CN111671886A

CN111671886A - A drug combination for preventing high-risk susceptible population from contracting coronavirus or developing coronavirus-infected disease and use thereof

Info

Publication number: CN111671886A
Application number: CN202010146698.3A
Authority: CN
Inventors: 李海
Original assignee: Shanghai Ganyi Biomedical Technology Co ltd
Current assignee: Beijing Puxi Technology Co.,Ltd.; Shanghai Ganyi Biomedical Technology Co ltd
Priority date: 2020-03-05
Filing date: 2020-03-05
Publication date: 2020-09-18
Anticipated expiration: 2040-03-05
Also published as: CN111671886B

Abstract

本发明提出了一种预防高危易感人群感染冠状病毒或发生冠状病毒感染疾病的药物组合及其用途，所述的药物组合包含干扰素和胸腺肽α。所述药物组合能够有效阻止新型冠状病毒的感染，显著降低人群和医护人员的感染率，避免疫情扩散，能够有效应用于新型冠状病毒感染的预防。The present invention provides a pharmaceutical combination for preventing high-risk susceptible people from contracting coronavirus or developing coronavirus infection diseases, and the use thereof, wherein the pharmaceutical combination comprises interferon and thymosin alpha. The drug combination can effectively prevent the infection of the novel coronavirus, significantly reduce the infection rate of the population and medical staff, avoid the spread of the epidemic, and can be effectively applied to the prevention of the novel coronavirus infection.

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 (SevereAcute 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 pathway of the novel coronavirus is mainly through droplet transmission, and after the virus is inhaled into the nasal cavity through air, the finally infected main target organ is the 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 major 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 less. Approximately half of patients develop dyspnea after one week, and severe patients rapidly progress to acute respiratory distress syndrome, septic shock, refractory metabolic acidosis, and procoagulant 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 shows that the virus is very high in infectivity and can cause large outbreaks, and R0 of the novel coronavirus is reported to be between 2.2 and 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. With 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 of the novel coronavirus nor effective for preventing the infection of the novel coronavirus in healthy people is determined at present, and the prevention of the infection of the novel coronavirus in healthy people at present mainly depends on a physical barrier such as a mask and an isolation clothes.

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 the innate immunity and acquired immune response after infection, has broad spectrum biological functions of antivirus and immunoregulation, and is widely applied to the treatment of 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 to activate cell membrane adenylate cyclase, promote adenylate cyclase to increase, activate intracellular antiviral action mechanism, generate a group of antiviral substances, play a role in resisting viruses to enable cells to generate antiviral proteins and enzymes, inhibit virus replication and block virus diffusion, and interferon is widely used clinically at present to treat chronic hepatitis B and chronic hepatitis C. Meanwhile, the antiviral action of interferon has no specificity, i.e. it is difficult to generate specific killing action on a certain virus. In the early chronic hepatitis B prevention and treatment guideline, when small molecular nucleoside antiviral drugs do not appear, the recommended treatment scheme is interferon + ribavirin. Thereafter, in chronic hepatitis b control guidelines 2015 and 2019, treatment schemes of single injection of interferon/long-acting interferon and single use of nucleoside drugs are recommended, but generally, single use of interferon 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 guideline (2015), whereas nucleoside antiviral drugs can strongly inhibit virus replication and improve liver inflammation [ chronic hepatitis b control guideline (2019) ]. Meanwhile, the contraindication of interferon injection is more, and the clinical application is further limited.

