CN111671886B

CN111671886B - Pharmaceutical composition for preventing high-risk susceptible people from infecting coronavirus or generating coronavirus infection disease and application of pharmaceutical composition

Info

Publication number: CN111671886B
Application number: CN202010146698.3A
Authority: CN
Inventors: 李海
Original assignee: Shanghai Ganyi Biomedical Technology Co ltd
Current assignee: Shanghai Ganyi Biomedical Technology Co ltd
Priority date: 2020-03-05
Filing date: 2020-03-05
Publication date: 2022-11-15
Anticipated expiration: 2040-03-05
Also published as: CN111671886A

Abstract

The invention provides a pharmaceutical composition for preventing high-risk susceptible people from infecting coronavirus or generating coronavirus infection diseases and application thereof, wherein the pharmaceutical composition comprises interferon and thymosin alpha. The medicine composition can effectively prevent the infection of the novel coronavirus, remarkably reduce the infection rate of people and medical care personnel, avoid epidemic spread and can be effectively applied to the prevention of the infection of the novel coronavirus.

Description

Pharmaceutical composition for preventing high-risk susceptible people from infecting coronavirus or generating coronavirus infection disease and application of pharmaceutical composition

Technical Field

The invention relates to the technical field of biological medicines, in particular to a pharmaceutical composition for preventing high-risk susceptible people from infecting coronavirus or generating coronavirus infection diseases and application thereof.

Background

The novel Coronavirus (2019-nCoV) is a novel virus, belongs to Coronavirus according to nucleotide sequencing analysis results of the virus, belongs to different categories of pathogenicSARS and MERS virus of atypical pneumonia and Respiratory Syndrome in the middle east, and is formally named as SARS-CoV-2 (Severe acid Respiratory Syndrome Coronavir 2) by the international committee for virus classification at present. The disease WHO caused by the novel coronavirus infection human body is named as COVID-19. Wherein CO represents Corona VI represents Virus, D represents Disease and 19 represents 2019 according to the statement of WHO.

The transmission route of the novel coronavirus is mainly through droplet transmission, and after the virus is inhaled into a nasal cavity through air, the finally infected main target organ is lung, and a large amount of the coronavirus exists in alveolar epithelial cells. Infection of healthy individuals with the novel coronavirus causes a novel coronavirus disease (COVID-19), of which novel coronavirus pneumonia is the main disease type of COVID-19. The new type of coronary virus pneumonia is classified into mild disease and severe disease according to severity. Severe viral pneumonia may produce multi-organ failure caused by cytokine storm. The clinical manifestations of pneumonia patients infected with the novel coronavirus are as follows: it is mainly manifested as fever, fatigue and dry cough. The symptoms of upper respiratory tract such as nasal obstruction and nasal discharge are rare. Approximately half of patients develop dyspnea after one week, with the severe progressing rapidly to acute respiratory distress syndrome, septic shock, uncorrectable metabolic acidosis, and hemorrhagic dysfunction. It is noted that the severe and critically ill patients may have moderate or low fever during their course, even without significant fever. Some patients have mild onset symptoms and no fever, and recover after 1 week. The prognosis of most patients is good, and the disease of a few patients is critical and even death occurs [ the third edition of the novel pneumonia diagnosis and treatment scheme is tried ]. The infectivity of the novel coronavirus is very strong, the infectivity of the virus is represented by a basic replication number (R0), R0>1 indicates that the virus is very high in infectivity and can cause large outbreaks, and R0 of the novel coronavirus is reported to be 2.2-3.7 in different literatures. By far, over three thousand health care workers have become infected nationwide. Furthermore, it was found that a proportion of asymptomatic patients (so-called healthy carriers) were present in 2019-nCoV-infected patients. Asymptomatic persons have viral infectivity, while asymptomatic persons may also develop new coronavirus diseases. Under tight physical protection, the iatrogenic infection rate of the medical staff exposed to 2019-nCoV infected patients is 3-5%. However, no drug effective for treating the infection with the novel coronavirus or preventing the infection with the novel coronavirus in healthy people is determined, and the prevention of the infection with the novel coronavirus in the present stage mainly depends on a physical barrier such as a mask or an isolation suit.

The interferon is a kind of cell factor produced when the cell is infected by virus or stimulated by other IFN inducer, is a secretory protein (mainly glycoprotein), has many biological functions including regulating and controlling innate immunity and acquired immunity after infection, and has broad-spectrum biological functions of antivirus and immunoregulation, so that it is widely used for treating chronic hepatitis B and chronic hepatitis C in clinic.

However, interferon does not directly kill or inhibit viruses, but mainly acts on cell surface receptors, activates cell membrane adenylate cyclase, promotes adenylate cyclase to increase, activates an intracellular antiviral action mechanism, generates a group of antiviral substances, plays an antiviral role, enables cells to generate antiviral proteins and enzymes, inhibits the replication of viruses and blocks the diffusion of the viruses, and interferon is widely used for treating chronic hepatitis B and chronic hepatitis C clinically at present. Meanwhile, the antiviral action of interferon has no specificity, i.e. it is difficult to generate specific killing action on certain viruses. In the early chronic hepatitis B prevention and treatment guideline, when the micromolecule nucleoside antiviral drug does not exist, the recommended treatment scheme is interferon plus ribavirin. Thereafter, in the chronic hepatitis b control guidelines 2015 and 2019, treatment regimens in which interferon/long-acting interferon is separately injected and nucleoside drugs are separately used are recommended, but generally, interferon alone has a certain curative effect, and the serum conversion rate of common interferon is lower than that of long-acting interferon [ chronic hepatitis b control guidelines (2015), while nucleoside antiviral drugs can strongly inhibit virus replication and improve liver inflammation [ chronic hepatitis b control guidelines (2019) ]. Meanwhile, the injection of interferon has more contraindications, and the clinical application is further limited.

