Pharmaceutical composition and use thereof

Abstract

To provide an effective anti-rhinovirus infectious agent.SOLUTION: The present invention provides a pharmaceutical composition comprising α - pinene, paracymene, β - myrcene and β - phellandrene and uses thereof. The pharmaceutical composition has good inhibitory activity against rhinovirus, and can be used for relieving cough symptoms.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to the field of medicine, and in particular to pharmaceutical compositions and uses thereof. [Background technology]

[0002] Human rhinoviruses (HRVs) are non-coated virus particles with a circular outer shape and a diameter of approximately 27-30 nm. Their viral structure primarily consists of an outer capsid and internal nucleic acids. The HRV capsid exhibits icosahedral symmetry and is composed of four structural proteins, vp1, vp2, vp3, and vp4, arranged in a predetermined pattern. Different types of HRVs share similar genome structures, each consisting of a sense single-stranded RNA with a total length of approximately 7,200 bp.

[0003] In recent years, it has been discovered that HRV infection can cause lower respiratory tract infections such as bronchiolitis and pneumonia, and is closely associated with serious respiratory diseases such as acute asthma, asthma exacerbation, persistent cough, and dyspnea in children, and chronic obstructive pulmonary disease in adults. HRV can also co-infect with other respiratory viruses, increasing the patient's disease burden and risk of severe illness. In addition to mixed viral infections, HRV can also co-infect with bacterial infections, causing a range of illnesses, including otitis media, sinusitis, and pharyngitis. HRV can infect people of all ages, with infants, the elderly, and those with weakened immune systems more susceptible to infection and experiencing more severe symptoms.

[0004] Although the prevention and treatment of rhinovirus infections are receiving increasing attention, there are currently no approved rhinovirus vaccines or antiviral drugs for rhinovirus infections in China, and there is an urgent need to discover effective anti-rhinovirus infection drugs. Summary of the Invention

[0005] In response to the above problems existing in the prior art, the present invention provides a pharmaceutical composition and its use.

[0006] A first aspect of the present invention provides a pharmaceutical composition comprising α-pinene, para-cymene, β-myrcene, and β-phellandrene, wherein the mass ratio of α-pinene, para-cymene, β-myrcene, and β-phellandrene is (8-20):(1-10):(0.1-2):(0.1-1).

[0007] A second aspect of the present invention provides the use of a pharmaceutical composition as described above in the manufacture of a medicament for the prevention and / or treatment of human rhinovirus infection.

[0008] A third aspect of the present invention provides the use of a pharmaceutical composition as described above in the manufacture of a medicament for treating cough.

[0009] A fourth aspect of the present invention provides the use of a pharmaceutical composition as described above in the manufacture of a medicament for the prevention and / or treatment of pneumonia, bronchitis, sinusitis.

[0010] A fifth aspect of the present invention provides the use of a pharmaceutical composition as described above in the manufacture of a medicament for the prevention and / or treatment of pneumonia, bronchitis, sinusitis caused by human rhinovirus infection.

[0011] The positive and inventive effects of the present invention are as follows:

[0012] The pharmaceutical composition provided in the present application has a high rhinovirus-inhibiting effect (each component exhibits synergistic and cooperative effects), and can improve eating, mental status, respiratory and pulmonary changes, and mortality rate caused by rhinovirus infection.

[0013] The pharmaceutical compositions of the present application are expected to further relieve symptoms of cough, including cough caused by human rhinovirus infection.

[0014] The pharmaceutical composition of the present application may also be prepared as an enteric-coated capsule formulation or emulsion. The prepared formulation has stable appearance and related substances under high temperature conditions, and has good patent drug prospects. Enteric-coated capsules have good stability and are more clinically applicable. DETAILED DESCRIPTION OF THE INVENTION

[0015] In the pharmaceutical composition according to the present invention, the mass ratio of α-pinene, para-cymene, β-myrcene, and β-phellandrene may be any value selected from the above-mentioned ranges. For example, when the mass ratio of α-pinene, para-cymene, β-myrcene, and β-phellandrene is (8-20):(1-10):(0.1-2):(0.1-1), the ratio of the four components is any value of α-pinene, 8-20 (for example, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 10 1.3, 14, 15, 16, 17, 18, 19, 20) to any value of paracymene 1 to 10 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) to any value of β-myrcene 0.1 to 2 (e.g., 0.1, 0.2, 0.3, 14, 15, 16, 17, 18, 19, 20) to any value of β-phellandrene 0.1 to 1 (e.g., 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0). Specifically, for example, the mass ratio of α-pinene, para-cymene, β-myrcene, and β-phellandrene may be 10:3:0.5:0.3, 10:2:0.7:0.5, 14:2:0.7:0.5, or 14:3:0.5:0.3, etc.

