Pharmaceutical composition for treating nervous system diseases

Abstract

The invention provides a pharmaceutical composition for treating nervous system diseases, which comprises the following active ingredients: eslicarbasil acetate and natural borneol in a weight ratio of (4.5-7.5): 1. The pharmaceutical composition can be used for preparing medicines for treating nervous system diseases, especially Parkinson's disease, and improving dyskinesia.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a pharmaceutical composition for treating nervous system diseases. Background Art

[0002] Neurological diseases are a group of degenerative diseases of the nervous system with unclear causes and pathological mechanisms, but most of them are caused by abnormal aggregation of proteins in nerve cells, leading to neuronal degeneration and apoptosis. Currently, there is no mature and effective method for the treatment of neurological diseases.

[0003] Parkinson's disease (PD) is a serious degenerative neurological disease that mainly affects middle-aged and elderly people. Studies have shown that the incidence of PD in people over 60 years old in my country is about 1% to 2%. There are about 3 million Parkinson's patients in China, accounting for 50% of the global number of patients. China has become a major country for Parkinson's disease in the world.

[0004] There is no clear cause of Parkinson's disease yet, but it is speculated that it may be related to genetic factors, living environment, patient age, etc. The disease has the characteristics of long course, non-self-healing, and many complications. In the early stage, patients mainly show resting tremor. As the disease progresses, they will also have abnormal gait and slow movement. At the same time, they are accompanied by non-motor symptoms such as cognitive impairment, sleep disorders, anxiety, depression, constipation, and dysphagia, which seriously reduce the quality of life of patients.

[0005] Eslicarbazepine acetate is a drug developed by Portugal's Bial Pharmaceuticals for the treatment of epilepsy. It was approved for sale in Europe in 2009. Its structure is shown below. It is a new type of sodium ion channel blocker that specifically acts on ion channels, preventing them from returning to an active state, thereby further reducing their repeated activation efficiency.

[0006] Borneol is a commonly used Chinese medicine. It is an extracted and processed product of the fresh branches and leaves of the Lauraceae plant camphor. Its main ingredient is dextrorotatory borneol (borneo1um), and its dextrorotatory borneol content is not less than 96%; Artemisia annua tablets are the crystallization of the extract of the fresh leaves of the Asteraceae plant Artemisia balsamina, mainly L-borneol, and its L-borneol content is not less than 85% as borneol; synthetic borneol is a refined product (also called machine-made borneol) synthesized by chemical methods using turpentine as raw material. It is a racemic body and contains a certain amount of isoborneol (isoborneo1), and its borneol content is not less than 55%.

[0007] In addition, dextrorotatory borneol is also known as (+)-2-borneol and right-borneol, and levorotatory borneol is also known as (-)-2-borneol, also known as mugwort tablets.

[0008] Natural borneol has the best effect among all borneols, but due to resource limitations, synthetic borneol is often used in Chinese patent medicines to replace natural borneol. In addition, since the lower limit of the content of dextrorotatory borneol in natural borneol is 96%, it still contains a certain amount of impurities, which may affect the safety of medication. Therefore, people have purified natural borneol, and currently (+)-2-borneol with a purity of ≥98% is available on the market.

[0009] There is no report in the prior art on the combined use of eslicarbazepine acetate and borneol for the treatment of nervous system diseases, especially Parkinson's disease. Summary of the invention

[0010] The inventors unexpectedly discovered in their research that the pharmaceutical composition of eslicarbazepine acetate and borneol has a synergistic effect and significantly improves nervous system diseases, especially the movement disorder of Parkinson's disease, providing a new idea for the safe, effective and economical clinical treatment of Parkinson's disease.

[0011] The purpose of the present invention is to provide a pharmaceutical composition for treating nervous system diseases. The active ingredients are composed of eslicarbazepine acetate and borneol. The pharmaceutical composition has a synergistic effect and can significantly improve the symptoms of Parkinson's disease.

[0012] To achieve the above object, the present invention adopts the following technical solution: A pharmaceutical composition for treating nervous system diseases, wherein the active ingredients consist of licarbazepine acetate and borneol.

[0013] In the pharmaceutical composition, borneol is preferably natural borneol, more preferably natural borneol with a borneol content of not less than 98%.