In the section on the diagnosis and treatment of novel coronavirus pneumonia (trial fifth, revised), there is mentioned "trial of a treatment regimen by aerosolizing with interferon-alpha (500 ten thousand U per adult or equivalent dose, 2ml of sterile water for injection, 2 times daily), 2 tablets per lopinavir/ritonavir (200 mg/50mg, each), 2 tablets per day, 2 times daily, or ribavirin (500 mg/2 to 3 intravenous infusions per day)" but it also refers to: the method for treating the novel coronavirus pneumonia is characterized in that the effective antiviral treatment method is not confirmed at present, so that the treatment scheme is only an inference made according to the properties of the medicine, the effect of the medicine is not verified through clinical experiments, and the effective rate is unknown, meanwhile, the scheme is not a main treatment scheme for the novel coronavirus pneumonia according to the current treatment condition, and the scheme is not disclosed to be used for preventing the novel coronavirus. And in the scheme, the alpha-interferon is in a nebulized form and can be selected to be combined with ribavirin injection, and the relatively complicated application mode also determines that the treatment scheme cannot be widely applied to the prevention scheme of the novel coronavirus.

Thymosin (also known as Thymosin, thymosin) is a group of physiologically active polypeptides secreted from thymus tissue. Small molecules with non-specific immune effects were first discovered and purified from calf thymus. The polypeptide can induce lymphocyte differentiation, proliferation and maturation, enhance macrophage phagocytosis and antigen presentation functions, improve response level of interleukin-2, improve activity of Natural Killer (NK) cells and enhance activity of superoxide dismutase in serum, and has various biological activities, wherein at present, 2 major active ingredients of thymosin are thymosin alpha 1 (T alpha 1) consisting of 28 amino acids, and the preparation methods are mainly three: tissue extraction, artificial synthesis and gene recombination. In 14/2/2020, the national institutes of health and the national institutes of traditional Chinese medicine jointly issued "notification on diagnosis and treatment plans of severe and critical cases with the novel coronavirus pneumonia (trial second edition)" is mentioned: for patients with low lymphocyte counts and severe cellular immune dysfunction, thymalfasin (also known as thymosin alpha 1) is suggested for use, and is also only suggested, and no experimental data can support its therapeutic effect and efficiency on novel coronavirus infections or diseases caused by novel coronavirus infections, and only suggested for use in treatment of patients with low lymphocyte counts and severe cellular immune dysfunction is disclosed for use in prevention of diseases caused by novel coronavirus infections or novel coronavirus infections.

Therefore, there is a strong need for developing drugs for preventing new coronavirus infection or diseases caused by new coronavirus infection, and effective preventive drugs will be of great help to the prevention and control of epidemic situations, especially for susceptible people in high-risk infectious environments.

Disclosure of Invention

In order to solve the technical problems that no medicine for effectively treating SARS-CoV-2 infection exists at present, and no medicine and means for effectively preventing SARS-CoV-2 infection of high-risk susceptible people and preventing novel coronary virus diseases exist, the invention provides a medicine composition capable of effectively preventing SARS-CoV-2 infection of high-risk susceptible people and preventing diseases caused by SARS-CoV-2 infection and application thereof, wherein the medicine composition comprises interferon and thymosin.

In some embodiments of the invention, the interferon is an interferon at a concentration of 1000U to 300 ten thousand U/ml.

Preferably, the interferon is interferon with the concentration of 2000U-20 ten thousand U/ml.

More preferably, the interferon is at a concentration of 3000U/ml, 4000U/ml, 5000U/ml, 8000U/ml or 1 ten thousand U/ml.

In some embodiments of the invention, the combination is a combination of an interferon and a thymosin peptide.

Preferably, the ratio of interferon to thymosin is from 5.6 to 2.52 million: 1-256 (U/W (mg)).

More preferably, the interferon and thymosin are present in a ratio of 7000-105 ten thousand: 1-8 (U/W (mg)).

Further preferably, the ratio of interferon to thymosin is 10500-52500:1 (U/W (mg)).

In some embodiments of the invention, the interferon is one or more of the IFN-alpha, IFN-beta, IFN-gamma families.

Further, in a preferred embodiment of the present invention, the interferon is a combination of one or more of IFN- α subtypes, more preferably, the interferon is one or more of IFN- α 1b, IFN- α 2a, IFN- α 2b, or IFN- ω; more preferably, the interferon is IFN-alpha 1b or IFN-alpha 2b.

According to the application, the interferon is natural interferon or recombinant human interferon, and is further preferably recombinant human interferon.

In some embodiments, the interferon of the present invention may be a general interferon or a long-acting interferon.

In some embodiments, the interferon described in the present invention is a general interferon, which is commercially available.

In some embodiments, the long-acting interferon described in the present invention is PEG-IFN.

In some embodiments of the present invention, the thymosin peptide may be a thymosin peptide derived from a blood extract, or a recombinant thymosin peptide or a synthetic thymosin peptide.

Preferably, the thymosin is thymosin alpha, more preferably thymosin alpha 1, and optionally, the thymosin alpha 1 can be obtained from commercial sources.

Further, the present invention provides a kit or kit for preventing SARS-CoV-2 infection or SARS-CoV-2 infection-induced disease (COVID-19), comprising an interferon and a thymosin peptide packaged separately.

In some embodiments of the invention, the interferon is at a concentration of 1000U to 300 ten thousand U/ml.

In some embodiments of the invention, the kit or kit of parts comprises an interferon and a thymosin peptide.

Preferably, the ratio of interferon to thymosin is from 5.6 to 2.52 million: 1 to 256 (U/W (mg)).

More preferably, the interferon and thymosin peptide are present in a ratio of 7000-105 ten thousand: 1-8 (U/W (mg)).

In some embodiments of the present invention, the thymosin peptide may be derived from a blood extract, or may be a recombinant thymosin peptide or a synthetic thymosin peptide.

