CN113509434A - Nimodipine oral solution, preparation method and application thereof - Google Patents

Nimodipine oral solution, preparation method and application thereof Download PDF

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CN113509434A
CN113509434A CN202110455753.1A CN202110455753A CN113509434A CN 113509434 A CN113509434 A CN 113509434A CN 202110455753 A CN202110455753 A CN 202110455753A CN 113509434 A CN113509434 A CN 113509434A
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nimodipine
solution
buffer
disodium hydrogen
concentration
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朱旭伟
陈铁
黄奕睿
陈慧
傅苗青
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Guangdong Jincheng Jinsu Pharmacy Co ltd
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Guangdong Jincheng Jinsu Pharmacy Co ltd
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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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • A61P25/06—Antimigraine agents
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • 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

Abstract

The invention discloses a nimodipine oral solution, a preparation method and application thereof. The nimodipine solution comprises a bacteriostatic agent and the following components: 0.1-6 mg/mL of nimodipine, 200-500 mg/mL of solubilizer and 400-900 mg/mL of solvent; the pH value of the nimodipine solution is 6-9. The nimodipine solution can be used for oral administration or administration through a nasogastric tube or a gastric tube under the condition of ensuring the stability, so that the universality of patients is improved; the stability is higher, and is obviously better than that of a reference preparation particularly for inhibiting the increase of the impurity A, E, F, G; the antibacterial activity is good, and the detected test bacteria in 28 days is not more than 0.5 lg.

Description

Nimodipine oral solution, preparation method and application thereof
Technical Field
The invention relates to a nimodipine oral solution, a preparation method and application thereof.
Background
Subarachnoid hemorrhage is a very serious common disease, mainly caused by rupture of blood vessels on the brain fundus or brain surface and inflow of blood into subarachnoid cavity, and complications mainly comprise cerebral vasospasm, hydrocephalus, re-hemorrhage and the like. Migraine is the most common type of primary headache in clinic, and is clinically mainly manifested by paroxysmal moderate and severe headache and pulsatile headache, which mostly occur in children and adolescence, and the middle and young age reaches the peak of onset.
Nimodipine belongs to 1, 4-dihydropyridine calcium channel blocker, and can easily pass through blood brain barrier to act on cerebral vessels and nerve cells; the traditional Chinese medicine composition is mainly used for preventing and treating cerebral vasospasm after subarachnoid hemorrhage, ischemic nerve injury caused by the cerebral vasospasm, senile brain function injury, migraine, sudden deafness, mild and moderate hypertension and the like clinically.
Nimodipine currently exists in solid forms such as tablets, capsules, etc., but tablet and capsule administration is difficult for patients who cannot swallow.
CN109069651A discloses a stable nimodipine parenteral preparation, which is an injection, although the stability can reach 9 months, it does not relate to its bacteriostatic effect; in addition, the nimodipine in the preparation is contained in the micelle or the inclusion compound, if the preparation is taken orally, the micelle or the compound can be damaged, and the nimodipine has low solubility, cannot be absorbed after the structure is damaged, and is not suitable for being taken orally.
Based on the above, there is a need for a nimodipine preparation having good stability and bacteriostatic effect and capable of being orally administered.
Disclosure of Invention
The invention aims to solve the technical problem of providing a nimodipine solution, a preparation method and application thereof, wherein the nimodipine solution can promote a bacteriostatic agent to exert a bacteriostatic effect, has better stability, can be used for oral administration or administration through a nasogastric tube or a gastric tube, and has high universality for patients.
The invention solves the technical problem by the following scheme:
the invention provides a nimodipine solution, which comprises a bacteriostatic agent and the following components:
0.1-6 mg/mL of nimodipine, 200-500 mg/mL of solubilizer and 400-900 mg/mL of solvent;
the pH value of the nimodipine solution is 6-9.
In the present invention, "mg/mL" refers to the mass of nimodipine solution per milliliter.
In the invention, the density of the nimodipine solution is generally kept to be 1.04-1.29 g/mL.
In the present invention, the nimodipine may be nimodipine commercially available in the art.
In the present invention, the nimodipine solution preferably has a viscosity of 30 to 150 mPas at 25 ℃, for example, 34.56 mPas, 43.79 mPas, 63.99 mPas, 92.57 mPas, 132.90 mPas, 73.52 mPas, 79.33 mPas, 81.53 mPas or 88.21 mPas, more preferably 80 to 100 mPas. When the viscosity of the solution is controlled within this range, the stability of the solution is higher.
In the invention, the content of the nimodipine is preferably 3-6 mg/mL.
In the present invention, the solubilizer may be a solubilizer conventional in the art, such as one or more of glycerol, anhydrous ethanol, and glycerol formal, preferably glycerol and/or anhydrous ethanol, more preferably glycerol.
In the present invention, the content of the solubilizer is preferably 310-355 mg/mL, such as 315.9mg/mL, 344.8mg/mL, 348mg/mL or 353 mg/mL.
