Pharmaceutical composition, preparation as well as preparation method and application of pharmaceutical composition

Abstract

The invention provides a pharmaceutical composition, a preparation as well as a preparation method and application of the pharmaceutical composition. The pharmaceutical composition comprises bilobalide B and dextroborneol, the weight ratio of the bilobalide B to the dextroborneol is (0.02 to 50): 1. In the pharmaceutical composition disclosed by the invention, bilobalide B and dextroborneol can play a synergistic effect, and the pharmaceutical composition has an excellent effect, small side effects and an excellent clinical application prospect when being used for treating cerebral arterial thrombosis; the traditional Chinese medicine composition is novel in formula, simple in component, clear in action mechanism, remarkable in curative effect, not prone to tolerance generation and capable of achieving large-scale industrial production.

Description

Technical Field

[0001] This invention relates to a pharmaceutical composition, formulation, preparation method thereof, and use thereof. Background Technology

[0002] Cerebral ischemic stroke, also known as cerebral infarction, is a syndrome caused by impaired blood supply to the brain, leading to ischemia and hypoxia, resulting in necrosis and softening of brain tissue. Clinically, it mainly manifests as sudden focal or diffuse neurological deficits. Ischemic stroke is characterized by high incidence, high recurrence rate, high disability rate, and high mortality rate. Its prognosis is related to the severity of neurological deficits, age, and etiology. With timely treatment, some patients may recover some motor and sensory functions. Currently, treatment strategies for ischemic stroke mainly focus on two aspects: one is treatment aimed at improving blood supply, including thrombolysis, vasodilation, and endovascular therapy; the other is inhibiting the pathophysiological cascade induced by ischemic injury, i.e., neuroprotective therapy. However, the translational results of neuroprotective agents for stroke in clinical trials are currently poor, and the efficacy of single neuroprotective targets is unsatisfactory.

[0003] Dextroborneol ((+)-bomeol) is the main component of natural borneol (the 2020 edition of the Chinese Pharmacopoeia stipulates that the content of dextroborneol in natural borneol shall not be less than 96%). It is a bicyclic monoterpene compound found in the volatile oils of many traditional Chinese medicines. Dextroborneol can regulate the NF-κB and p38 signaling pathways, inhibit inflammatory neuroinflammation, and reduce various pro-inflammatory factors (TNF-α, IL-1β, etc.) and inflammatory proteins (iNOS and COX-2) in the brain (Eur J Pharmacol, 2014.740:p.522-31; Eur J Pharmacol, 2017.811:p.1-11). In addition, it can also stimulate inhibitory GABAAR receptors, which can regulate neuroexcitatory damage (Front Pharmacol, 2021.12:p.606682). As a traditional Chinese medicine, borneol has a wide range of clinical applications and is currently often used as an adjuvant in the treatment of cardiovascular and cerebrovascular diseases. Borneol is a cold-natured drug with some toxicity. Excessive dosage can irritate the gastrointestinal tract, potentially causing nausea, vomiting, and abdominal pain. It can also excite the central nervous system, leading to convulsions, loss of consciousness, spasms, and even respiratory failure and death. The chemical structure of dextroborneol is as follows:

[0004]

[0005] Ginkgolide B is an active ingredient extracted from the natural medicine ginkgo leaves. It has few side effects and strong activity, and is the strongest platelet-activating factor antagonist discovered to date. However, it is expensive, making its clinical use too costly.

[0006] To date, no literature reports have been found regarding the combination of ginkgolide B and dextroborneol for the prevention and / or treatment of ischemic stroke. Summary of the Invention

[0007] To address the problems and / or deficiencies of existing technologies, the present invention aims to provide a pharmaceutical composition, formulation, preparation method, and uses thereof. In the pharmaceutical composition of the present invention, ginkgolide B and dextroborneol exhibit a synergistic effect. This pharmaceutical composition demonstrates excellent efficacy in the prevention and / or treatment of ischemic stroke, with minimal side effects and promising clinical application prospects. The pharmaceutical composition of the present invention features a novel formulation, simple components, a clear mechanism of action, significant efficacy, and low tolerance, enabling large-scale industrial production.

