A pharmaceutical composition for treating epilepsy and its use

Abstract

The present invention belongs to the field of medical technology, and specifically relates to a pharmaceutical composition for treating epilepsy, and its pharmaceutical preparation and use. The pharmaceutical composition comprises rhynchophylline, paeonol and isoinulinol, and the weight ratio of rhynchophylline, paeonol and isoinulinol is 5:2-4:0.2-2. Pharmacological experiments show that the pharmaceutical composition of the present invention can significantly improve the symptoms of epilepsy model mice induced by pentylenetetrazol, significantly prolong the convulsion latency of mice, shorten the duration of convulsions, significantly reduce the incidence and mortality of tonic spasms of the body, and greatly improve the therapeutic effect of epilepsy. The effect is significantly better than the same dose of rhynchophylline, paeonol, and isoinulinol alone or in combination with any two of them, which shows that the combination of rhynchophylline, paeonol and isoinulinol has a significant synergistic effect. The pharmaceutical composition of the present invention has the prospect of being developed into a drug for treating epilepsy and has important social benefits.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and in particular relates to a pharmaceutical composition for treating epilepsy and a pharmaceutical preparation and use thereof. Background Art

[0002] Epilepsy is a common neurological disease in clinical practice. It is a disease with paroxysmal movement, sensation, consciousness, mental and autonomic nervous system dysfunction caused by paroxysmal abnormal discharges of brain neuron groups due to various reasons. The causes of epilepsy are varied, including brain trauma, stroke, autoimmune disease, infectious disease, gene mutation, etc. However, there are also many epilepsy patients without clear inducing factors. Clinically, patients mainly show symptoms such as limb convulsions, loss of consciousness, behavioral disorders and transient sensory disorders. Its prominent clinical characteristics are recurrent attacks and the unpredictability of each attack, which endangers people's health and seriously affects the quality of life of patients.

[0003] At present, drug therapy is the mainstream treatment for epilepsy. Classic drugs that effectively control epileptic seizures include sodium valproate, carbamazepine, phenytoin sodium, ethosuximide, diazepam and phenobarbital. New drugs that effectively control epileptic seizures include levetiracetam and tiagabine, of which levetiracetam is more effective. Although these drugs have a certain effect on controlling epileptic seizures, studies have shown that long-term use of anti-epileptic drugs will increase nitrogenic stress and oxidative stress, increase lipid peroxidation, and lead to endogenous damage. Adverse reactions such as dizziness, drowsiness, decreased appetite, ataxia, and liver damage are difficult to avoid, and are prone to cause drug-resistant epilepsy.

[0004] Rhyncholphylline is an alkaloid isolated from the plant Uncaria rhynchophylla of the Rubiaceae family. 22 H 28 N2O4, molecular weight is 384.46. Rhynchophylline has protective effects on the degenerative nervous system, including sedation, anti-spasmodic, anti-epileptic, anti-anxiety, brain neuron protection, etc., relieves the symptoms of patients, and helps in the treatment of degenerative nervous system diseases such as Parkinson's disease and Alzheimer's disease, so it has high medicinal value.

[0005] Paeonol is a Chinese herbal medicine extracted from the root bark of the Ranunculaceae plant Paeonia suffruticosa. Its chemical name is 2 ’ -Hydroxy-4 ’ -Methoxyacetophenone (2 ’ -Hydroxy-4 ’-methoxyacetopheone). Paeonol has anticonvulsant effects and can alleviate epileptic seizures. Studies have found that paeonol plays an antioxidant and reduces epileptic seizures by reducing the activity of catalase, T-AOC and SOD. Recent studies have shown that paeonol has a therapeutic effect on Alzheimer's disease mice with neurodegenerative diseases.

[0006] Isoalantolactone is a small molecule sesquiterpene lactone compound extracted from Inulahelenium L. 15 H 20 O2, molecular weight is 232.32. Inula is pungent, bitter and warm. It enters the liver and spleen meridians and is used to treat febrile diseases. It is widely used in the treatment of viral colds, colds and some plagues. Modern research shows that isoinula lactone has anti-inflammatory, antibacterial and anticancer pharmacological activities.

[0007] The inventors unexpectedly discovered a method for significantly improving the anti-epileptic effects of rhynchophylline and paeonol during in-depth research on the anti-epileptic effects of rhynchophylline and paeonol, and developed a safe and efficient pharmaceutical composition for treating epilepsy comprising rhynchophylline and paeonol. Summary of the invention

[0008] The purpose of the present invention is to provide a pharmaceutical composition for treating epilepsy with a synergistic effect, so as to provide a new idea for treating epilepsy clinically safely, effectively, conveniently and economically.