In the present invention, the bacteriostatic agent may be a bacteriostatic agent conventional in the art, such as one or more of parabens, soluble salts of parabens, benzoic acid, soluble salts of benzoic acid, sorbic acid, soluble salts of sorbic acid, and benzyl alcohol; preferably parabens, more preferably methylparaben. The soluble salt of benzoic acid is preferably sodium benzoate. Methyl paraben is also commonly referred to as methyl paraben or methylparaben as is conventional in the art.
In the present invention, the content of the bacteriostatic agent is preferably 0.2-2 mg/mL, such as 1mg/mL or 1.6 mg/mL. In the invention, the nimodipine solution can still keep good bacteriostatic effect under the condition of a lower content of bacteriostatic agent.
In the present invention, the solvent may be a solvent conventional in the art, such as propylene glycol and/or polyethylene glycol 400.
In the present invention, the content of the solvent is preferably 450 to 720mg/mL, for example, 480mg/mL, 540mg/mL, 600mg/mL, 713mg/mL, 473mg/mL or 660 mg/mL.
In the present invention, the pH is preferably 6.5 to 9, for example, the pH is 6.8, 7, 7.2, 7.7, 8, 8.4 or 8.6.
In the present invention, the pH of the nimodipine solution may be adjusted by using a pH buffer, i.e. the nimodipine solution comprises a pH buffer. The pH buffering agent may be selected as is conventional in the art, for example, any one of a solution of citric acid and sodium citrate, a solution of sodium dihydrogen phosphate and disodium hydrogen phosphate, and a solution of acetic acid and sodium acetate, preferably a solution of sodium dihydrogen phosphate and disodium hydrogen phosphate. Wherein, the 'any group' is conventionally understood as a group of 'citric acid and sodium citrate', a group of 'sodium dihydrogen phosphate and disodium hydrogen phosphate', and a group of 'acetic acid and sodium acetate'. If a pH buffer is employed, the pH buffer may be present in the form of an aqueous solution. The disodium hydrogen phosphate is generally anhydrous disodium hydrogen phosphate.
When the pH buffering agent is a solution of sodium dihydrogen phosphate and disodium hydrogen phosphate, the mass ratio of the sodium dihydrogen phosphate to the disodium hydrogen phosphate can be (4-6): 1, for example, 5: 1. In the present invention, when the nimodipine solution further comprises a pH buffer, the mass concentration of the pH buffer in the nimodipine solution is preferably 180-390 mg/mL, such as 368.1mg/mL, 308.1mg/mL, 248.1mg/mL, 188.1mg/mL, 261.1mg/mL, 385.1mg/mL, 218.1mg/mL, 213.1mg/mL, 209.1mg/mL, 208.5mg/mL or 208.1 mg/mL.
In a preferred embodiment of the present invention, the nimodipine solution comprises the following components: 3mg/mL of nimodipine, 2mg/mL of methyl hydroxybenzoate, 600mg/mL of polyethylene glycol 400, 345mg/mL of glycerol, 3mg/mL of absolute ethyl alcohol, 210-215 mg/mL of pH buffering agent, 80-100 mPa & s of viscosity of nimodipine solution and 6-8 of pH value.
In a preferred embodiment, the nimodipine solution comprises the following components: nimodipine 0.1mg/mL, methyl hydroxybenzoate 2mg/mL, polyethylene glycol 400 480mg/mL, glycerol 312.9mg/mL, absolute ethanol 3mg/mL, pH buffer 368.1mg/mL, nimodipine solution viscosity 34.56mPa · s, pH 6, wherein the pH buffer is a solution of sodium dihydrogen phosphate and anhydrous disodium hydrogen phosphate: the concentration of sodium dihydrogen phosphate was 0.105mol/L, and the concentration of disodium hydrogen phosphate was 0.0176 mol/L.
In a preferred embodiment, the nimodipine solution comprises the following components: nimodipine 6mg/mL, methylparaben 2mg/mL, polyethylene glycol 400 540mg/mL, glycerol 310mg/mL, pH buffer 308.1mg/mL, nimodipine solution viscosity 43.79mPa · s, pH 7, wherein the pH buffer is a solution of sodium dihydrogen phosphate and anhydrous disodium hydrogen phosphate: the concentration of sodium dihydrogen phosphate was 0.105mol/L, and the concentration of disodium hydrogen phosphate was 0.0176 mol/L.
In a preferred embodiment, the nimodipine solution comprises the following components: nimodipine 3mg/mL, methylparaben 2mg/mL, polyethylene glycol 400 713mg/mL, glycerol 197mg/mL, absolute ethanol 3mg/mL, pH buffer 248.1mg/mL, nimodipine solution viscosity 63.99mPa · s, pH 8, wherein the pH buffer is a solution of sodium dihydrogen phosphate and anhydrous disodium hydrogen phosphate: the concentration of sodium dihydrogen phosphate was 0.105mol/L, and the concentration of disodium hydrogen phosphate was 0.0176 mol/L.
