Pharmaceutical composition for improving neurological symptoms of stroke patients and preparation method thereof

Abstract

The invention provides a pharmaceutical composition for improving neurological symptoms of cerebral apoplexy patients and a preparation method thereof, active ingredients comprise pentoxifylline, honokiol and borneol, and in the pharmaceutical composition, the weight ratio of pentoxifylline to honokiol to borneol is (10-15): (4-6): (6-10); the preferable weight ratio is (11-13): (4-6): (6-8); the most preferable weight ratio is 12: 5: 7, and the effect of the composition is obviously superior to that of pentoxifylline or honokiol or natural borneol or a combination of the pentoxifylline or honokiol or natural borneol with the same dosage.

Description

Technical Field

[0001] The present invention belongs to the technical field of medicine, and particularly relates to a pharmaceutical composition for improving neurological symptoms of stroke patients and a preparation method thereof. Background Art

[0002] Stroke is one of the main causes of disability and death in humans. In China, there are more than 2 million new stroke patients every year, and with the aggravation of the aging problem, the incidence rate is still increasing. And acute ischemic stroke patients account for more than 70% of all strokes. Patients suffer from the disease due to the stenosis or blockage of cerebral artery blood vessels, resulting in ischemic and hypoxic necrosis of brain tissue. Stroke patients all have varying degrees of neurological function impairment symptoms, often accompanied by hemiplegia, language disorders, cognitive disorders; dysphagia, etc., which have a serious impact on the daily living ability of patients.

[0003] Pentoxifylline is a methylxanthine derivative and a non-specific phosphodiesterase inhibitor, which can improve hemorheology, including reducing blood and plasma viscosity, reducing plasma fibrinogen, promoting fibrinolysis, and can improve blood permeability in tissues by enhancing the dilatability of red blood cells and reducing the activation of neutrophils. The structure is shown as follows. It is mainly used for improving cerebral circulation after ischemic cerebrovascular diseases, such as the treatment of chronic occlusive vasculitis with intermittent claudication, etc., and the clinical effect is remarkable.

[0004] Honokiol is isolated from the bark of Magnolia officinalis, a small molecular weight natural bisphenol compound derived from magnolia bark, and has a variety of pharmacological activities. It has analgesic, anti-inflammatory, antioxidant, anti-tumor and neuroprotective effects. It also has the ability to cross the blood-brain barrier, showing anti-anxiety and anti-depression and improving memory deficits induced by cerebral ischemia / reperfusion. The structural formula is as follows.

[0005] Among borneols, natural borneol has the best effect. However, due to resource limitations, synthetic borneol is mostly used in traditional Chinese medicines to replace natural borneol. In addition, since the minimum content of dextrorotatory borneol in natural borneol is 96%, and it still contains a certain amount of impurities, which may affect the drug safety. Therefore, people have purified natural borneol, and currently, commercially available (+)-2-camphanol with a purity ≥ 98% is available.

[0006] There is no report in the prior art on the combined use of pentoxifylline, honokiol and borneol for the treatment of nervous system diseases, especially for improving the neurological symptoms of stroke patients. Summary of the Invention

[0007] The inventor of the present invention unexpectedly found in the research that the pharmaceutical composition of pentoxifylline, honokiol and borneol has a synergistic effect and can significantly improve neurological diseases, especially the motor disorders and cognitive impairments of stroke patients, providing a new idea for safely, effectively and economically improving the neurological symptoms of stroke patients clinically.

[0008] The purpose of the present invention is to provide a pharmaceutical composition for improving the neurological symptoms of stroke patients. The active ingredients are composed of pentoxifylline, honokiol and borneol. This pharmaceutical composition has a synergistic effect and can significantly improve the neurological symptoms of stroke patients.

[0009] To achieve the above purpose, the present invention adopts the following technical scheme: A pharmaceutical composition for improving the neurological symptoms of stroke patients, the active ingredients are composed of pentoxifylline, honokiol and borneol.

[0010] In the said pharmaceutical composition, the weight ratio of pentoxifylline, honokiol and borneol is 10-15:4-6:6-10; preferably the weight ratio is 11-13:4-6:6-8; the most preferred weight ratio is 12:5:7.

[0011] In the said pharmaceutical composition, the purity of honokiol is not less than 98%, preferably not less than 98.5%, more preferably not less than 99%.

[0012] In the said pharmaceutical composition, borneol is preferably natural borneol, and more preferably natural borneol with the content of camphene hydrate not less than 98%.

[0013] The above pharmaceutical composition of the present invention can be made into various dosage forms suitable for clinical administration by using any suitable excipients according to the commonly used methods well known in the pharmaceutical field.