[0016] In a specific embodiment, the mass ratio of α-pinene, para-cymene, β-myrcene, and β-phellandrene in the pharmaceutical composition is (10-16):(1-5):(0.3-0.9):(0.1-0.7), and may further be (10-16):(1-3):(0.3-0.7):(0.1-0.7).

[0017] In a specific embodiment, the mass ratio of α-pinene, para-cymene, β-myrcene, and β-phellandrene in the pharmaceutical composition is (10-14):(2-3):(0.5-0.7):(0.3-0.5).

[0018] In a specific embodiment, the pharmaceutical composition may further comprise one or more other ingredients, which refer to substances that do not inhibit the biological activity of the pharmaceutical composition.

[0019] In one specific embodiment, the pharmaceutical composition may further comprise α-phellandrene.

[0020] In a specific embodiment, the pharmaceutical composition comprises α-pinene, para-cymene, β-myrcene, β-phellandrene, and α-phellandrene, wherein the mass ratio of α-pinene, para-cymene, β-myrcene, β-phellandrene, and α-phellandrene is (8-20):(1-10):(0.1-2):(0.1-1):(0.1-1).

[0021] In the pharmaceutical composition according to the present invention, the mass ratio of α-pinene, para-cymene, β-myrcene, β-phellandrene, and α-phellandrene may be a ratio of any value selected from the above-mentioned numerical ranges. For example, when the mass ratio of α-pinene, para-cymene, β-myrcene, β-phellandrene, and α-phellandrene is (8-20):(1-10):(0.1-2):(0.1-1):(0.1-1), the ratio of the five components is any value of α-pinene from 8 to 20 (for example, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) and any value of para-cymene from 1 to 10 (for example, 10.5, 11.5, 12.5, 13.5, 14.5, 15.5, 16.5, 17.5, 18.5, 19.5, 20 ... The ratio may be a ratio of any value of β-phellandrene from 0.1 to 1 (for example, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0), any value of β-phellandrene from 0.1 to 1 (for example, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0), or any value of α-phellandrene from 0.1 to 1 (for example, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0). Specifically, for example, the mass ratio of α-pinene, para-cymene, β-myrcene, β-phellandrene and α-phellandrene may be 10:2:0.7:0.3:0.2, 10:3:0.5:0.5:0.6, 14:2:0.5:0.7:0.6, or 14:3:0.7:0.3:0.6.

[0022] In a specific embodiment, the mass ratio of α-pinene, para-cymene, β-myrcene, β-phellandrene, and α-phellandrene in the pharmaceutical composition is (10-16):(1-5):(0.3-0.9):(0.1-0.7):(0.1-0.6).

[0023] In a specific embodiment, the mass ratio of α-pinene, para-cymene, β-myrcene, β-phellandrene, and α-phellandrene in the pharmaceutical composition is (10-14):(2-3):(0.5-0.7):(0.3-0.5):(0.2-0.6).

[0024] In a specific embodiment, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0025] The term "pharmaceutically acceptable excipient" as used herein refers to an excipient that does not significantly irritate the body and does not inhibit the biological activity and properties of the administered active ingredient (e.g., the pharmaceutical composition described herein). Specifically, pharmaceutically acceptable excipients can be selected depending on their specific function in the composition. Pharmaceutically acceptable excipients include, but are not limited to, diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, wetting agents, solvents, solubilizers, suspending agents, emulsifiers, sweeteners, flavoring agents, taste-masking agents, colorants, antiblocking agents, humectants, chelating agents, plasticizers, tackifiers, antioxidants, preservatives, stabilizers, surfactants, and buffers.

[0026] The pharmaceutical compositions of the present invention can be prepared in dosage forms suitable for administration to a patient via a desired route, such as (1) oral dosage forms, such as tablets, capsules (e.g., soft capsules, soft gelatin capsules, hard capsules), caplets, pills, buccal tablets, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and wafers, (2) parenteral dosage forms, such as sterile solutions, suspensions, reconstituted powders, ointments, or salves, and (3) inhalable dosage forms, such as sprays, aerosols, solutions, and dry powders.

