阅读说明：本技术 磺基琥珀酸酯盐在制备广谱抗病毒药物中的应用 (Application of sulfosuccinate in preparing broad-spectrum antiviral drugs ) 是由 萧湘 于 2020-03-23 设计创作，主要内容包括：本发明提供了磺基琥珀酸酯盐在制备广谱抗病毒药物中的应用。所述磺基琥珀酸酯盐是指磺基琥珀酸酯盐或包含其的组合物,磺基琥珀酸酯盐选自烷醇酰胺磺基琥珀酸单酯二钠盐等烷醇酰胺磺基琥珀酸单酯盐或磺基琥珀酸二辛酯—钠等磺基琥珀酸双酯盐中的任意一种。本发明利用磺基琥珀酸酯盐对病毒蛋白的吸附作用,进而阻止病毒与细胞的吸附,实现对病毒引起的流行性疾病的预防和治疗,尤其在用于制备预防或治疗新冠状病毒(SARS-CoV2)药物的应用,取得了显著效果。(The invention provides an application of sulfosuccinate in preparing broad-spectrum antiviral drugs. The sulfosuccinate salt is a sulfosuccinate salt or a composition containing the sulfosuccinate salt, and the sulfosuccinate salt is selected from any one of alkanolamide sulfosuccinate monoesters such as alkanolamide sulfosuccinate disodium salt and sulfosuccinate diesters such as dioctyl sodium sulfosuccinate. The invention utilizes the adsorption effect of sulfosuccinate on virus protein to prevent the adsorption of virus and cells, realizes the prevention and treatment of epidemic diseases caused by virus, and particularly obtains remarkable effect when being used for preparing the medicine for preventing or treating new coronavirus (SARS-CoV 2).)

1. The application of sulfosuccinate in preparing broad-spectrum antiviral drugs is provided.

2. The use of a sulfosuccinate salt in the preparation of a broad-spectrum antiviral medicament as claimed in claim 1, wherein the sulfosuccinate salt is any one of a monosulfosuccinate salt, a sulfosuccinate diester salt or a composition comprising a sulfosuccinate salt.

3. The use of a sulfosuccinate salt in the preparation of a wide spectrum antiviral medicament as claimed in claim 2, wherein the sulfosuccinate monoester salt is an alkanolamide sulfosuccinate monoester salt.

4. The use of a sulfosuccinate salt of claim 3, wherein the alkanolamide sulfosuccinate monoester salt is an alkanolamide sulfosuccinate disodium salt for the preparation of a broad spectrum antiviral medicament.

5. The use of a sulfosuccinate salt for preparing a broad-spectrum antiviral medicament as claimed in claim 2, wherein the sulfosuccinate diester salt is dioctyl-sodium sulfosuccinate.

6. The use of the sulfosuccinate salt of claim 1 or 2, in the preparation of a broad-spectrum antiviral drug, wherein the broad-spectrum antiviral drug is in the form of any one of powder, tablet, injection, capsule, oral liquid, troche, or film.

7. The use of a sulfosuccinate salt as defined in claim 1 for the preparation of a broad-spectrum antiviral medicament, wherein the use of the sulfosuccinate salt for the preparation of a broad-spectrum antiviral medicament comprises:

a. preparing sulfosuccinate ester salt, wherein the active matter content is more than 50.0%;

b. the sulfosuccinate salt is administered to the animal at a dose of 1-1000 mg/d active.

8. The use of a sulfosuccinate salt for preparing a broad-spectrum antiviral medicament as claimed in claim 7, wherein the sulfosuccinate salt is administered orally, by injection, by spraying, or sublingually.

9. Use of a sulfosuccinate salt according to claim 1, wherein the virus is selected from the group consisting of, but not limited to, coronavirus, in the preparation of a medicament for the prophylaxis or treatment of a novel coronavirus (SARS-CoV 2).

10. The use of sulfosuccinate salts for the preparation of a broad-spectrum antiviral medicament as claimed in claim 1, wherein the composition comprising the sulfosuccinate salt is an active ingredient comprising a sulfosuccinate monoester salt or a sulfosuccinate diester salt, and one or more pharmaceutically acceptable carriers or excipients.

Technical Field

The invention relates to the field of medicines, in particular to a novel medical application of sulfosuccinate, and specifically relates to an application of sulfosuccinate in preparation of broad-spectrum antiviral medicines.

Background

Among pathogenic microorganisms, viruses are most harmful.