[0014] Preferably, the above pharmaceutical composition may further contain pharmaceutically acceptable excipients and be prepared into oral preparations or injections; the oral preparations are selected from capsules, tablets, granules, oral liquids; the injections are selected from sterile powders for injection, aqueous injections, sodium chloride or glucose intravenous infusions, and are further preferably made into oral preparations In the above pharmaceutical composition, the pharmaceutically acceptable excipients include additives, and the additives are selected from at least one of fillers, diluents, disintegrants, binders, lubricants, glidants, surfactants, solvents, flavoring agents, preservatives.

[0015] The fillers or diluents described above include saccharides such as lactose, sucrose, glucose, mannitol, sorbitol, dextrin; starches such as starch, pregelatinized starch, α-starch, dextrin; celluloses such as microcrystalline cellulose, gum arabic, dextran; inorganic salts such as calcium sulfate, calcium hydrogen phosphate, medicinal calcium carbonate, light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, magnesium aluminum silicate.

[0016] The lubricants or glidants or anti-adhesives described above include stearic acid; metal salts of stearic acid such as calcium stearate or magnesium stearate; talc powder; colloidal silica; microcrystalline silica gel, hydrogenated vegetable oil; polyethylene glycol, lauryl sulfates such as sodium lauryl sulfate or magnesium lauryl sulfate; silicates such as silicon anhydride or hydrated silicate salts, etc.

[0017] The binders described above include distilled water, ethanol of different concentrations, starch paste, hydroxypropyl methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, ethyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, polyethylene glycol, and compounds similar to the above excipients.

[0018] The disintegrants described above include cellulose derivatives such as low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose or cross-linked sodium carboxymethyl cellulose; cross-linked polyvinylpyrrolidone; and chemically modified starches / celluloses, such as carboxymethyl starch or sodium carboxymethyl starch.

[0019] The surfactants described above include Tween-80, sodium dodecyl sulfate, sodium stearyl sulfonate, etc.

[0020] The antioxidants described above include sodium bisulfite, sodium metabisulfite, sodium sulfite, anhydrous sodium sulfite, sodium thiosulfate, ascorbic acid, methionine, thiourea, phosphoric acid, citric acid, etc.

[0021] The preservatives or antibacterial agents described above include benzoic acid and sodium benzoate, sorbic acid, ethanol, parabens (parabens), benzalkonium bromide, o-phenylphenol, benzyl alcohol, phenethyl alcohol, sodium propionate, sorbic acid, eucalyptus oil, cinnamon oil, and peppermint oil, etc.

[0022] The flavoring agents described above include sweeteners such as sodium saccharin, aspartame, syrup, stevioside, mannitol, sorbitol, mannose, galactose, maltose, fructose, glucose, sucrose, etc.; sour flavoring agents such as citric acid, malic acid or tartaric acid; and flavoring agents such as anise oil, peppermint oil, menthol, peppermint water, cinnamon oil, lemon essence, lemon oil, and various flavored spices, etc.

[0023] The present invention further provides a preparation method of the above drug composition.

[0024] A preparation method of a pharmaceutical composition for improving neurological symptoms of stroke patients, comprising the step of mixing active ingredients with pharmaceutically acceptable excipients.

[0025] Another object of the present invention is to provide the application of the above pharmaceutical composition, that is, the application of the pharmaceutical composition in the preparation of a drug for improving neurological symptoms of stroke patients.

[0026] Compared with the prior art, the present invention has the following advantages: The present invention firstly discovers that combining pentoxifylline, honokiol, and natural borneol in a specific dosage ratio can effectively improve the neurological score of stroke model rats, and the effect is significantly better than that of pentoxifylline or honokiol or natural borneol or their combination at the same dose, which indicates that combining pentoxifylline, honokiol, and natural borneol has a significant synergistic effect.

[0027] The pharmaceutical composition of the present invention can be developed into a drug for treating and improving neurological symptoms of stroke patients, and is expected to have good social and economic benefits. Detailed implementation manners

[0028] The present invention discloses a pharmaceutical composition for treating and improving neurological symptoms of stroke patients and its preparation method. Those skilled in the art can draw on the content of the present invention and, in combination with the relevant principles of pharmaceutics and pharmacology, appropriately modify the process parameters to achieve it. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are all considered to be included within the scope of the present invention. The application of the present invention has been described through preferred embodiments, and those skilled in the art can obviously make changes or appropriate modifications and combinations to the methods and applications described herein without departing from the content, spirit, and scope of the present invention to implement and apply the technology of the present invention.