[0027] In a specific embodiment, the pharmaceutically acceptable excipient is one or more selected from edible oils, gelatin, glycerol, castor oil, polyacrylic acid resins, polydiethylphthalate, polyethylene glycol, polysorbate, carbomer, poloxamer, methylcellulose, ethylcellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, hydroxymethylcellulose, cellulose acetate phthalate, carmellose sodium, microcrystalline cellulose, shellac, polyvinyl alcohol acetate phthalate, acrylic acid resins, povidone, polyvinyl alcohol, sodium starch glycolate, crospovidone, croscarmellose sodium, carmellose calcium, sodium carboxymethyl starch, colloidal silica, nonionic surfactants, and osmolality adjusters.

[0028] In a specific embodiment, the pharmaceutical composition as described above may be prepared as a capsule, for example, a soft capsule, a soft gelatin capsule, or a hard capsule, preferably a soft capsule.

[0029] In a specific embodiment, the soft capsule may further be prepared as an enteric-coated capsule.

[0030] When prepared as a capsule, the pharmaceutical composition becomes the content of the capsule (e.g., soft capsule). When used as a content, the pharmaceutical composition further contains an edible oil. Furthermore, the edible oil includes, but is not limited to, soybean oil, corn oil, sesame oil, rapeseed oil, peanut oil, olive oil, camellia oil, palm oil, sunflower oil, linseed oil, grapeseed oil, walnut oil, and peony seed oil. The edible oil can specifically be used as a carrier.

[0031] In a specific embodiment, the pharmaceutical composition is placed as a filler in a soft capsule molding machine and pressed into a soft capsule.

[0032] In a specific embodiment, the pharmaceutical composition as described above may be further prepared as an enteric capsule. Specifically, the enteric capsule as described above is prepared by applying an enteric coating to the enteric capsule.

[0033] Those skilled in the art can select the enteric coating liquid based on the prior art, and preferably, the enteric coating liquid described in the present application includes polyacrylic acid resin II, polyacrylic acid resin III, castor oil, polydiethyl phthalate, polysorbate 80, and polyethylene glycol 6000.

[0034] In a specific embodiment, the enteric coating solution comprises 4 to 20 parts by weight of polyacrylic acid resin II, 4 to 20 parts by weight of polyacrylic acid resin III, 4 to 20 parts by weight of castor oil, 4 to 20 parts by weight of diethyl phthalate, 1 to 20 parts by weight of polysorbate 80, and 1 to 20 parts by weight of polyethylene glycol 6000.

[0035] In one specific embodiment, the enteric coating material specifically comprises 6 parts by weight of polyacrylic acid resin II, 12 parts by weight of polyacrylic acid resin III, 4.3 parts by weight of castor oil, 4.3 parts by weight of polydiethylphthalate, 2 parts by weight of polysorbate 80, and 1.2 parts by weight of polyethylene glycol 6000.

[0036] In some specific embodiments, when the pharmaceutical composition as described above is prepared as a soft capsule (e.g., an enteric-coated capsule), the weight percentage of α-pinene in the contents is 7% to 15% (which may be any value between 7% and 15%, for example, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15%).

[0037] In a specific embodiment, the pharmaceutical composition as described above may be prepared as an emulsion.

[0038] In the present invention, the term "emulsion" refers to a heterogeneously dispersed liquid preparation in which one of two liquid phases that are insoluble in each other is dispersed in the liquid phase in the form of small droplets.

[0039] In one specific embodiment, the emulsion is an oil-in-water emulsion.

[0040] In a specific embodiment, when the pharmaceutical composition is prepared as an emulsion, the pharmaceutical composition further comprises an oil and water. The oil is selected from the group consisting of edible oils, medium-chain triglycerides, and ethyl oleate. Specific examples of the edible oil include, but are not limited to, soybean oil, corn oil, sesame oil, rapeseed oil, peanut oil, olive oil, camellia oil, palm oil, sunflower oil, linseed oil, grapeseed oil, walnut oil, and peony seed oil.

[0041] In a specific embodiment, when the pharmaceutical composition as described above is prepared as an emulsion, said pharmaceutical composition further comprises an emulsifier and an emulsion enhancer.

