Nimodipine composition and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a nimodipine composition and a preparation method thereof.The nimodipine composition is an oil-phase composition and comprises nimodipine, an oil phase and a surfactants, the components and the mass ratio of the components are redesigned, the preparation method is improved, dependence on organic solvents can be completely eliminated, and the nimodipine composition is suitable for large-scale production. A clear solution composition can be obtained by adding a water phase, and the composition has good stability and is not separated out under a low-temperature storage condition, so that the concentration of the medicine is ensured. The materials are easy to obtain, the preparation process is simple and rapid, the defects of conventional means in the prior art are overcome on the whole, and a large reference basis is provided for research and further clinical application of a clinical nimodipine solvent.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of pharmaceutical preparation, in particular to a nimodipine composition and a preparation method thereof. BACKGROUND

[0002] Nimodipine is a calcium channel blocker, chemical formula is C 21 H 26 N2O7, used for blood circulation improvement in acute cerebrovascular disease recovery period, cerebral vasospasm after subarachnoid hemorrhage of various causes, and ischemic neurological disorders caused by hypertension, migraine, etc., also used as ischemic neuronal protection and treatment of vascular dementia, and has certain effect on sudden deafness.

[0003] The reference preparation specification of the marketed nimodipine injection is 50ml / 10mg, the prescription composition includes ethanol, polyethylene glycol 400, sodium citrate, anhydrous citric acid and water for injection, wherein the proportion of ethanol is 23.7% (v / v), the proportion of polyethylene glycol 400 is 17% (v / v), and the sum of the proportions of the two as organic solvents exceeds 40%. In clinical application, due to the high content of organic solvents, the incidence of phlebitis caused by injection is as high as 35%, at the same time, ethanol is easy to produce disulfiram reaction with antibiotics such as cephalosporin, and there is a large metabolic and safety risk. In addition, nimodipine is dissolved in ethanol, and the solubility in water is low, and under the temperature fluctuation of low temperature circulation, it is easy to appear the phenomenon of precipitation, and after being compatible with other infusion solutions, there is also the risk of precipitation of crystals, so that the content is reduced, resulting in uncontrollable curative effect.

[0004] To solve these problems, the prior art also provides some solutions, such as: a Chinese patent with the publication number CN117338708A and the title of A nimodipine clathrate injection and a preparation method thereof, which adopts the solubilization mode of sulfobutyl betadex, but the sulfobutyl betadex is as high as 100 times of nimodipine, and such a high dose of sulfobutyl betadex has a serious adverse effect on patients with kidney damage. For example: a Chinese patent with the publication number CN116350586B and the title of A nimodipine micelle injection and a preparation method thereof, which contains nimodipine, phospholipid, cholate, and a surface modifier, but the preparation process is relatively complex, and the nimodipine micelle solution is obtained by dissolving nimodipine, phospholipid, cholate, and a surface modifier in an organic solvent, removing the organic solvent to obtain a film, and then hydrating again. Such a preparation process has the risk of residual organic solvent, and the process amplification is difficult. In addition, a Chinese patent with the publication number CN109069651A and the title of Stable nimodipine parenteral preparation still needs to use an organic solvent to increase the solubility of nimodipine. In addition to the above problems, the present inventors have found in the research process that when the nimodipine injection solution is stored at a low temperature such as 2℃-8℃, drug crystallization occurs, which poses a risk for use in some areas, and the prescription needs to be further optimized to avoid potential precipitation risk.

[0005] Based on the above reasons, the present application designs a nimodipine composition and a preparation method thereof, which can obtain a clear and stable nimodipine solution without using any organic solvent, reduces the influence of the reaction of the organic solvent and other drugs on the human body, and effectively avoids drug precipitation under low-temperature storage conditions, thereby ensuring the stability of the drug content. SUMMARY

[0006] The purpose of the present application is to overcome the shortcomings of the prior art, provide a nimodipine composition and a preparation method thereof, which can obtain a clear and stable nimodipine solution without using any organic solvent, reduces the influence of the reaction of the organic solvent and other drugs on the human body, and effectively avoids drug precipitation under low-temperature storage conditions, thereby ensuring the stability of the drug content.

[0007] To achieve the above purpose, the present application provides a nimodipine composition, which is an oil phase composition and comprises: nimodipine, an oil phase, and a surfactant, wherein the surfactant is polyethylene glycol-15 hydroxystearate (abbreviated as HS15) or a combination of HS15 and Tween 80.

[0008] The ratio of the oil phase to nimodipine is 3-7.5:1; The oil phase is selected from soybean oil, medium-chain triglyceride (abbreviated as MCT), or a combination thereof.

[0009] The surfactant is not more than 96% in the oil phase composition.

[0010] The oil phase composition and the water phase are formulated into a clear solution, and the particle size is detected after adding water, and the particle size D90 is less than 100 nm, which indicates that the combination of the oil phase and the surfactant of the present application can self-emulsify in the water phase to form nanoemulsion or micelles, and nimodipine can be uniformly distributed in the nanoparticles to ensure the solubility and stability of the drug.

