Pharmaceutical composition and use thereof

Abstract

Provided are a pharmaceutical composition and a use thereof, wherein the pharmaceutical composition comprises α-pinene, p-cymene, β-myrcene, and β-phellandrene. The pharmaceutical composition has good inhibitory activity on rhinovirus and can be used for relieving cough symptoms.

Description

A pharmaceutical composition and its use Technical Field

[0001] The present invention relates to the medical field, and in particular to a pharmaceutical composition and use thereof. Background Art

[0002] Human rhinovirus (HRV) particles lack an envelope and are approximately round in shape, with a diameter of approximately 27 to 30 nm. Their structure primarily consists of a capsid and an internal nucleic acid. The HRV capsid exhibits icosahedral symmetry and is composed of four structural proteins, vp1, vp2, vp3, and vp4, arranged in a regular pattern. The genome structure of different HRV strains is similar, consisting of single-stranded positive-sense RNA approximately 7200 base pairs in length.

[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 severe respiratory diseases such as acute wheezing, asthma exacerbations, persistent cough, and dyspnea in children, as well as chronic obstructive pulmonary disease in adults. Furthermore, HRV can cause co-infections with other respiratory viruses, increasing the patient's disease burden and risk of severe illness. In addition to mixed viral infections, HRV can also be combined with bacterial infections, leading to a range of conditions such as otitis media, sinusitis, and pharyngitis. HRV can infect people of all ages, but infants, the elderly, and those with weakened immune systems are more susceptible to infection and experience relatively severe illness.

[0004] The prevention and treatment of rhinovirus infection are receiving more and more attention, but there is no approved rhinovirus vaccine or antiviral drug for rhinovirus infection in China. Therefore, there is an urgent need to discover an effective anti-rhinovirus drug. Summary of the Invention

[0005] In view of the above problems existing in the prior art, the present invention provides a pharmaceutical composition and use thereof.

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

[0007] In a second aspect, the present invention provides a use of the pharmaceutical composition described above in the preparation of a medicament for preventing and / or treating human rhinovirus infection.

[0008] In a third aspect, the present invention provides a use of the pharmaceutical composition described above in preparing a medicament for treating cough.

[0009] In a fourth aspect, the present invention provides a use of the pharmaceutical composition described above in the preparation of a medicament for preventing and / or treating pneumonia, bronchitis, and sinusitis.

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

[0011] The positive progress effect of the present invention is:

[0012] (1) The present application provides a pharmaceutical composition that has a good inhibitory effect on rhinovirus (the components show a synergistic effect) and can improve the diet, mental state, respiratory and lung changes and mortality caused by rhinovirus infection.

[0013] (2) The pharmaceutical composition of the present application is expected to further improve cough symptoms, including cough caused by human rhinovirus infection.

[0014] (3) The pharmaceutical composition of the present application can be further prepared into enteric-coated capsules or emulsions. The appearance and related substances of the prepared formulations are generally stable under high temperature conditions, and have good drug development prospects. Enteric-coated capsules have good stability and are more promising for clinical application. DETAILED DESCRIPTION

[0015] In the pharmaceutical composition of the present invention, the mass ratio of α-pinene, p-cymene, β-myrcene and β-phellandrene can be a ratio formed by any point value selected from the above numerical range, for example: the mass ratio of α-pinene, p-cymene, β-myrcene and β-phellandrene is (8-20): (1-10): (0.1-2): (0.1-1), then the ratio of the four components can be any value (e.g., 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) of α-pinene and any value (e.g., 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) of p-cymene from 1 to 10. The ratio of any value (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) of β-myrcene to any value from 0.1 to 2 (e.g., 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) of β-phellandrene to any value from 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, p-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, and so on.