In a preferred embodiment, the nimodipine solution comprises the following components: nimodipine 3mg/mL, methylparaben 2mg/mL, polyethylene glycol 400 473mg/mL, glycerol 497mg/mL, absolute ethanol 3mg/mL, pH buffer 188.1mg/mL, nimodipine solution viscosity 92.57mPa · s, pH 9, wherein the pH buffer is a solution of sodium dihydrogen phosphate and anhydrous disodium hydrogen phosphate: the concentration of sodium dihydrogen phosphate was 0.105mol/L, and the concentration of disodium hydrogen phosphate was 0.0176 mol/L.
In a preferred embodiment, the nimodipine solution comprises the following components: nimodipine 3mg/mL, methylparaben 2mg/mL, polyethylene glycol 400mg/mL, glycerol 497mg/mL, absolute ethanol 3mg/mL, pH buffer 261.1mg/mL, nimodipine solution viscosity 132.9mPa · s, pH 6.5, wherein the pH buffer is a solution of sodium dihydrogen phosphate and anhydrous disodium hydrogen phosphate: the concentration of sodium dihydrogen phosphate was 0.105mol/L, and the concentration of disodium hydrogen phosphate was 0.0176 mol/L.
In a preferred embodiment, the nimodipine solution comprises the following components: nimodipine 3mg/mL, methylparaben 2mg/mL, polyethylene glycol 400 600mg/mL, glycerol 335mg/mL, absolute ethanol 3mg/mL, pH buffer 385.1mg/mL, nimodipine solution viscosity 73.52mPa · s, pH 7.2, wherein the pH buffer is a solution of sodium dihydrogen phosphate and anhydrous disodium hydrogen phosphate: the concentration of sodium dihydrogen phosphate was 0.105mol/L, and the concentration of disodium hydrogen phosphate was 0.0176 mol/L.
In a preferred embodiment, the nimodipine solution comprises the following components: nimodipine 3mg/mL, methylparaben 0.2mg/mL, polyethylene glycol 400 600mg/mL, glycerol 340mg/mL, absolute ethanol 4.8mg/mL, pH buffer 218.1mg/mL, nimodipine solution viscosity 79.33mPa · s, pH 8.4, wherein the pH buffer is a solution of sodium dihydrogen phosphate and anhydrous disodium hydrogen phosphate: the concentration of sodium dihydrogen phosphate was 0.105mol/L, and the concentration of disodium hydrogen phosphate was 0.0176 mol/L.
In a preferred embodiment, the nimodipine solution comprises the following components: nimodipine 3mg/mL, methylparaben 2mg/mL, polyethylene glycol 400 600mg/mL, glycerol 345mg/mL, absolute ethanol 3mg/mL, pH buffer 213.1mg/mL, nimodipine solution viscosity 81.53mPa s, pH 8, wherein the pH buffer is a solution of sodium dihydrogen phosphate and anhydrous disodium hydrogen phosphate: the concentration of sodium dihydrogen phosphate was 0.105mol/L, and the concentration of disodium hydrogen phosphate was 0.0176 mol/L.
In a preferred embodiment, the nimodipine solution comprises the following components: nimodipine 3mg/mL, methylparaben 2mg/mL, polyethylene glycol 400 600mg/mL, glycerol 350mg/mL, absolute ethanol 3mg/mL, pH buffer 208.1mg/mL, nimodipine solution viscosity 88.21mPa · s, pH 7.7, wherein the pH buffer is a solution of sodium dihydrogen phosphate and anhydrous disodium hydrogen phosphate: the concentration of sodium dihydrogen phosphate was 0.105mol/L, and the concentration of disodium hydrogen phosphate was 0.0176 mol/L.
In a preferred embodiment, the nimodipine solution comprises the following components: 3mg/mL of nimodipine, 1mg/mL of methylparaben, 600mg/mL of polyethylene glycol 400, 350mg/mL of glycerol, 3mg/mL of absolute ethyl alcohol, 209.1mg/mL of pH buffering agent, 30-150 mPa & s of viscosity of nimodipine solution and 6.8 of pH value.
In a preferred embodiment, the nimodipine solution comprises the following components: 3mg/mL of nimodipine, 1.6mg/mL of methylparaben, 600mg/mL of polyethylene glycol 400, 350mg/mL of glycerol, 3mg/mL of absolute ethyl alcohol, 208.5mg/mL of pH buffering agent, 30-150 mPa & s of viscosity of nimodipine solution and 8.6 of pH value.
The invention also provides a preparation method of the nimodipine solution, which comprises the following steps: mixing the nimodipine, the solubilizer, the bacteriostatic agent and the solvent until the solution is clear; the pH value of the nimodipine solution is 6-9.
The nimodipine solution is preferably prepared by a method in which a pH buffer is used to adjust the pH of the solution, the method comprising: mixing the pH buffering agent with a mixed solution of the nimodipine, the solubilizer, the bacteriostatic agent and the solvent until the solution is clear; the pH value of the nimodipine solution is 6-9.