In the section of "new coronavirus pneumonia diagnosis and treatment protocol" (trial fifth edition, revised edition), although "inhalation of interferon-alpha nebulization (2 ml per day with addition of sterile water for injection at 500 ten thousand U per adult or equivalent dose, 2 times per day), lopinavir/ritonavir (200mg/50mg, per capsule) 2 capsules per day, 2 times per day, or ribavirin (500 mg/capsule, 2 to 3 times per day)" is mentioned, it also refers to: "no effective antiviral treatment method is confirmed at present", therefore, the treatment scheme is only an inference made according to the properties of the medicines, the effect is not verified through clinical experiments, and how the effective rate is unknown, meanwhile, the scheme is still not a main treatment scheme of the novel coronavirus pneumonia according to the current treatment situation, 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 can not 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. The first was the small molecules with nonspecific immune effects found 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 2 thymosin peptides mainly comprise thymosin alpha 1(T alpha 1) consisting of 28 amino acids as main active ingredients, and the preparation methods mainly comprise the following three steps: tissue extraction, artificial synthesis and gene recombination. In 14 days 2/2020, the notification of "diagnosis and treatment plan for severe and critical cases with new type of coronavirus pneumonia" (second trial) issued by the national health and health committee and the national traditional Chinese medicine administration is mentioned: thymalfasin (also called thymosin alpha 1) is recommended for severe patients with low lymphocyte count and low cellular immune function, and is also only recommended, no experimental data can support the treatment effect and the effective rate of thymalfasin on diseases caused by novel coronavirus infection or novel coronavirus infection, and the thymalfasin is recommended for treatment of severe patients with low lymphocyte count and low cellular immune function, and the thymalfasin is not disclosed for preventing diseases caused by novel coronavirus infection or novel coronavirus infection.

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 viral 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 ratio of interferon to thymosin is 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 2 b.

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, thymosin alpha 1 is commercially available.

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 kit or kit comprises an interferon and a thymosin peptide.

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.

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 combination or the medicine box or the complete set of medicines, the thymosin 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 protective 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 protein hydrolase inhibitors, glycyrrhetinic acid and its derivatives, metal ion chelators; the protective agent is one or more of human albumin, artificial plasma, erythrotropin, 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 coronary viral pneumonia.

Preferably, the interferon is given to the patient according to 800-3600 ten thousand U/day and the thymosin is given to the patient according to the 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 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, and even more preferably 4 times per day; the thymosin peptide is administered 1-4 times per week, more preferably 1-2 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 peptide 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 all such modifications, variations, and alterations of the dosage and times based on the teachings of the invention should be considered as falling within the scope of the invention.

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

In other aspects of the invention, the invention also provides the use of the pharmaceutical combination comprising interferon and thymosin for the preparation of a medicament for the prevention of infection by coronavirus or other diseases caused by 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.

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 some 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 defined otherwise herein, scientific and technical terms used in connection with the present invention shall have the meanings that are commonly understood by one 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 Severe acid response synergy SyndromeCoronavir 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", and is named as "Corona Virus Disease 2019" by the world health organization, abbreviated as "COVID-19", and named as "Novel Coronavir Pneumonia" and "NCP" by Wei-Jian Commission in 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) 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 "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) direct close-range contacts with SARS-CoV-2 patients, including but not limited to patients' 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 the people infected with the novel coronavirus from continuously progressing 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 species 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 in the range of the invention.

The natural interferon in the invention is the interferon extracted from human cells by a blood extraction mode.

The recombinant interferon is obtained by a gene recombination technology, a gene 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 invention, the thymosin peptide may be extracted from animal or human blood and prepared by purification by methods well 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, the vector is 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 the trade names of 4 of the 5 medicaments are respectively 'Ridaxian' (produced by Semian crude drug products, Ltd), 'Myoproxin' (produced by Chengdu Olympic group), 'Jietai' (produced by Hainan Shuangcheng double-ingredient pharmaceutical Co., Ltd.) and 'Heri' (produced by Hainan Zhongyao and pharmaceutical industry, Ltd.), and the other one is marketed thymalfasin of Jiangsuotai Australian biopharmaceutical, Ltd. (Chinese medicine registration lot number: 2019S00621), and the commercialized thymosin alpha 1 can be used in the medicine combination or the medicine box.

