Application of pharmaceutical composition in treating migraine

Abstract

The present invention relates to a drug combination, the drug composition comprises cobra cardiotoxin (CDX) and a pharmaceutically acceptable carrier thereof, and the drug composition is also characterized in that it further comprises cobra cardiotoxin (CDX) and any one of other drugs for treating migraine, cobra phospholipase A2 (PLA2) and cobra neurotoxin (NTX), or a combination of both. The drug composition can be used to prevent and treat migraine, and lower the concentration of nitric oxide (NO) in the body of a migraine patient, which is of great significance for the treatment of migraine.

Description

Technical Field

[0001] The present invention relates to use of a composition in preparing a medicine for treating migraine in patients. Background Art

[0002] Migraine is a common, recurrent headache disorder characterized by throbbing, severe headache on one or both sides, often accompanied by nausea, vomiting, and hypersensitivity to sound and light stimulation. Common types include migraine without aura, migraine with aura, and chronic migraine. The causes of migraine may be related to genetics, endocrine metabolism, environmental factors, mental factors, etc., and often have a genetic background. Female patients are 2-3 times more likely to develop the disease in adolescence, and a small number may develop the disease in childhood. In terms of symptoms, the typical manifestation of migraine is severe headache, which may be pain on one side of the head and migrate to the other side, and may also be sensitive to light, noise, and smell. Common associated symptoms include nausea, vomiting, stomach discomfort, abdominal pain, feeling very hot or cold, pale skin color, etc.

[0003] In terms of treatment, migraine cannot be cured at present. Most treatments aim to reduce headache attacks, relieve associated symptoms, and prevent headache recurrence. There are drug treatments and non-drug treatments. Drug treatments are divided into attack treatment and preventive treatment. Clinical drugs include opioid analgesics, non-steroidal analgesics, monoclonal antibodies, etc. However, they cannot produce satisfactory therapeutic effects, and some drugs have very serious side effects. Frequent use will cause patients to have other clinical symptoms. Therefore, the current drug pain relief for migraine treatment has not been able to truly meet the clinical needs of patients, so migraine has always been a disease that seriously affects the quality of human life.

[0004] The causes of migraine are generally believed to include genetics, endocrine metabolism, environmental factors, and psychological factors. Further studies have found that migraine is related to pathological factors such as increased serum nitric oxide (NO) concentrations. This is because increased serum nitric oxide (NO) concentrations can lead to dilation of cerebral blood vessels, leading to migraines. At the same time, nitric oxide can cause pain hypersensitivity and inflammatory reactions, which in turn aggravate the severity of migraines. [1-5] Treatments such as lowering nitric oxide (NO) levels are effective in improving the severity of migraines.

[0005] Currently, migraine treatment options mainly include acute and preventive treatments. With the exploration of signal pathways related to migraine attacks, more and more treatment methods will be developed for migraine treatment. Downregulating nitric oxide (NO) concentration can be used as an effective method for migraine treatment. Summary of the invention

[0006] The present invention relates to the use of a composition in the preparation of a drug for treating migraine in patients, characterized in that the composition comprises cobra cardiotoxin (CDX), and the pharmaceutical composition of the present invention has an analgesic effect on a rat nitroglycerin type migraine test model. Its mechanism may be related to blocking or down-regulating the signaling pathway of nitric oxide (NO). Cobra cardiotoxin can simultaneously treat and prevent the occurrence of migraine, and has no serious toxic side effects in animal experiments, so it is a drug candidate worthy of expectation.

[0007] Cobra cardiotoxins all have the commonality of a three-finger protein structure in terms of functional structure. Not only do they have the same spatial structure, but the amino acid sequences of their mature proteins are also highly homologous. Therefore, the commonality of cardiotoxins in functional structure enables them to achieve consistent function of regulating the signaling pathway of nitric oxide (NO), which also makes the cardiotoxins consistent in treating the rat nitroglycerin-type migraine model.