[0009] Specifically, the present invention is realized through the following technical solutions.

[0010] In the first aspect, the present invention provides a pharmaceutical composition for treating epilepsy, the pharmaceutical composition comprising rhynchophylline, paeonol and isoindulenolide, the weight ratio of the rhynchophylline, paeonol and isoindulenolide being 5:2-4:0.2-2, wherein the rhynchophylline and paeonol are the main active ingredients for treating epilepsy, and the isoindulenolide is an auxiliary ingredient for enhancing the efficacy of rhynchophylline and paeonol in treating epilepsy.

[0011] As an optional manner, in the above-mentioned pharmaceutical composition, the weight ratio of rhynchophylline, paeonol and isoinulactone is 5:2.5-3.5:0.6-1.2.

[0012] As an optional manner, in the above-mentioned pharmaceutical composition, the weight ratio of rhynchophylline, paeonol and isoinulactone is 5:3:0.8-1.2.

[0013] As an optional manner, in the above-mentioned pharmaceutical composition, the weight ratio of rhynchophylline, paeonol and isoinulactone is 5:3:1.

[0014] As an optional mode, the pharmaceutical composition consists of rhynchophylline, paeonol and isoinulin, and the weight ratio of rhynchophylline, paeonol and isoinulin is 5:2-4:0.2-2.

[0015] As an optional mode, in the above-mentioned pharmaceutical composition, by using rhynchophylline, paeonol and isoinulactone in combination, the effect of rhynchophylline and paeonol in treating epilepsy can be significantly enhanced.

[0016] In a second aspect, the present invention provides a pharmaceutical preparation, comprising the pharmaceutical composition described in the first aspect, and a pharmaceutically acceptable carrier.

[0017] As an optional mode, in the above-mentioned pharmaceutical preparation, the dosage form of the pharmaceutical preparation is an oral dosage form.

[0018] As an optional mode, in the above-mentioned pharmaceutical preparation, the oral dosage form is tablets, capsules, granules, powders or oral liquids.

[0019] Preferably, the oral dosage form is a capsule or a tablet.

[0020] In addition, those skilled in the art will understand that the rhynchophylline, paeonol and isoinulin in the pharmaceutical composition of the present invention can also be administered sequentially or simultaneously in different pharmaceutical preparations.

[0021] In a third aspect, the present invention provides use of the pharmaceutical composition described in the first aspect or the pharmaceutical preparation described in the second aspect in the preparation of a drug for treating epilepsy.

[0022] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] The present invention combines my country's advantages in the research of natural compounds, and for the first time finds that the combination of rhynchophylline, paeonol and iso-inulinol in a specific dosage ratio can significantly improve epilepsy symptoms, significantly prolong the latency of convulsions in mice, shorten the duration of convulsions, significantly reduce the incidence and mortality of tonic spasms, and greatly improve the therapeutic effect of epilepsy. This shows that the combination of rhynchophylline, paeonol and iso-inulinol has a significant synergistic effect. The pharmaceutical composition of the present invention also has fewer toxic and side effects, has the prospect of being developed into a drug for the treatment of epilepsy, and has important social and economic benefits. DETAILED DESCRIPTION

[0025] The inventors have conducted in-depth research on the pharmacological mechanism of rhynchophylline and paeonol in treating epilepsy, and through extensive screening, have found for the first time that the combined use of rhynchophylline, paeonol and isoinulactone can significantly enhance the effect of rhynchophylline and paeonol in treating epilepsy. Based on this, the present invention was completed.

[0026] As used herein, the rhynchophylline, paeonol and isoinulinol in the pharmaceutical composition of the present invention can be administered in the same pharmaceutical preparation or in different pharmaceutical preparations. In the case of administration in different pharmaceutical preparations, the dosage forms of rhynchophylline, paeonol and isoinulinol can be the same or different. Furthermore, rhynchophylline, paeonol and isoinulinol can be administered simultaneously or sequentially.

[0027] As used herein, "auxiliary ingredients" generally refer to substances that have no or almost no target pharmacological activity but can enhance the target pharmacological activity of the main active ingredient. The target pharmacological activity of the present invention is mainly the effect of treating epilepsy.

[0028] As used herein, "pharmaceutically acceptable carrier" refers to any excipient that can be prepared into a pharmaceutical preparation with rhynchophylline and isoindolactone and used for clinical treatment, selected from one or more of adhesives, lubricants, fillers, disintegrants, suspending agents, solvents, wetting agents, surfactants, pigments, and flavoring agents.