Preferably, the thymosin is thymosin alpha, more preferably thymosin alpha 1, and optionally, thymosin alpha 1 is commercially available.

In the above combination or kit, the interferon may be combined with a pharmaceutically acceptable carrier or excipient to form a suitable dosage form, preferably, the dosage form is a nasal preparation.

In the above combination or kit or complete set of drugs, the thymosin peptide dosage form is an injection dosage form.

In some embodiments, the nasal preparation of interferon provided by the present invention can be nasal drops, nasal washes, nasal sprays or absorbents attached to the skin on the surface of the nose, preferably nasal drops or nasal sprays.

Preferably, the nasal preparation of interferon provided by the invention comprises a buffer solution, wherein the buffer solution is physiological saline, phosphate buffer solution, citric acid buffer solution, sugar saline (5% glucose injection), sodium bicarbonate buffer solution, acetate buffer solution, tris-hydrochloric acid buffer solution, and preferably physiological saline.

In some embodiments, the pharmaceutically acceptable carrier or excipient of the present invention further comprises one or more of a mucosal absorption enhancer, a protectant, a bacteriostatic agent.

Further, the concentration of the mucosal absorption enhancer in the above carrier or excipient is 4 to 28% (v/v), preferably 6 to 14% (v/v), and more preferably 10% (v/v).

Further, the concentration of the protecting agent in the above-mentioned carrier or excipient is 0.3 to 2.5% (w/v), preferably 0.8 to 1.6% (w/v), and more preferably 1.2% (w/v).

Further, the concentration of the bacteriostatic agent in the above carrier or excipient is 0.2 to 0.6% (w/v), preferably 0.25 to 0.4% (w/v), and more preferably 0.3% (w/v).

In some embodiments, the mucosal absorption enhancer is a surfactant, cyclodextrin and its derivatives, phospholipids, peptide and proteolytic enzyme inhibitors, glycyrrhetinic acid and its derivatives, metal ion chelators; the protective agent is one or more of human albumin, artificial plasma, erythropoietin, brain-derived neurotrophic factor, nerve growth factor, epidermal growth factor, fibroblast growth factor, basic fibroblast growth factor, insulin-like growth factor 1, hyaluronidase, neuregulin, leukemia inhibitory factor, interleukin, interferon-like active substances, tumor necrosis factor, glial growth factor, growth differentiation factor and nerve growth related protein; the bacteriostatic agent is one or more of sorbic acid, potassium sorbate, benzoic acid and p-hydroxybenzoate.

The pH value of the nasal interferon preparation prepared by the invention is 5.0-8.0.

When the nasal preparation of the interferon is prepared, the interferon can be directly combined with the pharmaceutically acceptable carrier or excipient to prepare the nasal preparation, or the nasal preparation can be prepared by firstly mixing the interferon with the buffer solution to prepare an interferon buffer solution and then combining the interferon buffer solution with the pharmaceutically acceptable carrier or excipient.

The concentration of the interferon in the invention is the concentration of the interferon in the finally prepared nasal preparation.

Preferably, the injection formulation is subcutaneous injection or intradermal injection.

In another aspect of the present invention, there is also provided the use of the above pharmaceutical combination or kit of parts for preventing SARS-CoV-2 infection or preventing SARS-CoV-2 infection-caused disease (COVID-19), preferably, the SARS-CoV-2 infection-caused disease (COVID-19) is a novel type of coronary viral pneumonia.

Preferably, the interferon is administered to the patient at a dose of 800-3600 ten thousand U/day and the thymosin peptide is administered at a dose of 0.1-25.6 mg/week; more preferably, the interferon is administered to the patient at a dose of 1600 to 24 million U per day and the thymosin peptide is administered at a dose of 1.6 to 12.8mg per week; further preferably, the interferon is administered to the patient at a dose of 2400-12000U/day and the thymosin peptide is administered at a dose of 1.6 mg/week.

More preferably, the interferon is administered 1 to 6 times per day, further preferably 4 times per day; the thymosin peptide is administered 1 to 4 times per week, more preferably 1 to 2 times per week. Further, in some aspects of the invention, the interferon is administered 1 to 6 times per day, and the thymosin peptide is administered 1 to 7 times per week; preferably, the interferon is administered 2-5 times per day, and the thymosin peptide is administered 1-3 times per week; further preferably, the interferon is administered 4 times per day and the thymosin is administered 1 time per week.

The above dosage and frequency of administration are preferred by the inventors in combination with the effect and cost of administration, and it is understood that the above dosage and frequency can also achieve the prophylactic effect of the present invention. And dose and frequency adjustments made on the basis of the inventive concept should also be included in the scope of the present invention.

Furthermore, the invention also provides the application of the medicine combination containing the interferon and the thymosin in the preparation of medicines for preventing SARS-CoV-2 infection or diseases (COVID-19) caused by SARS-CoV-2 infection, preferably, the diseases (COVID-19) caused by SARS-CoV-2 infection are novel coronary viral pneumonia.

In other aspects of the invention, the invention also provides the use of the pharmaceutical composition comprising interferon and thymosin for the preparation of other medicaments for the prevention of coronavirus infection or other diseases caused by coronavirus infection, optionally, the other coronavirus is mainly infected through droplet-nose-respiratory tract; preferably, the other coronavirus comprises SARS-CoV, MERS-CoV, or an unknown coronavirus.

In another aspect of the present invention, the above pharmaceutical combination or kit provided by the present invention can also be used for preventing other coronavirus infection or preventing diseases caused by other coronavirus infection, optionally, the other coronavirus is mainly infected via the droplet-nose-respiratory tract; preferably, the other coronavirus comprises SARS-CoV, MERS-CoV, or an unknown coronavirus.