[0029] For a better understanding of the present invention rather than limiting its scope, all numbers representing dosages, percentages, and other numerical values used in this application should be understood to be modified by the word "about" in all cases. Each numerical parameter should be regarded as obtained at least according to the reported significant figures and by the conventional rounding method.

[0030] Natural borneol: The content of d-borneol is 98.8%.

[0031] Artificial borneol: The content of l-borneol is 88.9%.

[0032] Synthetic borneol: The content of borneol is 63.5%.

[0033] Honokiol: The content is 99.1%.

[0034] Test example: Neurological function test of stroke mice 1 Animal experiment materials 1.1 Drugs: The test drugs are: pentoxifylline, natural borneol, synthetic borneol (synthetic camphor), honokiol, pentoxifylline + natural borneol composition, pentoxifylline + honokiol composition, pentoxifylline + honokiol + natural borneol composition, pentoxifylline + honokiol + synthetic borneol composition.

[0035] 1.2 Experimental animals and grouping Animals: SPF-grade Wistar rats, male, weighing 270 - 300 g.

[0036] The experimental animals were divided into 10 groups: normal control group, model control group, positive drug group (edaravone 2.5 mg / kg + d-camphene hydrate 0.5 mg / kg), and 10 dosing groups of the present invention, with 8 rats in each group.

[0037] The 10 dosing groups of the present invention are: ① pentoxifylline group at 30 mg / kg, ② natural borneol group at 30 mg / kg, ③ synthetic borneol group at 30 mg / kg, ④ honokiol group at 30 mg / kg, ⑤ pentoxifylline 15 mg / kg + natural borneol 15 mg / kg composition, ⑥ pentoxifylline 15 mg / kg + honokiol 15 mg / kg composition, ⑦ pentoxifylline 15 mg / kg + honokiol 6.25 mg / kg + natural borneol 8.75 mg / kg composition, ⑧ pentoxifylline 15 mg / kg + honokiol 6.25 mg / kg + synthetic borneol 8.75 mg / kg composition, ⑨ pentoxifylline 15 mg / kg + honokiol 10 mg / kg + natural borneol 5 mg / kg composition, ⑩ pentoxifylline 15 mg / kg + honokiol 5 mg / kg + natural borneol 10 mg / kg composition Model establishment: Anesthetize with 10% chloral hydrate (350 mg / kg) by intraperitoneal injection, fix in the dorsal position, make a median incision in the neck, separate the common carotid artery, ligate the proximal end of the common carotid artery, clamp the distal end with an artery clamp, make a "V"-shaped incision with a diameter of about 2 mm between the two, gently insert a nylon thread into the common carotid artery from the incision, release the artery clamp, and insert the nylon thread into the internal carotid artery through the bifurcation of the internal carotid artery and the external carotid artery, slowly push the nylon thread in the direction of the internal carotid artery entering the cranial cavity, insert to a depth of about 18.5 ± 0.5 mm until slight resistance is felt, so that the tip of the nylon thread passes through the origin of the middle cerebral artery to block the entrance of the middle artery and cause ischemia. After 2 hours of ischemia, remove the ligature and perform reperfusion for 24 hours. In the normal control group, the insertion depth of the ligature is about 12.0 ± 0.5 mm but without blocking blood flow, and the rest is the same.

[0038] After the model establishment was completed, gavage administration was immediately started. Before each daily gavage experiment, the mice in each group were weighed, and the dosage was calculated based on the body weight. In the 10 groups of the drug administration group of the present invention, gavage was performed with 60 mg / kg of the drug or drug combination, and in the positive drug group, edaravone 2.5 mg / kg + dextrorotatory borneol 0.5 mg / kg was administered by gavage. The normal control group and the model control group were given corresponding volumes of normal saline by gavage once a day for 28 consecutive days.

[0039] 1.3 Neurological deficit score: The rats were subjected to behavioral scoring according to the Longa 5-point scoring standard 28 days later.

[0040] 2. Test results Note: ※※ P < 0.01, compared with the normal control group (C57BL / 6) Note: *P < 0.05, **P < 0.01, compared with the model control group Note: # P < 0.05, compared with pentoxifylline 30 mg / kg Note: & P < 0.05, compared with the positive control group As can be seen from the table: (1) Compared with the normal control group (C57BL / 6), the neurological score of the model control group increased significantly (p < 0.01), showing a very significant difference, indicating that the ischemic stroke model was successfully established.

[0041] (2) Compared with the model control group, the neurological score of the positive drug edaravone dextrorotatory borneol group decreased significantly (p < 0.01), showing a very significant difference; indicating that edaravone dextrorotatory borneol can improve the neurological symptoms of stroke patients (3) Compared with the model control group, the neurological score of the pentoxifylline group decreased significantly (p < 0.01), showing a very significant difference; indicating that the use of pentoxifylline alone can improve the neurological symptoms of stroke patients.