[0042] In a particular embodiment, preferentially, the emulsifier is one or more selected from polysorbate 80, polysorbate 20, Span 80, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil and poloxamer 188.

[0043] In a specific embodiment, the emulsification enhancer is preferentially one or more selected from ethanol, propanediol, glycerol and polyethylene glycol, preferably one or more of propanediol, glycerol and polyethylene glycol 400, more preferably propanediol, and most preferably 1,2-propanediol.

[0044] In a specific embodiment, when the pharmaceutical composition as described above is prepared as an emulsion, said pharmaceutical composition may further comprise one or more of a flavoring agent, a preservative, and a stabilizer.

[0045] In one specific embodiment, the emulsion comprises the following oil and water phases:

[0046] Oil phase: the α-pinene, β-myrcene, paracymene, β-phellandrene, oils and fats, emulsifiers, and emulsification enhancers (which may further contain α-phellandrene) constitute the oil phase; Aqueous phase: The aqueous phase is water or a complex water, which is a complex water to which one or more substances selected from flavoring agents, preservatives, and stabilizers are optionally added.

[0047] A specific embodiment further provides a method for preparing the emulsion, specifically comprising pouring the oil phase as described above into an aqueous phase and mixing uniformly to obtain the drug emulsion.

[0048] In a specific embodiment, the human rhinovirus is selected from human rhinovirus 14.

[0049] The invention encompasses all numerical values ​​subsumed within the range and the recited endpoints, where the numerical ranges are expressed by endpoints.

[0050] In the present invention, the mass ratio of each substance refers to the mass ratio of each component, and all mass ratios included in the range of the ratio of the present invention after multiplying or dividing the corresponding range of the ratio by any coefficient fall within the scope of protection of the present invention. For example, when the mass ratio of α-pinene, para-cymene, β-myrcene, and β-phellandrene is 10:3:0.5:0.3, the ratio of 20:6:1:0.6 obtained by multiplying by a coefficient of 2 also falls within the scope of protection of the present application.

[0051] Additional features and advantages of the present invention will be set forth in part in the description that follows, and in part will be obvious from the description, or may be learned by practice of the present invention.

[0052] The embodiments or solutions with different preferred levels described in this application may be combined in any combination unless otherwise specified.

[0053] The solutions of the present invention are explained below through examples. Those skilled in the art should understand that the following examples are merely illustrative of the present invention and do not limit the scope of the present invention. Examples in which specific techniques or conditions are not specified are carried out according to the techniques or conditions described in literature in the field or according to the product specifications. Reagents or equipment used without specifying the manufacturer are all common products that can be purchased commercially. In this example, α-pinene is purchased from Shanghai McGraw-Hill Biotechnology Co., Ltd.

[0054] β-Myrcene is purchased from Jiangsu Aikang Biopharmaceutical Research and Development Co., Ltd.

[0055] Paracymene is purchased from Shanghai McKelin Biotechnology Co., Ltd.

[0056] α-Phellandrene is purchased from Jiangsu Aikang Biopharmaceutical Research and Development Co., Ltd.

[0057] β-Phellandrene is purchased from Shanghai Saikerui Bioscience and Technology Co., Ltd.

[0058] Example Example 1 Preparation of pharmaceutical compositions and anti-rhinovirus activity test Antirhinovirus activity test method: Test principle: H1-Hela cells are used as virus hosts to measure the inhibition of viral cytopathic effect (CPE) by the single components and pharmaceutical compositions.

[0059] Test materials and methods: 1) Virus strain: Human rhinovirus 14 (strain 1059) provided by ATCC. Cultured intracellularly and passaged, then stored at -80°C.

[0060] 2) Sample treatment: Just before use, prepare a stock solution with DMSO (initial concentration 1000 μg / ml), and further dilute it three-fold with culture medium to make eight dilutions.

[0061] 3) Positive control drug: Ribavirin (RBV) obtained from Shanghai Hefeng Pharmaceutical Co., Ltd.

[0062] 4) Test method: H1-Hela cells were seeded into a 96-well plate and cultured at 37°C in 5% CO2. After 24 hours, rhinovirus 10 -3 The cells were infected with β-glucan and allowed to adsorb for 2 hours, after which the virus solution was discarded. Maintenance solution containing different dilutions of the sample and positive control drug was added, and cell control wells and virus control wells were simultaneously set up and cultured at 5% CO2 and 37°C. When the cytopathic effect (CPE) of the virus control group reached 4+, the cytopathic effect (CPE) of each group was observed. The median toxic concentration (TC) of the sample to the cells was determined using the Reed-Muench method. 50 ) and the half inhibitory concentration (IC 50 ) and calculate the selectivity index SI. SI = TC 50 / I C 50 is.