[0008] The amino acid sequences of the mature proteins of cobra cardiotoxins have the following common features:

[0009] lkcnklxpx xxktcxagkn lcykmfmxxx xxxpvkrgci dvcpkxsxlv kyvccntdrc n(SEQ ID No.1)

[0010] In some embodiments, the amino acid sequence of cobra cardiotoxin in the composition is

[0011] lkcnklvpl fyktcpagkn lcykmfmvat pkvpvkrgci dvcpkssllv kyvccntdrc n(SEQ ID No2)

[0012] In some embodiments, the amino acid sequence of cobra cardiotoxin in the composition is

[0013] lkcnklipi asktctagkn lcykmfmmsd ltipvkrgci dvcpknsllv kyvccntdrc n(SEQ ID No3)

[0014] In some embodiments, the amino acid sequence of cobra cardiotoxin in the composition is

[0015] lkcnklipi asktcpagkn lcykmfmmsd ltipvkrgci dvcpknsllv kyvccntdrc n(SEQ ID No4)

[0016] In some embodiments, the amino acid sequence of cobra cardiotoxin in the composition is

[0017] lkcnklipi asktcpagkn lcykmfmvat pkvpvkrgci dvcpknsllv kyvccntdrc n(SEQ ID No5)

[0018] In some embodiments, the amino acid sequence of cobra cardiotoxin in the composition is

[0019] lkcnklvpl fyktcpagkn lcykmfmvat pkvpvkrgci dvcpknsalv kyvccntdrc n(SEQ ID No6)

[0020] In some embodiments, the amino acid sequence of cobra cardiotoxin in the composition is

[0021] lkcnklvpl fyktcpagkn lcykmfmvsn kmvpvkrgci dvcpknsalv kyvccntdrc n(SEQ ID No7)

[0022] In some embodiments, the amino acid sequence of cobra cardiotoxin in the composition is

[0023] lkcnklvpl fyktcpagkn lcykmfmvsn ltvpvkrgci dvcpknsalv kyvccntdrc n(SEQ ID No8)

[0024] In some embodiments, the amino acid sequence of cobra cardiotoxin in the composition is

[0025] lkcnklipi asktcpagkn lcykmfmvat pkvpvkrgci dvcpkssllv kyvccntdrc n(SEQ ID No9)

[0026] In some embodiments, the amino acid sequence of cobra cardiotoxin in the composition is

[0027] lkcnklipia sktcpagknl cykmfmmsdl tipvkrgcid vcpknsllvk yvccntdrcn(SEQID No10)

[0028] In some embodiments, the amino acid sequence of cobra cardiotoxin in the composition is

[0029] lkcnklipla yktcpagknl cykmfmvsnk tvpvkrgcid acpknsllvk yvccntdrcn(SEQID No11)

[0030] In some embodiments, the amino acid sequence of cobra cardiotoxin in the composition is

[0031] lkcnklvplf yktcpagknl cykmfmvatp kvpvkrgcid vcpkssllvk yvccntdrcn(SEQID No12)

[0032] In some embodiments, the amino acid sequence of cobra cardiotoxin in the composition is

[0033] lkcnklipla yktcpagknl cykmfmvaap kvpvkrgcid acpknsllvk yvccntdrcn(SEQID No13)

[0034] In some embodiments, the amino acid sequence of cobra cardiotoxin in the composition is

[0035] lkcnklvpl fyktcpagkn lcykifmvat pkvpvkrgci dvcpknsalv kyvccntdrc n(SEQ ID No14)

[0036] In some embodiments, the composition is administered once daily for 3-120 consecutive days.

[0037] In some embodiments, the composition is administered once every 12 hours, twice daily, for 3-120 consecutive days.

[0038] In some embodiments, the composition is administered once every 8 hours, 3 times a day, for 3-120 consecutive days.

[0039] In some embodiments, the dosage of cobra cardiotoxin in the composition is 0.01-100 μg / kg per administration.