[0042] (4) Compared with the model control group, the neurological scores of the natural borneol group, synthetic borneol group, and honokiol group decreased slightly, and there were no significant differences (P > 0.05), indicating that the use of natural borneol, synthetic borneol, and honokiol alone has basically no improvement effect on the neurological symptoms of stroke mice.

[0043] (5)Compared with the model control group, the scores of the pentoxifylline 15 mg / kg + borneol 15 mg / kg combination group and the pentoxifylline 15 mg / kg + honokiol 15 mg / kg combination group were significantly reduced (p<0.01), showing a very significant difference, indicating that these two groups of drugs can improve the neurological symptoms of stroke patients. However, compared with the pentoxifylline group, the neurological score was slightly reduced, but there was no significant difference (P>0.05).

[0044] (6)Compared with the model control group, the score of the pentoxifylline 15 mg / kg + honokiol 6.25 mg / kg + borneol 8.75 mg / kg combination group was significantly reduced (p<0.01), showing a very significant difference, indicating that this combination drug can improve the neurological symptoms of stroke patients. Compared with the pentoxifylline group, the score was significantly reduced (p<0.05), indicating that this combination was significantly superior to pentoxifylline. Compared with the positive drug group, the score was significantly reduced (p<0.05), indicating that this combination was significantly superior to the positive drug edaravone dextrorotatory camphorol.

[0045] (7)Compared with the model control group, the neurological scores of the pentoxifylline 15 mg / kg + honokiol 6.25 mg / kg + synthetic borneol 8.75 mg / kg combination group, the pentoxifylline 15 mg / kg + honokiol 10 mg / kg + borneol 5 mg / kg combination group, and the pentoxifylline 15 mg / kg + honokiol 5 mg / kg + borneol 10 mg / kg combination group were significantly reduced (p<0.01), showing a very significant difference, indicating that these three combination drugs can improve the neurological symptoms of stroke patients. However, compared with the pentoxifylline group, the neurological score was slightly reduced, but there was no significant difference (P>0.05), indicating that the therapeutic effects of these three groups of drugs were equivalent to that of pentoxifylline and there was no significant difference.

[0046] The above tests suggest that a combination of pentoxifylline, honokiol, and borneol at a specific weight ratio (pentoxifylline 15 mg / kg + honokiol 6.25 mg / kg + borneol 8.75 mg / kg) can greatly improve the neurological score of stroke patients, not only with a significantly higher effect than that of pentoxifylline alone, but also significantly superior to the positive drug edaravone dextrorotatory camphorol.

[0047] The above tests suggest that a combination of pentoxifylline, honokiol, and borneol at a specific weight ratio (pentoxifylline 15 mg / kg + honokiol 6.25 mg / kg + borneol 8.75 mg / kg) has a significant synergistic effect. The pharmaceutical composition of the present invention has the prospect of being developed into a drug for treating nervous system diseases, especially a drug for improving the nerve function of stroke patients, and has important social and economic benefits.

Claims

1. A pharmaceutical composition for improving neurological symptoms in stroke patients, wherein the active ingredients are composed of pentoxifylline, magnolol and borneol.

2. The composition according to claim 1, characterized in that In the pharmaceutical composition, the weight ratio of pentoxifylline, honokiol and borneol is 10-15: 4-6: 6-10.

3. The composition according to claim 2, characterized in that In the pharmaceutical composition, the weight ratio of pentoxifylline, honokiol and borneol is 11-13: 4-6: 6-8.

4. The composition according to claim 3, characterized in that In the pharmaceutical composition, the weight ratio of pentoxifylline, honokiol and borneol is 12:5:

7.

5. The composition according to claim 1, characterized in that In the pharmaceutical composition, the purity of honokiol is not less than 98.5%, and more preferably not less than 99%.

6. The composition according to claim 1, characterized in that In the pharmaceutical composition, the borneol is natural borneol with a borneol content of not less than 98%.

7. The composition according to claim 1, characterized in that The pharmaceutical composition may also contain pharmaceutically acceptable excipients to be prepared into oral preparations or injections.

8. The composition according to claim 7, characterized in that The oral preparation is selected from capsules, tablets, granules and oral liquids.

9. The composition according to claim 7, characterized in that The injection is selected from sterile powder for injection, aqueous injection, sodium chloride or glucose intravenous infusion.

10. Use of any pharmaceutical composition according to claim 1 to claim 9 in the preparation of a drug for improving neurological symptoms in stroke patients.

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