In the present invention, preferably, the preparation steps of the mixed solution of nimodipine, the solubilizer, the bacteriostatic agent and the solvent are as follows: firstly, mixing a part of the solubilizer with the bacteriostatic agent to obtain a first mixed solution; and mixing the residual solubilizer with the solvent to obtain a second mixed solution, and mixing the first mixed solution, the second mixed solution and the nimodipine.
Wherein the mass ratio of "a part of the solubilizer" to "the remaining solubilizer" is preferably 1 (100-120). The "a portion of the solubilizing agent" and "the remaining solubilizing agent" may be different solubilizing agents suitable for use in the present invention.
In the present invention, the mixing method and conditions may be any method and conditions that are conventional in the art, and may be used for the purpose of sufficiently mixing the objects to be mixed, for example, mechanical stirring.
The invention also provides application of the nimodipine solution in preparing medicaments for preventing and/or treating ischemic cerebrovascular diseases, migraine, cerebral vasospasm caused by mild subarachnoid hemorrhage, sudden deafness and mild and moderate hypertension.
On the basis of the common knowledge in the field, the above preferred conditions can be combined randomly to obtain the preferred embodiments of the invention.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows:
1) the nimodipine solution provided by the invention can be used for oral administration or administration through a nasogastric tube or a gastric tube under the condition of ensuring the stability, so that the universality of patients is improved.
2) The nimodipine solution provided by the invention has higher stability, and is obviously superior to a reference preparation particularly for inhibiting the increase of the impurity A, E, F, G.
3) The nimodipine solution provided by the invention has good antibacterial activity, and the detected test bacteria in 28 days is not more than 0.5 lg.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
TABLE 1 concentrations of the components of examples 1-11
Figure BDA0003040461660000071
(1) Nimodipine solution is prepared according to the mass concentration of each component in the table 1 and the required preparation volume. Firstly, weighing absolute ethyl alcohol and methyl hydroxybenzoate, and mechanically stirring and mixing to obtain a first mixed solution;
(2) weighing polyethylene glycol 400 and glycerol, mechanically stirring and mixing for 2h, and clarifying to obtain a second mixed solution;
(3) mixing the first mixed solution obtained in the step (1), the second mixed solution obtained in the step (2) and nimodipine;
(4) weighing sodium dihydrogen phosphate and anhydrous disodium hydrogen phosphate according to the mass ratio of 5:1, adding water to prepare a pH buffering agent (sodium dihydrogen phosphate: 0.105 mol/L; anhydrous disodium hydrogen phosphate: 0.0176mol/L), weighing according to the dosage in the table 1, and mechanically stirring and mixing with the mixed solution in the step (3) for 10 minutes until the solution is clear.
Effects of the embodiment
(I) detection of bacteriostatic Properties
The bacteriostatic efficacy of each of examples 8, 10 and 11 was measured according to the bacteriostatic efficacy test method of "chinese pharmacopoeia" 2020 edition-rules of four parts <1121>, and the following test results of test bacteria at 14 days were obtained with respect to the test bacteria in the solution immediately after preparation, and the results are shown in table 2:
table 2: result of testing bacteriostatic efficacy
Figure BDA0003040461660000081
The increase of the NI is not increased, namely the increase of the test bacteria does not exceed 0.5lg for the last test time.
The result of the bacteriostatic efficacy test shows that: in examples 10 and 11, although the content of the antibacterial agent is reduced, the antibacterial effect same as that of the formulation in example 8 can be achieved by matching with other components, and the requirement of guaranteeing the microbial limit of oral solution dosage form products is met.
(II) stability detection
HPLC spectra of impurity A, impurity B, impurity C, impurity E, impurity F and impurity G (methanol-acetonitrile-water (35: 38: 27) and octadecylsilane chemically bonded silica detection wavelength 235nm for a U3000 high performance liquid chromatograph mobile phase and a stationary phase adopting Sammerfei, respectively, column temperature 30 ℃, flow rate 1.0mL per minute) involved in the following stability detection process are shown in FIG. 1, and retention time of characteristic peaks thereof is shown in Table 3.
TABLE 3
Peak name Retention time (min) Peak area (mAU min) Relative area (%)
Hydroxybenzene methyl ester (QBJZ) 3.867 112.47128 23.59
Impurity E 5.133 1.81313 0.38
Impurity F 5.353 1.61290 0.34
Impurity C 6.677 0.85526 0.18
Nimodipine (NMDP) 10.373 356.86535 74.85
Impurity A 11.727 0.97769 0.21
Impurity B 17.940 0.98933 0.21
Impurity G 32.807 1.21710 0.26
1. Stability influencing factor investigation
The effects of each influencing factor were examined on the reference preparation (reagent prepared from nimodipine original drug, company name: Arbor Pharmaceuticals, trade name: nyxalze, concentration: 3mg/mL) at 40 ℃, 60 ℃, under the conditions of light irradiation and freeze-thawing, and the Relative Retention Time (RRT) in tables 4 and 5 is the ratio of the retention time of the corresponding impurity to the retention time of nimodipine in table 3.
