH value; the pH value should be between 4.0 and 7.0

[0214] (3) Related substances

[0215] Detection method: HPLC method

[0216] Experimental conditions:

[0217] Chromatographic column: C18 column (model: Ultinate XB-C18, XDB-C18, 125 cm, inner diameter 4.6 mm, filler particle size 5.0 μm)

[0218] Column temperature: 40°C

[0219] Detector: UV detector (detection wavelength 235nm)

[0220] Mobile phase: methanol-tetrahydrofuran-water (20:20:60)

[0221] Flow rate: 2.0 mL / min

[0222] Injection volume: 20 μL

[0223] Run time: 40 minutes

[0224] System suitability: In the system suitability solution chromatography, the resolution between the nimodipine peak and the impurity I peak should be greater than 3.0.

[0225] Specific experimental operations:

[0226] At each specified time point, the concentrated solution was accurately weighed, dissolved in mobile phase, and quantitatively diluted to a solution containing approximately 1.6 mg per 1 mL. This served as the test solution. An appropriate amount of nimodipine reference substance was accurately weighed and diluted with mobile phase to a solution containing approximately 3.2 μg of nimodipine per 1 mL. This served as control solution A. Separately, appropriate amounts of nimodipine reference substance and impurity I reference substance were dissolved in mobile phase and diluted to a mixed solution containing approximately 1.6 μg of nimodipine and 1.6 μg of impurity I per 1 mL. This served as the system suitability solution. Determine by HPLC under the above conditions. Record the chromatogram to three times the retention time of the principal component peak. In the system suitability solution chromatogram, the resolution between the nimodipine peak and the impurity I peak should be greater than 3.0.

[0227] Accurately measure 20 μL each of the test solution and reference solution, inject them into the liquid chromatograph, and record the chromatogram. In the chromatogram of the test solution, if a chromatographic peak with the retention time consistent with that of impurity I appears, calculate the peak area by external standard method, and the content of impurity I shall not exceed 0.5% of the labeled amount of nimodipine. For other impurities, use the main peak area in the chromatogram of the reference solution A as a reference. Calculate the peak area by external standard method, and the other individual impurities shall not exceed 0.2% of the labeled amount of nimodipine. The total amount of impurities shall not exceed 1.0%.

[0228] (4) Nimodipine content

[0229] Detection method: HPLC method

[0230] Experimental conditions:

[0231] Chromatographic column: C18 column (model: Ultinate XB-C18, XDB-C18, 125 cm, inner diameter 4.6 mm, filler particle size 5.0 μm)

[0232] Column temperature: room temperature

[0233] Detector: UV detector (detection wavelength 235nm)

[0234] Mobile phase: methanol-tetrahydrofuran-water (20:20:60)

[0235] Flow rate: 2.0 mL / min

[0236] Injection volume: 20 μL

[0237] Run time: 40 minutes

[0238] System suitability: The tailing factor of the chromatographic peak of the reference solution is not greater than 2.0.

[0239] Specific experimental operations:

[0240] Accurately weigh the concentrate, dissolve it in mobile phase, and dilute it to approximately 0.2 mg of nimodipine per 1 mL. This will serve as the test solution. Accurately weigh the nimodipine reference solution, dissolve it in mobile phase, and dilute it to approximately 0.2 mg of nimodipine per 1 mL. This will serve as the reference solution. Accurately measure 20 μL of the test solution and reference solution, inject them into the liquid chromatograph, and record the chromatograms. Calculate the peak area using the external standard method.

[0241] 4. Experimental results

[0242] The experimental results show that:

[0243] Brown packaging: concentrate of the present invention and original research product After being placed under high temperature test conditions of 60℃ for 30 days, all indicators showed no significant changes and all met the requirements. There was no significant difference; when placed under the conditions of 5000 Lux (10 days) for 30 days, the content of related substances in Nimotong exceeded the acceptable limit, while the indicators of the concentrate of the present invention met the requirements.

[0244] Transparent packaging: concentrate of the present invention and original research product Under the conditions of 5000 Lux for 30 days, the properties and pH value did not change significantly, but the related substances increased significantly and the content decreased significantly. This is because nimodipine will degrade when placed under light. The content of nimodipine in the formula dropped to 3.06%, almost completely degraded.

[0245] Therefore, the stability of the concentrate of the present invention is significantly better than that of the original product.

[0246] Dilution stability test:

[0247] Investigate this product and the original research Stability of the dilution.

[0248] 1. Sample information: Nimodipine injection, batch number 2022012201

[0249] 2. Dilution stability test conditions:

[0250] Table 19 - Sampling conditions for dilution stability test

[0251] 3. Analysis methods

[0252] (1) Properties

[0253] Inspection method: visual inspection.

[0254] (2) pH value

[0255] Determine the pH of the dilution.

[0256] (3) Crystallization state

[0257] Inspection methods: visual inspection and electron microscopy.

[0258] 4. Experimental results

[0259] Table 20 - Dilution stability test results

[0260] From the experimental results in the table above, it can be seen that no matter it is diluted with 5% glucose injection or 0.9% sodium chloride, After dilution, nimodipine crystals precipitate rapidly. In clinical practice, nimodipine must be slowly dripped at a rate of 1-2 mg / h, otherwise patients cannot tolerate its side effects, resulting in a 10 mg drug drip time of at least 5 hours. The original preparation is solubilized with a high concentration of organic solvent. After dilution with glucose and sodium chloride injection, the concentration of the organic solvent decreases, resulting in drug crystallization, which increases adverse reactions and reduces efficacy. In order to solve this problem, in clinical practice, A special three-way valve infusion set (Figure 1) is required for infusion, which is inconvenient to use.

