CN113694031A - Nimodipine polymer composition - Google Patents

Nimodipine polymer composition Download PDF

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CN113694031A
CN113694031A CN202010458777.8A CN202010458777A CN113694031A CN 113694031 A CN113694031 A CN 113694031A CN 202010458777 A CN202010458777 A CN 202010458777A CN 113694031 A CN113694031 A CN 113694031A
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Abstract

The invention discloses a polymer composition of a nimodipine compound and a preparation method thereof. The nimodipine polymer injection of the invention not only greatly improves the solubility of nimodipine and the stability thereof, but also has no organic solvent, greatly reduces the toxic and side effect of clinical administration, has small irritation to blood vessels, can be quickly infused or injected by patients, improves the compliance of the patients and greatly simplifies the clinical application mode.

Description

Nimodipine polymer composition
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a polymer composition of water-insoluble nimodipine, and specifically relates to a nimodipine polymer micelle composition, a preparation method and an application thereof.
Background
Nimodipine (Nimodipine) is a 1, 4 dihydropyridine calcium channel antagonist, selectively acts on cerebrovascular smooth muscle, is fat-soluble, is easy to pass through a blood-cerebrospinal fluid barrier, is combined with a specific receptor of a central nerve to expand a cerebral blood vessel and increase cerebral blood flow, can antagonize cerebral vasospasm caused by 5-HT, arachidonic acid, TXA2 and the like, and effectively prevents or reverses cerebral tissue ischemic damage caused by cerebral vasospasm caused by subarachnoid hemorrhage of a laboratory dog. Has small effect on peripheral blood vessels, has protective effect on ischemic brain injury, and particularly has more obvious effect on ischemic cerebral vasospasm. When the dosage of the nimodipine is increased, the coronary blood flow can be increased and the blood pressure can be reduced at the same time, but the blood pressure is reduced without reducing the cerebral blood flow. Nimodipine has direct action on neurons, changes the function of the neurons, has neuro-and psychopharmacological activity, and animal experiments show that nimodipine has an effect of improving dysmnesia caused by hypoxia and electric shock. Has the functions of resisting depression and improving consciousness and memory, has excellent curative effect on senile depression, and has the intelligence promoting effect 60 times and 1000 times stronger than that of piracetam and vincamine. Meanwhile, the extracellular Ca inflow in the brain infarction area can be prevented, and the brain infarction area is reduced. It is also reported that nimodipine can block or prevent the interaction and polymerization between tumor cells and platelets, significantly reduce the metabolism of cancer cells, and prevent the spread of cancer cells. Recent data show that the medicine also has the effects of protecting and promoting memory and promoting intelligence recovery.
Currently, nimodipine is available in the form of tablets, sustained release, small hydro-acupuncture. Since nimodipine is light yellow clean powder, odorless and tasteless, it is soluble in acetone and chloroform, soluble in ethanol, slightly soluble in diethyl ether, and almost insoluble in water. Since nimodipine solid preparation has low solubility in gastrointestinal fluid, obvious liver first pass effect, low bioavailability and short biological half-life (1.06 + -0.16 h), the activity of metabolite is very weak or almost no activity, and the concentration in plasma is reduced very fast and can be totally excreted in vivo by biotransformation, which results in low bioavailability of oral nimodipine. Based on the oral administration determination, the injection preparation has faster effect and better effect than an oral preparation, so the injection preparation has wide clinical application.
However, the poor water-solubility of nimodipine has greatly limited its clinical application. For example, commercial infusion solutions typically require the addition of a co-solvent (e.g., povidone, etc.) to form a complex with nimodipine to increase the solubility of nimodipine. However, the effectiveness of these measures is limited. Generally, 20% (V/V) ethanol is used as a solvent in infusion, while the ethanol in a small water needle is larger in amount, and the large amount of ethanol has larger irritation and side effects on patients in use, such as pain, vasculitis and the like; and the medicaments incompatible with the ethanol can not be added into the same infusion bottle together, so the use is very inconvenient.