TABLE 4
Figure BDA0003040461660000091
Figure BDA0003040461660000101
TABLE 5
Figure BDA0003040461660000102
Figure BDA0003040461660000111
Note: in tables 4 and 5 above, NA, not detected; ND, not detected; "%" refers to the mass percentage of the corresponding substance relative to nimodipine; when the detection is carried out for 0 day, the relative density of the nimodipine solution is 1.163; the labeled amount refers to the content of the main drug specified in the preparation of the dosage unit dose.
As can be seen from tables 4 and 5 above: the nimodipine solution and the reference preparation in example 8 have almost no change in properties, contents of methylparaben and pH value under the conditions of illumination and freeze-thaw test, and the contents of nimodipine also meet the standard; wherein the nimodipine solution of example 8 has an increase in the content of impurity A, E, F, G that is less than the corresponding impurity content of the reference formulation under both light and freeze-thaw conditions.
For the nimodipine solution of example 8, the contents of the impurities A, B, C, E, F and G are increased under the test conditions of illumination and freeze-thaw, but the contents both meet the standard. Impurity E increased from 0.016% to 0.574% beyond the declared standard, and continued to increase to 0.69% at 30 days, looking for 10 days at 60 ℃; when the impurity F is examined for 30 days at 60 ℃, the content of the impurity F is increased from 0.009% to 1.35%, and the impurity F exceeds the declared standard; impurity a was investigated at 60 ℃ for 10 days, increasing from 0.093% to 0.692%, beyond the declared standard, and continuing to increase to 1.326% at 30 days; the impurity G is inspected at 60 ℃ for 30 days, the content of the impurity G is increased from zero to 0.89 percent, and the impurity G exceeds the declared standard; the impurity B and the impurity C are examined for 30 days at the temperature of 60 ℃, and the impurity content always meets the declaration standard.
For the reference formulation, impurity E increased significantly from 0.061% to 1.541% and continued to 2.158% at 30 days, for 10 days at 60 ℃, not only exceeding the declared standard, but also far exceeding the nimodipine solution of the present application; impurity F, when examined at 60 ℃ for 10 days, had increased from 0.031% to 0.643%, exceeded the declared standard, and continued to increase to 2.158% at 30 days; impurity a was investigated at 60 ℃ for 10 days, increasing from 0.298% to 1.368%, well beyond the declared standard, and continuing to increase to 2.426% at 30 days; when the impurity G is examined at 60 ℃ for 10 days, the content of the impurity G is rapidly increased to 1.205% from 0.123%, and the content of the impurity G is continuously increased to 2.143% in 30 days, which is far beyond the declaration standard; the impurity B and the impurity C are examined for 30 days at the temperature of 60 ℃, and the impurity content always meets the declaration standard.
From the above, the nimodipine solution of the present application is particularly excellent in the inhibition of the impurities A, E, F and G while ensuring the inhibition of the impurities B and C.
In addition, other unknown single impurities in the example 8 basically meet the declaration standard, and the total impurities are only 2.42 percent when the mixture is examined at 60 ℃ for 10 days and are 4.56 percent when the mixture is examined at 30 days; however, several unknown individual impurities in the reference preparation were out of the reported standard at 60 ℃ for 10 days, with the total impurity increasing to 5.23% at 10 days and up to 10.23% at 30 days.
2. Accelerated stability test
The Relative Retention Times (RRT) in tables 6 and 7 are the ratio of the retention time of the corresponding impurities to the retention time of nimodipine in table 3.
3 batches of the sample prepared in example 8 of the present application (specification: 360mg/120mL, that is, nimodipine concentration is 3 mg/mL; lot Nos. 200101, 200102 and 200103 are all nimodipine solutions of example 8, lot No. 490L/lot) and 1 batch of the reference preparation (specification: 60mg/20mL, lot No. 357607) were taken, and tested for properties, pH values, related substances, methylparaben, contents, microbial limits and package compatibility under the test conditions of "30 ℃. + -. 2 ℃ and 35% RH. + -. 5% RH" for 3 months and 6 months, respectively, using a commercially available package (specification: 60mg/20mL and carton), with the test results shown in Table 6.
After 6 months of investigation, the nimodipine solution and the reference preparation have no obvious changes in properties, pH value, contents of methylparaben and nimodipine, microbial limit and package material compatibility, and meet the standard.
For both impurity A, E, F, G, B and C, the nimodipine solutions of the present application showed some increase in impurity levels, but at 6 months both met the declared standards, while the reference formulation exceeded the declared standards for impurity A at 3 months. In addition, the level of impurity A, E, F, G in the nimodipine solution of the present application has been lower than the corresponding impurity level in the reference formulation. The quality of the upright and inverted samples has no obvious difference.
TABLE 6
Figure BDA0003040461660000131
Figure BDA0003040461660000141
Note: in the table above, NA, not detected; ND, not detected; "%" refers to the mass percentage of the corresponding substance relative to nimodipine; when the detection is carried out for 0 day, the relative density of the nimodipine solution is 1.163; the labeled amount refers to the content of the main drug specified in the preparation of the dosage unit dose.
