Application of a drug in the prevention or treatment of hydrocephalus

Abstract

This invention discloses the application of a drug in the prevention or treatment of hydrocephalus, belonging to the field of pharmaceutical formulation technology. The drug comprises a pharmaceutically acceptable formulation of one or more of the following active ingredients: compound A, compound B, or compound C, and their pharmaceutically acceptable salts, solvates, or crystal forms; compound A is carbaspirin calcium, compound B is aspirin, and compound C is salicylic acid. This invention utilizes the above-mentioned drug in the prevention or treatment of hydrocephalus. Carbaspirin calcium and its metabolites can significantly reduce ventricular enlargement in a hydrocephalus model rat, and carbaspirin calcium and its metabolites show promise in the preparation of drugs for treating hydrocephalus, providing an effective candidate drug to alleviate the suffering of hydrocephalus patients, reduce treatment risks and costs; it broadens the scope of action of carbaspirin calcium and optimizes the stability formulation of carbaspirin calcium.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical formulation technology, and in particular to the application of a drug in the prevention or treatment of hydrocephalus, specifically to the optimization and stabilization of the buffer system of a carbaspirin calcium nasal administration formulation. Background Technology

[0002] Hydrocephalus is a condition characterized by the abnormal accumulation of cerebrospinal fluid (CSF) within the brain. It is typically caused by impaired CSF circulation, absorption, or excessive secretion. Based on its cause, hydrocephalus is mainly classified into two categories: obstructive hydrocephalus and communicating hydrocephalus. Obstructive hydrocephalus results from a blockage in the CSF's flow pathway. This blockage can be caused by congenital defects (such as Chiari malformation), tumors, infections (such as meningitis), hemorrhages (such as blood clots after subarachnoid hemorrhage), or other inflammatory diseases. The blockage may occur somewhere within the ventricles, such as the foramen between the ventricles or the passageway between the ventricles and the subarachnoid space. Communicating hydrocephalus occurs when the CSF's flow pathway is not physically blocked, but rather due to absorption disorders. This can be caused by meningitis, head trauma, treatment of certain types of brain tumors (such as radiotherapy), or decreased CSF absorption capacity during natural aging. Furthermore, hydrocephalus may also be associated with genetic factors, congenital defects, or certain disease states.

[0003] In existing technologies, carbaspirin calcium mainly consists of aspirin and calcium salts. It combines the antipyretic, analgesic, and anti-inflammatory effects of aspirin with the function of calcium supplementation. Clinically, it is mainly used for fever caused by the common cold or influenza, and also to relieve mild to moderate pain, such as headache, joint pain, migraine, toothache, muscle pain, neuralgia, and dysmenorrhea. However, there are no specific reports in existing technologies regarding the use of carbaspirin calcium and its metabolites in hydrocephalus. Furthermore, carbaspirin calcium solutions are prone to degradation, producing impurities such as aspirin and salicylic acid. Its solubility also varies in different buffer systems, leading to drug precipitation problems, which seriously affect the stability and efficacy of nasal administration formulations. Currently, there is no dedicated buffer system or stabilization scheme for carbaspirin calcium nasal administration formulations. Summary of the Invention

[0004] The purpose of this invention is to provide an application of a drug in the prevention or treatment of hydrocephalus. Carbaspirin calcium and its metabolites can significantly reduce ventricular enlargement in a hydrocephalus model rat, and carbaspirin calcium and its metabolites show promise in the preparation of drugs for treating hydrocephalus, providing an effective candidate drug to alleviate the suffering of hydrocephalus patients, reduce treatment risks and costs, and broaden the scope of action of carbaspirin calcium. Furthermore, the buffer system of its nasal administration formulation has been optimized to solve the problems of easy degradation and precipitation of carbaspirin calcium solution, improve the room temperature storage stability of the formulation, and provide a stable and effective nasal administration formulation of carbaspirin calcium for clinical use.

[0005] To achieve the above objectives, the present invention provides an application of a medicament in the prevention or treatment of hydrocephalus, said medicament comprising a pharmaceutically acceptable formulation of one or more of the following active ingredients: compound A, compound B, or compound C, and their pharmaceutically acceptable salts, solvates, or crystal forms, wherein: Compound A is calcium carbaspirin, with the structural formula shown in Formula I: Formula I; Compound B is aspirin, and its structural formula is shown in Formula II: Formula II; Compound C is salicylic acid, and its structural formula is shown in Formula III: Formula III.

