Application of combined use of baicalin and magnesium ions in preparation of nasal cavity medicine for treating cerebral apoplexy, and pharmaceutical composition for treating cerebral apoplexy

Abstract

The invention provides application of combined use of baicalin and magnesium ions in preparation of nasal cavity medicines for treating cerebral apoplexy. The invention also provides a pharmaceutical composition for treating cerebral apoplexy. The bioavailability of baicalin and magnesium ions in the brain is improved. Magnesium ions can block calcium ions and inhibit glutamic acid excitatory toxicity in the stroke incidence process, and baicalin has multiple biological activities such as inflammation resistance, oxidation resistance and neuroprotection. Experiments prove that the combined application of magnesium ions and baicalin prolongs the survival time, neurological scoring, weight recovery and behavioral improvement of cerebral apoplexy model mice; when the two medicines are combined for use, after respective dosages are halved, the treatment effect on cerebral apoplexy is stronger than that of a single medicine.

Description

Technical Field

[0001] The present invention relates to the use of baicalin in combination with magnesium ions in the preparation of a nasal drug for the treatment of stroke, and a pharmaceutical composition for the treatment of stroke, belonging to the field of pharmaceuticals. Background Art

[0002] At present, the clinical treatment methods for stroke are limited and the effects are not ideal. When traditional therapeutic drugs reach the brain lesions through blood circulation, they are often blocked by the blood-brain barrier, resulting in a low effective concentration of the drug in the brain and a greatly reduced therapeutic effect. Therefore, it is of great clinical significance to develop a new method that can efficiently and safely deliver therapeutic drugs to the brain, improve the bioavailability of the drug in the brain, and thus effectively treat stroke.

[0003] Nasal administration, as a non-invasive administration route, can bypass the blood-brain barrier, enable the drug to directly enter the brain, avoid the first-pass effect of the drug in the liver, and improve the bioavailability of the drug. Baicalin is a flavonoid compound extracted from the traditional Chinese medicine Scutellaria baicalensis Georgi, which has various biological activities such as anti-inflammatory, antioxidant, and neuroprotective effects, and has potential application value in the treatment of stroke. However, the poor water solubility of baicalin limits its application and bioavailability in preparations. Nanocrystal technology can reduce the particle size of the drug to the nanometer level, increase the specific surface area of the drug, improve the solubility and dissolution rate of the drug, and thus improve the bioavailability of the drug. At the same time, as an excellent drug carrier, hydrogel has good biocompatibility, degradability, and sustained-release performance, can prolong the residence time of the drug in the nasal cavity, and improve the absorption efficiency of the drug.

[0004] Magnesium ions can inhibit glutamate excitotoxicity and calcium overload. Shen Fei, et al., Potential neuroprotective effects of magnesium in ischemic stroke, Chinese Journal of Clinical Rehabilitation, Vol. 28, 2004. Animal experiments have confirmed that magnesium can extend the treatment time window and significantly reduce the infarct volume after acute cerebral ischemia. Some small-sample clinical studies have also shown the neuroprotective effect of magnesium. The latest large-scale international study found that magnesium is beneficial for lacunar stroke, while another prospective study showed that magnesium deficiency increases the incidence of stroke. Ou Cehua, et al., Experimental study on the neuroprotective effect of magnesium preconditioning on global cerebral ischemia in rabbits, Sichuan Journal of Zoology, Vol. 3, 2009, explored the neuroprotective effect and its mechanism of magnesium sulfate preconditioning on global cerebral ischemia in rabbits. However, at present, intravenous injection is mostly used for administration, resulting in its inability to rapidly reach the peak concentration in the brain and affecting the therapeutic effect.