In addition, nimodipine is very unstable to light (especially obvious in a solution state), and most of the commercially available injection adopts a lightproof packaging material such as a brown ampoule and a bottle with an additional lightproof foam layer, which not only increases the cost, but also is inconvenient to use. Typically, an antioxidant such as sodium bisulfite is added to the solution to increase the stability of the solution. The trade names of the existing nimodipine injection in China market are nimodipine, nimesu and the like, and the injection contains 23.7 percent (V/V) ethanol (1 ml of medicine contains 200mg of ethanol) and 17 percent of excipients such as polyethylene glycol 400 and the like. Because of containing a large amount of organic solvents, the irritation to blood vessels is large, and nimodipine has high expansibility, the permeability of the blood vessels is increased, the venous leakage is caused, and the phlebitis symptoms such as red, swelling, heat, pain and the like appear around the venipuncture. The infusion pump is used for treating the patient with subarachnoid hemorrhage by continuous intravenous infusion at the speed of 0.5 mug/(kg.min), the blood pressure is monitored for a long time, 10 hours are needed every day, the treatment time is 10-14 days, and in the process of veins, the patient often feels local pain, red swelling and the like, and the phlebitis stimulation symptom is up to 90.0%. Therefore, there is an urgent need to improve the formulation composition to reduce the incidence rate and degree of phlebitis, the pain and mental burden of patients and the workload of medical workers.
In the prior art, there are various methods for increasing the solubility of nimodipine, such as:
patent document CN102525917B discloses a nimodipine micelle injection and its preparation method, wherein the patent uses 40-70 parts of bile salt, 40-80 parts of phospholipid and a proper amount of injection solvent. But the highest compatibilization concentration is 0.5mg/ml, and the drug loading rate is lower and is lower than 2%. Patent document CN103315948B discloses a nimodipine polymer blending micelle preparation and a preparation method thereof, wherein the patent adopts polyethylene glycol-polylactic acid (PEG-PLA) and polyethylene glycol 1000 vitamin E succinate (TPGS) to load nimodipine, the weight average molecular weight of the polyethylene glycol-polylactic acid is 7000-45000, wherein the molecular weight of polyethylene glycol is 2000-15000, and the molecular weight of polylactic acid is 5000-30000; the particle size is 150-200 nm, and the process adopts a mixed solvent of tetrahydrofuran and water, wherein the ratio of tetrahydrofuran: water (1: 4), the drug loading is 2-20%, preferably 14.8%. However, from the results of the examples, the yield is very low, which should be less than 80%. The block ratio of the selected polyethylene glycol-polylactic acid is not the optimal block ratio, the polylactic acid is not definite levorotatory polylactic acid, racemic polylactic acid or dextrorotatory polylactic acid, the solubilization is assisted by polyethylene glycol 1000 vitamin E succinate (TPGS), and tetrahydrofuran which is a toxic solvent is adopted brings potential safety hazard.
Patent document CN200910021091.6 discloses nimodipine lipid microsphere injection and its preparation method, but lipid microsphere preparation has complex process and high cost, and the package of lipid microsphere is easy to be damaged and leak during long-term storage, which brings clinical risk, and the particle size is large, and it is not possible to inject intravenously. Patent document CN02155645.8 discloses a formulation of nimodipine lyophilized injection, which adopts phospholipid, cyclodextrin and its derivatives or surfactant, cosolvent, etc. to increase the solubility and stability of nimodipine, but the preparation process is complicated, the quality of the final product is difficult to control, and cyclodextrin has great anaphylaxis and hemolysis, has potential renal toxicity, and limits the wide application of its preparation.
Patent document CN200510081668.4 discloses a nimodipine emulsion injection and a preparation method thereof, which adds a proper amount of benzyl alcohol in the preparation process to improve the solubility of nimodipine in the emulsion and the stability of the preparation, so that the concentration of the nimodipine emulsion is relatively high. However, in 10 th 6 th 2005, the national food supervision authorities issue notifications, and due to the detection of adverse reactions, the use management of the benzyl alcohol injection is required to be strengthened, and the use of the benzyl alcohol injection in children intramuscular injection is strictly prohibited, which severely limits the clinical application of the benzyl alcohol injection. Patent document CN200610095295.0 discloses a method for preparing nimodipine lyophilized emulsion for injection, but the drug release is difficult to control, and the use of surfactant such as tween as emulsifier is liable to bring hypersensitivity.
Therefore, the technical problem that the toxic and side effects of the solubilizer are not effectively solved and the curative effect of the nimodipine is kept/improved is solved by the method. After the toxicity of the known organic solvent is reduced, other surfactants are introduced into certain new formulations, so that risks are brought to patients, or the process yield is low, the drug loading effect is poor, and the cost problem is brought.