[0006] Preferably, the pharmaceutically acceptable salt includes one or more of the following: sodium salt, potassium salt, lithium salt, calcium salt, magnesium salt, ammonium salt, methylamine salt, ethylamine salt, diethylamine salt, triethylamine salt, tris(hydroxymethyl)aminomethane salt, N-methylglucamine salt, lysine salt, arginine salt, or ornithine salt.

[0007] Preferably, the solvate includes one or more of the following: monohydrate, dihydrate, trihydrate, solvate formed with methanol, ethanol, propanol, isopropanol, propylene glycol, polyethylene glycol, or solvate formed with ethyl acetate, acetone, acetonitrile, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, or dimethyl sulfoxide.

[0008] Preferably, the crystal form includes one or more of the following: the amorphous form, the hydrated form, or the solvated form of compound A, compound B, or compound C.

[0009] Preferably, the drug dosage form includes one of an oral preparation, a nasal preparation, or an injection; Preferably, the oral preparation includes one of tablets, capsules, granules, oral solutions, or oral suspensions.

[0010] Preferably, the nasal delivery formulation includes one of nasal drops, nasal sprays, nasal powders, nasal gels, or adhesive formulations.

[0011] Preferably, the injectable includes one of the following: a water-soluble injectable solution, a fat emulsion, a microemulsion, a long-acting sustained-release microsphere, or an implant.

[0012] Furthermore, the carbaspirin calcium solution for nasal administration is prepared using a citrate-anhydrous sodium citrate buffer system with a pH of 5.5-7.0 and a carbaspirin calcium concentration of 2 mg / mL.

[0013] Furthermore, the citric acid-anhydrous sodium citrate buffer system has a pH of 6.5. At this pH, no carbaspirin calcium solution precipitates, and the pH changes little when stored at room temperature, exhibiting optimal stability.

[0014] Furthermore, the citric acid-anhydrous sodium citrate buffer system contains a chelating agent EDTA-2Na, with a mass percentage of 0.01%-0.03%.

[0015] Furthermore, the EDTA-2Na content is 0.02% by mass, which provides the best inhibitory effect on the degradation of carbaspirin calcium, and there are no toxic side effects from additional excipients.

[0016] Preferably, the effective dose of the drug, based on the subject's body weight, is 0.1-100 mg / kg / day.

[0017] The present invention also provides a kit for preparing a combination pharmaceutical composition for the prevention or treatment of hydrocephalus, the kit comprising a first pharmaceutical composition and a second pharmaceutical composition, wherein the first pharmaceutical composition and the second pharmaceutical composition are used simultaneously or in staggered combinations, wherein: The first pharmaceutical composition comprises one or more of compound A, compound B and compound C as described in claim 1, and a pharmaceutically acceptable carrier or excipient. The second pharmaceutical composition includes one or more of acetazolamide, furosemide, topiramate, corticosteroids, and MMP-9 inhibitors, as well as a pharmaceutically acceptable carrier or excipient.

[0018] Therefore, the application of the above-mentioned drug in the prevention or treatment of hydrocephalus has the following beneficial effects: (1) The application of carbaspirin calcium in the preparation of nasal administration formulations for the treatment of hydrocephalus can significantly reduce the ventricular enlargement phenomenon in hydrocephalus model rats; (2) Experimental data provided by the present invention show that the prepared drug has great application prospects in the treatment of hydrocephalus, and provides an effective candidate drug formulation to alleviate the treatment pain of hydrocephalus patients, reduce treatment risks and costs; and broadens the scope of action of carbaspirin calcium.

[0019] (3) Experimental data provided by the present invention show that the prepared drug can quickly enter the central nervous system and be metabolized in the brain into aspirin and / or salicylic acid.