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 acids of the invention or fragments thereof may be inserted into suitable vectors to form cloning vectors or expression vectors carrying the nucleic acid fragments 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 may be propagated and in the presence or absence of said 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 said 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 nasal interferon formulation may further comprise a pharmaceutically acceptable diluent, excipient or carrier. It will be appreciated 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, acid-base number, reduce/increase 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, a monohydric alcohol or a polyhydric alcohol, and for example, the 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 medicament of the present invention may also be used in conjunction with other supplements or prepared as other combinations or kits.

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. Those whose specific conditions are not specified in the examples are carried out under the conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by manufacturers, and are all conventional products available on the market.

Example 1 preparation of recombinant human Interferon formulations

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

Preparation 2 recombinant human interferon alpha 2b 3000U/ml, buffer solution for normal saline (0.9% sodium chloride injection).

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

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

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

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

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

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

Preparation 9 recombinant human interferon alpha 1b 10000U/ml, normal 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 recombinant human interferon alpha 2b is 10 ten thousand U/ml, 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 recombinant human interferon alpha 2b is 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).

Preparation 15 recombinant human interferon alpha 1b 5000U/ml, citric acid buffer solution, human albumin 0.3% (w/v), 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 solution, epidermal growth factor 0.8% (w/v), benzoic acid 0.25% (w/v).

Preparation 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), sorbic acid 0.6% (w/v).

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

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

The preparation 27 recombinant human interferon alpha 1b is 5000U/ml, TW-806% (w/v), epidermal growth factor 0.8% (w/v), benzoic acid 0.25% (w/v), acetate buffer solution.

The preparation 28 recombinant human interferon alpha 2b 5000U/ml, TW-806% (w/v), epidermal growth factor 0.8% (w/v), benzoic acid 0.25% (w/v), 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), 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), 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-4010% (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-4010% (w/v), human albumin 1.2% (w/v), sorbic acid 0.3% (w/v), and normal saline.

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

The preparation components are mixed to prepare the recombinant human interferon nasal drops or nasal sprays, the original preparation of the recombinant human interferon alpha 1b used in the preparation is purchased from Beijing ternary genetic engineering company Limited, the product name is Yundesu, the spray or injection can be used, the original preparation is diluted according to the requirement and then is mixed with a pharmaceutically acceptable carrier or excipient to prepare the 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 Limited company, the spray is diluted according to the requirement and then is mixed with the pharmaceutically acceptable carrier or excipient to prepare the 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 are 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) subcutaneous injection preparation, 1.6 mg/time, thrice weekly

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 and once every other day

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

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

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

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

Combination 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

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

The composition 26 is prepared into a preparation 10, 4 times a day, and 2-3 drops/nostril each time

The composition 27 is prepared into a preparation 10, 4 times a day, and 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

Combination 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 weekly combined 43. preparation 20, 4 times daily, 2-3 drops/nostril each time

The composition 44 is prepared into 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 the city of deca-weir, up to 2020, 2/5 days ago, there were a total of 353 patients diagnosed with 2019-nCoV, of which a significant proportion were admitted to the infection isolation ward of a local hospital in the third department.

Medical staff in an isolation ward of the patient are selected as experimental study objects in the invention, and the medical staff are directly and definitely directly exposed to the confirmed diagnosis of the 2019-nCoV patient and have fixed frequency contact with the patient, so that the prevention effect of the pharmaceutical composition on high-risk susceptible people can be effectively verified. Therefore, 130 of the patients were evaluated for their prophylactic effect against the infection with the novel coronavirus by using the interferon preparation of the present invention in comparison with other three hospitals.