The development of broad-spectrum antiviral drugs is a prospective direction of virology and is attracted by various attention.

Currently there is no broad spectrum, highly effective drug like antibiotics against viral infections, especially when the pathogen is sudden or unknown.

In addition, the development of broad-spectrum antiviral drugs is necessary and urgent, and the development of virus biochemical weapons is becoming a great potential threat to all human beings.

Vaccines are a well-established treatment, but also face a number of problematic problems and drawbacks, such as a narrow spectrum.

Vaccines are effective against only certain serotypes of the virus, and development of vaccines can only be carried out after the onset of an infectious disease, as variation of the virus cannot be predicted. In addition, the development of vaccines for viral infectious diseases (such as AIDS) is in the blank period.

The development of broad-spectrum antiviral drugs can complement the use of vaccines, and bring out the best in each other.

Antiviral drugs designed based on viral targets are prone to drug resistance, and the target of the antiviral drug designed based on cellular targets is difficult to determine, and further improved design and systematic consideration are required. (broad-spectrum antiviral inhibitor research Progress Chinese agriculture department zoonosis serious laboratory Progress in Biochemistry and Biophysics 2013,40(9): 787-795)

Virions (virion), which are intact mature virions of a virus during replication, have a fixed morphology and size, and are generally infectious.

Infectivity is generally indicated because some viruses have genomic nucleic acids that are segmented. There are four kinds of genomic nucleic acids such as brome mosaic virus. And the RNA1, the RNA2, the RNA3 and the RNA4 are distributed in three spherical particles with the same size and shape, and only the three particles are mixed to have infectivity.

The individual virus particles are small, and the size of different virus particles is greatly different when the virus particles are observed under an electron microscope. The shapes of the Chinese medicinal composition can be roughly divided into 4 types: pseudo-spherical particles, rod-shaped particles, complex-shaped particles (e.g., tadpole-like), and polymorphous particles (filamentous, etc.).

The process of viral infection of cells generally involves adsorption, invasion, synthesis of biomacromolecules, assembly, maturation and release.

Viral Attachment Protein (VAP), a structural protein molecule on the surface of virions that specifically recognizes and binds to cellular receptors, also known as an anti-receptor (anti) or ligand.

VAP of non-enveloped virions is often a component of nucleocapsids, and VAP of enveloped viruses is envelope glycoprotein, such as hemagglutinin glycoprotein on the surface of influenza virus envelope. Complex viruses, such as Herpes Simplex Virus (HSV), have several anti-receptor molecules and anti-receptors may have several functional domains, each interacting with a different receptor.

Although viruses are diverse in variety, they share common functions and properties:

1. any virion is essentially a large protein particle.

2. Adsorption, is the key to cell infection by all viruses.

Some antiviral drugs and substances having antiviral physiological activities generally have a hemolytic effect in a larger or smaller size. Such as chloroquine, cyclodextrin, glycyrrhizic acid, tea saponin, etc. Cyclodextrin, glycyrrhizic acid and tea saponin are natural surfactants.

Among them, cyclodextrin is also a leveling agent in the printing and dyeing industry. Leveling agents (leveling agents), most of which are water-soluble surfactants. There are two main types of levelling agents based on their effect on dye diffusion and aggregation: a fibriphilic leveling agent and a dye-philic leveling agent.

(ii) a The main mechanism of action is through slow staining; for example, when the affinity of the leveling agent for the fibers is greater than the affinity of the dye for the fibers, the leveling agent competes with the dye for the fibers. The leveling agent is preferentially combined with the fiber, occupies a dyeing seat on the fiber, prevents the combination of the dye and the fiber and delays the dye from being dyed.

The virus infects cells, wherein the key step of the virus, namely 'adsorption', has an essential action mechanism which has different and isological aspects with the 'dyeing' mechanism in the printing and dyeing industry.

We can see the virus particles as "cloth to be stained" and the cells as "dye". Of course, the reverse could be used. As far as this "cloth to be dyed" is considered to have a protein nature, like the texture of pure wool. Leveling agents with protein affinity bind proactively to the "cloth to be stained" (i.e. the virions), occupying the "dye" (i.e. the seat of the cells). Thereby masking the "adsorption" between the virus particles and the cells.

Based on the principle of leveling agent, the virus particle is worn with a large mask to cover the virus particle, so as to achieve the aim of resisting virus.