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

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

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

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

[0020] In a specific embodiment, the pharmaceutical composition comprises α-pinene, p-cymene, β-myrcene, β-phellandrene and α-phellandrene; wherein the mass ratio of α-pinene, p-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 of the present invention, the mass ratio of α-pinene, p-cymene, β-myrcene, β-phellandrene and α-phellandrene can be a ratio formed by any point value selected from the above numerical range, such as the mass ratio of α-pinene, p-cymene, β-myrcene, β-phellandrene and α-phellandrene (8-20): (1-10): (0.1-2): (0.1-1): (0.1-1), then the ratio of the five components can be any point value (e.g., 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) of α-pinene and any point value (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) of p-cymene 1-10. , 8, 9, 10) and any point value of β-myrcene from 0.1 to 2 (e.g., 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) and any point value of β-phellandrene from 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) and any point value of α-phellandrene from 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, p-cymene, β-myrcene, β-phellandrene and α-phellandrene can 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, and the like.

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

[0023] In a specific embodiment, in the pharmaceutical composition, the mass ratio of α-pinene, p-cymene, β-myrcene, β-phellandrene and α-phellandrene 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] As used herein, the term "pharmaceutically acceptable excipient" refers to an excipient that does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered active ingredient (e.g., the pharmaceutical composition described herein). Pharmaceutically acceptable excipients can be selected specifically based 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, cosolvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity enhancers, antioxidants, preservatives, stabilizers, surfactants, and buffers.

[0026] The pharmaceutical compositions of the present invention can be formulated into dosage forms suitable for administration to a patient via a desired route. For example, (1) oral administration, such as tablets, capsules (e.g., soft capsules, gelcaps, hard capsules), caplets, pills, lozenges, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets, and cachets; (2) parenteral administration, such as sterile solutions, suspensions, reconstituted powders, liniments, or ointments; and (3) inhalation, such as sprays, aerosols, solutions, and dry powders.

[0027] In a specific embodiment, the pharmaceutically acceptable excipient is selected from one or more of edible oil, gelatin, glycerin, castor oil, polyacrylic acid resin, polyethylene diethyl phthalate, polyethylene glycol, polysorbate, carbomer, poloxamer, methylcellulose, ethylcellulose, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose, cellulose acetate phthalate, sodium carboxymethyl cellulose, microcrystalline cellulose, shellac, polyvinyl acetate phthalate, acrylic resin, povidone, polyvinyl alcohol, sodium carboxymethyl starch, cross-linked polyvinyl phthalate, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium starch glycolate, colloidal silicon dioxide, nonionic surfactant and osmotic pressure regulator.

[0028] In a specific embodiment, the pharmaceutical composition described above can be prepared into capsules, such as soft capsules, soft capsules, and hard capsules; preferably soft capsules.

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

[0030] When prepared into capsules, the pharmaceutical composition serves as the contents of the capsules (e.g., soft capsules). When used as contents, the pharmaceutical composition further comprises 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, peony seed oil, and the like. The edible oil can specifically be used as a carrier.

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

[0032] In a specific embodiment, the pharmaceutical composition described above can be further prepared into enteric-coated capsules. Specifically, the enteric-coated capsules described above are enteric-coated to obtain the enteric-coated capsules.

[0033] Those skilled in the art can select the enteric coating solution according to the existing technology. Preferably, the enteric coating solution described in the present application includes: polyacrylic acid resin II, polyacrylic acid resin III, castor oil, polyethylene glycol 6000, polyethyl phthalate, Tween 80, and polyethylene glycol 6000.

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

[0035] In a specific embodiment, specifically, the enteric coating material includes: 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 polyethylene phthalate, 2 parts by weight of Tween 80 and 1.2 parts by weight of polyethylene glycol 6000.

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

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

[0038] In the present invention, the term "emulsion" refers to a non-uniformly dispersed liquid preparation formed by two immiscible liquid phases, one of which is dispersed in the other liquid phase in the form of small droplets.

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

[0040] In one embodiment, when the pharmaceutical composition described above is prepared as an emulsion, the pharmaceutical composition further comprises oil and water. Furthermore, the oil is selected from one or more of edible oil, medium-chain triglycerides, and ethyl oleate. Specifically, 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, peony seed oil, and the like.

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

[0042] In a specific embodiment, preferably, the emulsifier is selected from one or more of Tween 80, Tween 20, Span 80, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil and Poloxamer 188.