[0008] During the research process, the inventors of this application discovered that the combination of ginkgolide B and dexborneol can more effectively prevent and / or treat ischemic stroke. The mechanisms of action are complementary, exerting a synergistic effect, thereby reducing the side effects caused by the use of large amounts of dexborneol. It can also reduce the use of ginkgolide B, reduce costs, and achieve better therapeutic effects with a smaller dosage.

[0009] The present invention provides a pharmaceutical composition comprising ginkgolide B and dextroborneol; wherein the weight ratio of ginkgolide B to dextroborneol is (0.02-50):1.

[0010] In this invention, the weight ratio of ginkgolide B to dextromethorphanol can be 0.02:1, 0.05:1, 0.1:1, 1:1, 2:1, 4:1, 5:1, 6:1, 10:1, 20:1 or 50:1; preferably (1-10):1, more preferably (2-6):1.

[0011] The present invention also provides a method for preparing the above-mentioned pharmaceutical composition, which includes the following steps: taking raw materials in each weight ratio and mixing them with a solvent.

[0012] In this invention, the solvent may be propylene glycol. The amount of solvent used may be conventional in the art, and the volume ratio of the solvent to the raw material is preferably 1:(2-51), for example 1:2, 1:3, 1:5, 1:6, 1:7, 1:11, 1:21 or 1:51, more preferably 1:(2-11).

[0013] The present invention also provides a pharmaceutical formulation comprising the above-described pharmaceutical composition and pharmaceutically acceptable excipients.

[0014] In this invention, the pharmaceutically acceptable excipients can be commonly used excipients in pharmaceutical preparations in the art, or conventional selections, and generally may include one or more of the following: starch, pregelatinized starch, lactose, sucrose, talc, dextrin, cyclodextrin, microcrystalline cellulose, croscarmellose sodium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, croscarmellose, glucose, meglumine, magnesium stearate, dextran, glycerin, ethanol, propylene glycol, polyethylene glycol, mannitol, sorbitol, xylitol, cellulose vegetable oil, sodium benzoate, sodium salicylate, hydrochloric acid, citric acid, sodium citrate, sodium dihydrogen phosphate, disodium hydrogen phosphate, gelatin, lecithin, and vitamin C.

[0015] In this invention, the pharmaceutical preparation may be in the form of tablets, capsules, soft capsules, oral liquids, granules, pills, drop pills, powders, ointments, elixirs, injections, suppositories, patches, drops, sprays, creams, suspensions, tinctures, emulsions, water injections, powder injections, targeted preparations, sustained-release preparations, or controlled-release preparations.

[0016] In this invention, the pharmaceutical preparation can be prepared using conventional processes in the art.

[0017] The present invention also provides the use of the above-mentioned pharmaceutical composition or pharmaceutical preparation in the preparation of a medicament for ischemic stroke.

[0018] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0019] The reagents and raw materials used in this invention are all commercially available.

[0020] The positive and progressive effects of this invention are as follows:

[0021] This invention combines ginkgolide B with dexborneol, which can exert a synergistic effect, effectively inhibiting cerebral infarction and improving neurological function. In clinical application, the dosage of dexborneol and ginkgolide B can be reduced, thus lowering costs, and the clinical application prospects are excellent.

[0022] The pharmaceutical composition of this invention has a novel formulation, simple components, a clear mechanism of action, significant therapeutic effect, and is not prone to inducing tolerance, making it suitable for large-scale industrial production. Detailed Implementation

[0023] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0024] In the embodiments of the present invention, ginkgolide B was purchased from Jiangsu Kangyuan Pharmaceutical Co., Ltd., batch number 230101; dexborneol was purchased from Sigma, product number 139114, batch number 100103795.

[0025] In the following examples, "1 part" corresponds to 0.4 mL.

[0026] Example 1

[0027] (1) Composition:

[0028] Ginkgolide B1 parts

[0029] 1 part of dextroborneol

[0030] Pharmaceutically acceptable conventional excipients

[0031] (2) Preparation method:

[0032] After mixing the above-mentioned ginkgolide B and dextromethorphanol in the specified proportion, add 0.4 mL of propylene glycol and sonicate until fully dissolved. Before administration, add physiological saline to make up to 50 mL and vortex to mix well for later use.

[0033] Pharmaceutically acceptable excipients are added and the mixture is prepared into pills using conventional processes.