[0063] Preparation of pharmaceutical compositions and activity testing As shown in Tables 1 to 3, α-pinene, β-myrcene, paracymene, β-phellandrene, and α-phellandrene are weighed, and the components are uniformly mixed at room temperature to obtain the corresponding pharmaceutical compositions, which are then subjected to antiviral activity tests.

[0064] [Table 1]

[0065] The applicant investigated the rhinovirus inhibitory effects of a single component and a combination of four components and found that only α-pinene had a weak inhibitory effect when used alone. However, when the four components were combined, the anti-rhinovirus effects were significantly enhanced compared to the single components, and this was also related to the amounts of the four components used. For example, the antiviral activity of the pharmaceutical compositions was significantly reduced when the proportion of paracymene used in the pharmaceutical compositions was reduced (Comparative Examples 1-3), when β-phellandrene was not added (Comparative Examples 4-6), or when the proportion of myrcene used was too high (Comparative Examples 7-9). Therefore, pharmaceutical compositions in which the mass ratio of α-pinene, paracymene, β-myrcene, and β-phellandrene was controlled to (8-20):(1-10):(0.1-2):(0.1-1) exhibited high anti-rhinovirus activity (SI index of 4 or higher).

[0066] Based on this, the applicant further investigated the amount of each component to be used in order to obtain a more effective composition, as shown in Table 2.

[0067] [Table 2]

[0068] A pharmaceutical composition prepared with a mass ratio of α-pinene, paracymene, β-myrcene, and β-phellandrene of (10-16):(1-5):(0.3-0.9):(0.1-0.7) can further enhance the antirhinovirus effect (SI index of 5 or more). Furthermore, a pharmaceutical composition prepared with a mass ratio of α-pinene, paracymene, β-myrcene, and β-phellandrene of (10-14):(2-3):(0.5-0.7):(0.3-0.5) has a stronger antirhinovirus effect and an SI index of 6 or more.

[0069] The applicant further investigated the antiviral effect after adding α-phellandrene (Table 3) and found that the pharmaceutical composition containing 0.2% to 0.6% α-phellandrene still retains high antiviral activity (SI index of 6 or more).

[0070] [Table 3]

[0071] Example 2: Effect of pharmaceutical compositions on behavior and mortality in mice infected with rhinovirus HRV-14 Test principle: Human rhinovirus (HRV-14) is infected into ICR mice, and the behavior and mortality of the mice are observed.

[0072] Test materials and methods: For the treatment group (Pharmaceutical Composition 8 / 11 / 19), the pharmaceutical composition was dissolved in a small amount of soybean oil and then prepared as a milk suspension in 0.9% saline. Experimental ICR mice were provided by the Animal Center of Kanglong Chemical (Beijing) New Drug Technology Co., Ltd. Experimental animals were randomly divided into a normal group, a model group, and a pharmaceutical composition group, with 20 animals in each group. Except for the normal group, mice in all other groups were lightly anesthetized with ether and then infected nasally with 0.1 ml of virus solution per mouse. The normal group served as a control, receiving nasal administration of 0.9% sodium chloride solution. On the day of viral infection, the Pharmaceutical Composition 8 / 11 / 19 group and the ribavirin group were administered intragastrically at 0.2 ml per mouse per day. The normal and model groups received an equal volume of 0.9% sodium chloride solution for 7 days.

[0073] On the day of infection, the mice's diet, mental state, and respiratory changes were observed and recorded every day for 10 days. From the day of modeling, the mice were observed continuously for 10 days, and the mortality rate of the animals was calculated. Mortality rate (%) = number of animals that died from disease in the same group / experimental animals * 100%, lifespan extension rate (%) = (average survival days of the test group - average survival days of the model group) / average survival days of the model group × 100%, and average survival days (d) = total survival days of each animal in the same group / number of experimental animals. Statistical tests for intergroup variation were performed using the SPSS software package. The experimental results are shown in Table 4.