Disclosure of Invention
Based on the problems, the inventor screens a plurality of carriers and preparation processes through a plurality of attempts, provides a novel nimodipine composition, has no organic solvent, has high drug loading rate up to 20 percent, an encapsulation rate of 98-100 percent and a yield of more than 95 percent, and the prepared nimodipine composition aqueous solution has a small particle size of 10-100nm and a maximum concentration of 10mg/ml, greatly reduces the toxic and side effects of the existing preparation, improves the compliance of patients, can be quickly infused by the patients, and improves the curative effect of the nimodipine.
The invention comprises the following concrete steps:
(1) the biodegradable polymer carrier is amphiphilic block polymer methoxy polyethylene glycol-poly (D, L-lactic acid), and the average molecular weight ratio of methoxy polyethylene glycol to poly (D, L-lactic acid) in the diblock polymer is 0.5-2; wherein the average molecular weight of the methoxy polyethylene glycol in the diblock polymer is 1500-5000, and preferably 2000.
(2) The preparation method of the polymer powder injection containing the nimodipine comprises the following steps: co-dissolving the block polymer and nimodipine in an organic solvent such as absolute ethyl alcohol or tert-butyl alcohol to obtain a clear solution; then removing the organic solvent by spraying or vacuum pumping under reduced pressure to obtain a co-dispersion; and injecting water for injection into the co-dispersion to dissolve the co-dispersion, filtering, adding a prepared solution for dissolving the freeze-drying excipient, uniformly mixing, filtering the solution, subpackaging and freeze-drying to obtain the nimodipine polymer freeze-dried powder injection. When in clinical use, the injection water or normal saline or glucose for injection is added to dilute and dissolve the mixture.
(3) The invention solves the problem of water solubility of nimodipine, has higher drug loading rate, can achieve higher drug loading rate and drug concentration without the need of polyethylene glycol 1000 vitamin E succinate (TPGS) which is described in patent CN102525917B, and shows that the screened carrier block ratio and the preparation process have better advantages.
(4) The prepared nimodipine polymer powder injection has higher drug-loading rate which can reach 20 percent, and the highest concentration after redissolution can reach 10 mg/ml; meanwhile, the particle size is adjustable and controllable, and the particle size range is 10-200 nm; the nano micelle formed after hydration can penetrate blood brain barrier more easily in blood circulation, and is beneficial to improving the blood circulation of cerebral vasospasm after subarachnoid space bleeding and acute cerebrovascular disease recovery period.
(5) The prepared nimodipine polymer powder injection does not need a special administration device for clinical administration, does not cause the phenomena of red, swelling, heat, pain and the like of an administration part due to the absence of any organic solvent, does not cause phlebitis symptoms, can finish the infusion within 1 hour, and greatly improves the compliance of patients.
Drawings
FIG. 1 is a photograph of nimodipine polymer powder injection;
FIG. 2 is a photograph of nimodipine polymer powder injection after redissolution
FIG. 3 is a transmission electron micrograph of nimodipine polymer powder for injection after redissolution;
figure 4 is a graph of the measured particle size of the nimodipine polymer powder injection after redissolution.
FIG. 5 tissue section: a group of commercially available nimodipine injections, B group of nimodipine polymers and C group of normal saline
Detailed Description
The invention will be illustrated in more detail in the following non-limiting examples, the following being a description of the Chinese names and corresponding abbreviations for the materials used in the present invention:
1. methoxypolyethylene glycol-poly (D, L-lactic acid), MPEG-PDLLA for short
2. Nimodipine (Nimodipine), NP for short
3. Nimodipine polymer micelle NP-PM.
Example 1
Will MPEG2000-PDLLA2000Dissolving NP and water in 2mL of absolute ethyl alcohol according to a certain mass ratio (15 mg: 85mg), quickly removing organic solvent, then adding 3mL of water for injection to dissolve, pressurizing and filtering by 0.22um, filling the filtrate into 2 mL/bottle, quickly freezing the filtrate in a freeze dryer to-40 ℃, pre-freezing, and carrying out sublimation drying to obtain NP polymer freeze-dried powder for later use. When in use, 2ml of water for injection or 0.9% sodium chloride water for injection or glucose water for injection is added into 1 bottle of NP polymer freeze-dried powder, the mixture is shaken to dissolve, and after bubbles dissipate, the mixture is drawn out and directly injected, or 50ml to 250ml of normal saline or glucose water for injection is added into the mixture for intravenous infusion.