[0034] Example 2

[0035] (1) Composition:

[0036] Ginkgolide B 2 parts

[0037] 1 part of dextroborneol

[0038] Pharmaceutically acceptable conventional excipients

[0039] (2) Preparation method:

[0040] After mixing the above-mentioned ginkgolide B and dextromethorphanol in the specified proportion, add 0.4 mL of propylene glycol and sonicate until fully dissolved. Before administration, add physiological saline to make up to 50 mL and vortex to mix well for later use.

[0041] It is prepared into capsules or soft capsules by adding pharmaceutically acceptable conventional excipients and following conventional processes.

[0042] Example 3

[0043] (1) Composition:

[0044] Ginkgolide B 4 parts

[0045] 1 part of dextroborneol

[0046] Pharmaceutically acceptable conventional excipients

[0047] (2) Preparation method:

[0048] After mixing the above-mentioned ginkgolide B and dextromethorphanol in the specified proportion, add 0.4 mL of propylene glycol and sonicate until fully dissolved. Before administration, add physiological saline to make up to 50 mL and vortex to mix well for later use.

[0049] The tablets are prepared by adding pharmaceutically acceptable excipients and following conventional processes.

[0050] Example 4

[0051] (1) Composition:

[0052] Ginkgolide B 5 parts

[0053] 1 part of dextroborneol

[0054] Pharmaceutically acceptable conventional excipients

[0055] (2) Preparation method:

[0056] After mixing the above-mentioned ginkgolide B and dextromethorphanol in the specified proportion, add 0.4 mL of propylene glycol and sonicate until fully dissolved. Before administration, add physiological saline to make up to 50 mL and vortex to mix well for later use.

[0057] It is prepared into an oral liquid by adding pharmaceutically acceptable excipients and following conventional processes.

[0058] Example 5

[0059] (1) Composition:

[0060] Ginkgolide B 6 parts

[0061] 1 part of dextroborneol

[0062] Pharmaceutically acceptable conventional excipients

[0063] (2) Preparation method:

[0064] After mixing the above-mentioned ginkgolide B and dextromethorphanol in the specified proportion, add 0.4 mL of propylene glycol and sonicate until fully dissolved. Before administration, add physiological saline to make up to 50 mL and vortex to mix well for later use.

[0065] Pharmaceutically acceptable excipients are added and the product is prepared into drop pills using conventional processes.

[0066] Example 6

[0067] (1) Composition:

[0068] Ginkgolide B1 parts

[0069] 10 parts of dextroborneol

[0070] Pharmaceutically acceptable conventional excipients

[0071] (2) Preparation method:

[0072] After mixing the above-mentioned ginkgolide B and dextromethorphanol in the specified proportion, add 0.4 mL of propylene glycol and sonicate until fully dissolved. Before administration, add physiological saline to make up to 50 mL and vortex to mix well for later use.

[0073] The product is prepared into a spray by adding pharmaceutically acceptable excipients and following conventional processes.

[0074] Example 7

[0075] (1) Composition:

[0076] Ginkgolide B10 parts

[0077] 1 part of dextroborneol

[0078] Pharmaceutically acceptable conventional excipients

[0079] (2) Preparation method:

[0080] After mixing the above-mentioned ginkgolide B and dextromethorphanol in the specified proportion, add 0.4 mL of propylene glycol and sonicate until fully dissolved. Before administration, add physiological saline to make up to 50 mL and vortex to mix well for later use.

[0081] It is prepared into a water-based injection or a powder injection by adding pharmaceutically acceptable conventional excipients and following conventional processes.

[0082] Example 8

[0083] (1) Composition:

[0084] Ginkgolide B 20 parts

[0085] 1 part of dextroborneol

[0086] Pharmaceutically acceptable conventional excipients

[0087] (2) Preparation method:

[0088] After mixing the above-mentioned ginkgolide B and dextromethorphanol in the specified proportion, add 0.4 mL of propylene glycol and sonicate until fully dissolved. Before administration, add physiological saline to make up to 50 mL and vortex to mix well for later use.

[0089] Pharmaceutically acceptable excipients are added and the formulation is prepared into a sustained-release or controlled-release formulation using conventional processes.