[0020] (4) The present invention screened out the citric acid-anhydrous sodium citrate buffer system as a dedicated buffer system for carbaspirin calcium nasal administration formulations. This system can stably dissolve 2 mg / mL carbaspirin calcium in the pH range of 5.5-7.0 without drug precipitation problems. The present invention also clarifies that the sodium dihydrogen phosphate-anhydrous disodium hydrogen phosphate buffer system cannot stabilize carbaspirin calcium solution. Carbaspirin calcium solution prepared by this system will show varying degrees of drug precipitation and is not suitable for the preparation of carbaspirin calcium nasal administration formulations. (5) By adding 0.01%-0.03% EDTA-2Na to the buffer system, the present invention significantly inhibits the degradation of calcium in carbaspirin, reduces the generation of impurities such as aspirin and salicylic acid, and improves the room temperature storage stability of the preparation.

[0021] (6) By comparing different pH conditions and different EDTA-2Na contents, this invention clarifies the optimal pH value and EDTA-2Na content for preparing carbaspirin calcium solution.

[0022] The technical solution of the present invention will be further described in detail below with reference to the accompanying drawings and embodiments. Attached Figure Description

[0023] Figure 1 This is the molecular structural formula of the carbaspirin calcium of the present invention; Figure 2 This is the molecular structural formula of the aspirin of this invention; Figure 3 This is the molecular structural formula of salicylic acid in this invention; Figure 4 This is the statistical result of the ratio of ventricular volume to whole brain volume in rats in the sham surgery group, hydrocephalus group, hydrocephalus + carbaspirin calcium nasal drops group and hydrocephalus + carbaspirin calcium nasal spray group of the present invention. Figure 5 The magnetic resonance imaging results are those of the sham surgery group, hydrocephalus group, hydrocephalus + carbaspirin calcium nasal drops group, and hydrocephalus + carbaspirin calcium nasal spray group of this invention. Figure 6 This is a pharmacokinetic curve of the aspirin of this invention; Figure 7 This is a pharmacokinetic curve of salicylic acid according to the present invention; Figure 8 This is a diagram showing the aspirin content in the carbaspirin calcium solution of this invention; Figure 9 This is a diagram showing the salicylic acid content in the carbaspirin calcium solution of this invention; Figure 10 This invention presents the statistical results of measuring the size of the ventricles of zebrafish treated with salicylic acid. Figure 11 These are body micrographs of zebrafish juveniles from the blank control group, hydrocephalus group, and hydrocephalus + SA group, which are test examples of this invention. Detailed Implementation

[0024] The technical solution of the present invention will be further described below with reference to the accompanying drawings and embodiments.

[0025] Unless otherwise defined, the technical or scientific terms used in this invention shall have the ordinary meaning as understood by one of ordinary skill in the art to which this invention pertains.

[0026] Carbaspirin Calcium: C 18 H 14 CaO8·CH4N2O, structural formula as follows Figure 1 As shown, CAS number: 5749-67-7; Aspirin: CH3COOC6H4COOH, structural formula as follows Figure 2 As shown, CAS number: 50-78-2; Salicylic acid: HOC6H4COOH, structural formula as follows Figure 3 As shown, CAS number: 69-72-7.

[0027] Example 1 This invention provides an application of a drug in the prevention or treatment of hydrocephalus. The preparation steps of the nasal drops are as follows: Step 1: Weigh out carbaspirin calcium at a concentration of 100 mg / mL and dissolve it in deionized water; Step 2: Turn on the magnetic stirrer and stir at medium speed until all solids are completely dissolved; Step 3: Add deionized water to a volume of 1 mL; Step 4: Sterilize the solution obtained in Step 3 by passing it through a 0.22μm filter membrane; Step 5: Store the sterilized solution from Step 4 at 4°C.

[0028] Example 2 This invention provides an application of a drug in the prevention or treatment of hydrocephalus. The raw materials and dosage of carbaspirin calcium nasal spray are shown in Table 1.