[0040] In some embodiments, the dosage of cobra cardiotoxin administered in the composition is 80 μg / kg per administration.

[0041] In some embodiments, the dosage of cobra cardiotoxin administered in the composition is 60 μg / kg per administration.

[0042] In some embodiments, the dosage of cobra cardiotoxin administered in the composition is 40 μg / kg per administration.

[0043] In some embodiments, the dosage of cobra cardiotoxin administered in the composition is 20 μg / kg per administration.

[0044] In some embodiments, the dosage of cobra cardiotoxin administered in the composition is 10 μg / kg per administration.

[0045] In some embodiments, the dosage of cobra cardiotoxin administered in the composition is 5.0 μg / kg per administration.

[0046] In some embodiments, the dosage of cobra cardiotoxin administered in the composition is 2.5 μg / kg per administration.

[0047] In some embodiments, the dosage of cobra cardiotoxin administered in the composition is 1.0 μg / kg per administration.

[0048] In some embodiments, the dosage of cobra cardiotoxin administered in the composition is 0.5 μg / kg per administration.

[0049] Our animal model experiments also found that the combined use of cobra cardiotoxin (CDX) and cobra phospholipase A2 (PLA2) or cobra neurotoxin (NTX) has a better analgesic effect on the rat nitroglycerin-type migraine experimental model; and the combined use of cobra cardiotoxin (CDX) and cobra phospholipase A2 (PLA2) and cobra neurotoxin (NTX) will achieve the strongest analgesic effect, although any one of cobra cardiotoxin (CDX), cobra phospholipase A2 (PLA2), or cobra neurotoxin (NTX) used alone has an analgesic effect on migraine. The amino acid sequence (FASTA) of the mature protein of cobra phospholipase A2 used in combination with cobra cardiotoxin (CDX) or in combination with cobra cardiotoxin (CDX) and cobra neurotoxin (NTX) has the following common features: nly qfknmiqctv psrswwdfad ygcycgkggs gtpvddldrc cqvhdxcyxe aekisgcwpyxktysyecsq gtltckggnn acaaavcdcd rlaaicfaga pyxxxxynix lkarcq (SEQ ID No.15)

[0050] Further, in some combined use embodiments, the following four amino acid sequences of phospholipase A2 all showed more effective effects in treating the rat nitroglycerin type migraine model.

[0051] In some combined use embodiments, the amino acid sequence of phospholipase A2 in the composition is

[0052] nly qfknmiqctv psrswwdfad ygcycgrggs gtpvddldrc cqvhdncyne aekisgcwpyfktysyecsq gtltckggnn acaaavcdcd rlaaicfaga pynnnnynid lkarcq(SEQ ID No.16)

[0053] In some combined use embodiments, the amino acid sequence of phospholipase A2 in the composition is

[0054] nly qfknmiqctv psrswwdfad ygcycgrggs gtpvddldrc cqvhdhcyne aekisgcwpysktysyecsq gtltckggnn acaaavcdcd rlaaicfaga pynnnnynid lkarcq(SEQ ID No.17)

[0055] In some combined use embodiments, the amino acid sequence of phospholipase A2 in the composition is

[0056] nly qfknmvqctv pnrswwdfad ygcycgrggs gtpvddldrc cqvhdncyge aekisrcwpyfktysyecsq gtltckggnn acaaavcdcd rlaaicfaga pyndnnynid lkarcq(SEQ ID No.18)

[0057] In some combined use embodiments, the amino acid sequence of phospholipase A2 in the composition is

[0058] nlyqfknmiq ctvpsrswwd fadygcycgr ggsgtpvddl drccqvhdnc yneaekisgcwpyfktysye csqgtltckg gnnacaaavc dcdrlaaicf agapyndndy ninlkarc(SEQ ID No.19)

[0059] The amino acid sequences (FASTA) of the mature proteins of cobra neurotoxin (NTX) used in combination with cobra cardiotoxin (CDX), or used in combination with cobra cardiotoxin (CDX) and cobra phospholipase A2 (PLA2) have the following common features:

[0060] lechnqqsxq tptttgcsgg etncykkrwr dhrgyrterg cgcpxvkngi einccttdrc nn(SEQ ID No.20)

[0061] Further, in some combined use embodiments, the following three amino acid sequences of cobra neurotoxins all showed more effective effects in treating the rat nitroglycerin type migraine model.