[0261] In contrast, the nimodipine concentrate of the present invention, after being diluted with 5% glucose injection or 0.9% sodium chloride injection and stored at 25°C for 48 hours, showed no significant changes in properties and pH, and no drug crystals appeared. Therefore, the nimodipine concentrate of the present invention overcomes the shortcomings of commercially available nimodipine injections, exhibits good stability after dilution, and can be infused using a conventional infusion set. BRIEF DESCRIPTION OF THE DRAWINGS

[0262] Figure 1 is a diagram of the intravenous infusion used clinically Photo of a three-way valve, where the port marked with number "1" is the "venous end" connected to the patient's vein, the port marked with number "2" is the "pump liquid end" connected to the aqueous solvent controlled by the pump, and the port marked with number "3" is the "nimodipine end" connected to the nimodipine injection The purpose of using this three-way valve is to make nimodipine injection After mixing with the aqueous solvent, the solution should be immediately infused into the patient's vein to avoid the problem of nimodipine crystallization caused by the diluent being left for a long time.

[0263] All patent and non-patent documents listed herein are incorporated by reference in their entirety, as if individually set forth in their entirety.

[0264] Although specific embodiments and examples are provided herein to illustrate the present invention, this is not intended to limit the scope of the invention. Based on this disclosure, it will be apparent to those skilled in the art that other modifications or equivalents can be readily obtained without departing from the spirit and substance of the present invention, and these modifications and equivalents are within the scope of the present invention.

Claims

1. A nimodipine composition free of phospholipids and ethanol, characterized in that: The composition comprises: (1) Nimodipine; (2) a non-phospholipid surfactant selected from polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, 15-hydroxystearate polyethylene glycol, vitamin E polyethylene glycol 1000 succinate (TPGS), polysorbate, caprylic and capric monoglycerides, and a mixture of any two or more thereof; (3) a cosolvent, which is propylene glycol, Wherein, based on the total weight of nimodipine, non-phospholipid surfactant and cosolvent, 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 cosolvent, The composition is terminally sterilized by moist heat sterilization.

2. The composition of claim 1 , wherein the non-phospholipid surfactant is selected from the group consisting of polyoxyl 35 castor oil, pure polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polyoxyl 60 hydrogenated castor oil, polyethylene glycol 15-hydroxystearate, vitamin E polyethylene glycol 1000 succinate (TPGS), polysorbate 20, polysorbate 21, polysorbate 40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80, polysorbate 81, polysorbate 85, polysorbate 120, caprylic and capric mono- and diglycerides, and mixtures of any two or more thereof.

3. The composition of claim 2, wherein the non-phospholipid surfactant is polyethylene glycol 15-hydroxystearate.

4. The composition according to claim 1 , wherein the composition further comprises a pH regulator and an antioxidant, wherein the pH regulator is preferably selected from one or more of citric acid, citrates (such as sodium citrate), maleic acid, tartaric acid, hydrochloric acid, sodium hydroxide, acetic acid, acetates (such as sodium acetate), phosphoric acid, and phosphates (such as sodium monohydrogen phosphate, sodium dihydrogen phosphate, or sodium phosphate), and the antioxidant is preferably selected from one or more of α-tocopheryl succinate, ascorbyl palmitate, butylated hydroxyanisole, and butylated hydroxytoluene.

5. The composition according to any one of claims 1 to 3, wherein the composition consists of nimodipine, a non-phospholipid surfactant, and a cosolvent.

6. The composition according to claim 5, wherein the composition consists of nimodipine, 15-hydroxystearate polyethylene glycol and propylene glycol, and based on the total weight of the composition, 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 15-hydroxystearate polyethylene glycol is 42-50% w / w, preferably 44-46% w / w; the balance is propylene glycol, The composition is terminally sterilized by moist heat sterilization.

7. The composition according to any one of claims 1 to 6, wherein the composition is prepared in the absence of light.

8. The composition according to any one of claims 1 to 7, wherein the composition is prepared by a process comprising a nitrogen filling step.

9. A method for preparing a composition according to any one of claims 1 to 5, comprising the steps of: (1) mixing nimodipine, a non-phospholipid surfactant, and a cosolvent to form a solution, and heating to dissolve the solution if necessary; (2) filling the resulting solution into a container; (3) sterilizing the filled solution with moist heat; Optionally, the method is carried out in the absence of light; Optionally, before step (2), the solution obtained in step (1) is filled with nitrogen; Preferably, the moist heat sterilization is performed at 115°C for 30 minutes or at 121°C for 15 minutes.

10. A solution obtained by diluting the composition of any one of embodiments 1 to 7 with an aqueous solvent, wherein the aqueous solvent is preferably a solvent suitable for injection, such as water for injection, 5% glucose injection, 0.9% sodium chloride injection, lactated Ringer's solution, dextran 40 solution, hydroxyethyl starch 130 / 0.4 sodium chloride injection, or hydroxyethyl starch 200 / 0.5 sodium chloride injection.

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