The invention has the beneficial effects that: the medicine combination and the medicine box have unexpected technical effects, and a hospital acquired SARS-CoV-2 infection does not appear in 2 weeks for people (high-risk susceptible people) in isolation wards, so that the technical scheme of the invention can effectively prevent the infection of SARS-CoV-2, obviously reduce the infection rate of the high-risk susceptible people and high-risk medical care personnel, and avoid spreading of epidemic situation. The nasal preparation provided by the invention can effectively keep high concentration of interferon in the nose, and can be effectively applied to prevention of SARS-CoV-2 virus infection after combination.

Detailed Description

The present invention may be understood more readily by reference to the following description of certain embodiments of the invention and the detailed description of the examples included therein.

Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described, as such embodiments are necessarily varied. It is also to be understood that the terminology used in the description is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have the meanings that are commonly understood by those of ordinary skill in the art. The meaning and scope of a term should be clear, however, in the event of any potential ambiguity, the definition provided herein takes precedence over any dictionary or extrinsic definition. In this application, the use of "or" means "and/or" unless stated otherwise. Furthermore, the use of the term "including" and other forms is not limiting.

In order that the invention may be more readily understood, selected terms are defined below.

The novel Coronavirus is a novel virus, which is formally named as SARS-CoV-2 by the world health organization at present, and the novel 2019 Coronavirus, the novel 2019 nCoV and the novel serum acid response Syndrome Coronavir 2 are also the alias of the virus.

The SARS-CoV-2 infection is an infectious Disease caused by a Novel Coronavirus (SARS-CoV-2), including but not limited to Novel Coronavirus Pneumonia, which is named as Corona Virus Disease 2019, abbreviated as COVID-19 by the world health organization, and named as Novel Coronavir Pneumonia and NCP by the Wei and construction Commission of China.

The purpose of preventing SARS-CoV-2 infection includes the purpose of preventing the new type coronavirus from infecting healthy people, and refers to the preventive measures for protecting or preventing individuals not infected by the virus.

The applicable subjects (the healthy population described above) for preventing SARS-CoV-2 infection in the present invention are high-risk susceptible healthy subjects of the new coronavirus, and the "high-risk susceptible population" and the "high-risk population" referred to in the present invention are the same concept.

The high-risk susceptible population includes but is not limited to: 1) Those who are in direct exposure to the SARS-CoV-2 patient, including but not limited to a doctor, nurse or other hospital staff in a hospital exposure to the SARS-CoV-2 patient; 2) There are close contacts with SARS-CoV-2 patients directly, including but not limited to those in close proximity to the patient's family, community/meeting/restaurant/public transportation/movie theater/meeting, etc.

The application of the novel coronavirus disease caused by SARS-CoV-2 infection comprises preventing people infected with the novel coronavirus from continuing to progress to the novel coronavirus disease or other serious infection consequences.

The subject to be used for the prevention of the novel coronary viral disease in the present invention is preferably a subject infected with SARS-CoV-2 but having no significant symptoms of SARS-CoV-2.

The human race of a healthy person broadly refers to all human races including, but not limited to, the yellow, white, black and red races or the mixed blood of the above.

Interferons are classified into two types, I-type interferons and II-type interferons according to their effects. Type I interferons include alpha interferon (IFN-. Alpha.) and beta interferon (IFN-. Beta.), and type II interferons include gamma interferon (IFN-. Gamma.). The interferon is divided into three types of alpha, beta and gamma according to different antigenicity, wherein the Le interferon is alpha-interferon (IFN-alpha), the F interferon is beta-interferon (IFN-beta), and the T-interferon is gamma-interferon (IFN-gamma). The three types of alpha, beta and gamma interferon can be divided into several subtypes due to different amino acid sequences in each type, and the subtypes of alpha-interferon include IFN-alpha l, IFN-alpha 2, IFN-alpha 3 or IFN-alpha A, IFN-alpha B, IFN-alpha C and IFN-omega. The interferon comprises I-type interferon, II-type interferon, natural interferon, artificial recombinant interferon and subtypes thereof, wherein the subtypes, IFN-alpha 1b, IFN-a2a, IFN-a2b, IFN-a2a, PEG-IFN-alpha 2b and the like are all within the scope of the invention.

The natural interferon is extracted from human body cells by a blood extraction mode.

The recombinant interferon disclosed by the invention is obtained by a gene recombination technology, a gene for coding the interferon is cloned to a vector, the vector is transferred to a host cell for culture, and a culture is collected and purified to obtain the interferon.

In some embodiments of the present invention, the thymosin peptide may be extracted from animal or human blood and purified by methods known to those skilled in the art.

In other embodiments, the thymosin peptide can also be a recombinant thymosin peptide or a synthetic thymosin peptide.

The recombinant thymosin disclosed by the invention is obtained by a gene recombination technology, a gene for coding the thymosin is cloned to a vector, transferred to a host cell for culture, and a culture is collected and purified to obtain the thymosin.

The thymosin alpha 1 (T alpha 1) is also called thymalfasin, 5 medicaments are currently marketed in China, wherein 4 of the tradenames are respectively 'Ridaxian' (produced by Setarian drugs, ltd), 'Meipu' xin '(produced by Chengdu Olympic group),' Kittai '(produced by Hainan Shuanghua pharmaceutical Co., ltd.) and' Heri '(produced by Hainan Nakan Heyao pharmaceutical Co., ltd.), and the other is marketed thymalfasin of Jiangsu Nutai Aussono biopharmaceutical Co., ltd' (Chinese drug registration batch No.: 2019S 00621), and the commercialized thymosin alpha 1 can be used in the pharmaceutical composition or the kit.