Example 2
Will MPEG2000-PDLLA1750Dissolving NP and the mixture in 3mL of absolute ethyl alcohol according to a certain mass ratio (20 mg: 180mg), quickly removing organic solvents, then adding 5mL of water for injection to dissolve, pressurizing and filtering by 0.22um, filling the filtrate into 1 mL/bottle, quickly freezing the filtrate in a freeze dryer to-40 ℃, pre-freezing, and carrying out sublimation drying to obtain NP polymer freeze-dried powder for later use. When in use, 2ml of water for injection or 0.9% sodium chloride water for injection or glucose water for injection is added into 1 bottle of NP polymer freeze-dried powder, the mixture is shaken to dissolve, and after bubbles dissipate, the mixture is drawn out and directly injected, or 50ml to 250ml of normal saline or glucose water for injection is added into the mixture for intravenous infusion.
Example 3
Will MPEG2000-PDLLA1750Dissolving NP and the mixture in 5mL of absolute ethyl alcohol according to a certain mass ratio (20 mg: 380mg), quickly removing organic solvents, adding 3mL of water for injection to dissolve, adding 2mL of lactose (50mg/mL) aqueous solution to mix uniformly, filtering under pressure of 0.22um, filling the filtrate into 1 mL/bottle, quickly freezing the filtrate in a freeze dryer to-40 ℃, pre-freezing, and carrying out sublimation drying to obtain the NP polymer freeze-dried powder for later use. When in use, 1 bottle of NP polymer freeze-dried powder is taken and added with 2ml of water for injection or 0.9 percent sodium chloride for injectionDissolving the mixture in water or glucose injection water by shaking, and pumping out the mixture for direct injection after air bubbles dissipate, or adding 50-250 ml of normal saline or glucose injection water for intravenous infusion.
Example 4
Will MPEG2000-PDLLA4000Dissolving NP and the mixture in 5mL of absolute ethyl alcohol according to a certain mass ratio (20 mg: 380mg), quickly removing an organic solvent, adding 3mL of water for injection to dissolve, adding 2mL of mannitol (50mg/mL) aqueous solution to mix uniformly, filtering under pressure with 0.22um, filling the filtrate into 2 mL/bottle, quickly freezing the filtrate in a freeze dryer to-40 ℃, pre-freezing, and carrying out sublimation drying to obtain the NP polymer freeze-dried powder for later use. When in use, 2ml of water for injection or 0.9% sodium chloride water for injection or glucose water for injection is added into 1 bottle of NP polymer freeze-dried powder, the mixture is shaken to dissolve, and after bubbles dissipate, the mixture is drawn out and directly injected, or 50ml to 250ml of normal saline or glucose water for injection is added into the mixture for intravenous infusion.
Example 5
Will MPEG2000-PDLLA2000Dissolving NP and the mixture in 5mL (water: tert-butyl alcohol is 1: 4) mixed solvent according to a certain mass ratio (20 mg: 113mg), uniformly mixing the mixture with 0.22um, pressurizing and filtering, filling the filtrate into 1 mL/bottle, quickly freezing the filtrate in a freeze dryer to-40 ℃, pre-freezing, and carrying out sublimation drying to obtain NP polymer freeze-dried powder for later use. When in use, 1 bottle of NP polymer freeze-dried powder is added with 1ml of water for injection or 0.9 percent of sodium chloride water for injection or glucose water for injection, the mixture is shaken to dissolve, and after bubbles dissipate, the mixture is drawn out for direct injection, or is added with 50ml to 250ml of normal saline or glucose water for injection and is infused intravenously.