3 batches of the sample prepared in example 8 of the present application (specification: 360mg/120mL, i.e., nimodipine concentration of 3 mg/mL; lot Nos. 200101, 200102 and 200103 are all nimodipine solutions of example 8, lot No. 490L/lot) and 1 batch of the reference formulation (specification: 60mg/20mL, lot No. 357607) were taken, and tested for properties, pH values, related substances, methylparaben, contents, microbial limits and package compatibility under the test conditions of "40 ℃. + -. 2 ℃ and RH ≦ 25% for 6 months using a commercially available package (specification: 60mg/20mL and carton), with the test results shown in Table 7.
After 6 months of investigation, the nimodipine solution and the reference preparation have no obvious changes in properties, pH value, contents of methylparaben and nimodipine, microbial limit and package material compatibility, and meet the standard.
For impurities B and C, after 6 months of investigation, both impurities in the nimodipine solution and the reference formulation of the present application met the declared standards; for impurity E, impurity E in the present application meets the declared standard at 6 months, but the reference formulation has reached 0.611% at 3 months, exceeding the declared standard; for impurity F, at 3 months, the impurity F content in this application was still lower than the reference formulation; for the impurity A, the impurity A in the preparation is overproof in 3 months, but the content of the reference preparation is far higher than that of the reference preparation; as for impurity G, impurity G in the present application meets the declared standard, but impurity G in the reference formulation is much higher than 0.5%; the reference formulation at 3 months was also far out of tolerance for total impurities. The quality of the upright and inverted samples has no obvious difference.
TABLE 7
Figure BDA0003040461660000151
Figure BDA0003040461660000161
Note: in table 7 above, NA, not detected; ND, not detected; "%" refers to the mass percentage of the corresponding substance relative to nimodipine; when the detection is carried out for 0 day, the relative density of the nimodipine solution is 1.163; the labeled amount refers to the content of the main drug specified in the preparation of the dosage unit dose.
3. Long term stability test
The Relative Retention Time (RRT) in table 8 is the ratio of the retention time of the corresponding impurity to the retention time of nimodipine in table 3.
3 batches of the sample prepared in example 8 of the present application (specification: 360mg/120mL, that is, nimodipine concentration is 3 mg/mL; batch Nos. 200101, 200102 and 200103 are all nimodipine solutions of example 8, batch No. 490L/batch) and 1 batch of the reference preparation (specification: 60mg/20mL, batch No. 357607) were taken, and tested for properties, pH values, related substances, methylparaben and contents, respectively, using a commercially available package (high density polyethylene bottle and then placed in a carton) under test conditions of "25 ℃ plus or minus 2 ℃ and 40% RH plus or minus 5% RH" for 6 months, and the test results are shown in Table 8.
After 6 months of investigation, the nimodipine solution has no obvious change in properties, pH value, methylparaben and nimodipine content, and meets the standard.
For impurities A, E, F, G, B and C, after 6 months of investigation, these impurities in the nimodipine solution of the present application met the declared standards; especially A, E, F, G, were also present in lower amounts than the reference formulation when initially formulated. Even for impurities with relative retention times of 1.42-1.43, the nimodipine solutions of the present application were all lower in content than the reference formulation when initially formulated.
TABLE 8
Figure BDA0003040461660000171
Figure BDA0003040461660000181
Note: NA, not detected; ND, not detected; "%" refers to the mass percentage of the corresponding substance relative to nimodipine; when the detection is carried out for 0 day, the relative density of the nimodipine solution is 1.163; the labeled amount refers to the content of the main drug specified in the preparation of the dosage unit dose.

Claims (10)

1. The nimodipine solution is characterized by comprising a bacteriostatic agent and the following components: 0.1-6 mg/mL of nimodipine, 200-500 mg/mL of solubilizer and 400-900 mg/mL of solvent;
the pH value of the nimodipine solution is 6-9.
2. The nimodipine solution according to claim 1, wherein the viscosity of the nimodipine solution at 25 ℃ is 30 to 150 mPa-s, such as 34.56 mPa-s, 43.79 mPa-s, 63.99 mPa-s, 92.57 mPa-s, 132.90 mPa-s, 73.52 mPa-s, 79.33 mPa-s, 81.53 mPa-s or 88.21 mPa-s, preferably 80 to 100 mPa-s;
and/or the content of the nimodipine is 3-6 mg/mL;
and/or the density of the nimodipine solution is 1.04-1.29 g/mL;
and/or the solubilizer is one or more of glycerol, absolute ethyl alcohol and glycerol formal, preferably glycerol and/or absolute ethyl alcohol;
and/or the content of the solubilizer is 310-355 mg/mL, such as 315.9mg/mL, 344.8mg/mL, 348mg/mL or 353 mg/mL.