Optionally, the invention also relates to an isolated nucleic acid molecule, which is DNA or RNA, encoding an interferon protein as described above. The nucleic acid of the invention or fragments thereof may be inserted into a suitable vector to form a cloning or expression vector carrying the nucleic acid fragment of the invention. Such novel vectors are also part of the present invention. The vector may comprise a plasmid, phage, cosmid, minichromosome, or virus, as well as naked DNA that is transiently expressed only in a particular cell. The cloning and expression vectors of the invention are capable of autonomous replication and thus provide high copy numbers for high level expression or high level replication purposes for subsequent cloning. The expression vector may comprise a promoter for driving expression of the nucleic acid fragment of the invention, optionally a nucleic acid sequence encoding a signal peptide for secretion or integration of the peptide expression product into a membrane, a nucleic acid fragment of the invention, and optionally a nucleic acid sequence encoding a terminator. When the expression vector is manipulated in a production strain or cell line, the vector, when introduced into a host cell, may or may not be integrated into the genome of the host cell. Vectors typically carry a replication site, as well as a marker sequence capable of providing phenotypic selection in transformed cells.

The term "vector" refers to a molecule or agent comprising a nucleic acid of the invention or a fragment thereof, capable of carrying genetic information and capable of delivering the genetic information into a cell. Typical vectors include plasmids, viruses, bacteriophages, cosmids, and minichromosomes. The vector may be a cloning vector (i.e. a vector for transferring genetic information into a cell, which cell may be propagated and in which the presence or absence of the genetic information may be selected) or an expression vector (i.e. a vector comprising the necessary genetic elements to allow expression of the genetic information of the vector in a cell). Thus, a cloning vector may contain a selectable marker, as well as an origin of replication compatible with the cell type specified by the cloning vector, while an expression vector contains the regulatory elements necessary to effect expression in a specified target cell.

Alternatively, host cells for expression of the above vectors are well known in the art and include prokaryotic cells, including E.coli, eukaryotic cells including yeast, insect cells, and mammalian cells, including many immortalized cell lines such as, but not limited to, COS-7 cells, chinese Hamster Ovary (CHO) cells, baby Hamster Kidney (BHK) cells, and many others, including cell lines of lymphoid origin such as lymphoma, myeloma, or hybridoma cells.

In some aspects of the invention, long-acting interferons may be obtained by modifying interferons with polyethylene glycol (PEG), or long-acting interferons that have been approved for marketing may be used.

Further, in the embodiments of the present invention, the interferon nasal formulation may further comprise a pharmaceutically acceptable diluent, excipient or carrier. It will be understood that the above pharmaceutically acceptable diluents, excipients or carriers are compatible with the active ingredient and are not deleterious to the subject to which they are administered. In some embodiments, the diluent may include, but is not limited to, physiological saline, potassium chloride, potassium hydrogen phosphate, potassium dihydrogen phosphate, sodium sulfate, sodium chloride, potassium hydroxide, or a combination thereof. The above diluents may be used to adjust the osmotic pressure, the pH, decrease/increase the consistency or solubility of the drug of the invention.

In some embodiments, the excipient may be an antioxidant, a colorant, a bacteriostatic agent, or a combination thereof.

In some embodiments, the carrier may include, but is not limited to, various absorption enhancers, protectants, emulsifiers, alcoholic liquids, polysorbates, glycerin, or combinations thereof. The above alcohol liquid may be, but is not limited to, monohydric alcohol or polyhydric alcohol, for example, monohydric alcohol includes methanol, ethanol, n-propanol, isopropanol, n-butanol, second butanol, third butanol, isobutanol, n-hexanol, n-heptanol, n-octanol or n-decanol.

According to some embodiments, the medicaments of the present invention may also be used or prepared in other combinations or kits in conjunction with other supplements.

The 'U/W' in the invention represents a ratio symbol of unit/mass, wherein the ratio is the effective component ratio of interferon and thymosin, and the mass unit of the effective content of thymosin is milligram (mg).

Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.

Example 1 preparation of recombinant human Interferon formulations

Preparation 1 recombinant human interferon alpha 1b 3000U/ml, and the buffer solution is physiological saline (0.9% sodium chloride injection).

Preparation 2 recombinant human interferon alpha 2b 3000U/ml, and the buffer solution is physiological saline (0.9% sodium chloride injection).

Preparation 3 recombinant human interferon alpha 1b 4000U/ml, buffer solution as physiological saline (0.9% sodium chloride injection)

Preparation 4 recombinant human interferon alpha 2b 4000U/ml, and the buffer solution is physiological saline (0.9% sodium chloride injection).

Preparation 5 recombinant human interferon alpha 1b 5000U/ml, and the buffer solution was physiological saline (0.9% sodium chloride injection).

Preparation 6 recombinant human interferon alpha 2b 5000U/ml, and the buffer solution is physiological saline (0.9% sodium chloride injection).

Preparation 7 recombinant human interferon alpha 1b 8000U/ml, physiological saline (0.9% sodium chloride injection).

Preparation 8 recombinant human interferon alpha 2b 8000U/ml, and the buffer solution is physiological saline (0.9% sodium chloride injection).

Preparation 9 recombinant human interferon alpha 1b 10000U/ml, physiological saline (0.9% sodium chloride injection).

10 recombinant human interferon alpha 1b 10 ten thousand U/ml, normal saline (0.9% sodium chloride injection).

The preparation 11 is 10 ten thousand U/ml of recombinant human interferon alpha 2b, and the buffer solution is normal saline (0.9% sodium chloride injection).

Preparation 12 recombinant human interferon alpha 1b 20 ten thousand U/ml, normal saline (0.9% sodium chloride injection).

The preparation 13 is recombinant human interferon alpha 2b 20 ten thousand U/ml, and the buffer solution is normal saline (0.9% sodium chloride injection).

Preparation 14 recombinant human interferon alpha 2b (10000U/ml, buffer solution is normal saline (0.9% sodium chloride injection).

15 recombinant human interferon alpha 1b 5000U/ml, citric acid buffer solution, human albumin 0.3% (w/v) and potassium sorbate 0.2% (w/v).

Preparation 16 recombinant human interferon alpha 2b 5000U/ml, citric acid buffer solution, human albumin 0.3% (w/v), potassium sorbate 0.2% (w/v)

Preparation 17 recombinant human interferon alpha 1b 5000U/ml, acetate buffer, epidermal growth factor 0.8% (w/v), benzoic acid 0.25% (w/v).