[0090] Example 9

[0091] (1) Composition:

[0092] Ginkgolide B 50 parts

[0093] 1 part of dextroborneol

[0094] Pharmaceutically acceptable conventional excipients

[0095] (2) Preparation method:

[0096] After mixing the above-mentioned ginkgolide B and dextromethorphanol in the specified proportion, add 0.4 mL of propylene glycol and sonicate until fully dissolved. Before administration, add physiological saline to make up to 50 mL and vortex to mix well for later use.

[0097] The targeted formulation is prepared by adding pharmaceutically acceptable excipients and using conventional processes.

[0098] Example 10

[0099] (1) Composition:

[0100] Ginkgolide B1 parts

[0101] 20 parts of dextroborneol

[0102] Pharmaceutically acceptable conventional excipients

[0103] (2) Preparation method:

[0104] After mixing the above-mentioned ginkgolide B and dextromethorphanol in the specified proportion, add 0.4 mL of propylene glycol and sonicate until fully dissolved. Before administration, add physiological saline to make up to 50 mL and vortex to mix well for later use.

[0105] It is prepared into granules or suspensions by adding pharmaceutically acceptable excipients and following conventional processes.

[0106] Example 11

[0107] (1) Composition:

[0108] Ginkgolide B1 parts

[0109] 50 parts of dextroborneol

[0110] Pharmaceutically acceptable conventional excipients

[0111] (2) Preparation method:

[0112] After mixing the above-mentioned ginkgolide B and dextromethorphanol in the specified proportion, add 0.4 mL of propylene glycol and sonicate until fully dissolved. Before administration, add physiological saline to make up to 50 mL and vortex to mix well for later use.

[0113] It is prepared into granules or suspensions by adding pharmaceutically acceptable excipients and following conventional processes.

[0114] Efficacy Study of the Drug in Acute Ischemic Stroke (Example)

[0115] 1. Materials and Methods

[0116] 1.1 Laboratory Animals

[0117] One hundred and fifty male Sprague-Dawley (SD) rats, SPF grade, weighing (210-230) g, were provided by Sprague-Dawley (Suzhou) Biotechnology Co., Ltd.

[0118] Environmental adaptation period after entering the laboratory: Before entering the laboratory, the rats were allowed to adapt to the environment for 3 days and underwent relevant examinations, including: general condition of the animals and weight. All rats entering the experiment were healthy and qualified animals.

[0119] 1.2 Experimental Drugs

[0120] All proportions below are by weight. Ginkgolide B; dextroborneol; butylphthalide (China National Institutes for Food and Drug Control, batch number: 101035-201903).

[0121] Composition 1 (Ginkgolide B: Dextroborneol = 1:1)

[0122] Composition 2 (Ginkgolide B: Dextroborneol = 2:1)

[0123] Composition 3 (Ginkgolide B: Dextroborneol = 4:1)

[0124] Composition 4 (Ginkgolide B: Dextroborneol = 5:1)

[0125] Composition 5 (Ginkgolide B: Dextroborneol = 6:1)

[0126] Composition 6 (Ginkgolide B: Dextroborneol = 1:10)

[0127] Composition 7 (Ginkgolide B: Dextroborneol = 10:1)

[0128] Composition 8 (Ginkgolide B: Dextroborneol = 20:1)

[0129] Composition 9 (Ginkgolide B: Dextroborneol = 50:1)

[0130] Composition 10 (Ginkgolide B: Dextroborneol = 1:20)

[0131] Composition 11 (Ginkgolide B: Dextromethorphanol = 1:50)

[0132] 1.3 Main Reagents and Instruments

[0133] 1.3.1 Main Reagents

[0134]

[0135] 1.3.2 Main Instruments and Equipment

[0136] Electronic balance (Sartorius Scientific Instruments, model BS224S); Low-temperature centrifuge (Eppendorf, Germany, model 5804R); Purified water system (Milli-Q Plus, Germany); Animal weighing scale (Shanghai Xiangchuan Electronic Weighing Instrument Co., Ltd., model CX-SC-DA).

[0137] 1.4 Modeling Method

[0138] 1.4.1 Anesthesia protocol and preparation

[0139] Anesthetic drugs: Sutacetin 50, Xylazine Hydrochloride Injection;

[0140] Anesthesia dosage: 40 mg / kg Sutacetin + 5 mg / kg Xylazine hydrochloride, per 1 mL of combined anesthetic solution.