[0062] lechnqqssq tptttgcsgg etncykkrwr dhrgyrterg cgcpsvkngi einccttdrc nn(SEQ ID No.21)cobotidelechnqqssq tptttgcsgg etncykkrwr dhrgyrterg cgcpivkngiesnccttdrc nn(SEQ ID No.22)

[0063] lechnqqsiq tptttgcsgg etncykkrwr dhrgyrterg cgcpsvkngi einccttdrc nn(SEQ ID No.23)

[0064] In some embodiments of combined use, the amino acid sequence of the mature protein of cobra neurotoxin in the composition is SEQ ID No. 21

[0065] In some embodiments of combined use, the amino acid sequence of the mature protein of cobra neurotoxin in the composition is SEQ ID No. 22

[0066] In some embodiments of combined use, the amino acid sequence of the mature protein of cobra neurotoxin in the composition is SEQ ID No. 23

[0067] In some embodiments of combined use, the weight ratio of cobra cardiotoxin (CDX) to cobra phospholipase A2 (PLA2) in the composition is any ratio of 0.01% to 100% of cobra cardiotoxin (CDX) to 99.9% to 0% of cobra phospholipase A2 (PLA2).

[0068] In some embodiments of combined use, the weight ratio of cobra cardiotoxin and phospholipase A2 in the composition is 0.01% to 90%: 99.9% to 10%.

[0069] In some embodiments of combined use, the weight ratio of cobra cardiotoxin and phospholipase A2 in the composition is 0.01% to 80%: 99.9% to 20%.

[0070] In some embodiments of combined use, the weight ratio of cobra cardiotoxin and phospholipase A2 in the composition is 0.01% to 70%: 99.9% to 30%.

[0071] In some embodiments of combined use, the weight ratio of cobra cardiotoxin and phospholipase A2 in the composition is 0.01% to 60%: 99.9% to 40%.

[0072] In some embodiments of combined use, the weight ratio of cobra cardiotoxin (CDX) to cobra neurotoxin (NTX) in the composition is any ratio of 0.01% to 100% of cobra cardiotoxin (CDX) to 99.9% to 0% of cobra neurotoxin (NTX).

[0073] In some embodiments of combined use, the weight ratio of cobra cardiotoxin and neurotoxin in the composition is 0.01% to 80%: 99.9% to 20%.

[0074] In some embodiments of combined use, the weight ratio of cobra cardiotoxin and neurotoxin in the composition is 0.01% to 70%: 99.9% to 30%.

[0075] In some embodiments of combined use, the weight ratio of cobra cardiotoxin and neurotoxin in the composition is 0.01% to 60%: 99.9% to 40%.

[0076] In some embodiments of combined use, the weight ratio of cobra cardiotoxin and neurotoxin in the composition is 0.01% to 50%: 99.9% to 50%

[0077] In some embodiments of combined use, the weight ratio of cobra cardiotoxin (CDX), cobra phospholipase A2 (PLA2) and cobra neurotoxin (NTX) used in combination in the composition is any ratio of cobra cardiotoxin (CDX) 0.01%-100%, cobra neurotoxin (NTX) 50%-0% and phospholipase A2 (PLA2) 49.9%-0%.