18 recombinant human interferon alpha 2b 5000U/ml, acetate buffer solution, epidermal growth factor 0.8% (w/v), benzoic acid 0.25% (w/v)

Preparation 19 recombinant human interferon alpha 1b 5000U/ml, tris-hydrochloric acid buffer solution, erythropoietin 1.6% (w/v) and p-hydroxybenzoate 0.4% (w/v).

Preparation 20 recombinant human interferon alpha 2b 5000U/ml, tris-hydrochloric acid buffer solution, erythropoietin 1.6% (w/v), p-hydroxybenzoate 0.4% (w/v)

Preparation 21 recombinant human interferon alpha 1b 5000U/ml, physiological saline, hyaluronidase 2.5% (w/v) and sorbic acid 0.6% (w/v).

Preparation 22 recombinant human interferon alpha 2b 5000U/ml, physiological saline, hyaluronidase 2.5% (w/v) and sorbic acid 0.6% (w/v).

Preparation 23 recombinant human interferon alpha 1b 5000U/ml, physiological saline, human albumin 1.2% (w/v) and sorbic acid 0.3% (w/v).

Preparation 24 recombinant human interferon alpha 2b 5000U/ml, physiological saline, human albumin 1.2% (w/v), sorbic acid 0.3% (w/v)

Preparation 25 recombinant human interferon alpha 1b 5000U/ml, cyclodextrin 4% (w/v), human albumin 0.3% (w/v), potassium sorbate 0.2% (w/v) and citric acid buffer solution.

Preparation 26, recombinant human interferon alpha 2b 5000U/ml, cyclodextrin 4% (w/v), human albumin 0.3% (w/v), potassium sorbate 0.2% (w/v) and citric acid buffer solution.

27 recombinant human interferon alpha 1b 5000U/ml, TW-80% (w/v), epidermal growth factor 0.8% (w/v), benzoic acid 0.25% (w/v), acetate buffer solution.

28 recombinant human interferon alpha 2b 5000U/ml, TW-80% (w/v), epidermal growth factor 0.8% (w/v), benzoic acid 0.25% (w/v) and acetate buffer solution.

Preparation 29 recombinant human interferon alpha 1b 5000U/ml, PEG-400 monooleate 14% (w/v) erythropoietin 1.6% (w/v), p-hydroxybenzoate 0.4% (w/v), and Tris-hydrochloric acid buffer solution.

Preparation 30 recombinant human interferon alpha 2b 5000U/ml, PEG-400 monooleate 14% (w/v) erythropoietin 1.6% (w/v), p-hydroxybenzoate 0.4% (w/v) and Tris-hydrochloric acid buffer solution.

Preparation 31 recombinant human interferon alpha 1b 5000U/ml, phospholipid 28% (w/v), hyaluronidase 2.5% (w/v), sorbic acid 0.6% (w/v) and normal saline.

Preparation 32 recombinant human interferon alpha 2b 5000U/ml, phospholipid 28% (w/v), hyaluronidase 2.5% (w/v), sorbic acid 0.6% (w/v) and normal saline.

Preparation 33 recombinant human interferon alpha 1b 5000U/ml, TW-40% (w/v), human albumin 1.2% (w/v), sorbic acid 0.3% (w/v), and physiological saline.

Preparation 34 recombinant human interferon alpha 2b 5000U/ml, TW-40% (w/v), human albumin 1.2% (w/v), sorbic acid 0.3% (w/v) and physiological saline.

The preparation 35 recombinant human interferon alpha 1b 2000U/ml and the buffer solution are physiological saline (0.9% sodium chloride injection).

The preparation components are mixed to prepare recombinant human interferon nasal drops or nasal sprays, the original recombinant human interferon alpha 1b preparation used in the preparation is purchased from Beijing three-element genetic engineering company Limited, the trade name is Yundesu, and spray or injection thereof can be used and is mixed with pharmaceutically acceptable carriers or excipients after being diluted according to requirements to prepare nasal preparations of the recombinant human interferon alpha 1b with different concentrations, the spray of the recombinant human interferon alpha 2b is purchased from Tianjin unknown biological medicine company Limited and is mixed with pharmaceutically acceptable carriers or excipients after being diluted according to requirements to prepare nasal preparations of the recombinant human interferon alpha 1b with different concentrations; the concentrations of recombinant human interferon alpha 1b and recombinant human interferon alpha 2b given in the above preparations 1 to 35 were the final concentrations of interferon in the preparations 1 to 35.

EXAMPLE 2 pharmaceutical combination

Composition 1, preparation 5, 4 times a day, 2-3 drops/nostril each time

Thymalfasin (thymosin alpha 1) subcutaneous injection preparation, 1.6 mg/time, once a week

Composition 2, preparation 5, 4 times a day, 2-3 drops/nostril each time

Thymalfasin (thymosin alpha 1) subcutaneous injection preparation, 1.6 mg/time, twice a week

Composition 3, preparation 5, 4 times a day, 2-3 drops/nostril each time

Thymalfasin (thymosin alpha 1) was injected subcutaneously at 1.6 mg/time three times a week

Composition 4. Preparation 5, 4 times a day, 2-3 drops/nostril each time

Thymalfasin (thymosin alpha 1) subcutaneous injection preparation, 1.6 mg/time, once every other day

Composition 5, preparation 6, 4 times a day, 2-3 drops/nostril each time

Thymalfasin (thymosin alpha 1) was injected subcutaneously at 1.6 mg/time, once a week

Composition 6, preparation 6, 4 times a day, 2-3 drops/nostril each time

Thymalfasin (thymosin alpha 1) was injected subcutaneously at 1.6 mg/time twice a week

Composition 7, preparation 6, 4 times a day, 2-3 drops/nostril each time

The composition 8 is prepared into preparation 6, 4 times a day, 2-3 drops/nostril each time