3. The nimodipine solution according to claim 1, wherein the bacteriostatic agent is one or more of parabens, soluble salts of parabens, benzoic acid, soluble salts of benzoic acid, sorbic acid, soluble salts of sorbic acid, and benzyl alcohol;
and/or the content of the bacteriostatic agent is 0.2-2 mg/mL, such as 1mg/mL or 1.6 mg/mL;
and/or the solvent is propylene glycol and/or polyethylene glycol 400;
and/or the solvent content is 450-720 mg/mL, such as 480mg/mL, 540mg/mL, 600mg/mL, 713mg/mL, 473mg/mL or 660 mg/mL.
4. The nimodipine solution according to claim 1 or 3, wherein when the bacteriostatic agent is a paraben, the paraben is methyl paraben;
and/or when the bacteriostatic agent is soluble salt of benzoic acid, the soluble salt of benzoic acid is sodium benzoate;
and/or the pH is 6.5 to 9, for example pH 6.8, 7, 7.2, 7.7, 8, 8.4 or 8.6.
5. The nimodipine solution according to claim 1, wherein when the nimodipine solution further comprises a pH buffer, the pH buffer is any one of a citric acid and sodium citrate solution, a sodium dihydrogen phosphate and disodium hydrogen phosphate solution, and an acetic acid and sodium acetate solution; when the pH buffering agent is a solution of sodium dihydrogen phosphate and disodium hydrogen phosphate, the mass ratio of the sodium dihydrogen phosphate to the disodium hydrogen phosphate is preferably (4-6): 1, for example 5: 1;
and/or, when the nimodipine solution further comprises a pH buffer, the mass concentration of the pH buffer in the nimodipine solution is 180-390 mg/mL, such as 368.1mg/mL, 308.1mg/mL, 248.1mg/mL, 188.1mg/mL, 261.1mg/mL, 385.1mg/mL, 218.1mg/mL, 213.1mg/mL, 209.1mg/mL, 208.5mg/mL or 208.1 mg/mL;
and/or, when the nimodipine solution further comprises a pH buffer, the pH buffer is present in the form of an aqueous solution.
6. The nimodipine solution according to claim 1, comprising the following components: 3mg/mL of nimodipine, 2mg/mL of methylparaben, 600mg/mL of polyethylene glycol 400, 345mg/mL of glycerol, 3mg/mL of absolute ethyl alcohol, 210-215 mg/mL of pH buffering agent, 80-100 mPa & s of viscosity of nimodipine solution and 6-8 of pH value;
alternatively, the nimodipine solution comprises the following components: nimodipine 0.1mg/mL, methyl hydroxybenzoate 2mg/mL, polyethylene glycol 400 480mg/mL, glycerol 312.9mg/mL, absolute ethanol 3mg/mL, pH buffer 368.1mg/mL, nimodipine solution viscosity 34.56mPa · s, pH 6, wherein the pH buffer is a solution of sodium dihydrogen phosphate and anhydrous disodium hydrogen phosphate: the concentration of sodium dihydrogen phosphate is 0.105mol/L, and the concentration of disodium hydrogen phosphate is 0.0176 mol/L;
alternatively, the nimodipine solution comprises the following components: nimodipine 6mg/mL, methylparaben 2mg/mL, polyethylene glycol 400 540mg/mL, glycerol 310mg/mL, pH buffer 308.1mg/mL, nimodipine solution viscosity 43.79mPa · s, pH 7, wherein the pH buffer is a solution of sodium dihydrogen phosphate and anhydrous disodium hydrogen phosphate: the concentration of sodium dihydrogen phosphate is 0.105mol/L, and the concentration of disodium hydrogen phosphate is 0.0176 mol/L;
alternatively, the nimodipine solution comprises the following components: nimodipine 3mg/mL, methylparaben 2mg/mL, polyethylene glycol 400 713mg/mL, glycerol 197mg/mL, absolute ethanol 3mg/mL, pH buffer 248.1mg/mL, nimodipine solution viscosity 63.99mPa · s, pH 8, wherein the pH buffer is a solution of sodium dihydrogen phosphate and anhydrous disodium hydrogen phosphate: the concentration of sodium dihydrogen phosphate is 0.105mol/L, and the concentration of disodium hydrogen phosphate is 0.0176 mol/L;
alternatively, the nimodipine solution comprises the following components: nimodipine 3mg/mL, methylparaben 2mg/mL, polyethylene glycol 400 473mg/mL, glycerol 497mg/mL, absolute ethanol 3mg/mL, viscosity 92.57mPa · s of nimodipine solution with pH buffer 188.1mg/mL, pH 9, wherein the pH buffer is a solution of sodium dihydrogen phosphate and anhydrous disodium hydrogen phosphate: the concentration of sodium dihydrogen phosphate is 0.105mol/L, and the concentration of disodium hydrogen phosphate is 0.0176 mol/L;
alternatively, the nimodipine solution comprises the following components: nimodipine 3mg/mL, methylparaben 2mg/mL, polyethylene glycol 400mg/mL, glycerol 497mg/mL, absolute ethanol 3mg/mL, pH buffer 261.1mg/mL, nimodipine solution viscosity 132.9mPa · s, pH 6.5, wherein the pH buffer is a solution of sodium dihydrogen phosphate and anhydrous disodium hydrogen phosphate: the concentration of sodium dihydrogen phosphate is 0.105mol/L, and the concentration of disodium hydrogen phosphate is 0.0176 mol/L;