Example 6
Will MPEG2000-PDLLA1750Dissolving NP and the mixture in 5mL of tert-butanol according to a certain mass ratio (20 mg: 380mg), ultrasonically dissolving, pressurizing and filtering by 0.22um, subpackaging filtrate according to the dosage containing 8mg of NP, quickly freezing the filtrate in a freeze dryer to-40 ℃, pre-freezing, and carrying out sublimation drying to obtain NP polymer freeze-dried powder for later use. When in use, 2ml of water for injection or 0.9 percent of sodium chloride water for injection or glucose water for injection is added into 1 bottle of NP polymer freeze-dried powder, the mixture is shaken to be dissolved, and after bubbles are dissipated, the mixture is drawn out and directly injected, or 50ml to 250ml of raw water is addedSaline or glucose water for injection, and intravenous infusion.
Example 7
Will MPEG2000-PDLLA2000Dissolving NP and the mixture in 3mL of absolute ethyl alcohol according to a certain mass ratio (20 mg: 113mg), quickly removing organic solvents, then adding 5mL of water for injection to dissolve, pressurizing and filtering by 0.22um, filling the filtrate into 1 mL/bottle, quickly freezing the filtrate in a freeze dryer to-40 ℃, pre-freezing, and carrying out sublimation drying to obtain NP polymer freeze-dried powder for later use. When in use, 1 bottle of NP polymer freeze-dried powder is added with 1ml of water for injection or 0.9 percent of sodium chloride water for injection or glucose water for injection, the mixture is shaken to dissolve, and after bubbles dissipate, the mixture is drawn out for direct injection, or is added with 50ml to 250ml of normal saline or glucose water for injection and is infused intravenously.
Example 8
Will MPEG2000-PDLLA2000Dissolving NP and the mixture in 5mL of absolute ethyl alcohol according to a certain mass ratio (60 mg: 340mg), quickly removing organic solvents, adding 10mL of water for injection to dissolve, adding 5mL of lactose (100mg/mL) aqueous solution to mix uniformly, filtering under pressure of 0.22um, filling filtrate into 2 mL/bottle, quickly freezing the filtrate in a freeze dryer to 40 ℃, pre-freezing, and carrying out sublimation drying to obtain NP polymer freeze-dried powder for later use. When in use, 2ml of water for injection or 0.9% sodium chloride water for injection or glucose water for injection is added into 1 bottle of NP polymer freeze-dried powder, the mixture is shaken to dissolve, and after bubbles dissipate, the mixture is drawn out and directly injected, or 50ml to 250ml of normal saline or glucose water for injection is added into the mixture for intravenous infusion.
Table 1 shows the drug loading parameters of the lyophilized formulations prepared in the different examples.
Figure BSA0000209827220000061
Investigation of tissue pathology
1. Medicine preparation: inventive example 8 prepared sample NP-PM (8 mg/vial), a control group nimodipine injection (10 ml: 2mg) from Jiangsu Diisono pharmaceuticals
2. The experimental process comprises the following steps:
nine male rabbits (2.5-3.0 kg body weight) were randomly divided into three groups. A group of sodium chloride injection (NP-PM freeze-dried powder 1 bottle is taken, and 2ml of 0.9% sodium chloride injection is added for dissolving for later use). Another group was injected with a commercial nimodipine injection (10 ml: 2mg) from Jiangsu Diisono pharmaceuticals as a positive control, and the other group was injected with physiological saline as a negative control. Each group was injected for 5 days according to a clinical dosing schedule of 0.4mg/kg, and the negative control group was injected with the same volume of physiological saline. A first group of animals was infused on the right with clinical concentrations of NP-PM via the auricular vein and a second group was infused with clinical concentrations of marketed nimodipine injection via the right auricular vein. The third group was visually observed on the right side by auricular vein infusion of clinical concentrations of NP-PM intervals at the injection site and surrounding tissues for up to 48 hours. After completion of the experiment, the rabbits of each group were sacrificed and the tissues were removed, washed with physiological saline, and fixed with 10% v/v formaldehyde for 48 hours, and then the obtained samples were dehydrated continuously with ethanol of various concentrations (each concentration was 100%, 95%, 85%, 70%, 2-5 minutes, respectively). The dehydrated samples were embedded in paraffin, cut and stained with hematoxylin and eosin. All sections were observed at x 100 magnification using Axiovert200(Zeiss, Oberkochen, germany) and pathological changes were analyzed and evaluated.