[0005] Application No.: 202210337091.2, Invention Title: A Nasal Administration Thermosensitive In-situ Gel Preparation of Scutellarin Magnesium and Its Preparation Method, discloses a nasal administration thermosensitive in-situ gel of scutellarin magnesium and its preparation method, which uses scutellarin magnesium as the raw material drug, poloxamer 407 and poloxamer P188 as the matrix, and hydroxypropyl-β-cyclodextrin as the absorption promoter. The mass concentrations of each component are: scutellarin magnesium 0.5% - 15%, poloxamer 407 17% - 25%, poloxamer 188 0% - 2%, and hydroxypropyl-β-cyclodextrin 0% or 0.5%. The raw material used in this literature is the scutellarin magnesium compound. Scutellarin (C21H18O12), also known as scutellarin II, is derived from the leaves of the Lamiaceae plant Scutellaria altissima L., the stems and leaves of Scutellaria baicalensis Georgi, and the whole herb of Scutellaria barbata D. Don, etc. The aglycone is scutellarein, and the glycosyl group is glucose. 21 H 18 O 11 ) is the characteristic flavonoid glycoside of Scutellaria baicalensis, its aglycone is baicalein, and the glycosyl group is glucuronic acid; the hydroxyl substitution sites of the two are significantly different (baicalin: 6-OH, 7-O-glucuronic acid; scutellarin: 4'-OH, 5,6,7-OH), resulting in differences in physical and chemical properties (such as liposolubility, membrane permeability) and action mechanisms. The treatment of stroke with baicalin is mainly through strong anti-inflammatory and antioxidant effects; while the core mechanism of scutellarin is to selectively inhibit the PDE4D enzyme, increase the cAMP level to improve cerebral microcirculation, and at the same time promote angiogenesis by regulating VEGF. The two have different focuses on the intervention targets of the key signaling pathways in the treatment of stroke, and there is clear evidence of mechanism classification. At the same time, scutellarin also has a certain clinical basis in the treatment of stroke, while the use of baicalin in stroke is still in the pre-research stage.

[0006] Application No.: 201610068926.3, Invention Title: A Baicalin Magnesium Compound and Its Preparation Method and Its Use, relates to a baicalin magnesium compound, and also relates to the preparation method and extraction method of the baicalin magnesium compound. The preparation method includes steps such as preparing a baicalin suspension, preparing a magnesium ion-containing suspension, reaction and drying, etc.; the extraction method includes steps such as macroporous adsorption resin pretreatment, extraction, adsorption and elution, concentration and drying, purification, etc. The baicalin magnesium prepared in the present invention restores the existence mode of baicalin in Scutellaria baicalensis and can be used as a substitute for baicalin in medicine. The administration method disclosed in this patent literature is oral administration. Among them, the mass ratio of baicalin to magnesium ion in baicalin magnesium is: 53:3.

[0007] Except for the reports of the above compounds, there is no report on the nasal administration of baicalin and magnesium ions in the form of a composition for the treatment of stroke. Summary of the invention

[0008] The technical scheme of the present invention is to provide the use of baicalin and magnesium ions in combination in the preparation of nasal medicine for treating stroke, and a pharmaceutical composition for treating stroke

[0009] The present invention provides use of baicalin in combination with magnesium ions in preparing a nasal medicine for treating stroke, wherein the weight ratio of baicalin to magnesium ions is 4.6-0.21:1.

[0010] Preferably, the weight ratio of baicalin to magnesium ions is 0.57:1.

[0011] The present invention provides a pharmaceutical composition for treating cerebral stroke, which is prepared from the following raw materials in weight ratio:

[0012] 4.6-0.21 parts of baicalin and 1 part of magnesium ion.

[0013] Preferably, it is prepared from the following raw materials in weight ratio:

[0014] 0.57 parts of baicalin and 1 part of magnesium ion.

[0015] The invention is prepared from baicalin and magnesium ion as active ingredients, and pharmaceutically acceptable auxiliary materials or auxiliary ingredients are added to form a commonly used pharmaceutical nasal preparation.

[0016] Among them, the nasal preparations are nasal drops, nasal washes, nasal aerosols, nasal sprays, nasal ointments, and nasal gels.

[0017] The nasal gel is prepared by encapsulating baicalin nanocrystals with magnesium ion hydrogel, wherein the preparation method of the magnesium ion hydrogel is as follows: weighing sodium alginate in ultrapure water to fully dissolve it; placing it in a dialysis bag with a molecular cutoff of 3500, placing the dialysis bag in MgCl 2 The solution was dialyzed for 12 hours to obtain magnesium alginate gel;

[0018] The baicalin nanocrystals are prepared by dissolving baicalin in an organic solvent to form a baicalin solution, then dropping the baicalin solution into an aqueous phase containing a surfactant, and obtaining the baicalin nanocrystals by high-speed stirring or ultrasonic treatment.

[0019] Wherein, the organic solvent is ethanol; the surfactant is one or more of TW80, HPMC, SDS, TPGS, and PVPK30.