[0029] Table 1. Raw materials and dosage of carbaspirin calcium nasal spray

[0030] The preparation steps are as follows: Step 1: Weigh out 75 mg / mL of carbaspirin calcium and dissolve it in deionized water; Step 2: Turn on the magnetic stirrer and stir at medium speed until all solids are completely dissolved; Step 3: Weigh 0.5 mg of sodium hyaluronate and add it to the solution from Step 2. Shake well to dissolve. Step 4: Weigh 1 mg of potassium sorbate and add it to the solution from Step 2. Shake well to dissolve. Step 5: Turn on the magnetic stirrer and stir at medium speed until all solids are completely dissolved; Step 6: Add deionized water to a final volume of 1 mL; Step 7: The above solution is sterilized by passing it through a 0.22μm filter membrane; Step 8: Store the solution at 4°C.

[0031] Examples 3-10 were prepared according to the following steps: Prepare citric acid-anhydrous sodium citrate buffer and sodium dihydrogen phosphate-anhydrous disodium hydrogen phosphate buffer respectively, and adjust the pH to four gradients of 5.5, 6.0, 6.5 and 7.0; Add carbaspirin calcium to the buffer solutions with different pH values ​​to prepare a carbaspirin calcium solution with a concentration of 2 mg / mL, and stir at room temperature until completely dissolved.

[0032] See Table 2 for specific prescriptions.

[0033] Table 2 Prescriptions for Examples 3-10

[0034] The above solution was sealed and stored, and observed continuously for 10 days. The changes in solution state and pH value were recorded. The results are shown in Table 3.

[0035] Table 3. 10-day stability study of samples prepared in Examples 3-10

[0036] As shown in Table 3, the citric acid-anhydrous sodium citrate buffer system showed no drug precipitation in carbaspirin calcium solutions within the pH range of 5.5-7.0, and the pH value did not change significantly after 10 days of storage at room temperature, indicating that the system was stable. However, the sodium dihydrogen phosphate-anhydrous disodium hydrogen phosphate buffer system showed varying degrees of drug precipitation at all pH gradients, and could not stabilize carbaspirin calcium, making it unsuitable for formulation preparation.

[0037] Example 11 Take the citrate-anhydrous sodium citrate buffer solution with pH 5.5-7.0 from Examples 3-6, and add 0.01%, 0.02%, and 0.03% EDTA-2Na respectively to prepare buffer solutions containing different concentrations of chelating agent; Add carbaspirin calcium to the above-mentioned buffer solutions of different concentrations to prepare carbaspirin calcium solutions with a concentration of 2 mg / mL, and store them in a sealed container at room temperature. Samples were taken on day 0 and day 5 of storage, and the peak areas of aspirin and salicylic acid in the solution were detected by high performance liquid chromatography-mass spectrometry (LC-MS). The peak area was used to characterize the impurity content and reflect the degree of degradation of carbaspirin calcium. The instrument used for detection was an Agilent 1260 Infinity ultra-high performance liquid chromatograph connected in series with a 6420 triple quadrupole mass spectrometer, and the chromatographic column was an Agilent ZORBAX SB-C18 5μm.

[0038] Samples were taken on day 0 and day 5 of storage, and the mass spectrometric peak areas of aspirin and salicylic acid in the solution were measured. The changes in the peak areas of impurities over 5 days are shown below. Figure 8 and Figure 9 As shown in the figure, the group with a pH of 6.5 and an EDTA-2Na content of 0.02% had the lowest levels of aspirin and salicylic acid impurities, and the group with the best inhibitory effect on calcium degradation by carbaspirin.

[0039] Application example: The experiment was conducted on rats anesthetized with isoflurane under sterile conditions, with their body temperature maintained at 37°C using a heating pad. The rats were placed in a stereotactic frame (Reward), and the skull was exposed through a midline incision. A hole was drilled above the left ventricle (0.6 mm posterior to the anterior fontanelle and 1.6 mm lateral to the anterior fontanelle) using a cranial drill. Then, within 30 minutes, 100 μL of LPA2 receptor activator (hydrocephalus group) or saline (sham-operated group) was injected into the left ventricle (ventral 4.5 mm) through the drilled hole using a 33G needle (Hamilton instrument), anticipating diffusion throughout the ventricular system. The needle was kept in place for 5 minutes before retraction to prevent backflow. The skin incision was sutured, and the rats were allowed to recover before being returned to their housing. The sham-operated and hydrocephalus groups received no further special treatment.