[0078] In some embodiments of combined use, the weight ratio of cobra cardiotoxin, neurotoxin, and phospholipase A2 in the composition is 0.01%-60%: 50%-30%: 49.9%-10%

[0079] In some embodiments of combined use, the weight ratio of cobra cardiotoxin, neurotoxin, and phospholipase A2 in the composition is 0.01%-59%: 50%-29%: 49.9%-12%

[0080] In some embodiments of combined use, the weight ratio of cobra cardiotoxin, neurotoxin, and phospholipase A2 in the composition is 0.01%-58%: 50%-28%: 49.9%-14%

[0081] In some embodiments of combined use, the weight ratio of cobra cardiotoxin, neurotoxin, and phospholipase A2 in the composition is 0.01%-54%: 50%-30%: 49.9%-16%

[0082] In some embodiments, cobra cardiotoxin, cobra phospholipase A2, and cobra neurotoxin can be extracted from snake venom or obtained by recombinant or synthetic techniques.

[0083] In some embodiments, the composition is in the form of a sublingual film.

[0084] In some embodiments, the composition is in an oral dosage form.

[0085] In some embodiments, the composition is in the form of an injection.

[0086] In some embodiments, the composition is in the form of a nasal spray.

[0087] In some embodiments, the composition is in a transdermal dosage form.

[0088] In some embodiments, the pharmaceutically acceptable excipient is selected from one or more of a protein stabilizer, a membrane excipient, a mucosal permeation promoter, a solubilizing agent, a solvent, and a preservative.

[0089] In some embodiments, the protein stabilizer is mannitol.

[0090] In some embodiments, the film excipient is propylene glycol, polyethylene glycol, hydroxypropyl beta-cyclodextrin, Tween 80, hydroxypropyl methylcellulose (HPMC), methylcellulose, xanthan gum.

[0091] In some embodiments, the mucosal permeation promoting agent is laurocapram, poloxamer, borneol, or dextroborneol.

[0092] In some embodiments, the co-solvent is propylene glycol.

[0093] In some embodiments, the solvent is sodium chloride or ammonium acetate.

[0094] In some embodiments, the preservative is benzyl alcohol, benzalkonium chloride.

[0095] Another advantage of the present invention is in production. Because the cobra cardiotoxin, phospholipase A2, and neurotoxin disclosed in the present invention all have clear amino acid sequences, they can be produced through genetic engineering, solving the practical problem of scarce snake venom resources. Even if the cardiotoxin is obtained by separation and purification of natural snake venom, it is easier to achieve quality and purity control because of the clear amino acid sequence in the process, which lays a necessary foundation for the development of drugs of monomer components in snake venom.

[0096] The present invention is further described below in conjunction with specific embodiments, but the following embodiments are not intended to limit the present invention; at the same time, any equivalent replacements in the art made according to the disclosure of the present invention belong to the protection scope of the present invention. DETAILED DESCRIPTION

[0097] Example:

[0098] Example 1: Obtaining cobra cardiotoxin protein (SEQ ID No. 2)

[0099] 1g of crude cobra venom was dissolved in 25ml of 0.025mol ammonium acetate buffer at pH 6.0, centrifuged at low temperature, and the supernatant was collected; a TSK CM-650 (M) column was equilibrated with a 0.025mol ammonium acetate solution at pH 6.0; after loading, a two-compartment step gradient elution (0.1-0.5mol and 0.6-1mol) was performed with 0.1-0.5mol and 0.7-1.0mol ammonium acetate buffer at pH 5.9, and the ultraviolet detection parameters were 280nm; the elution flow rate was 48ml / h; various toxin components were collected according to the recorded spectra, and multiple protein peaks were eluted from the collected solution, and N-terminal sequencing was performed on each protein peak, and the protein with N-terminal lkcnkl was further sequenced by Edman degradation method, and finally various sequence proteins of cobra cardiotoxin were obtained.