Combination 9. Preparation 1, 4 times a day, 2-3 drops/nostril each time

Combination 10, preparation 1, 4 times a day, 2-3 drops/nostril each time

Composition 11, preparation 1, 4 times a day, 2-3 drops/nostril each time

Thymalfasin (thymosin alpha 1) subcutaneous injection preparation, 1.6 mg/time, thrice weekly

Composition 12, preparation 1, 4 times a day, 2-3 drops/nostril each time

Combination 13 preparation 2, 4 times a day, 2-3 drops/nostril each time

Combination 14, preparation 2, 4 times a day, 2-3 drops/nostril each time

The composition 15 is applied to the nasal cavity 2, 4 times a day, 2-3 drops/nostril each time

Composition 16, preparation 2, 4 times a day, 2-3 drops/nostril each time

Composition 17, preparation 1, 4 times a day, 2-3 drops/nostril each time

The composition 18 is administered 4 times a day, 2-3 drops/nostril each time

Combination 19 preparation 1, 4 times a day, 2-3 drops/nostril each time

Combination 20, preparation 1, 4 times a day, 2-3 drops/nostril each time

Thymalfasin (thymosin alpha 1) subcutaneous injection preparation, 1.6 mg/time and once every other day

Combination 21, preparation 2, 4 times a day, 2-3 drops/nostril each time

Combination 22. Preparation 2, 4 times a day, 2-3 drops/nostril each time

The composition 23 is prepared 4 times a day, 2-3 drops/nostril each time

The composition 24 is prepared for 2 times a day, 4 times a day, and 2-3 drops/nostril each time

The composition 25 is prepared into a preparation 10, 4 times a day, and 2-3 drops/nostril each time

Combination 26, preparation 10, 4 times a day, 2-3 drops/nostril each time

Composition 27, preparation 10, 4 times a day, 2-3 drops/nostril each time

The composition 28 is applied to the nasal cavity 4 times a day, 2-3 drops/nostril each time

Composition 29, preparation 11, 4 times a day, 2-3 drops/nostril each time

The composition 30, preparation 11, 4 times a day, 2-3 drops/nostril each time

Combination 31. Preparation 11, 4 times a day, 2-3 drops/nostril each time

Composition 32, preparation 11, 4 times a day, 2-3 drops/nostril each time

Thymalfasin (thymosin alpha 1) subcutaneous injection preparation, 0.1 mg/time and one time every other day

Composition 33, preparation 12, 4 times a day, 2-3 drops/nostril each time

Thymalfasin (thymosin alpha 1) subcutaneous injection, 6.4 mg/time, once a week

Composition 34, preparation 12, 4 times a day, 2-3 drops/nostril each time

Composition 35, preparation 12, 2 times a day, 2-3 drops/nostril each time

Composition 36, preparation 12, 4 times a day, 2-3 drops/nostril each time

Thymalfasin (thymosin alpha 1) subcutaneous injection preparation, 3.2 mg/time and once every other day

Composition 37, preparation 35, 4 times a day, 2-3 drops/nostril each time

Composition 38, preparation 35, 5 times a day, 2-3 drops/nostril each time

Composition 39, preparation 35, 4 times a day, 2-3 drops/nostril each time

Composition 40, preparation 35, 4 times a day, 2-3 drops/nostril each time

Composition 41, preparation 20, 6 times a day, 2-3 drops/nostril each time

The composition 42 is prepared into preparation 20,4 times a day, 2-3 drops/nostril each time

Thymalfasin (thymosin alpha 1) subcutaneous injection, 6.4 mg/time, twice a week

The composition 43 is administered 4 times a day, 2-3 drops/nostril each time

Composition 44, preparation 20, 1 time a day, 2-3 drops/nostril each time

Thymalfasin (thymosin alpha 1) subcutaneous injection preparation, 6.4 mg/time and once every other day

EXAMPLE 3 preventive Effect of drug combinations on medical personnel in isolation ward

In Shibatan, 353 patients diagnosed with 2019-nCoV were collected 5 days 2.2.2020, and a significant portion of the patients were admitted to the infection isolation ward of a local hospital.

Medical staff in an isolation ward of the patient are selected as experimental study objects, and the medical staff are directly and definitely directly exposed to the diagnosed 2019-nCoV patient and are in contact with the patient at a fixed frequency, so that the prevention effect of the medicine combination on high-risk susceptible people can be effectively verified. Therefore, 130 of the patients were administered the interferon preparation of the present invention and compared with other patients in the third hospital to evaluate the preventive effect against the infection with the novel coronavirus.

All subjects in the hospital isolation ward were given the drug in combination 9 above and observed for 14 days (1 month 31 days to 2 months 13 days from 2020). According to the observation result of the day 13 after 2 months, no fever and cough people are found in all the medical care personnel in the non-isolation ward of the hospital within 14 days of the subcutaneous injection of the interferon nasal drops and the alpha thymosin. The number of cases of new SARS-CoV-2 infection and the development of the novel coronary viral disease (COVID-19) by the medical staff is zero.

3019 cases of medical staff (including confirmed, suspected and clinical diagnosis cases and asymptomatic infectors, wherein 1716 cases are confirmed) are treated nationwide from 12/18/2019 to 2/11. The data are published in epidemiology groups of the novel coronavirus pneumonia emergency response mechanism in the chinese disease prevention and control center in 2 months in 2020, and an article on epidemiological characteristics of the new coronavirus pneumonia is published in the china epidemiology journal (reference 2, page 149, left column, paragraph 3).