[0014] In the pharmaceutical composition, the weight ratio of eslicarbazepine acetate to borneol is 20:1 to 1:20; preferably, the weight ratio is 1 to 20:1; more preferably, the weight ratio is 2 to 20:1; further preferably, the weight ratio is 3-10:1; and the most preferably, the weight ratio is 4.5 to 7.5:1.

[0015] Furthermore, in the above composition, the weight ratio of eslicarbazepine acetate to natural borneol is 4.5-7.5:1, more preferably 6:1.

[0016] The above-mentioned pharmaceutical composition may also contain pharmaceutically acceptable excipients and be prepared into oral preparations or injections; the oral preparations include but are not limited to capsules, tablets, granules, and oral liquids; the injections include but are not limited to sterile powder for injection, water injection, sodium chloride or glucose intravenous infusion, and are further preferably made into oral preparations.

[0017] In the above-mentioned 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, and preservatives.

[0018] The fillers or diluents include sugars such as lactose, sucrose, glucose, mannitol, sorbitol, and dextrin; starches such as starch, pregelatinized starch, α-starch, and dextrin; celluloses such as microcrystalline cellulose, gum arabic, and dextran; and inorganic salts such as calcium sulfate, calcium hydrogen phosphate, medicinal calcium carbonate, light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, and magnesium aluminosilicate.

[0019] The lubricant, glidant or anti-adhesive agent includes stearic acid; metal stearate such as calcium stearate or magnesium stearate; talc; colloidal silicon dioxide; micro powder silica gel, hydrogenated vegetable oil; polyethylene glycol, lauryl sulfate such as sodium lauryl sulfate or magnesium lauryl sulfate; silicate such as silicic anhydride or silicate hydrate, etc.

[0020] The adhesive comprises distilled water, ethanol of different concentrations, starch slurry, hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, ethyl cellulose, sodium carboxymethyl cellulose, polyvinyl pyrrolidone, polyethylene glycol and compounds similar to the above excipients.

[0021] The disintegrants include cellulose derivatives such as low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium or cross-linked carboxymethyl cellulose sodium; cross-linked polyvinyl pyrrolidone; and chemically modified starch / cellulose, such as carboxymethyl starch or carboxymethyl starch sodium.

[0022] The surfactant includes Tween-80, sodium lauryl sulfate, sodium stearate sulfonate and the like.

[0023] The antioxidants include sodium bisulfite, sodium pyrosulfite, sodium sulfite, dried sodium sulfite, sodium thiosulfate, ascorbic acid, methionine (methionine), thiourea, phosphoric acid, citric acid and the like.

[0024] The preservatives or antibacterial agents include benzoic acid and sodium benzoate, sorbic acid, ethanol, parabens (parabens), benzalkonium bromide, o-phenylphenol, benzyl alcohol, phenylethyl alcohol, sodium propionate, sorbic acid, eucalyptus oil, cinnamon oil and peppermint oil.

[0025] The flavoring agents include sweeteners such as saccharin sodium, 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 aromatics such as fennel oil, peppermint oil, menthol, peppermint water, cinnamon oil, lemon essence, lemon oil and spices of various flavors.

[0026] The pharmaceutical composition of the present invention can be prepared into various dosage forms suitable for clinical administration by using appropriate auxiliary materials according to any commonly used method known in the field of pharmacy.

[0027] Another object of the present invention is to provide an application of the above-mentioned pharmaceutical composition, namely, an application of the pharmaceutical composition in the preparation of a drug for treating a nervous system disease; the nervous system disease is preferably Parkinson's disease, and the pharmaceutical composition can significantly improve movement disorders caused by nervous system diseases.

[0028] Compared with the prior art, the present invention has the following advantages: The present invention discovers for the first time that a combination of eslicarbazepine acetate and natural borneol in a specific dosage ratio can effectively improve the condition of Parkinson's model mice, and the effect is significantly better than the same dose of eslicarbazepine acetate or natural borneol, which indicates that eslicarbazepine acetate and natural borneol have a significant synergistic effect.