[0100] The amino acid sequence of the primary structure of cobra cardiotoxin (SEQ ID No. 2) obtained by sequencing is in the form of Fasta: lkcnklvpl fyktcpagkn lcykmfmvat pkvpvkrgci dvcpkssllv kyvccntdrc n

[0101] Example 2: Analgesic efficacy of cobra cardiotoxin (CDX); or cobra cardiotoxin (CDX) combined with cobra phospholipase A2 (PLA2); or cobra cardiotoxin (CDX) combined with cobra phospholipase A2 (PLA2) and cobra neurotoxin (NTX) on nitroglycerin-induced experimental migraine model rats

[0102] 1. Grouping and modeling of experimental animals

[0103] 1.1 Grouping

[0104] A total of 80 SD rats weighing 180-220 g were randomly divided into 8 groups: normal control group (n=10), model control group (n=10), CDX treatment group (n=10), CDX prevention group (n=10), CDX+PLA2 treatment group (n=10), CDX+PLA2 prevention group (n=10), CDX+PLA2+NTX treatment group (n=10), and CDX+PLA2+NTX prevention group (n=10).

[0105] 1.2 Modeling method: Except for the normal control group, the other groups were intraperitoneally injected with 10 mg / kg nitroglycerin for 3 consecutive days.

[0106] The CDX prevention group was given nasal drops for 7 consecutive days before modeling until the day of modeling, 80 μg / kg each time, 2 times / day; the CDX+PLA2 prevention group was given nasal drops for 7 consecutive days before modeling until the day of modeling, 80 μg / kg CDX+20 μg / kg PLA2 each time, 2 times / day; the CDX+PLA2+NTX prevention group was given nasal drops for 7 consecutive days before modeling until the day of modeling, 60 μg / kg CDX+30 μg / kg NTX+10 μg / kg PLA2 each time, 2 times / day.

[0107] During modeling, except for the normal control group injected with normal saline, the other groups were intraperitoneally injected with 10 mg / kg nitroglycerin for 3 consecutive days as mentioned above. The CDX treatment group, CDX+PLA2 treatment group, and CDX+PLA2+NTX treatment group were given drugs at the same time during the modeling stage: 80 g / kg for the CDX treatment group, 2 times / day; 80 μg / kg CDX+20 μg / kg PLA2 for the CDX+PLA2 treatment group, 2 times / day; 60 μg / kg CDX+30 μg / kg NTX+10 μg / kg PLA2 for the CDX+PLA2+NTX treatment group, 2 times / day.

[0108] Cobra cardiotoxin (CDX) SEQ ID No. 2, phospholipase A2 (PLA2) SEQ ID No. 16 and neurotoxin (NTX) SEQ ID No. 21 were used for animal experiments.

[0109] 2 Observation indicators and detection methods

[0110] 2.1 Observation indicators

[0111] Number of head scratching in rats in each time period: Observe animal behavior indicators 30-120 minutes after the last modeling. From the last modeling, take every 30 minutes as a time period, and use the duration segmented counting method to observe the results of head scratching in rats in each time period after modeling. (As shown in Table 1)

[0112] 2.2 Detection methods

[0113] Serum nitric oxide (NO) level detection: After the behavioral experiment, the mice in the normal group, model control group, CDX treatment group, and CDX prevention group were anesthetized, and blood was collected from the periorbital area. After standing, the blood was centrifuged at 3000r / min at 4°C for 20 minutes, and the supernatant was obtained and stored in a -80°C refrigerator. The ELISA kit instructions were used for detection. (As shown in Table 2)

[0114] 3 Experimental results

[0115] Table 1 Number of head scratching in rats

[0116] ( n=10)

[0117]

[0118] *Indicates that there are significant differences between the CDX treatment group, CDX prevention group, CDX+PLA2 treatment group and CDX+PLA2 prevention group and the model control group (P<0.05); **Indicates that there are significant differences between the CDX treatment group, CDX prevention group, CDX+PLA2 treatment group, CDX+PLA2 prevention group, CDX+NTX+PLA2 treatment group and CDX+NTX+PLA2 prevention group and the model control group (P<0.01).