[0141] Table 1. Combined anesthesia regimen of Shutai and Xerazine hydrochloride

[0142]

[0143] 1.4.2 MCAO Model Preparation

[0144] Rats were given a combined intraperitoneal injection of a combination of acetaminophen and xylazine hydrochloride anesthetic. After anesthesia, the animals were transferred to a rat board for fixation, the hair on their necks was shaved, and the rat skin was cut along the midline with scissors to a length of about 2 cm. Approaching the rat from the right side of the neck, the muscles on the right side of the neck were bluntly dissected and retracted with forceps to expose the right common carotid artery (CCA). The CCA was then dissected upwards to expose the external carotid artery (ECA) and internal carotid artery (ICA). The proximal end of the CCA was ligated with sutures, temporarily clamping the ICA and ECA. A suture was threaded from the ligation site of the CCA to the temporary closure site of the ICA, and a loose knot (pre-ligation) was tied for later use. A small incision was made proximal to the pre-ligation. The suture plug was inserted through the incision in the CCA and then slowly and gently pushed into the internal carotid artery, stopping at the arterial clamp of the ICA. The pre-ligation suture was further tightened (to avoid excessive bleeding when pushing the suture plug). The arterial clamps blocking blood flow in the ICA and the ECA were then removed. The suture plug was pushed into the ICA, stopping when slight resistance was encountered, and the time was recorded. After observing the sutured incision without active bleeding, the ischemic rats were placed at room temperature and the suture embolus was slowly removed after 120 min of ischemia to achieve reperfusion of the middle cerebral artery.

[0145] Group 2 design and dosing information

[0146] 2.1 Group Design

[0147] 150 SD rats were randomly divided into 15 groups of 10 rats each: (1) model group, (2) positive drug butylphthalide group, (3) ginkgolide B group, (4) dextroborneol group, (5) composition 1 group, (6) composition 2 group, (7) composition 3 group, (8) composition 4 group, (9) composition 5 group, (10) composition 6 group, (11) composition 7 group, (12) composition 8 group, (13) composition 9 group, (14) composition 10 group, (15) composition 11 group.

[0148] 2.2 Dosage Information

[0149] The dosing information for each group is as follows:

[0150] Table 2. Dosage information for each group

[0151]

[0152] Administration route: slow injection via tail vein;

[0153] Dosage frequency and cycle: Administer once immediately after reperfusion on the day of surgery (within 10 minutes), and once each at 24 hours and 48 hours postoperatively, for a total of 3 administrations.

[0154] The day of model creation is defined as D0 (Day 1).

[0155] 3. Rats' neurological function scores

[0156] Testing time: 1 day (D1) and 3 days (D3) after modeling;

[0157] Animals to be tested: All surviving laboratory animals for which testing is planned;

[0158] Testing methods: Motor function tests, sensory tests, balance tests, and reflex and abnormal movement tests were conducted on the animals, with specific reference to the Rat Neurological Score (NSS).

[0159] Table 3. Rat Neurological Function Scoring Scale (NSS)

[0160]

[0161] 4. Animal dissection and TTC staining

[0162] 4.1 Anatomical Information

[0163] Dissection time: 3 days after drug administration (D3).

[0164] Animals dissected: All surviving animals included in the study.

[0165] Anesthesia method: The rats to be dissected were anesthetized with 10% chloral hydrate (intraperitoneal injection, 0.4 mL / 100 g), and then euthanized by exsanguination of the abdominal aorta.

[0166] 4.2 Evaluation of TTC staining

[0167] After euthanizing the animals, the brains were quickly removed and frozen at -20°C until the brain tissue hardened. The rat brains were then cut into 2mm thick slices, with the slices positioned from the olfactory bulb backward, for a total of 6 slices. Each slice was placed in a six-well plate containing 2% TTC solution (prepared with PBS solution) and then incubated in a 37°C incubator in the dark for 15–20 minutes.