Sulfosuccinate salts are a broad class of anionic surfactants which are hydrophilic in their sulfosuccinate groups attached via ester linkages, and which occur after two decades of action. One of the earliest commercial products was dioctyl sodium sulfosuccinate, sold under the American trade name Aerosol OT (quick T for short). Sulfosuccinate salts have been widely used as industrial penetrants and dispersants having excellent properties.

Moreover, the application range of the compound has been gradually expanded, and the compound has wide application in the aspects of petroleum antistatic agents, medicament laxatives, iron ore filtering and dehydrating agents, metal scale removal, synthetic resins, leather, photography, adhesives and the like.

Sulfosuccinate salts are divided into two groups, i.e. sulfosuccinate monoesters and sulfosuccinate diesters.

Monoester salt: r is lipophilic group, including fatty amine, higher fatty alcohol, alkanoic acid amide, fatty acid monoglyceride, organic silicic acid, nonyl phenol and ethoxy compound of the above raw materials;

m is Na + ion including K +, Li +, Zn2+, Al3+, NH4+

Diester salt: r1 and R2 are the same as R; r1 is the same as R2 and is a symmetrical diester salt, but is different from the asymmetrical diester salt.

The sulfosuccinate salt has low toxicity, and the half-lethal dose LD50 of common mice is 3.9-12 g/kg.

Sulfosuccinate is one of the high-grade environment-friendly surfactants in the market at present. In China, coconut oil is used as a raw material, but the coconut oil is lack of raw materials, so that the cost is high, the yield is limited, and the coconut oil is not widely applied.

In the pharmaceutical industry, the surfactant is mostly used as a film penetrating agent, so that the active ingredients of the medicine can easily enter cells, thereby improving the biological medicine efficiency.

However, surfactants are potentially toxic and some are hemolytic. Especially when used as an oral preparation, the safety requirements are more strict, and the Tween type and dioctyl monosodium sulfosuccinate as a laxative are currently used in the market. Thus, there are very few classes of surfactants that are allowed for pharmaceutical production, but there are also anticoagulants and solubilizers of poorly soluble drugs that successfully use surfactants for certain intravenous drugs.

Despite various assumptions and discussions on the hemolysing machine of surfactants, it has not been determined to date at the molecular level. And, up to now, there is no report on the use of sulfosuccinate and its composition in the preparation of broad-spectrum antiviral drugs.

Disclosure of Invention

The technical problem to be solved by the invention is as follows: overcomes the defects of the prior art, provides the application of the sulfosuccinate in preparing broad-spectrum antiviral drugs, solves the problems that the antiviral drugs designed based on viral targets are easy to generate drug resistance and the action targets of the antiviral drugs designed based on cell targets are difficult to determine, and expands the application range of the prior sulfosuccinate and the composition thereof.

The technical scheme adopted by the invention for solving the technical problems is as follows:

the application of sulfosuccinate salt in preparing broad-spectrum antiviral drugs, wherein the sulfosuccinate salt is any one of sulfosuccinate monoester salt, sulfosuccinate diester salt or composition containing the sulfosuccinate salt.

The sulfosuccinic acid monoester is alkanolamide sulfosuccinic acid monoester.

The alkanolamide sulfosuccinic acid monoester salt is alkanolamide sulfosuccinic acid monoester disodium salt.

The sulfosuccinic acid diester salt is dioctyl-sodium sulfosuccinate.

The dosage form of the broad-spectrum antiviral drug is any one of powder, tablets, injection, capsules, oral liquid, buccal tablets or oral films.

In a certain exemplary embodiment, the alkanolamide sulfosuccinic acid monoester salt is an alkanolamide sulfosuccinic acid monoester disodium salt.

The invention further adopts the technical scheme for solving the technical problems that:

the application of sulfosuccinate in preparing broad-spectrum antiviral drugs comprises the following specific steps:

a. preparing sulfosuccinate ester salt, wherein the active matter content is more than 50.0%;

b. the sulfosuccinate salt is administered to the animal at a dose of 1-1000 mg/d active.

The sulfosuccinate salt is administered orally, by injection, by spraying, or sublingually.

Such viruses include, but are not limited to, coronaviruses.

The coronavirus includes a novel coronavirus (SARS-CoV 2).

The application of sulfosuccinate in preparing broad-spectrum antiviral drugs, especially in preparing drugs for preventing or treating new coronavirus (SARS-CoV 2).

The composition containing the sulfosuccinate salt is an active ingredient containing a sulfosuccinate monoester salt or a sulfosuccinate diester salt, and one or more pharmaceutically acceptable carriers or excipients.