[0011] A preparation method of a nimodipine composition, comprising the following steps: S1, weighing the oil phase, the surfactant and nimodipine in corresponding proportions; S2, stirring under a water bath at 50-60 DEG C to dissolve nimodipine to obtain a clear liquid; S3, adding 5-50 ml of water under continuous stirring; S4, filtering the drug solution obtained in S3 with a 0.22 um filter membrane.

[0012] The amount of water added in S3 accounts for more than 87.07% in the composition.

[0013] Compared with the prior art, the oil phase and the specific surfactant are used as one of the components of the nimodipine composition, which can effectively dissolve the nimodipine that is not soluble in water, and the mass ratio of each component is designed, a clear solution is obtained after adding water, and the precipitation of drug crystals can be effectively avoided after low-temperature preservation, which proves that it has good stability. Compared with the prior art, the physical stability of the composition is higher, and the drug content can be ensured to be stable. In addition, the present application does not use any organic solvent, compared with the prior art, the disulfiram reaction is further avoided, and there is no need to increase the complex process of removing organic solvents, which to some extent overcomes the technical prejudice that the nimodipine is still generally dissolved by using organic solvents in the prior art. The components of the present application are simple and safe, and the preparation process does not need too many steps, the implementation difficulty is low, the cost is more reliable, and the implementation is fast and accurate, so it has good popularization value. DETAILED DESCRIPTION

[0014] Example 1 (Prescription 2): The present application provides a nimodipine composition, which comprises: nimodipine, soybean oil and HS15.

[0015] The ratio of soybean oil to nimodipine is 5.17.

[0016] The proportion of HS15 in the oil phase composition is 93.1%.

[0017] A preparation method of a nimodipine composition, comprising the following steps: S1, weigh the soybean oil, HS15 and nimodipine in the above corresponding proportions; S2, under a water bath at 50°C, magnetic stirring (100 rpm) to dissolve nimodipine to obtain a clear liquid; S3, continue to stir and add water to 50 ml; S4, filter the drug solution obtained in S3 with a filter membrane of 0.22 um.

[0018] Example 2 (Prescription 11): The present application provides a nimodipine composition, which comprises: nimodipine, soybean oil, MCT, HS15 and Tween 80.

[0019] The ratio of the combination of MCT and soybean oil to nimodipine is: 5.

[0020] The ratio of HS15 and Tween 80 in the oil phase composition is: 88.4%.

[0021] A preparation method of a nimodipine composition, comprising the following steps: S1, weigh the soybean oil, MCT, HS15, Tween 80 and nimodipine in the above corresponding proportions; S2, under a water bath at 60°C, stirring to dissolve nimodipine to obtain a clear liquid; S3, continue to stir and add water to 20 ml; S4, filter the drug solution obtained in S3 with a filter membrane of 0.22 um.

[0022] Example 3 (Prescription 6): The present application provides a nimodipine composition, which comprises: nimodipine, soybean oil, HS15 and Tween 80.

[0023] The ratio of soybean oil to nimodipine is: 3.3.

[0024] The ratio of HS15 and Tween 80 in the oil phase composition is: 92.8%.

[0025] A preparation method of a nimodipine composition, comprising the following steps: S1, weigh the soybean oil, HS15, Tween 80 and nimodipine in the above corresponding proportions; S2, under a water bath at 55°C, stirring to dissolve nimodipine to obtain a clear liquid; S3, continue to stir and add water to 50 ml; S4, filter the drug solution obtained in S3 with a filter membrane of 0.22 um.

[0026] Example 4 (Prescription 10): The present application provides a nimodipine composition, which comprises: nimodipine, MCT, HS15 and Tween 80.

[0027] The ratio of MCT to nimodipine is: 5.

[0028] The ratio of HS15 and Tween 80 in the oil phase composition is: 88.4%.

[0029] A preparation method of a nimodipine composition comprises the following steps: S1, taking the above corresponding mass percentage of MCT, HS15, Tween 80 and nimodipine; S2, stirring under a water bath at 55℃ to dissolve nimodipine to obtain a clear liquid; S3, adding 20ml of water under continuous stirring; S4, filtering the drug solution obtained in S3 with a filter membrane of 0.22um.

[0030] Example 5 (Prescription 3): The present application provides a nimodipine composition, which comprises: nimodipine, soybean oil, HS15 and Tween 80.

[0031] The ratio of soybean oil to nimodipine is: 7.5.

[0032] The ratio of HS15 and Tween 80 in the oil phase composition is: 88.1%.

[0033] A preparation method of a nimodipine composition comprises the following steps: S1, taking the above corresponding mass percentage of MCT, HS15, Tween 80 and nimodipine; S2, stirring under a water bath at 55℃ to dissolve nimodipine to obtain a clear liquid; S3, adding 20ml of water under continuous stirring; S4, filtering the drug solution obtained in S3 with a filter membrane of 0.22um.

[0034] Example 6 (Prescription 5): The present application provides a nimodipine composition, which comprises: nimodipine, soybean oil, HS15 and Tween 80.