[0020] The present invention also provides a preparation method of the pharmaceutical composition for treating stroke, which comprises the following steps:

[0021] a. Preparing baicalin nanocrystals: Dissolve baicalin in an organic solvent to form a baicalin solution, and then drop the baicalin solution into an aqueous phase containing a surfactant, and obtain baicalin nanocrystals through high-speed stirring or ultrasonic treatment;

[0022] b. Preparing magnesium ion gel: Weigh sodium alginate in ultrapure water and dissolve it fully. Place it in a dialysis bag with a molecular cut-off of 3500, and place the dialysis bag in a MgCl 2 solution for dialysis for 12 hours to obtain magnesium alginate gel;

[0023] c. Mixing: Mix the baicalin nanocrystals and the magnesium ion gel and stir evenly to obtain a baicalin nanocrystal composite magnesium ion gel.

[0024] Wherein, the organic solvent is ethanol, and the surfactant is one or more of TW80, HPMC, SDS, TPGS, and PVPK30; the rotation speed of the high-speed stirring is 600 - 1200 r / min, and the stirring time is 15 - 120 min; the power of the ultrasonic treatment is 100 W, and the ultrasonic time is 0 - 30 min.

[0025] The present invention prepares baicalin into nanocrystals and uses magnesium ion hydrogel as a carrier for nasal administration, and is expected to develop a new preparation for treating stroke with high efficiency and safety.

[0026] Through a large number of previous experiments, the present invention has screened out the optimal process for preparing baicalin nanocrystals, and prepared a gel dosage form by compounding with magnesium ions. While improving the solubility and bioavailability of baicalin, the two are combined to play a synergistic role. At the same time, the safety and tolerance are good, the single drug dosage is reduced, the adverse reactions are reduced, the recovery of the patient's nerve function is promoted, the disability rate and mortality rate are reduced, and the prognosis of the patient is effectively improved. Description of the Drawings

[0027] Figure 1 Survival curve of MCAO mice after nasal instillation of drugs;

[0028] Figure 2 Comparison of body weight data and neurological scores of each group;

[0029] Figure 3 Open field test and rotarod test 7 days after administration;

[0030] Figure 4 Survival curve of MCAO mice after nasal instillation of drugs;

[0031] Figure 5 Neurological score graphs and body weight data changes of each group of mice after 7 days;

[0032] Figure 6 Open field test and rotarod test after 7 days of drug administration;

[0033] Figure 7 Baicalin nanocrystals;

[0034] Figure 8 Particle size result graph of baicalin nanocrystals;

[0035] Figure 9 Baicalin nanocrystal composite magnesium ion gel;

[0036] Figure 10 In vivo imaging result graph. Specific implementation manners

[0037] The following are the sources of the raw and auxiliary materials used in the present invention:

[0038] Baicalin: Shanghai Yuanye Bio-Technology Co., Ltd.

[0039] Tween 80: Chengdu Kelong Chemical Co., Ltd.

[0040] Hydroxypropyl methylcellulose: Shanghai Aladdin Biochemical Technology Co., Ltd.

[0041] Sodium dodecyl sulfate: Chengdu Kelong Chemical Co., Ltd.

[0042] Vitamin E polyethylene glycol succinate: Shanghai Aladdin Biochemical Technology Co., Ltd.

[0043] Polyvinylpyrrolidone K30: Chengdu Kelong Chemical Co., Ltd.

[0044] Magnesium chloride: Fuchen (Tianjin Chemical Reagent Co., Ltd.)

[0045] Sodium alginate: Chengdu Kelong Chemical Co., Ltd.

[0046] Test Example 1 Baicalin-magnesium ion synergistic effect test

[0047] The purpose of this test is to explore whether the therapeutic effects of nasal instillation of baicalin and magnesium ions on stroke model mice are superior to those of single agents. The stroke model of animals uses the commonly used tMCAO model in pharmacological experiments. After different drugs are given to tMCAO model mice through the nasal cavity, the body weight changes, survival time, neurological scores, and behavioral observation results are detected. The differences between different drugs and the model group are compared, and the significance of the differences is tested. At the same time, the differences between the drug combination group and the single drug administration group are compared, indicating that the drug combination has a better therapeutic effect on stroke than a single drug.