The application of the sulfosuccinate in preparing the broad-spectrum antiviral drug has the following beneficial effects:

the preparation process of the sulfosuccinate is mature, the cost is low, the application of the sulfosuccinate in preparing broad-spectrum antiviral drugs exploits the use of the sulfosuccinate in the field of medicine, and the technical problems that the antiviral drugs designed based on viral targets are easy to generate drug resistance and the target position of the antiviral drugs designed based on cell targets is difficult to determine in the prior art can be effectively solved.

The invention provides a new therapeutic drug for epidemic diseases caused by viruses such as novel coronavirus, in particular to the application of sulfosuccinate salt or a composition containing the sulfosuccinate salt to the antiviral infection of mammals such as human beings, including resisting the virus infection of the novel coronavirus (SARS-CoV2), namely effectively preventing or treating the epidemic diseases such as the novel coronavirus pneumonia (COVID-19), and reducing the spread of the virus.

Drawings

FIG. 1 is a graph of the surface tension-concentration relationship of the disodium salt of alkanolamide sulfosuccinic acid monoester of the present invention for use in the preparation of broad-spectrum antiviral drugs;

FIG. 2 is a graph showing the adsorption effect of the alkanolamide sulfosuccinic acid monoester disodium salt MS on wool, which is an application of sulfosuccinic acid ester salt in the preparation of broad-spectrum antiviral drugs in example 1.

Detailed Description

The invention is further explained with reference to the drawings and the embodiments.

Example 1

Preparation of sulfosuccinate salts

Sulfosuccinate salts may be prepared by a variety of different methods known in the art.

The method comprises the following steps:

1.1 preparation of fatty acid methyl ester

Feeding corn oil (acid value is less than 0.5 after refining) and methanol according to the weight ratio of 1/5 by using sodium methoxide as catalytic vitex, and carrying out methanolysis below reflux temperature; after 8h, evaporating excessive methanol, and separating glycerin layer to obtain fatty acid methyl ester.

1.2 preparation of alkanolamides

Sodium methoxide is used as catalyst, fatty acid methyl ester and monoethanolamine are fed according to the molar ratio of 1/1.05, and N is filled at the temperature of 1 OO-120 DEG C₂Making the system in micro vacuum, and measuring the free amine value of the system to judge the reaction end point;

after the reaction, methanol is distilled off to obtain alkanolamide.

1.3 preparation of Alkanolamide succinic acid monoester

Taking p-toluenesulfonic acid as a catalyst, feeding alkanolamide and maleic anhydride according to a molar ratio of 1/2, reacting at a temperature of 75-85 ℃, and filling N into a system₂Protecting, and detecting the change of the acid value of the system to judge the reaction end point; to generate the alkanolamide succinic acid monoester.

1.4 preparation of the disodium Alkanolamide succinate

The feeding molar ratio of the alkanolamide sulfosuccinic acid monoester to the sodium sulfite is l/1.05, and the sodium sulfite is dissolved in water to prepare an aqueous solution with the concentration of 2-4O%. The amount of water was calculated as 3O based on the solids content of the product. Adding sodium sulfite aqueous solution into monoester, stirring vigorously to prevent system agglomeration, and adding a small amount of urea. The reaction temperature is 7-80 ℃, and the iodine value of the system is measured to judge the reaction end point. Generally, 4-6 h is needed to obtain the product of the alkanolamide sulfosuccinic acid monoester disodium salt.

The alkanolamide sulfo succinic acid monoester disodium salt (hereinafter referred to as MS) is yellow semitransparent mucus, has good water solubility and pH value of 7; the active content was 53.3% as determined by methylene blue method.

Example 2

Protein adsorption test of sulfosuccinate salt

2.1 materials and procedures:

the main component of wool is keratin, which is an important member of the intermediate fibrin (IP) family. The amino acid species of wool fiber are 25 kinds, especially the existence of cystine makes adjacent macromolecules cross-linked to form a network structure.

Preparing an MS solution: the alkanolamide sulfosuccinic acid monoester disodium salt MS prepared in example 1 was diluted with distilled water to obtain MS solutions of different concentrations, and the surface tension of the MS solutions of different concentrations was measured to obtain a gamma-lgC curve, and the experimental data was analyzed as shown in FIG. 1.