[0040] The carbaspirin calcium nasal drop treatment group (hydrocephalus + carbaspirin calcium nasal drops prepared in Example 1) was treated 3 days after surgery. The treatment procedure was as follows: After anesthesia, the rats were kept in a supine position with their necks slightly elevated to 45°. A total dose of 30 mg / kg / day was administered bilaterally via alternating nostrils, with each nostril containing 20 μL of the drug. An interval was left between administrations to ensure absorption. This procedure was performed twice daily, each administration lasting approximately 20 minutes, for 14 days.

[0041] In the carbaspirin calcium nasal spray treatment group (hydrocephalus + carbaspirin calcium nasal spray from Example 2), rats were anesthetized and kept in a supine position with their necks slightly elevated to 45°. The drug solution was loaded into an Aptar nebulizer. A total dose of 30 mg / kg / day was administered bilaterally alternately through both nostrils, with each nostril containing 20 μL of the solution, with an interval between administrations to ensure absorption. This procedure was performed twice daily, each administration lasting approximately 20 minutes, for 14 days.

[0042] Two weeks after drug treatment, rats in all groups underwent magnetic resonance imaging (MRI). The ventricular enlargement phenotype was assessed by calculating the ratio of ventricular volume to total brain volume. MRI image analysis results are as follows: Figures 4-5 As shown, rats in the hydrocephalus group exhibited significant ventricular dilation compared to the control group, displaying typical characteristics of hydrocephalus, and the difference was statistically significant. The degree of ventricular dilation in the carbaspirin calcium nasal drop treatment group was significantly lower than that in the hydrocephalus group, and the difference was statistically significant, indicating that carbaspirin calcium nasal drops have a therapeutic effect on communicating hydrocephalus in rats. Similarly, the degree of ventricular dilation in the carbaspirin calcium nasal spray treatment group was significantly lower than that in the hydrocephalus group, and the difference was statistically significant, indicating that carbaspirin calcium nasal spray has a therapeutic effect on communicating hydrocephalus in rats.

[0043] To clarify the exposure mode and active ingredient of carbaspirin calcium in brain tissue after intranasal administration, the pharmacokinetic characteristics of carbaspirin calcium were studied in Sprague-Dawley rats. Sprague-Dawley rats were randomly divided into 6 groups (n=4), and carbaspirin calcium solution was prepared and administered intranasally at a concentration of 30 mg / kg. Brain tissue samples were collected at predetermined times (10 min, 0.5 h, 1 h, 4 h, 8 h, and 16 h). Each brain tissue sample (50 mg) was mixed with pre-cooled deionized water, ethyl acetate, and anhydrous sodium sulfate. Magnetic beads were added to the mixed tissue sample, and the mixture was ground at 4°C for 30 s, incubated overnight at -80°C, centrifuged, and the supernatant was dried to dryness. The supernatant was reconstituted with an equal proportion of methanol and water, vortexed, and centrifuged for analysis. In addition to the above samples, blank brain tissue and carbaspirin calcium were used to prepare standards for calibration. As described above, carbaspirin calcium was added to blank brain tissue (50 mg) extract to make its final concentrations 0.2, 0.5, 1, 2, 5, 50 and 100 µg / mL to construct a standard curve for quantification of brain tissue samples, and then all reference samples were subjected to the same instrumentation procedure as described above.

[0044] The instrument used was a Q Exactive HF Orbitrap ultra-high resolution ultra-high performance liquid chromatograph. The column was an ACQUITY UPLC BEH C18 1.7 μm. The mobile phase was a 6:4 volume methanol:water mixture containing formic acid and ammonium acetate, filtered through a 0.22 μm filter, and degassed ultrasonically for 15 min; the solution was freshly prepared and used immediately. The mobile phase flowed through the column at a rate of 300 μL / min. The injection volume was 5 μL. The mass spectrometer was set at m / z with positive ion (ESI)... + ) mode or negative ion (ESI) - It runs in mode ).

[0045] The time-dependent drug delivery process in tissues after intranasal administration was fitted using WinNonlin 8.3.5 pharmacokinetic software. Pharmacokinetic parameters were calculated using a non-compartmental model. Results are shown in [Figure number missing]. Figures 6-7 See Table 4. Results are expressed as mean ± standard deviation. T max Peak time; C max Peak concentration; HL_Lambda_z: Elimination half-life; AUCINF_obs: Observed 0→∞ time AUC; AUC_% Extrap_obs: AUC extrapolation percentage.