[0035] The ratio of soybean oil to nimodipine is: 4.76.

[0036] The ratio of HS15 and Tween 80 in the oil phase composition is: 91.1%.

[0037] A preparation method of a nimodipine composition comprises the following steps: S1, taking the above corresponding mass percentage of MCT, HS15, Tween 80 and nimodipine; S2, stirring under a water bath at 55℃ to dissolve nimodipine to obtain a clear liquid; S3, add 5ml of water under continuous stirring; S4, filter the liquid obtained in S3 with a 0.22um filter membrane.

[0038] Water test of nimodipine composition prepared by different proportions of the composition of the present application: First, each component is obtained according to different prescription compositions, and after adding water, each prescription shows the following table 1: Table 1 Prescription table and comparison table

[0039] From table 1, the composition of the present application can be seen. The drug is dissolved by heating the oil phase and surfactant. After adding water, the amount of oil phase has a significant effect on the clarity of the solution. It can be seen that the oil phase ratio of prescription 1 is 96.2%, which makes the amount of soybean oil low, and the drug cannot be completely dissolved. The high oil phase (soybean oil) of prescription 4 and the low proportion of surfactant lead to obvious turbidity after the composition is added with water. The type and combination of surfactant affect the drug dissolution performance. The drug precipitates after adding water in prescription 1 (only a large proportion of HS15 is used), which shows that the amount of oil phase and surfactant will affect the drug solution dissolution. When the oil phase and drug ratio is low (for example, prescription 8, the ratio is 2.5), the drug precipitates after 10 days of storage at 2℃-8℃. When the oil phase and drug ratio is between 3 and 7.5, the drug does not precipitate after 10 days of storage at 2℃-8℃, which shows that the stability is better. Therefore, in the above precipitation stability test, a use amount ratio range is obtained, in which the interaction of each component can ensure that the composition remains stable after adding water.

[0040] Comparative example: investigate other surfactants, according to prescription 10, investigate different surfactants, prepare samples and investigate, the results are shown in table 2.

[0041] Table 2 comparison table of different surfactant combinations

[0042] From the comparison of the results of table 2, it can be seen that other common surfactant combinations cannot guarantee the complete dissolution of the drug or the low temperature storage stability after adding water. Therefore, the surfactant defined in the present application is HS15 or its combination with Tween 80. The addition of other surfactants, even in combination with HS15 or Tween 80, will also present the problems of opaque liquid preparation and crystal precipitation during low temperature storage.

[0043] It should be emphasized that the present application aims to design a composition of nimodipine, which is intended to solve the shortcomings in the prior art, and the composition is not a solvent that can be directly applied to clinical treatment or clinical trial, so the pharmacological experiment and side effect test of the composition are not within the scope of verification and description required by the present application.

[0044] The above are only preferred embodiments of the present application, which are used to help understand the method and its core idea of the present application, and the protection scope of the present application is not limited to the above-mentioned embodiments only, and any technical solution within the idea of the present application belongs to the protection scope of the present application. It should be noted that, for ordinary skilled persons in the art, some improvements and refinements without departing from the principles of the present application are also considered as the protection scope of the present application.

[0045] The present application solves the problems of phlebitis and crystallization caused by the dependence of nimodipine solution on organic solvents in the prior art, and the shortcomings of complex preparation process, high cost, or high side effects of other components in other solutions. Through the redesign of each component and its mass ratio, the dependence on organic solvents can be completely eliminated, a clear composition is obtained, and good precipitation stability is obtained in low-temperature cycle conditions and water test, which ensures the concentration of the drug. The material of the present application is easy to obtain, the preparation process is simple and fast, and the shortcomings of the conventional means in the prior art are solved as a whole, which provides a great reference for the research and further clinical application of nimodipine solvent in clinical.

Claims

1. A nimodipine composition, characterized in that: The composition is an oil phase composition, comprising nimodipine, an oil phase and a surfactant, wherein the surfactant is polyethylene glycol-15 hydroxystearate or a combination of polyethylene glycol-15 hydroxystearate and Tween 80.

2. The nimodipine composition according to claim 1, characterized in that The surfactant accounts for no more than 96% of the oil phase composition.

3. The nimodipine composition according to claim 1, wherein The ratio of the oil phase to nimodipine is 3-7.5:

1.

4. The nimodipine composition according to claim 1, characterized in that The oil phase is selected from soybean oil, medium chain triglycerides or a combination thereof.

5. The nimodipine composition according to claim 1, characterized in that The oil phase composition is formulated with the water phase to form a clear solution.

6. A method for preparing a nimodipine composition, comprising the following steps: S1, weighing the oil phase, the surfactant and the nimodipine in corresponding proportions; S2, stirring in a water bath at 50° C. to 60° C. to dissolve the nimodipine to obtain a clear liquid; S3, add 5ml~50ml of water while continuing to stir; S4, filtering the liquid medicine obtained in S3 through a 0.22 μm filter membrane.

7. The nimodipine composition according to claim 6, characterized in that The amount of water added in S3 accounts for more than 87.07% of the total amount of the composition.

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