[0074] [Table 4]

[0075] The mice in the normal group were mentally healthy, alert, had normal breathing and eating patterns, and gained weight naturally. The mice in the model group showed no obvious symptoms after infection, but from the third day onwards, symptoms such as rapid breathing, slow movement, and decreased appetite appeared, and from the fourth day onwards, some of them died of the disease.

[0076] In the groups of Pharmaceutical Compositions 8 and 19, mice began to die from illness from day 8, with the majority of mice dying from illness between days 8 and 10. In the group of Pharmaceutical Composition 11, mice began to show decreased activity, food intake, and weight loss from day 6 of the observation period, and some mice died from illness. From day 8, the condition of the mice improved, activity increased, and no mice died from illness.

[0077] In addition, lesions appeared in the lungs of most mice in each group, and the lungs of the mice in the normal group were observed with the naked eye to be pale pink, containing gas, and no active areas. In the model group, the lungs of the infected mice were found to be enlarged, and most of them had active areas in one or more lung lobes, appearing dark red. In contrast, the lung lesions of the mice in each of the pharmaceutical composition groups 8, 11, and 19 were alleviated to different degrees compared to the model group, indicating that the pharmaceutical composition of the present application has the role of alleviating pneumonia to some extent.

[0078] Example 3: Test of the effect of pharmaceutical composition on the onset of coughing in mice caused by sulfur dioxide Sixty Kunming mice were randomly divided into a positive control group (administered codeine), a blank control group (administered water), and a treatment group (administered pharmaceutical composition 8 / 11 / 19). The dose was 15 mg / kg, and the volume was 20 ml / kg. The mice were intragastrically administered once daily for five consecutive days. One hour after the final administration, each mouse was placed in a sulfur dioxide gas generator to induce coughing with sulfur dioxide. The cough latency period and the number of coughs within 60 and 90 seconds were recorded and compared with the blank group. The results are shown in Table 5.

[0079] [Table 5]

[0080] The results showed that the cough latency periods of pharmaceutical composition groups 8, 11, and 19 were all longer than those of the blank group, and this difference was significant. After intraperitoneal administration, the pharmaceutical composition had a certain anti-cough effect on the onset of coughing in mice induced by sulfur dioxide. Furthermore, pharmaceutical composition 19 was superior to the other groups in both cough latency period and the number of coughs within 60 and 90 seconds.

[0081] Among lower respiratory tract infections caused by rhinovirus, persistent cough is a common symptom. Since the pharmaceutical composition described in the present application has a good effect in alleviating cough, the pharmaceutical composition described in the present application has a good effect in both antiviral infection and alleviating cough caused by rhinovirus infection.

[0082] Example 4 Preparation of enteric capsules of pharmaceutical composition and testing of influencing factors Composition of the contents: (1) Pharmaceutical Composition 11: 14 g α-pinene, 0.7 g paracymene, 2 g β-myrcene, and 0.5 g β-phellandrene, to which soybean oil was added until the total weight of the contents reached 100 g; (2) Pharmaceutical Composition 19: 10 g α-pinene, 0.5 g paracymene, 3 g β-myrcene, 0.5 g β-phellandrene, and 0.6 g α-phellandrene, to which soybean oil was added until the total weight of the contents reached 100 g. The capsule shell consisted of 100 g gelatin, 120 g water, and 40 g glycerol; the coating material was 6 g polyacrylic acid resin II, 12 g polyacrylic acid resin III, 4.3 g castor oil, 4.4 g polydiethyl phthalate, 2 g polysorbate 80, and 1.2 g polyethylene glycol 6000.

[0083] The capsule is produced by pressing, molding, and immersing the contents, and then coating the capsule shell directly with a lumped polymer enteric coating material.

[0084] Referring to the method of the guidelines for pharmaceutical preparation stability testing in Part 4 of the 2020 edition of the Chinese Pharmacopoeia, the enteric-coated capsules containing the above pharmaceutical compositions were respectively left under high temperature (60°C) conditions, and samples were taken on the 5th day to observe the appearance of the samples and compare it with the appearance of the samples on the 0th day, and the content of the pharmaceutical composition in the samples was measured, and the measurement results are shown in Table 6.

[0085] [Table 6]

[0086] The appearance of the pharmaceutical compositions of Group 2 remained unchanged even after 5 days at high temperature. As can be seen from Table 6, the enteric capsules of Pharmaceutical Compositions 11 and 19 had good content stability under high temperature conditions, with the change values ​​both being less than 4.0%, indicating that the enteric capsules of the pharmaceutical compositions had good stability.