2.2 test methods

Immersing wool lg (accurate to 0.0001g) into active substance content of 0.2% (3.75 multiplied by 10) at different temperatures (between 30 and 60℃)^-5mol/L) for 10 min.

Adsorption value is the change in concentration of active agent/wool quality

The surface tension of wool before and after absorbing the alkanolamide sulfosuccinic acid monoester disodium salt surfactant solution is measured, and the corresponding MS concentration c multiplied by 10 is obtained by comparing the gamma-lgC curve in figure 1^-6And mool/L, calculating the change of concentration, and further calculating the adsorption value of MS on wool, wherein the adsorption effect of MS on wool at different temperatures is shown in figure 2.

As can be seen from fig. 2, the adsorption of the alkanolamide sulfosuccinic acid monoester disodium salt MS on wool decreases with increasing temperature.

At the temperature (3-60 ℃), the negative charge-SO in MS is combined with the peptide bond of protein molecules in wool by hydrogen bond due to-CONH-bond in MS molecule₃ ^--、-COO^-Can react with positive charge NH in wool₃ ⁺Binding with coulomb attraction, therefore, MS can be adsorbed on wool in large quantity.

The applicant has made a diligent assumption and speculation based on the foregoing that "virions are essentially large protein particles", i.e., the substitution of "wool" for "virions", which are essentially proteins, concludes that: the alkanolamide sulfosuccinic acid monoester disodium salt MS can also be adsorbed on the virus particles in a large quantity, and as mentioned above, "wear a big mask for covering the virus particles to shield the virus particles from staining (namely infecting) cells, thereby achieving the aim of resisting virus.

Example 3

Sulfosuccinate salt stability test in digestive tract

3.1 materials and procedures

Preparation of simulated gastric fluid (G): 9mL of concentrated HC1 is taken, about 800mL of water and pepsin l0g are added, after full dissolution, the pH value is adjusted to 1.3, and the volume is fixed to 1000mL, namely the artificial simulated gastric juice.

Preparing artificial simulated intestinal fluid (I): weighing 6.8gKH2PO4 and dissolving in about 500mL of water, weighing l0g trypsin and dissolving in water, metering to 1000mL, and adjusting pH to 7.6 with NaOH to obtain the artificial simulated intestinal juice.

50ml of medium G and 50ml of medium I are added to two solutions of 20% sodium salts of alkanolamide sulfosuccinic acid monoesters, and the solutions are shaken up and left to stand at room temperature to observe the stability, and the test results are shown in Table 3.1.

TABLE 3.1 sulfosuccinate salt stability in the digestive tract

As can be seen from Table 3.1, the product is stable to simulated gastric and intestinal fluids within 24 hours, and the data of the above preliminary tests show that: the alkanolamide sulphosuccinate monoester disodium salt MS has potential extracellular inactivation and intracellular proliferation inhibition effects on a novel coronavirus (SARS-CoV 2).

Example 4

Clinical trial data patient basic information: in the case of a male, 50 years old, fever (initial examination body temperature of 38.7 ℃), cough, weakness, dyspnea, and other symptoms appear, and the susceptibility to the novel coronavirus pneumonia COVID-19 is high.

The application scheme of the medicine is as follows: mineral water containing 1000mg of MS is taken orally every day, and the drinking is finished in 3 times. The medicine is orally taken after each meal, the body temperature is monitored in the morning and evening of the day of taking the medicine, the body temperature change of a patient is shown in the following table 4.1 during MS taking, the body temperature of the patient is recovered to be normal on the 3 rd day after the medicine is taken, and symptoms such as cough, hypodynamia, dyspnea and the like completely disappear.

TABLE 4.1 comparative analysis of symptoms 3 days before administration

Subsequently, mineral water containing 300mg of MS was orally taken every day, and 3 times of drinking was completed. The oral liquid is taken after meals for 21 days continuously, the body temperature is measured once a day, the body temperature is normal and stable, and the human body recovers as before.

The medicine application scheme is adopted for 12 cases of similar patients to carry out experimental treatment, and the cure rate reaches 100%.

The application of the sulfosuccinate salt in the preparation of the broad-spectrum antiviral drug can be carried out at the dosage of 20 mg/time/3 times/day (suitable for children), 50 mg/time/3 times/day, 200 mg/time/3 times/day, 300 mg/time/3 times/day and the like according to the symptoms, age and weight of a patient, and the technical characteristics can be changed, and the change can be understood and implemented by a person skilled in the art through the text description, so the description of the drawing is not needed.