[0029] The adhesive of the present invention includes but is not limited to water, ethanol, syrup, starch slurry, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, sodium alginate, etc.; the lubricant includes but is not limited to talc, silicon dioxide, stearic acid, magnesium stearate, sodium lauryl sulfate, sodium chloride, sodium oleate, poloxamer, etc.; the filler includes but is not limited to starch, sucrose, dextrin, microcrystalline cellulose, lactose, glucose, etc.; the disintegrant includes but is not limited to starch effervescent mixture, i.e. sodium bicarbonate and citric acid, low-substituted hydroxypropyl cellulose, tartaric acid, etc.; the suspending agent includes but is not limited to polysaccharides such as acacia gum, agar, alginic acid, cellulose ether and carboxymethyl chitosan, etc.

[0030] The pharmaceutical composition can be prepared into various solid oral preparations, liquid oral preparations, etc. Pharmaceutically acceptable solid oral preparations include granules, ordinary tablets, dispersible tablets, enteric-coated tablets, powders, capsules, etc., and oral liquid preparations include oral liquids, emulsions, etc.

[0031] The above-mentioned various dosage forms can be prepared according to conventional processes in the field of pharmaceutical preparations.

[0032] The rhynchophylline, paeonol and isoinulactone used in the pharmaceutical composition of the present invention can be extracted and separated from plants containing the components by conventional biological purification methods, or can be purchased from commercial products.

[0033] In the medical uses described above, the administration time, number of administrations and frequency of administration of the pharmaceutical composition of the present invention need to be determined according to the specific diagnosis results of the disease, which is within the technical scope mastered by those skilled in the art.

[0034] The treatment plan for mice can be applied to humans, and the effective doses of all drugs for humans can be converted by the effective doses of the drugs for mice, which is also easy to achieve for ordinary technicians in this field.

[0035] The present invention will be further described with reference to specific embodiments. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the scope of the present invention.

[0036] If no specific techniques or conditions are specified in the examples, the techniques or conditions described in the literature in the field or the product instructions are used. If no manufacturer is specified for the reagents or instruments used, they are all conventional products that can be purchased through regular channels.

[0037] The experimental methods in the following examples are conventional methods unless otherwise specified. The experimental materials used in the following examples are commercially available products unless otherwise specified.

[0038] Unless otherwise specified, all percentages and parts in the present invention are percentages and parts by weight.

[0039] Example: Pharmacodynamic study of the pharmaceutical composition of the present invention in treating epilepsy

[0040] 1. Main experimental materials

[0041] Animals: SPF grade male mice, weighing 16-20 g. Before the experiment, the mice were allowed to adapt to the experimental environment and related operations.

[0042] 2. Experimental Methods

[0043] 2.1 Establishment and administration of pentylenetetrazol-induced epilepsy mouse model

[0044] The mice were randomly divided into 10 groups according to their body weight, with 16 mice in each group, including blank group, model group, positive drug group (carbamazepine 90 mg / kg), rhynchophylline group, paeonol group, iso-indulactone group, rhynchophylline + paeonol group, rhynchophylline + iso-indulactone group, paeonol + iso-indulactone group, and rhynchophylline + paeonol + iso-indulactone group. The mice were fasted for 12 hours before oral gavage and had normal drinking water. The mice were gavaged once a day for 5 consecutive days. One hour after the last administration, all groups except the blank group were intraperitoneally injected with pentylenetetrazol (70 mg / kg), and the epileptic seizure level, convulsion latency, convulsion duration, incidence of body tonic spasm and mortality of the mice were observed and recorded. Each group was given the following dosage:

[0045] (1) Blank group: physiological saline, intragastric administration

[0046] (2) Model group: normal saline, intragastric administration

[0047] (3) Positive drug group: 90 mg / kg, intragastric administration

[0048] (4) Rhynchophylline group: 90 mg / kg, intragastric administration

[0049] (5) Paeonol group: 90 mg / kg

[0050] (6) Iso-indole lactone group: 90 mg / kg, intragastrically

[0051] (7) Rhynchophylline + Paeonol group: 55 mg / kg + 35 mg / kg, intragastric administration

[0052] (8) Rhynchophylline + iso-indole lactone group: 80 mg / kg + 10 mg / kg, intragastrically

[0053] (9) Paeonol + isoindulenolide group: 80 mg / kg + 10 mg / kg, intragastrically

[0054] (10) Rhynchophylline + Paeonol + Iso-indole lactone group: 50 mg / kg + 30 mg / kg + 10 mg / kg, gavage 2.2 The epileptic seizures of mice were graded according to the Racine standard

[0055] Grade 0: no convulsion; Grade I: oral and facial muscle clonus; Grade II: rhythmic nodding on the basis of Grade I; Grade III: forelimb clonus on the basis of Grade II; Grade IV: hindlimb extension on the basis of Grade III; Grade V: falling on the basis of Grade IV.