According to the comparison of the data, the medical staff who are directly exposed to SARS-CoV-2 confirmed patients who are diagnosed by interferon nose drops combined with alpha thymosin prophylactic intervention in Hospital, shibata, have zero COVID-19 number during the interferon prophylactic medication period of 14 days from 1 month to 13 months of 2 months in 2020, and the incidence rate of the medical staff in the same period (by 11 days of 2 months) in a super-huge city in the same epidemic area under the same working environment is obviously lower. This complete prevention of the onset of COIVD-19 in healthy populations exposed directly to diagnosed SARS-CoV-2 patients has significant implications for the prevention of SARS-CoV-2 infection and COVID-19 onset with unexpected results.

Since the current preventive recommendations of the Weijian Commission of China on 2019-nCoV are physical isolation measures, there are currently no official recommendations on the pharmaceutical prevention of 2019-nCoV. It is understood by those skilled in the art that other Hubei Hospital, also in Hubei epidemic areas, do not use any drugs to prevent 2019-nCoV and its resulting COVID-19..

The nosocomial infection rate of medical care personnel in the third hospital in the epidemic area using the alpha interferon nasal drops and the alpha thymosin is zero within 14 days, and is obviously lower than the infection rate of the medical care personnel in the third hospital in other epidemic areas, and the unexpected result has great significance for controlling the infection.

Reference 2 epidemiology group of emergency response mechanism for coronavirus pneumonia in Chinese disease prevention and control center novel characteristic analysis of epidemiology of coronavirus pneumonia [ J ]. J.China epidemiology, 2020,41 (2): 145-151

Finally, it should be noted that: the above embodiments are only used to illustrate the technical solution of the present invention, and not to limit the same; while the invention has been described in detail and with reference to the foregoing embodiments, it will be understood by those skilled in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some or all of the technical features may be equivalently replaced; and these modifications or substitutions do not depart from the spirit of the corresponding technical solutions of the embodiments of the present invention.

Claims

1. The application of a kit or a complete set of medicines containing independently packaged interferon and thymosin in preparing medicines for preventing SARS-CoV-2 infection or SARS-CoV-2 infection diseases of high-risk susceptible people is characterized in that the interferon is a nasal preparation of recombinant human interferon alpha 1b, and the thymosin is a subcutaneous injection dosage form of thymosin alpha 1.

2. Use according to claim 1, characterized in that the interferon is an interferon at a concentration of 1000U to 300 ten thousand U/ml.

3. The use according to claim 2, characterized in that the interferon is at a concentration of 2000U to 20 ten thousand U/ml.

4. Use according to claim 3, characterized in that the interferon is at a concentration of 3000U/ml, 4000U/ml, 5000U/ml or 8000U/ml or 1 ten thousand U/ml.

5. The use as claimed in claim 1, characterized in that the interferon and thymosin peptides are present in a ratio of 5.6 ten thousand to 2.52 hundred million: 1 to 256 (U/W (mg)).

6. Use according to claim 5, characterized in that the interferon and thymosin are present in a ratio comprised between 7000 and 105 ten thousand: 1-8 (U/W (mg)).

7. Use according to claim 6, characterized in that the interferon and thymosin peptides are present in a ratio of 10500-52500:1 (U/W (mg)).

8. The use according to any one of claims 1 to 7, wherein the interferon is a general interferon or a long-acting interferon.

9. The use according to any one of claims 1 to 7, wherein said thymosin peptide is a thymosin peptide derived from a blood extract, or a recombinant thymosin peptide or a synthetic thymosin peptide.

10. Use according to claim 1, characterized in that the interferon is combined with a pharmaceutically acceptable carrier or excipient to form a nasal preparation.

11. Use according to claim 10, characterized in that the nasal preparation is a nasal drop, a nasal wash, a nasal spray or an absorbent applied to the skin on the nasal surface.

12. Use according to claim 11, characterized in that the nasal preparation is a nasal drop or a nasal spray.

13. The use as claimed in claim 12, characterized in that the nasal formulation comprises a buffer solution, which is physiological saline, phosphate buffer, citric acid buffer, 5% glucose injection, sodium bicarbonate buffer, acetate buffer, tris-hydrochloric acid buffer.

14. Use according to claim 13, characterized in that the buffer is physiological saline.

15. The use according to claim 10, wherein the pharmaceutically acceptable carrier or excipient further comprises one or more of a mucosal absorption enhancer, a protectant, a bacteriostatic agent.

16. Use according to claim 15, characterized in that the concentration of the mucosal absorption enhancer is between 4 and 28% (v/v).

17. Use according to claim 16, characterized in that the concentration of said mucosal absorption enhancer is between 6 and 14% (v/v).

18. Use according to claim 17, characterized in that the concentration of the mucosal absorption enhancer is 10% (v/v).

19. Use according to claim 15, characterized in that the concentration of the protective agent is between 0.3 and 2.5% (w/v).

20. Use according to claim 19, characterized in that the concentration of the protective agent is between 0.8 and 1.6% (w/v).

21. Use according to claim 20, characterized in that the concentration of the protective agent is 1.2% (w/v).

22. The use according to claim 15, characterized in that the bacteriostatic agent is present in a concentration of 0.2-0.6% (w/v).

23. The use according to claim 22, characterized in that the bacteriostatic agent is present in a concentration of 0.25-0.4% (w/v).

24. The use according to claim 23, characterized in that the bacteriostatic agent is present at a concentration of 0.3% (w/v).

25. The use according to claim 15, wherein the mucosal absorption enhancer is one or more of a surfactant, cyclodextrin and its derivatives, phospholipids, peptide and proteolytic enzyme inhibitors, glycyrrhetinic acid and its derivatives, a metal ion chelating agent; the protective agent is one or more of human albumin, artificial plasma, erythropoietin, brain-derived neurotrophic factor, nerve growth factor, epidermal growth factor, fibroblast growth factor, basic fibroblast growth factor, insulin-like growth factor 1, hyaluronidase, neuregulin, leukemia inhibitory factor, interleukin, interferon-like active substances and tumor necrosis factor; the bacteriostatic agent is one or more of sorbic acid, potassium sorbate, benzoic acid and p-hydroxybenzoate.