[0168] Normal tissue appears rose-red after staining, while infarcted tissue appears white. Each brain plane was placed sequentially on filter paper with a ruler attached. After photographing, the infarct area was calculated using ImageJ image processing software. The infarct area was defined as the percentage of the total brain area covered by the infarcted tissue. The inhibition rate (%) of each drug treatment group was then calculated based on the infarct area. The formula for calculating the inhibition rate is as follows:

[0169]

[0170] 5. Statistical Analysis

[0171] The measured indicators are expressed as mean ± standard deviation. Data were entered and statistically analyzed using Excel 2307 and GraphPad Prism 8 software.

[0172] 6. Test Results

[0173] 6.1 Effects of each drug group on the extent of cerebral infarction in model animals

[0174] The TTC staining results of brain tissue from each group of animals at the experimental endpoint showed that the model animals had significant cerebral infarction, and the infarct size was calculated for each group. Compared with the model group, the positive control group (butylphthalide) showed a good effect in reducing the infarct size (P<0.001), while the groups treated with ginkgolide B (GB) and dextroborneol (YCK) also showed some improvement in the infarct size of the model animals (P<0.05). The infarct size of animals in the treatment groups of compositions 1–11 was significantly reduced compared with that of the model control group (P<0.05, P<0.01, P<0.001). The corresponding infarct inhibition rates of each composition treatment group were 21.78%, 29.56%, 40.17%, 28.87%, 24.91%, 13.62%, 13.03%, 16.66%, 16.35%, 17.25%, and 16.84%, respectively.

[0175] The results above indicate that GB, YKC, and the combination therapy all have significant ameliorative effects on cerebral infarction, and the combination therapy, when used in combination, has a superior anti-infarction effect compared to GB and YKC alone. Among them, the effect of combination therapy 3 was the most significant (P<0.001), comparable to the therapeutic effect of the positive control drug. The extent of cerebral infarction and the cerebral infarction inhibition rate in animals are shown in Table 4.

[0176] Table 4. Infarct extent and infarct inhibition rate in each group of animals

[0177]

[0178] Note: All data in the table are expressed as mean ± standard deviation (Mean ± SD); “N” represents the number of animals in each group for statistical analysis, “—” indicates that there is no data for this item, * indicates P < 0.05 compared with the model control group, ** indicates P < 0.01 compared with the model control group, and *** indicates P < 0.001 compared with the model control group.

[0179] 6.2 Effects of each drug group on the neurological and behavioral scores of model animals

[0180] Neurobehavioral function of the animals was evaluated using the NSS scoring scale on days 1 and 3 post-modeling, and the neurological function improvement effect of each drug group was assessed. There was no significant difference in NSS scores among the groups on day 1 post-surgery. On day 3 post-surgery, the NSS scores of all groups were lower than on day 1 post-surgery. Specifically, the scores of GB, YKC, and combinations 8, 9, 10, and 11 were significantly lower than the model control group (P<0.05). The scores of combinations 5, 6, and 7 were also significantly different from the model control group (P<0.01). Furthermore, the NSS scores of the positive control drug butylphthalide group and combinations 2, 3, and 4 were even lower than the model group (P<0.001).

[0181] The above results suggest that the combined use of GB and YCK (combination) has a significant repairing effect on neurological function damage in MCAO rats. The NSS scores of each group are shown in Table 5.

[0182] Table 5. Animal behavioral scores for each group

[0183]

[0184]

[0185] Note: All data in the table are expressed as mean ± standard deviation (Mean ± SD). * indicates P < 0.05 compared with the model control group, ** indicates P < 0.01 compared with the model control group, and *** indicates P < 0.001 compared with the model control group.

[0186] 7. Experimental Conclusions

[0187] This experiment used the classic MCAO ischemia-reperfusion model with suture occlusion to conduct pharmacodynamic studies on GB, YKC, and GB+YKC against ischemic stroke. After 120 minutes of ischemia in the middle cerebral artery of rats, the suture occlusion was removed to simulate vascular recanalization. The first drug intervention was administered immediately upon reperfusion, followed by once-daily treatment for a total of three times. Three days post-surgery, changes in infarct size and NSS score were used to evaluate the protective effect of each drug against ischemic stroke in rats. The results showed that:

[0188] Compared with the model group, the cerebral infarction range and neurological function scores of the ginkgolide B (GB) group, dextroborneol (YKC) group, and ginkgolide B + dextroborneol (GB + YKC) groups were significantly reduced (P < 0.05, P < 0.01, P < 0.001), indicating that all compositions of the present invention have a significant ameliorative effect on cerebral infarction. Compared with GB and YKC alone, GB + YKC showed a higher cerebral infarction inhibition rate and a lower neurological function score, indicating that GB and YKC had a synergistic effect.