[0056] 2.3 Statistical methods

[0057] The results were analyzed using SPSS 23.0 statistical software, and the data were expressed as mean ± standard deviation. One-way analysis of variance was used for comparison among multiple groups, and t-test was used for comparison between two groups. P < 0.05 indicated that the difference was statistically significant, and P < 0.01 indicated that the difference was statistically significant.

[0058] 3. Experimental results

[0059] Table 1 Pharmacodynamic evaluation results of each group on the epilepsy mouse model induced by pentylenetetrazol

[0060]

[0061]

[0062] Note: Compared with the model group, ** p<0.01; compared with the rhynchophylline group, ## p<0.01; compared with the paeonol group, && p<0.01.

[0063] The results in Table 1 show that compared with the blank group, the mice in the model group had forelimb spasms accompanied by different degrees of hindlimb extension, tonic-clonic and falling, indicating that the mice in the model group had typical epilepsy symptoms. Compared with the model group, the rhynchophylline group, paeonol group and rhynchophylline + paeonol group could improve the epilepsy symptoms of mice, without grade V symptoms, but the degree was weaker than that of the positive drug group. Compared with the model group, the positive drug group and rhynchophylline + paeonol + isoinulinol group could significantly improve the epilepsy symptoms of mice, without grade III or above symptoms, and could significantly prolong the incubation period of convulsions in mice, shorten the duration of convulsions (P<0.01), and significantly reduce the incidence of body tonic spasm and mortality (P<0.01), among which the rhynchophylline + paeonol + isoinulinol group was better than the positive drug group. From these results, it can also be seen that when isoinulin lactone is used alone, it has almost no effect on improving the epilepsy symptoms of mice. When rhynchophylline and paeonol are used alone or in combination, the improvement of epilepsy symptoms in mice is not as good as the positive drug carbamazepine. However, when rhynchophylline, paeonol and isoinulin lactone are used in combination, the improvement of epilepsy symptoms in mice is significantly better than that of rhynchophylline, paeonol, isoinulin lactone used alone or in combination with any two of them (P<0.01), and the effect of the combination of the three is better than that of the positive drug carbamazepine.

[0064] It can be seen that the pharmaceutical composition of the present invention can significantly improve the epilepsy symptoms of epilepsy model mice induced by pentylenetetrazol, significantly prolong the incubation period of convulsions in mice, shorten the duration of convulsions, significantly reduce the incidence and mortality of tonic spasms, and greatly improve the therapeutic effect of epilepsy. The effect is significantly better than the same dose of rhynchophylline, paeonol, and isoinulinolactone alone or in combination with any two of them, which shows that the combination of rhynchophylline, paeonol and isoinulinolactone has a significant synergistic effect. The pharmaceutical composition of the present invention has the prospect of being developed into a drug for treating epilepsy, and has important social and economic benefits.

[0065] Obviously, the above embodiments are only examples for clearly explaining the present invention, and are not intended to limit the implementation methods of the present invention. Those skilled in the art may make various changes and modifications to the present invention without departing from the spirit and scope of the present invention. Thus, if these modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include these modifications and variations.

Claims

1. A pharmaceutical composition for treating epilepsy, characterized in that: The pharmaceutical composition comprises rhynchophylline, paeonol and isoinulinol, wherein the weight ratio of rhynchophylline, paeonol and isoinulinol is 5:2-4:0.2-2, wherein the rhynchophylline and paeonol are the main active ingredients for treating epilepsy, and the isoinulinol is an auxiliary ingredient for enhancing the efficacy of rhynchophylline and paeonol in treating epilepsy.

2. The pharmaceutical composition according to claim 1, characterized in that The weight ratio of rhynchophylline, paeonol and isoinulactone is 5:2.5-3.5:0.6-1.

2.

3. The pharmaceutical composition according to claim 1, characterized in that The weight ratio of rhynchophylline, paeonol and isoinulactone is 5:3:0.8-1.

2.

4. A pharmaceutical preparation, characterized in that The pharmaceutical preparation comprises the pharmaceutical composition according to any one of claims 1 to 3, and a pharmaceutically acceptable carrier.

5. The pharmaceutical preparation according to claim 4, characterized in that The dosage form of the pharmaceutical preparation is an oral dosage form.

6. The pharmaceutical preparation according to claim 5, characterized in that The oral dosage form is tablet, capsule, granule, powder or oral liquid.

7. Use of the pharmaceutical composition according to any one of claims 1 to 3 or the pharmaceutical preparation according to any one of claims 4 to 6 in the preparation of a drug for treating epilepsy.

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