[0046] Table 4 Pharmacokinetic Parameter Results

[0047] The results showed that aspirin (ASA) rapidly entered brain tissue after administration, with a peak time (T0) of [missing information]. max The peak concentration (C) was 0.5 h. max The concentration of ASA was 0.76 µg / mL, after which it rapidly decreased, with an elimination half-life (HL_Lambda_z) of 8.59 h. The extrapolated portion of its AUC curve (AUC_% Extrap_obs) was 28.9%, suggesting that ASA has poor stability in brain tissue, and some of the drug may have undergone hydrolysis within the tissue or during the assay. In contrast, salicylic acid (SA) has a Tg... max For 1.0h, C max The concentration of carbaspirin calcium in the brain was 14.14 µg / mL, and the area under the curve (AUCINF_obs) was 118.42 h·µg / mL, approximately 15 times that of ASA. Furthermore, the extrapolation ratio was only 0.96%, indicating that the exposure assessment results were highly reliable. In summary, the data show that intranasally administered carbaspirin calcium is rapidly converted to SA after entering brain tissue. SA constitutes the main form of drug exposure in the brain and may bear the main pharmacological effect, while the exposure level of the parent drug ASA in brain tissue is low and its stability is limited.

[0048] Test example: The specific steps for investigating the effects of saline on hydrocephalus in zebrafish juveniles are as follows: (1) Preparation of zebrafish fry; Wild-type zebrafish were all obtained from the China Zebrafish Resource Center and were routinely cared for at 28±0.5℃ under 14h light / 10h dark conditions. Zebrafish embryos were obtained after natural mating of wild-type zebrafish. The obtained zebrafish embryos were washed and stored in E3 culture medium containing 2mg / L methylene blue. During this period, the pH of the culture medium was maintained at 7.1, and the culture medium was changed daily.

[0049] The E3 culture medium consists of 5 mM NaCl, 0.17 mM KCl, 0.33 mM CaCl2, and 0.33 mM MgSO4, along with 75 μM PTU. PTU (phenylthiourea) is a Tyr (tyrosinase) inhibitor that inhibits melanin production in zebrafish embryos, increasing their optical transparency and facilitating better microscopic imaging for research.

[0050] (2) Experimental grouping and treatment; a. Blank control group: Zebrafish embryos at 6h (6hpf) were randomly transferred to 24-well cell culture plates, with 15 zebrafish embryos in each well. 1mL of E3 culture medium was added to ensure that all 6hpf zebrafish embryos were in E3 culture medium. The culture medium was changed every 24h.

[0051] b. Hydrocephalus group: 6 hpf zebrafish embryos were randomly transferred to 24-well cell culture plates, with 15 6 hpf zebrafish embryos per well. Then, 5 μg / mL of GRI977143 solution was added to expose all 6 hpf zebrafish embryos to the solution to induce hydrocephalus in zebrafish. The GRI977143 solution was changed every 24 hours.

[0052] c. Hydrocephalus + SA group: 6 hpf zebrafish embryos were randomly transferred to 24-well cell culture plates, with 15 6 hpf zebrafish embryos per well. Then, 5 μg / mL of GRI977143 solution was added to expose all 6 hpf zebrafish embryos to the solution. When the embryos developed to 24 h (24 hpf), SA solution was added to make the SA concentration 40 μM. The GRI977143 solution concentration was maintained at 5 μg / mL. The solution was changed every 24 h.

[0053] (3) Zebrafish ventricle imaging; When the zebrafish embryos reached 72 hours (72 hpf), each group of embryos was embedded in low-melting-point agarose for later use. After adjusting the stereomicroscope, images of the zebrafish ventricles were acquired. The size of the ventricles was measured using ImageJ software, and the statistical results are as follows: Figure 10 As shown, the area of ​​the fourth ventricle in zebrafish in the hydrocephalus group was significantly increased compared to the blank control group; after SA treatment, the area of ​​the fourth ventricle significantly recovered, as shown in the figure. Figure 11 As shown, this demonstrates that salicylic acid has a significant effect in treating hydrocephalus.