As a result: the rabbit ear vein irritation test was performed and the group of rabbits treated with the NP-PM formulation did not show deep breathing compared to the commercial nimodipine injection. In addition, rabbits struggled more frequently than the NP-PM group, saline group, during infusion of the commercial nimodipine injection. After 5 days of infusion, the ear veins of rabbits in the commercial nimodipine injection group showed blood vessel congestion, and the blood vessel lines were unclear. In this group, edema occurred in the surrounding tissues. In contrast, the auricular vein of the NP-PM-injected rabbits was asymptomatic. We also observed these results in histopathological sections, as shown in fig. 5. Histopathological lesions such as vasodilation, bleeding and degeneration around the vein wall, degeneration of vein wall, edema around vein, infiltration of inflammatory cells, swelling of vascular endothelial cells around vein were observed under microscope caused by the control group of commercially available nimodipine injection (fig. 5A). However, the results of the NP-PM group (FIG. 5B) and the saline group (FIG. 5C) showed no histopathological lesions.
In conclusion, the nimodipine polymer has the particle size of 8-100 nm, the drug-loading rate of 1-20% generally, the encapsulation rate of over 98%, excellent stability, greatly reduced toxic and side effects of the existing preparation, improved patient compliance, capability of rapid infusion of patients and improved curative effect of nimodipine.

Claims (8)

1. A nimodipine compound-loaded polymer composition, characterized in that: the nimodipine and amphiphilic block polymer methoxy polyethylene glycol-poly (D, L-lactic acid) are prepared, wherein the weight ratio of the nimodipine to the amphiphilic block polymer is as follows: 1 part of nimodipine and 2.5-35 parts of amphiphilic block polymer.
The average molecular weight ratio of the methoxy polyethylene glycol to the poly (D, L-lactic acid) in the diblock polymer is 0.5-2;
the average molecular weight of the methoxy polyethylene glycol in the diblock polymer is 1500-5000, and preferably 2000.
2. The polymer composition of claim 1, wherein: the polymer composition is stored as a lyophilized powder.
3. The polymer composition of claim 1, wherein: the polymer composition can be prepared by two methods:
(1) dissolving nimodipine and methoxypolyethylene glycol-poly (D, L-lactic acid) in an organic solvent to obtain a clear solution; then removing the organic solvent by spraying or vacuum pumping under reduced pressure to obtain a co-dispersion; injecting water for injection into the common dispersion, dissolving, and filtering to obtain solution; adding pharmaceutically acceptable aqueous solution of support agent to obtain solution with desired concentration, filtering with 0.22um filter bag, packaging, and lyophilizing to obtain lyophilized composition;
(2) dissolving nimodipine and methoxypolyethylene glycol-poly (D, L-lactic acid) or a scaffold agent in tert-butyl alcohol or a mixed solvent of the tert-butyl alcohol and water to obtain a clear solution; filtering the solution with 0.22um filter bag, packaging, and lyophilizing to obtain lyophilized composition.
4. The method of claim 3, wherein: the pharmaceutically acceptable carrier is lactose, mannitol, sucrose, xylitol, sorbitol, dextran, sodium chloride, glucose, etc. or their mixture, preferably lactose, sucrose, mannitol, etc.
5. A process for preparing a polymer composition according to claim 3, wherein: the organic solvent is one or a mixture of ethanol, propylene glycol, tert-butyl alcohol, acetonitrile, dichloromethane, acetone, trifluoroethanol or hexafluoroisopropanol, and preferably tert-butyl alcohol and pharmaceutically acceptable ethanol.
6. The polymer composition according to any one of claims 1 to 5, characterized in that: the polymer composition is dissolved by a diluent, and the particle size is 8nm-200 nm; the micelle diameter is preferably gnm-100 nm.
7. The diluent of claim 6, wherein: the diluent used may be water for injection, physiological saline for injection, glucose solution for injection or a mixture thereof.
8. The polymer composition according to claim 1, which is used for preventing and treating ischemic nerve damage caused by cerebral vasospasm after aneurysmal subarachnoid hemorrhage, ischemic cerebrovascular disease, senile cerebral dysfunction, intractable hiccup, cerebral infarction and post-infarction epilepsy, migraine, sudden deafness, peptic ulcer, pulmonary heart disease, viral encephalitis, hypertension, neonatal hypoxic-ischemic encephalopathy, cervical spondylosis, and diabetic peripheral neuropathy.
CN202010458777.8A 2020-05-20 2020-05-20 Nimodipine polymer composition Pending CN113694031A (en)

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