[0048] Experimental animals: Kunming mice, healthy adult males, weighing 25 - 30 g. The mice were randomly divided into groups of 15 each. In this experiment, there were 3 drug - administered groups and 1 model group. Throughout the experiment, the animals had access to sufficient food and water. The light - dark cycle of the feeding environment was 12 h (lights on at 07:00), room temperature was 21℃ ± 1℃, and humidity was 55% ± 5%. The experimental groups were as follows:

[0049] (1) Blank group: Sham operation was performed without adding drugs as a control

[0050] Model group: The MCAO model was established by the suture method without adding drugs as a control;

[0051] (2) Single drug: The MCAO model was established by the suture method, and nasal administration was carried out at a dose of 38 mg / kg of baicalin;

[0052] (3) Single drug: The MCAO model was established by the suture method, and nasal administration was carried out at a dose of 38 mg / kg of magnesium ions;

[0053] (4) Magnesium ion - baicalin drug combination: The MCAO model was established by the suture method, and administration was carried out according to the following dosage components: baicalin 20 mg / kg, magnesium ions 18 mg / kg.

[0054] Experimental procedure:

[0055] After the mice were acclimatized for 7 days, they were grouped. 12 h before the experiment, the mice were fasted but given water. After anesthesia, a nylon suture was inserted into the right internal carotid artery to block the middle cerebral artery. After 30 min of cerebral ischemia, the suture was removed to establish reperfusion. Nasal drip administration was carried out 30 min later for 7 days. At the same time, the body weight changes before modeling, 1 d, 2 d, 3 d, 5 d, and 7 d after modeling, as well as the survival time of the mice, were recorded. After 7 days, neurological scoring, open - field test, and rotarod test were performed. For those still alive at the end of the observation period, it was calculated as 168 h. The survival extension rate of each group was calculated according to the following formula.

[0056] Survival time = Death time - Modeling time

[0057] Extension rate = (Survival time of the drug - administered group - Survival time of the model group) / Survival time of the model group * 100%

[0058] After neurological scoring of the surviving mice on the 7th day, the scoring criteria were based on the Longa scoring method. Three experimenters used the Longa scoring method to conduct neurobehavioral scoring on the mice. Scoring criteria: 0 points: normal mice, without significant symptoms of neurobehavioral impairment. 1 point: increased muscle tone in the left forepaw or reduced grasping force of the left forepaw. 2 points: the mouse showed left-sided circling when moving on the platform. 3 points: the mouse showed left-sided circling when moving on the platform and had a tendency to fall. 4 points: the mouse had no obvious spontaneous activity. Open field test: The mouse was placed in the center of a dark open field (40 cm × 40 cm × 40 cm) and allowed to adapt to the environment for 2 min. The movement trajectory of the freely moving mouse was recorded for 10 min using a camera, and the number of entries into the center and the time were calculated. Each time the experiment was conducted, the floor and walls of the experimental device were thoroughly cleaned with 75% ethanol to eliminate any olfactory cues. Rotarod test: The mouse was placed on a rotating rod, and the speed was accelerated from 40 rpm to 5 rpm within 5 min. The duration of the mouse's stay on the rotating rod was recorded. Before tMCAO, the mice received 3 days of pre-training until they all reached the baseline: the duration on the rotating rod was approximately 350 s. After tMCAO, each animal was tested 3 times a day, and the average duration was calculated.

[0059] Experimental results:

[0060] The survival time, body weight change, neurological score, and behavioral results of MCAO mice are shown in (Table 1, Figure 1-3 ). The baicalin administration group, magnesium ion administration group, and magnesium ion-baicalin administration group had varying degrees of improvement in the survival time, body weight change, neurological score, and behavioral results of tMCAO mice (compared with the model group: *, p < 0.05; **, p < 0.005). At the same time, the results of the magnesium ion-baicalin administration group were also better than those of the single administration group, and the difference was statistically significant (#, P < 0.05). According to the results, the therapeutic effect of the magnesium ion-baicalin administration group on MACO mice was better than that of the single administration group.

[0061] Table 1 Survival time of MACO mice after nasal instillation of drugs

[0062]

[0063] Experimental Example 2 Screening of the optimal administration formula of baicalin-magnesium ion

[0064] The purpose of this experiment is to screen the optimal formulations of two drugs. Each group was administered drugs at the same dose but different weight ratios to treat stroke model mice. Group 1 was converted according to the molar ratio of baicalin magnesium salt in the existing invention. After administering the drugs to the modeled mice through nasal cavity, the body weight changes, neurological scores, survival time, and behavior were detected. The mathematical method of one-way analysis of variance with multiple comparisons was used to compare the differences between different drug groups (*, p < 0.05; **, p < 0.005; ***, P < 0.001) to test the significance of the differences.