[0119] Table 2 Comparison of blood nitric oxide (NO) content in rats in the normal group, model control group, CDX treatment group, and CDX prevention group

[0120] (μmol / ml n=10)

[0121]

[0122] **Indicates that there are significant differences between the CDX treatment group and the CDX prevention group and the model control group (P<0.01.)

[0123] Reference:

[0124] 1. Xu Xiaohui et al., Detection and clinical significance of serum 5-HT, NO, MMP-9 and CGRP in patients with vestibular migraine. Journal of Molecular Diagnosis and Therapy, March 2022, Vol.14No.3

[0125] 2. Liu Bin, Ma Yuanyuan, Mao Wenjing, et al., Experimental study on changes in plasma nitric oxide and calcitonin gene-related peptide levels in migraine model rats and the intervention effect of flunarizine. [J]. Shaanxi Medical Journal, 2020, 49(7): 5-7.

[0126] 3. Blaine Jacobs et al;,Neurovascular contributions to migraine:movingbeyond vasodilation.Neuroscience.2016Dec 3;338:130–144.

[0127] 4.L Neeb et al;,Nitric oxide in migraine.CNS Neurol Disord DrugTargets.2007Aug;6(4):258-64.

[0128] 5. Xiao Youmei. Clinical study of Zhennaoning capsule combined with sodium ferulate in the treatment of migraine. [J]. Modern Drugs and Clinic, 2019, 34(1): 41-44.

Claims

1. Use of a composition for preparing a drug for treating and / or preventing migraine, the composition comprising a therapeutically effective A dose of cobra cardiotoxin and pharmaceutically acceptable excipients; the amino acid sequence of the cobra cardiotoxin is shown in SEQ ID NO.

2.

2. The use according to claim 1, characterized in that: The drug has at least one of the following applications (1)-(3): (1) The drug is used to treat migraine; (2) The drug is used to prevent migraine; (3) The drug is used to downregulate the concentration of nitric oxide in the body of a migraine sufferer.

3. The use according to claim 1, further characterized in that: The composition also includes cobra cardiotoxin and other drugs for treating migraine, including cobra phospholipase A2 and cobra neurotoxin, any one of them or a combination of both; the amino acid sequence of the cobra phospholipase A2 is shown in SEQ ID NO.16, and the amino acid sequence of the cobra neurotoxin is shown in SEQ ID NO.

21.

4. The use according to claim 3, characterized in that: The weight ratio of the cobra cardiotoxin and the cobra phospholipase A2 used in the composition is any weight ratio of 0.01%-100% of the cobra cardiotoxin and 99.9%-0% of the cobra phospholipase A2; the weight ratio of the cobra cardiotoxin and the cobra neurotoxin used in the composition is any weight ratio of 0.01%-100% of the cobra cardiotoxin and 99.9%-0% of the cobra neurotoxin; or the weight ratio of the cobra cardiotoxin, the cobra phospholipase A2 and the cobra neurotoxin used in the composition is any weight ratio of 0.01%-100% of the cobra cardiotoxin and 50%-0% of the cobra neurotoxin and 49.9%-0% of the cobra phospholipase A2.

5. The use according to claim 1, characterized in that: The dosage form of the composition is an oral dosage form, a sublingual dosage form, a nasal dosage form, a transdermal dosage form or an injection dosage form.

6. The use according to claim 1, characterized in that: The pharmaceutically acceptable excipients in the composition are selected from one or more of protein stabilizers, membrane excipients, mucosal permeation promoters, cosolvents, solvents, and preservatives.

7. The use according to claim 1, further characterized in that the protein stabilizer in the drug-acceptable excipients is mannitol, the film excipients are propylene glycol, polyethylene glycol, hydroxypropyl β-cyclodextrin, Tween-80, hydroxypropyl methylcellulose, methylcellulose, xanthan gum, the mucosal permeation promoter is laurocapram, poloxamer, borneol, dextroborneol, the cosolvent is propylene glycol, the solvent is sodium chloride, ammonium acetate, and the preservatives are benzyl alcohol and benzalkonium chloride.

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