[0029] The pharmaceutical composition of the present invention can be developed into a pharmaceutical composition for treating nervous system diseases, and is expected to have good social and economic benefits. DETAILED DESCRIPTION

[0031] The present invention discloses a pharmaceutical composition for treating nervous system diseases and a method for preparing the same. Those skilled in the art can refer to the contents of the present invention, combine the relevant principles of pharmaceutics and pharmacology, and appropriately improve the process parameters to achieve the same. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art, and they are all deemed to be included within the scope of the present invention. The application of the present invention has been described through preferred embodiments, and relevant personnel can obviously modify or appropriately change and combine the methods and applications described herein without departing from the content, spirit and scope of the present invention to achieve and apply the technology of the present invention.

[0032] In order to better understand the present invention but not to limit the scope of the present invention, all the numbers expressing the amount, percentage, 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 at least be considered to be obtained based on the reported significant figures and by conventional rounding methods.

[0033] Natural borneol: the content of borneol (dextrorotatory borneol) is 98.5%.

[0034] Mugwort tablets: The content of L-borneol is 88.7%.

[0035] Synthetic borneol: borneol content is 63.1%.

[0036] Test Example 1: Neurological function test in Parkinson's mice 1 Animal Experiment Materials 1.1 Drugs: The tested drugs were: eslicarbazepine acetate, natural borneol, synthetic borneol (synthetic borneol), a combination of eslicarbazepine acetate + natural borneol, and a combination of eslicarbazepine acetate + synthetic borneol.

[0037] 1.2 Experimental animals and groups C57BL / 6 mice, male, 6-8 weeks old, were adaptively housed for one week under a standard feeding environment (free access to food and water, alternating day and night, 12 hours each).

[0038] Five days before modeling, practice rotating rod training twice a day; one day before modeling, perform rotating rod training, and only those who pass the training can be included in the group.

[0039] The experimental animals were divided into a normal control group, a model control group, a positive drug group (levodopa), and 11 groups of the drug-treated groups of the present invention (eslicarbazepine acetate group, natural borneol group, synthetic borneol group, Ai tablets group, eslicarbazepine acetate + natural borneol group 1 (weight ratio 3:1), eslicarbazepine acetate + natural borneol group 2 (weight ratio 4.5:1), eslicarbazepine acetate + natural borneol group 3 (weight ratio 6:1), eslicarbazepine acetate + synthetic borneol group (weight ratio 6:1), eslicarbazepine acetate + Ai tablets group (weight ratio 6:1), eslicarbazepine acetate + natural borneol group 4 (weight ratio 7.5:1), eslicarbazepine acetate + natural borneol group 5 (weight ratio 10:1)), with 8 animals in each group.

[0040] Modeling: The normal control group was intraperitoneally injected with 30 mg / kg saline once a day for 7 consecutive days. The model control group, the positive drug group, and the 11 groups of the drug administration of the present invention were intraperitoneally injected with 30 mg / kg MPTP once a day for 7 consecutive days.

[0041] After the modeling was completed, oral administration was performed starting from the 8th day. Before the daily oral administration experiment, each group of mice was weighed and the dosage was calculated according to the body weight. The 11 groups of the present invention were administered with 10 mg·kg-1 of the drug or drug composition by oral administration, and the positive drug group was administered with 10 mg·kg-1 of levodopa suspension by oral administration. The normal control group and the model control group were administered with the corresponding 10 ml·kg-1 of pure water by oral administration. Once a day for 28 consecutive days.

[0042] On day 28, the mice were given rotarod behavior test 1 hour after intragastric administration.

[0043] The mice were placed on a rotating rod with a diameter of 3 cm, and the speed was adjusted to 30 r / min. Eight mice were measured at the same time, with one in each compartment. The time from the beginning of the rotation of the rod to the falling of the rod was recorded within 5 minutes. The scoring criteria were: 0-10s-0 points, 10-30s-1 point, 30-50s-2 points, 50-70s-3 points, 70-90s-4 points, 90-120s-5 points, more than 120s-6 points 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 ,## P<0.01, compared with the eslicarbazepine acetate group From Table 1, we can see that: (1) Compared with the normal control group (C57BL / 6), the rotarod time and rotarod score of the model control group were significantly reduced (p<0.01), which was a very significant difference, indicating that the Parkinson's model was successful.