[0065] Table 2 Dose grouping of mice

[0066]

[0067] The experimental results are as follows: After administration, the survival time of mice was prolonged to a certain extent in each group, and the seventh group had the best effect.

[0068] Table 3 Survival time of MCAO mice after nasal drip of drugs

[0069]

[0070] The survival curve of MCAO mice after nasal drip of drugs is as Figure 4 shown.

[0071] Compared with the model group, the neurological function scores of mice in each group with different ratios of baicalin - magnesium ion decreased to varying degrees after 7 days of administration. Among them, the neurological function score of the seventh group (0.57:1) decreased most significantly, and the effect of reducing neurological function damage was the best (see Figure 5 ). According to the changes in body weight data 7 days after modeling, the seventh group had the best recovery effect.

[0072] The results of the open - field experiment 7 days after administration showed that, compared with the model group, after administration with different weight ratios, the number of times and time of mice crossing the central area increased significantly. Among them, the seventh group of mice had the strongest exploratory desire and had a significant difference from the model group. The rotarod test is often used to evaluate the motor coordination and balance ability of mice. The experimental results showed that, compared with the model group, after administration with different ratios, the staying time of mice on the rotating rod became longer, and the motor coordination and balance ability were improved to a certain extent, and the difference was statistically significant. Among them, the seventh group had the strongest motor coordination and balance ability (see Figure 6 ).

[0073] Experimental conclusion: Administration at a molar ratio of 1:2 (i.e., a weight ratio of 53:3) can treat MCAO mice to a certain extent. However, the therapeutic effect is better when the weight ratio of baicalin to magnesium ion is in the range of 4.6 - 0.21:1. Among them, when the weight ratio is 0.57:1, that is, 20 parts of baicalin and 36 parts of magnesium ion, the therapeutic effect is the most significant.

[0074] Single-factor investigation on the preparation of baicalin nanocrystals in Test Example 3

[0075] Baicalin nanocrystals were prepared by ultrasonic-assisted antisolvent-solvent precipitation method. 1 mL of baicalin ethanol solution was injected into 10 - 50 mL of water containing 0.5 - 2 mg / mL of stabilizer (TW80, HPMC, SDS, TPGS, PVPK30), and magnetically stirred at a speed of 600 - 1200 r / min for 15 - 120 min to obtain baicalin nanocrystals.

[0076] Table 4 Single-factor experimental variables for the preparation process of baicalin nanocrystals

[0077]

[0078] Test results:

[0079] Table 5 Results of single-factor investigation on the preparation process of baicalin nanocrystals

[0080]

[0081] Test conclusion:

[0082] In this test, the particle size of baicalin nanocrystals was used as the evaluation index, and the effects of different factors and different ratios of preparation conditions on the particle size of nanocrystals were evaluated in turn, including the type of stabilizer, the amount of stabilizer, the amount of antisolvent, stirring time, stirring speed, and ultrasonic time. At the same time, other preparation parameters were controlled at the same level. When the stabilizer was 0.5 mg / ml of HPMC, the amount of antisolvent was 20 mL, and magnetically stirred at a speed of 800 r / min for 15 min, it was a light yellow clear solution (see Figure 7 ), and the particle size remained at a relatively small level (see Figure 8 ).

[0083] Baicalin has poor solubility and low bioavailability. It is necessary to use nanopharmaceutical technology to improve its solubility and increase its bioavailability. The prepared baicalin nanocrystals have significantly improved solubility and increased drug release.

[0084] Test Example 4 Preparation of baicalin nanocrystal composite magnesium ion gel

[0085] Magnesium alginate was obtained from sodium alginate by ion exchange with magnesium chloride. The specific steps are as follows: 100 mg of NaAlg was dissolved in 10 mL of ultrapure water, and dialyzed against 1.5 L of 0.5 M MgCl 2 solution for 12 hours at 25 °C. Subsequently, using a dialysis bag with a molecular weight cut-off of 3500 Da, the sample was purified with 2 L of ultrapure water, and Mg(OH) 2Adjust the pH value of the solution to 8.0, and this process lasts for 36 hours. During this period, the dialysis fluid is changed four times. Finally, the obtained product is freeze-dried. Mix the above baicalin nanocrystals with magnesium alginate gel and stir evenly to obtain baicalin nanocrystal composite magnesium ion gel (see Figure 9 ).