[0087] Example 5 Preparation of pharmaceutical composition emulsion and its influence factor test 35 g of pharmaceutical composition (Pharmaceutical Composition 11 / 19) was added to 15 g of soybean oil and mixed uniformly. The mixture was then stirred at 50 rpm in a 30°C water bath for 1 hour to obtain a drug-containing oil. 20 g of emulsifier polysorbate 80 and 6 g of emulsifier 1,2-propanediol were added to the drug-containing oil and stirred at 50 rpm in a 30°C water bath for 2 hours to thoroughly mix the mixture. 300 g of purified water was added dropwise to the mixed oil phase while stirring, followed by shearing in a high-speed shear at 10,000 rpm for 10 minutes. After shearing was complete, the mixture was homogenized and homogenized at 20 bar for 3 minutes to obtain a pharmaceutical emulsion. The resulting pharmaceutical emulsion was dispensed into appropriate oral solution bottles.

[0088] Referring to the method of the pharmaceutical preparation stability test guideline in Part 4 of the 2020 edition of the Chinese Pharmacopoeia, the oral solutions containing the above pharmaceutical compositions were each left under high temperature (60°C) conditions, and samples were taken on the 5th day to observe the appearance uniformity of the oral solutions and compare them with those on the 0th day. At the same time, the content of the pharmaceutical composition in the sample was measured, and the content measurement results are shown in Table 7.

[0089] [Table 7]

[0090] The emulsions of Pharmaceutical Compositions 11 and 19 did not stratify and showed no obvious change in homogeneity even after 5 days at high temperature. As can be seen from Table 6, the contents of each substance in the oral solutions of Pharmaceutical Compositions 11 and 19 were basically stable under high temperature conditions, with the change being less than 10%.

[0091] While the present invention has been shown and described above with reference to exemplary embodiments, it should be understood that the above embodiments are illustrative and should not be construed as limiting the present invention, and that those skilled in the art may make changes, modifications, substitutions and variations to the above embodiments within the scope of the present invention.

Claims

1. A pharmaceutical composition comprising α-pinene, para-cymene, β-myrcene, and β-phellandrene, wherein the mass ratio of α-pinene, para-cymene, β-myrcene, and β-phellandrene is (8-20):(1-10):(0.1-2):(0.1-1).

2. 2. The pharmaceutical composition according to claim 1, wherein the mass ratio of α-pinene, para-cymene, β-myrcene, and β-phellandrene is (10-16):(1-5):(0.3-0.9):(0.1-0.7).

3. 2. The pharmaceutical composition according to claim 1, wherein the mass ratio of α-pinene, para-cymene, β-myrcene, and β-phellandrene is (10-14):(2-3):(0.5-0.7):(0.3-0.5).

4. 2. The pharmaceutical composition according to claim 1, further comprising α-phellandrene.

5. 5. The pharmaceutical composition according to claim 4, wherein the mass ratio of α-pinene, para-cymene, β-myrcene, β-phellandrene, and α-phellandrene is (8-20):(1-10):(0.1-2):(0.1-1):(0.1-1).

6. 10. The pharmaceutical composition according to claim 1, further comprising one or more pharmaceutically acceptable excipients.

7. 7. The pharmaceutical composition according to claim 6, which is prepared as a soft capsule or emulsion.

8. When prepared as a soft capsule, the pharmaceutically acceptable excipient comprises an edible oil, or 8. The pharmaceutical composition according to claim 7, wherein when prepared as an emulsion, the pharmaceutically acceptable excipients comprise fats and oils, water, emulsifiers and emulsion enhancers.

9. Use of the pharmaceutical composition according to any one of claims 1 to 8 in the manufacture of a medicament for the prevention and / or treatment of human rhinovirus infections.

10. Use of the pharmaceutical composition according to any one of claims 1 to 8 in the manufacture of a medicament for treating cough.

11. Use of the pharmaceutical composition according to any one of claims 1 to 8 in the manufacture of a medicament for the prevention and / or treatment of pneumonia, bronchitis, sinusitis.

12. 12. The use according to claim 11, characterized in that it is the use of the pharmaceutical composition in the manufacture of a drug for the prevention and / or treatment of pneumonia, bronchitis, sinusitis caused by human rhinovirus infection.

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