[0044] (2) Compared with the model control group, the rotarod time and rotarod score of the eslicarbazepine acetate group increased, but there was no significant difference (P>0.05), indicating that when used alone, it has only a weak improvement effect on Parkinson's mice.

[0045] (3) Compared with the model control group, the rotarod time and rotarod score of the natural borneol group, synthetic borneol group, and moxa tablet group increased slightly, but there was no significant difference (P>0.05). This indicates that the use of natural borneol, synthetic borneol, and moxa tablet alone has basically no improvement effect on Parkinson's mice.

[0046] (4) Compared with the model control group, the rotarod time and rotarod score of the eslicarbazepine acetate / natural borneol combination group (weight ratio of 3:1) and the eslicarbazepine acetate / natural borneol combination group (weight ratio of 10:1) were significantly increased, with significant differences (P < 0.05), indicating that they have a significant improvement effect on Parkinson's mice and can treat Parkinson's disease; however, there is no significant difference compared with eslicarbazepine acetate (P > 0.05).

[0047] (5) Compared with the model control group, the rotarod time and rotarod score of the eslicarbazepine acetate / natural borneol combination group with a weight ratio of 4.5:1, the eslicarbazepine acetate / natural borneol combination group with a weight ratio of 6:1, and the eslicarbazepine acetate / natural borneol combination group with a weight ratio of 7.5:1 were significantly increased, and the difference was very significant (P < 0.01), indicating that it had a significant improvement effect on Parkinson's mice and could treat Parkinson's disease; and compared with eslicarbazepine acetate, it was significantly different (P < 0.05), and was significantly better than eslicarbazepine acetate. It suggests that the eslicarbazepine acetate and natural borneol combination with a weight ratio of 4.5-7.5:1 have a synergistic effect and significantly enhance the therapeutic effect; especially the eslicarbazepine acetate / natural borneol combination group with a weight ratio of 6:1 has a better therapeutic effect.

[0048] (6) The rotarod time and rotarod score of the 6:1 weight ratio eslicarbazepine acetate / synthetic borneol combination group and the 6:1 weight ratio eslicarbazepine acetate / borneol combination group increased, but there was no significant difference (P>0.05), indicating that the two groups had only a slight improvement on Parkinson's mice, and the therapeutic effect was significantly worse than that of the 6:1 weight ratio eslicarbazepine acetate / natural borneol combination group.

[0049] The above experiments suggest that the combination of eslicarbazepine acetate and natural borneol can greatly improve the movement disorder of Parkinson's mice. The effect is not only significantly higher than that of eslicarbazepine acetate or natural borneol alone, but also slightly better than the control substance levodopa. The experimental results show that the combination of eslicarbazepine acetate and natural borneol can be used to prepare drugs for the treatment and prevention of Parkinson's disease.

[0050] The above experiments indicate that the combination of eslicarbazepine acetate and natural borneol has a significant synergistic effect. The pharmaceutical composition of the present invention has a good prospect of being developed into a drug for treating nervous system diseases, especially a drug for treating Parkinson's disease.

Claims

1. A pharmaceutical composition for treating a nervous system disease, characterized in that: The active ingredients consist of licarbazepine acetate and borneol.

2. The pharmaceutical composition according to claim 1, characterized in that The borneol is natural borneol.

3. The pharmaceutical composition according to claim 2, characterized in that The content of borneol in the natural borneol is not less than 98%.

4. The pharmaceutical composition according to claim 3, characterized in that The weight ratio of licarbazepine acetate to natural borneol is 4.5-7.5:

1.

5. The pharmaceutical composition according to claim 3, characterized in that The weight ratio of licarbazepine acetate to natural borneol is 6:

1.

6. The pharmaceutical composition according to claim 1, characterized in that It also contains pharmaceutically acceptable excipients.

7. The pharmaceutical composition according to claim 6, characterized in that It can be an oral preparation or an injection.

8. Any pharmaceutical composition according to claim 1 to claim 7, characterized in that: The nervous system disease is Parkinson's disease.

9. Use of any one of the pharmaceutical compositions according to claim 1 to claim 7 in the preparation of drugs for treating nervous system diseases.

10. The use according to claim 8, characterized in that The nervous system disease is Parkinson's disease.

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