alternatively, the nimodipine solution comprises the following components: nimodipine 3mg/mL, methylparaben 2mg/mL, polyethylene glycol 400 600mg/mL, glycerol 335mg/mL, absolute ethanol 3mg/mL, pH buffer 385.1mg/mL, nimodipine solution viscosity 73.52mPa · s, pH 7.2, wherein the pH buffer is a solution of sodium dihydrogen phosphate and anhydrous disodium hydrogen phosphate: the concentration of sodium dihydrogen phosphate is 0.105mol/L, and the concentration of disodium hydrogen phosphate is 0.0176 mol/L;
alternatively, the nimodipine solution comprises the following components: nimodipine 3mg/mL, methylparaben 0.2mg/mL, polyethylene glycol 400 600mg/mL, glycerol 340mg/mL, absolute ethanol 4.8mg/mL, pH buffer 218.1mg/mL, nimodipine solution viscosity 79.33mPa · s, pH 8.4, wherein the pH buffer is a solution of sodium dihydrogen phosphate and anhydrous disodium hydrogen phosphate: the concentration of sodium dihydrogen phosphate is 0.105mol/L, and the concentration of disodium hydrogen phosphate is 0.0176 mol/L;
alternatively, the nimodipine solution comprises the following components: nimodipine 3mg/mL, methylparaben 2mg/mL, polyethylene glycol 400 600mg/mL, glycerol 345mg/mL, absolute ethanol 3mg/mL, pH buffer 213.1mg/mL, nimodipine solution viscosity 81.53mPa s, pH 8, wherein the pH buffer is a solution of sodium dihydrogen phosphate and anhydrous disodium hydrogen phosphate: the concentration of sodium dihydrogen phosphate is 0.105mol/L, and the concentration of disodium hydrogen phosphate is 0.0176 mol/L;
alternatively, the nimodipine solution comprises the following components: nimodipine 3mg/mL, methylparaben 2mg/mL, polyethylene glycol 400 600mg/mL, glycerol 350mg/mL, absolute ethanol 3mg/mL, pH buffer 208.1mg/mL, nimodipine solution viscosity 88.21mPa · s, pH 7.7, wherein the pH buffer is a solution of sodium dihydrogen phosphate and anhydrous disodium hydrogen phosphate: the concentration of sodium dihydrogen phosphate is 0.105mol/L, and the concentration of disodium hydrogen phosphate is 0.0176 mol/L;
alternatively, the nimodipine solution comprises the following components: nimodipine 3mg/mL, methylparaben 1mg/mL, polyethylene glycol 400 600mg/mL, glycerol 350mg/mL, absolute ethyl alcohol 3mg/mL, pH buffer 209.1mg/mL, nimodipine solution viscosity 30-150 mPa & s, pH 6.8;
alternatively, the nimodipine solution comprises the following components: 3mg/mL of nimodipine, 1.6mg/mL of methylparaben, 600mg/mL of polyethylene glycol 400, 350mg/mL of glycerol, 3mg/mL of absolute ethyl alcohol, 208.5mg/mL of pH buffering agent, 30-150 mPa & s of viscosity of nimodipine solution and 8.6 of pH value.
7. A process for the preparation of a nimodipine solution as claimed in any of claims 1 to 6, comprising the steps of: mixing the nimodipine, the solubilizer, the bacteriostatic agent and the solvent until the solution is clear; the pH value of the nimodipine solution is 6-9.
8. The method for preparing nimodipine solution according to claim 7, wherein the mixed solution of nimodipine, the solubilizer, the bacteriostatic agent and the solvent is prepared by the following steps: firstly, mixing a part of the solubilizer with the bacteriostatic agent to obtain a first mixed solution; and mixing the residual solubilizer with the solvent to obtain a second mixed solution, and mixing the first mixed solution, the second mixed solution and the nimodipine.
9. The method of claim 7, wherein the nimodipine solution is prepared by the steps of, when the pH of the nimodipine solution is adjusted by a pH buffer: mixing the pH buffering agent with a mixed solution of the nimodipine, the solubilizer, the bacteriostatic agent and the solvent until the solution is clear; the pH value of the nimodipine solution is 6-9.
10. Use of a nimodipine solution according to any of claims 1-6 for the preparation of a medicament for the prevention and/or treatment of ischemic cerebrovascular diseases, migraine, cerebral vasospasm due to mild subarachnoid hemorrhage, sudden deafness, mild and moderate hypertension.
CN202110455753.1A 2021-04-26 2021-04-26 Nimodipine oral solution, preparation method and application thereof Pending CN113509434A (en)

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