The medicines in the combinations 9 and 13 are given to all tested medical care in the isolation ward of the hospital, and the infection conditions of medical care personnel are observed, and the observation result shows that in the novel coronavirus latent period, no new coronavirus infection or any new coronavirus infection (COVID-19) occurrence is found in all tested medical care personnel in the isolation ward of the hospital. Since the current preventive recommendation of Weijian Commission of China for 2019-nCoV is a physical isolation measure, the understanding of those skilled in the art is that other hospitals do not use any drugs to prevent 2019-nCoV and the resulting COVID-19. By 2/5/2020, a total of 13 hospitals with 15 and more medical staff who acquired iatrogenic infections. By 2/11 days of 2020, 3019 cases of hospital staff with iatrogenic infection (including confirmed cases, suspected cases, clinical diagnosis cases and asymptomatic infectors, wherein 1716 confirmed cases) have been reported, while the number of cases of iatrogenic infection obtained by the hospital staff in the isolation ward of the three hospitals using the pharmaceutical composition of the present invention within 14 days is 0, the infection ratio is extremely low, and is obviously lower than the infection rate of the hospital staff in other three hospitals, and this unexpected result has great significance for controlling infection.

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 such modifications and substitutions do not depart from the spirit and scope of the present invention as defined by the appended claims.

Claims

1. A drug combination for preventing high-risk susceptible people from contracting coronavirus or developing coronavirus infection disease, said drug combination comprising interferon and thymosin.

2. pharmaceutical combination according to claim 1, is characterized in that described interferon is the interferon that concentration is 1000U-3 million U/ml;

Preferably, described interferon is the interferon that concentration is 2000U-200,000 U/ml;

More preferably, the interferon is the interferon with a concentration of 3000U/ml, 4000U/ml, 5000U/ml, 8000U/ml or 10,000U/ml;

Preferably, the coronavirus is SARS-CoV-2, SARS-CoV, MERS-CoV or other coronaviruses; further preferably, the coronavirus is SARS-CoV-2, and the disease caused by the coronavirus (COVID-19) -19) is the novel coronavirus pneumonia.

3. The pharmaceutical combination according to claim 1 or 2, wherein the ratio of the interferon and thymosin is 56,000-252 million: 1-256 (U/W (mg));

Preferably, the ratio of the interferon and thymosin is 7000-1.05 million: 1-8 (U/W (mg));

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

4. The pharmaceutical combination according to any one of claims 1-3, wherein the interferon is one or more of the IFN-α, IFN-β, and IFN-γ families;

Preferably, the interferon is a combination of one or more of IFN-α subtypes, more preferably, the interferon is IFN-α1b, IFN-α2a, IFN-α2b or IFN-ω one or more of; further preferably, the interferon is IFN-α1b or IFN-α2b;

Preferably, the interferon is natural interferon or recombinant human interferon, more preferably recombinant human interferon;

Preferably, described interferon is common interferon or long-acting interferon;

Preferably, the thymosin is derived from blood extract or recombinant thymosin or synthetic thymosin;

Preferably, the thymosin is thymosin α, more preferably thymosin α1.

5. a medicine kit or a complete set of medicine for preventing high-risk susceptible people from infecting coronavirus or the occurrence of coronavirus infection disease, it is characterized in that, described medicine box or complete set of medicine comprise the interferon and thymosin of independent packaging, preferably, The coronavirus is SARS-CoV-2, SARS-CoV, MERS-CoV or other coronaviruses; further preferably, the coronavirus is SARS-CoV-2, the disease caused by the coronavirus (COVID-19) for novel coronavirus pneumonia;

Preferably, the interferon is an interferon with a concentration of 1000 U-3 million U/ml;

More preferably, described interferon is the interferon that concentration is 2000U-200,000 U/ml;

Further preferably, the interferon is an interferon with a concentration of 3000U/ml, 4000U/ml, 5000U/ml or 8000U/ml or 10000U/ml.

6. The kit or complete set of medicines according to claim 5, characterized in that it comprises interferon and thymosin that are packaged independently;

Preferably, the ratio of the interferon and thymosin is 56,000-252 million: 1-256 (U/W (mg));

More preferably, the ratio of the interferon and thymosin is 7000-1.05 million: 1-8 (U/W (mg))

Further preferably, the ratio of the interferon and thymosin is 10500-52500:16 (U/W (mg)).