[0054] Therefore, this invention utilizes the application of the aforementioned drug in the prevention or treatment of hydrocephalus. Carbaspirin calcium and its metabolites can significantly reduce ventricular enlargement in hydrocephalus model rats, and carbaspirin calcium and its metabolites show promise in the preparation of drugs for treating hydrocephalus, providing an effective candidate drug to alleviate the suffering of hydrocephalus patients, reduce treatment risks and costs; thus broadening the scope of action of carbaspirin calcium. The formulation of the carbaspirin calcium solution has been optimized, with the most stable formulation being: pH 6.5 and EDTA-2Na percentage of 0.02%.

[0055] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can still be made to the technical solutions of the present invention, and these modifications or equivalent substitutions cannot cause the modified technical solutions to deviate from the spirit and scope of the technical solutions of the present invention.

Claims

1. The application of a drug in the prevention or treatment of hydrocephalus, characterized in that: The drug comprises a pharmaceutically acceptable formulation of one or more of the following active ingredients: compound A, compound B, or compound C, and their pharmaceutically acceptable salts, solvates, or crystal forms, wherein: Compound A is calcium carbaspirin, with the structural formula shown in Formula I: Formula I; Compound B is aspirin, and its structural formula is shown in Formula II: Formula II; Compound C is salicylic acid, and its structural formula is shown in Formula III: Formula III.

2. The application of the drug according to claim 1 in the prevention or treatment of hydrocephalus, characterized in that: The pharmaceutically acceptable salts include one or more of the following: sodium salt, potassium salt, lithium salt, calcium salt, magnesium salt, ammonium salt, methylamine salt, ethylamine salt, diethylamine salt, triethylamine salt, tris(hydroxymethyl)aminomethane salt, N-methylglucamine salt, lysine salt, arginine salt, or ornithine salt.

3. The application of the drug according to claim 1 in the prevention or treatment of hydrocephalus, characterized in that: The solvates include one or more of the following: monohydrate, dihydrate, trihydrate, solvates formed with methanol, ethanol, propanol, isopropanol, propylene glycol, polyethylene glycol, or solvates formed with ethyl acetate, acetone, acetonitrile, 1,4-dioxane, tetrahydrofuran, N,N-dimethylformamide, or dimethyl sulfoxide.

4. The application of the drug according to claim 1 in the prevention or treatment of hydrocephalus, characterized in that: The crystal form includes one or more of the following: the amorphous crystal form, the hydrated crystal form, and the solvated crystal form of compound A, compound B, and compound C.

5. The application of the drug according to claim 1 in the prevention or treatment of hydrocephalus, characterized in that: The drug dosage form includes one of oral preparations, nasal preparations, or injections.

6. The application of the drug according to claim 5 in the prevention or treatment of hydrocephalus, characterized in that: Oral preparations include one of the following: tablets, capsules, granules, oral solutions, or oral suspensions.

7. The application of the drug according to claim 5 in the prevention or treatment of hydrocephalus, characterized in that: Nasal delivery formulations include one of the following: nasal drops, nasal sprays, nasal powders, nasal gels, or adhesive formulations.

8. The application of the drug according to claim 5 in the prevention or treatment of hydrocephalus, characterized in that: Injectables include one of the following: water-soluble injections, fat emulsions, microemulsions, long-acting sustained-release microspheres, or implants.

9. The application of the drug according to claim 1 in the prevention or treatment of hydrocephalus, characterized in that: The effective dose of the drug, based on the subject's body weight, is 0.1-100 mg / kg / day.

10. A kit for preparing a combination pharmaceutical composition for the prevention or treatment of hydrocephalus, characterized in that: The kit includes a first pharmaceutical composition and a second pharmaceutical composition, which are used simultaneously or in staggered combinations, wherein: The first pharmaceutical composition comprises one or more of compound A, compound B or compound C included in any one of claims 1-9, and a pharmaceutically acceptable carrier or excipient; The second pharmaceutical composition includes one or more of acetazolamide, furosemide, topiramate, corticosteroids, and MMP-9 inhibitors, as well as a pharmaceutically acceptable carrier or excipient.

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