[0189] Among the various groups of GB+YKC compositions, compositions 1, 2, 3, 4, 5, and 7 show better effects, compositions 2, 3, 4, and 5 are even better, and composition 3 shows the best effect. Therefore, the preferred ratio of ginkgolide B to dextromethorphanol in this invention is (1-10):1, more preferably (2-6):1, and most preferably 4:1. When the ratio of GB to YKC in the composition is (1-10):1, the amount of GB is higher and the amount of YKC is lower, resulting in a significantly higher cerebral infarction inhibition rate (19.49-40.17%). The neurological function scores at GB to YKC ratios of 1–10:1 (7.5±0.75, 7.25±0.42, 6.60±0.57, 7.30±0.63, 7.55±0.76, 7.65±0.47, 7.70±0.48) were significantly lower than those at GB to YKC ratios of 7.90±0.46 (7.95±0.55) at GB to YKC ratios of 7.90±0.46 (7.95±0.55). This indicates that within this ratio range, the synergistic effect of GB and YKC is very significant.

[0190] In summary, this invention combines ginkgolide B with dextroborneol in an animal model of ischemic stroke. The results show that the two have a synergistic effect and excellent therapeutic effect on ischemic stroke. The pharmaceutical composition of ginkgolide B and dextroborneol in this invention can effectively inhibit cerebral infarction and improve neurological function damage, with significant effects and excellent prospects for clinical application.

[0191] The above embodiments of the present invention are merely examples to clearly illustrate the present invention and are not intended to limit the implementation of the present invention. Those skilled in the art can make other variations or modifications based on the above description. It is neither necessary nor possible to exhaustively describe all embodiments here. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. A pharmaceutical composition, characterized in that, It includes ginkgolide B and dextroborneol; the weight ratio of ginkgolide B to dextroborneol is (0.02-50):

1.

2. The pharmaceutical composition according to claim 1, characterized in that, The weight ratio of ginkgolide B to dextromethorphanol is (1-10):

1.

3. The pharmaceutical composition according to claim 2, characterized in that, The weight ratio of ginkgolide B to dextromethorphan is (2-6):

1.

4. The pharmaceutical composition according to claim 3, characterized in that, The weight ratio of ginkgolide B to dextromethorphan is 4:

1.

5. A method for preparing a pharmaceutical composition according to any one of claims 1-4, characterized in that, It includes the following steps: Simply take the raw materials in the specified weight ratios and mix them with the solvent.

6. The preparation method according to claim 5, characterized in that, The solvent is propylene glycol; the volume ratio of the solvent to the raw material is 1:(2-51), preferably 1:(2-11).

7. A pharmaceutical preparation, characterized in that, It includes the pharmaceutical composition as described in any one of claims 1-4 and pharmaceutically acceptable excipients.

8. The pharmaceutical preparation according to claim 7, characterized in that, The pharmaceutically acceptable excipients include one or more of the following: starch, pregelatinized starch, lactose, sucrose, talc, dextrin, cyclodextrin, microcrystalline cellulose, croscarmellose sodium, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospovidone, glucose, meglumine, magnesium stearate, dextran, glycerin, ethanol, propylene glycol, polyethylene glycol, mannitol, sorbitol, xylitol, cellulose vegetable oil, sodium benzoate, sodium salicylate, hydrochloric acid, citric acid, sodium citrate, sodium dihydrogen phosphate, disodium hydrogen phosphate, gelatin, lecithin, and vitamin C.

9. The pharmaceutical preparation according to claim 7, characterized in that, The pharmaceutical preparations described herein are in the form of tablets, capsules, soft capsules, oral liquids, granules, pills, drop pills, powders, ointments, elixirs, injections, suppositories, patches, drops, sprays, creams, suspensions, tinctures, emulsions, water injections, powder injections, targeted preparations, sustained-release preparations, or controlled-release preparations.

10. Use of a pharmaceutical composition as described in any one of claims 1-4 or a pharmaceutical preparation as described in any one of claims 7-9 in the preparation of a medicament for ischemic stroke.

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