[0086] Experimental Example 5 In vivo imaging experiment of nanocrystal composite gel

[0087] An in vivo imaging experiment was used to study the sustained-release effect of the nanocrystal composite gel. A nanocrystal composite gel was prepared using Cy7 fluorescent dye, and it was administered intranasally to mice together with an aqueous solution of Cy7. The sustained-release effect of the nanocrystal composite gel was studied by comparing the fluorescence signal intensity of in vivo imaging.

[0088] Experimental results: As Figure 10 shown, the Cy7 nanocrystal composite gel still had strong fluorescence 3 hours after administration, indicating that the nasal residence time of the drug was prolonged, while the fluorescence signal of the Cy7 aqueous solution significantly weakened after 3 hours. This composite preparation uses the gel as a carrier, which can extend the adhesion time of the drug in the nasal cavity and maintain the effective blood drug concentration. At the same time, the continuously released drug can bypass the blood-brain barrier through the nose-brain pathway and effectively accumulate in the lesion site, forming a multi-target treatment network for pathological processes such as oxidative stress, inflammation, and excitotoxicity, and synergistically enhancing the effect.

Claims

1. Use of baicalin in combination with magnesium ions in the preparation of a nasal medicine for treating stroke, wherein: The weight ratio of baicalin to magnesium ion is 4.6-0.21:

1.

2. The use according to claim 1, characterized in that: The weight ratio of baicalin to magnesium ion is 0.57:

1.

3. A pharmaceutical composition for treating stroke, characterized in that: It is prepared from the following raw materials in weight ratio: 4.6-0.21 parts of baicalin and 1 part of magnesium ion.

4. The pharmaceutical composition for treating stroke according to claim 3, characterized in that: It is prepared from the following raw materials in weight ratio: 0.57 parts of baicalin and 1 part of magnesium ion.

5. The pharmaceutical composition for treating stroke according to claim 3 or 4, characterized in that: The invention is prepared from baicalin and magnesium ion as active ingredients, and pharmaceutically acceptable auxiliary materials or auxiliary ingredients are added to form a commonly used pharmaceutical nasal preparation.

6. The pharmaceutical composition for treating stroke according to claim 5, characterized in that: The nasal preparations are nasal drops, nasal washes, nasal aerosols, nasal sprays, nasal ointments and nasal gels.

7. The pharmaceutical composition for treating stroke according to claim 6, characterized in that: The nasal gel is prepared by encapsulating baicalin nanocrystals with magnesium ion hydrogel, wherein the preparation method of the magnesium ion hydrogel is as follows: weighing sodium alginate in ultrapure water to fully dissolve it; placing it in a dialysis bag with a molecular cutoff of 3500, placing the dialysis bag in a MgCl2 solution for dialysis for 12 hours to obtain magnesium alginate gel; The baicalin nanocrystals are prepared by dissolving baicalin in an organic solvent to form a baicalin solution, then dropping the baicalin solution into an aqueous phase containing a surfactant, and obtaining the baicalin nanocrystals by high-speed stirring or ultrasonic treatment.

8. The pharmaceutical composition for treating stroke according to claim 7, characterized in that: The organic solvent is ethanol; the surfactant is one or more of TW80, HPMC, SDS, TPGS, and PVPK30.

9. A method for preparing the pharmaceutical composition for treating stroke according to any one of claims 3 to 7, characterized in that: It includes the following steps: a. preparing baicalin nanocrystals: dissolving baicalin in an organic solvent to form a baicalin solution, then dropping the baicalin solution into an aqueous phase containing a surfactant, and obtaining baicalin nanocrystals by high-speed stirring or ultrasonic treatment; b. Preparation of magnesium ion gel: Weigh sodium alginate in ultrapure water to fully dissolve it; place it in a dialysis bag with a molecular cutoff of 3500, and place the dialysis bag in a MgCl2 solution for dialysis for 12 hours to obtain magnesium alginate gel; c. Mixing: The baicalin nanocrystals and the magnesium ion gel are mixed and stirred evenly to obtain the baicalin nanocrystals composite magnesium ion gel.

10. The method for preparing the pharmaceutical composition for treating stroke according to claim 9, characterized in that: The organic solvent is ethanol, the surfactant is one or more of TW80, HPMC, SDS, TPGS, and PVPK30; the rotation speed of the high-speed stirring is 600-1200 r / min, and the stirring time is 15-120 min; the power of the ultrasonic treatment is 100 W, and the ultrasonic time is 0-30 min.

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