7. The kit or drug set according to any one of claims 5 or 6, wherein the interferon is one or more of the IFN-α, IFN-β, and IFN-γ families.

Optionally, described interferon is common interferon or long-acting interferon;

Optionally, the thymosin is derived from blood extract, or recombinant thymosin or synthetic thymosin;

Preferably, the thymosin is thymosin α, more preferably thymosin α1.

8. The combination according to any one of claims 1-7 or a kit or a complete set of medicines, wherein the interferon and a pharmaceutically acceptable carrier or excipient form a suitable dosage form, preferably a nasal preparations; more preferably, the nasal preparations are nasal drops, nasal washes, nasal sprays or absorbents attached to the skin on the surface of the nose, more preferably nasal drops or nasal sprays;

Preferably, the interferon nasal preparation comprises a buffer, the buffer is physiological saline, phosphate buffer, citrate buffer, sugar saline (5% glucose injection), sodium bicarbonate buffer, Acetate buffer, Tris-hydrochloric acid buffer, more preferably physiological saline;

Preferably, the pharmaceutically acceptable carrier or excipient further comprises one or more of mucosal absorption enhancers, protective agents, and bacteriostatic agents;

Preferably, the concentration of the mucosal absorption enhancer in the above-mentioned carrier or excipient is 4-28% (v/v), preferably 6-14% (v/v), more preferably 10% (v/v);

Preferably, the concentration of the protective agent in the above-mentioned carrier or excipient is 0.3-2.5% (w/v), preferably 0.8-1.6% (w/v), more preferably 1.2% (w/v);

Preferably, the concentration of the bacteriostatic agent in the above-mentioned carrier or excipient is 0.2-0.6% (w/v), preferably 0.25-0.4% (w/v), more preferably 0.3% (w/v);

Preferably, the mucosal absorption enhancer is surfactant, cyclodextrin and its derivatives, phospholipids, peptides and proteolytic enzyme inhibitors, glycyrrhetinic acid and its derivatives, metal ion chelating agents; the protective agent is human white Protein, 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, nerve One or more of regulatory protein, leukemia inhibitory factor, interleukin, interferon-like active substance, tumor necrosis factor, glial growth factor, growth differentiation factor and nerve growth-related protein; bacteriostatic agents are sorbic acid, sorbic acid One or a combination of two or more of potassium, benzoic acid, and parabens;

Preferably, the thymosin dosage form is an injection dosage form, more preferably, the injection dosage form is a subcutaneous injection or an intradermal injection.

9. the purposes in the described pharmaceutical combination of any one in claim 1-8 or medicine box or complete set of medicine in preventing high-risk susceptible population from infecting coronavirus or the purposes in coronavirus infection disease, preferably, described coronavirus is SARS -CoV-2, SARS-CoV, MERS-CoV or other coronaviruses; further preferably, the coronavirus is SARS-CoV-2, and the disease caused by the coronavirus (COVID-19) is novel coronavirus pneumonia ;

Preferably, the interferon is administered at a dose of 8-3.6 million U/day, and the thymosin is administered to the patient at a dose of 0.1-25.6 mg/week; more preferably, the interferon is administered at a dose of 16-240,000 U/day, and the thymosin is administered at a dose of 1.6 million U/day. - The dose of 12.8 mg/week is administered to the patient; further preferably, the interferon is administered to the patient at a dose of 2400-12000 U/day, and the thymosin is administered to the patient at a dose of 1.6 mg/week.

10. the purposes of the pharmaceutical combination described in any one of claims 1-9 in the preparation of the medicine for preventing high-risk susceptible people from infecting coronavirus or the occurrence of coronavirus infection disease, alternatively, the other coronaviruses are mainly through droplets - nasal-respiratory infection; more preferably, the coronavirus is SARS-CoV-2, SARS-CoV, MERS-CoV or other coronaviruses; further preferably, the coronavirus is SARS-CoV-2, the The disease caused by coronavirus (COVID-19) is novel coronavirus pneumonia.