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

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

[0045] In a specific embodiment, the emulsion comprises:

[0046] (1) Oil phase: the α-pinene, β-myrcene, p-cymene, β-phellandrene, oil, emulsifier and co-emulsifier (which may further include α-phellandrene) constitute the oil phase,

[0047] (2) Aqueous phase: The aqueous phase is water or composite water, wherein the composite water refers to composite water obtained by optionally adding one or more substances selected from flavoring agents, preservatives, and stabilizers to water.

[0048] In a specific embodiment, a method for preparing the emulsion is also provided, which specifically comprises pouring the oil phase as described above into the water phase and mixing them evenly to obtain the pharmaceutical emulsion.

[0049] In a specific embodiment, the human rhinovirus is selected from human rhinovirus type 14.

[0050]

[0014] The recitation of numerical ranges herein by endpoints includes all numbers subsumed within the range as well as the recited endpoints.

[0051] In the present invention, the mass ratio of each substance refers to the ratio of the masses of the components. The range of corresponding ratios includes all mass ratios that fall within the ratio range of the present invention after multiplication or division by any coefficient. For example, if the mass ratio of α-pinene, p-cymene, β-myrcene, and β-phellandrene is 10:3:0.5:0.3, then multiplying by the coefficient of 2 to obtain a ratio of 20:6:1:0.6 is also within the scope of protection of this application.

[0052] Additional aspects and advantages of the present invention will be set forth in part in the description which follows and, in part, will be obvious from the description which follows, or may be learned by practice of the present invention.

[0053] Unless otherwise stated, the various embodiments or embodiments of different preferences described in this application can be arbitrarily combined.

[0054] The scheme of the present invention will be explained below with reference to the examples. Those skilled in the art will understand that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention. If no specific techniques or conditions are specified in the examples, the techniques or conditions described in the literature in this field or the product instructions shall be followed. If the manufacturer of the reagents or instruments used is not specified, they are all conventional products that can be purchased commercially. In this example,

[0055] α-Pinene was purchased from Shanghai MacLean Biochemical Technology Co., Ltd.

[0056] β-Myrcene was purchased from Jiangsu Aikon Biopharmaceutical Research and Development Co., Ltd.

[0057] p-Cymene was purchased from Shanghai MacLean Biochemical Technology Co., Ltd.

[0058] α-Pheretene was purchased from Jiangsu Aikang Biopharmaceutical Research and Development Co., Ltd.

[0059] β-Pheretene was purchased from Shanghai Sai Ke Rui Biotechnology Co., Ltd.

[0060] Example

[0061] Example 1 Preparation of pharmaceutical composition and anti-rhinovirus activity test

[0062] Anti-rhinovirus activity test method:

[0063] Test principle: Using H1-Hela cells as the virus host, the degree of inhibition of virus-induced cytopathic effect (CPE) by single components and drug combinations is determined.

[0064] Test materials and methods:

[0065] 1) Virus strain: Human rhinovirus 14 (strain 1059), provided by ATCC. Cultured and passaged in cells and stored at -80°C.

[0066] 2) Sample treatment: Before use, the sample was prepared into a stock solution with DMSO (initial concentration was 1000 μg / ml), and then diluted 3-fold with culture medium, with 8 dilutions each.

[0067] 3) Positive control drug: Ribavirin (RBV), Shanghai Wellcome Pharmaceutical Co., Ltd.

[0068] 4) Test method: H1-Hela cells were inoculated into 96-well culture plates and cultured at 37°C with 5% CO2. After 24 hours, they were infected with rhinovirus for 10 -3 After 2 hours of adsorption, the virus solution was discarded and maintenance solution containing samples of different dilutions and positive control drugs was added. At the same time, cell control wells and virus control wells were set up and cultured at 37°C with 5% CO2. When the cytopathic effect (CPE) of the virus control group reached 4+, the cytopathic effect (CPE) of each group was observed and the half toxic concentration (TC) of the sample to the cells was calculated using the Reed-Muench method. 50 ) and the half-maximal inhibitory concentration (IC 50 ), and calculate the selection index SI, SI = TC 50 / IC 50 .

[0069] Preparation and activity testing of pharmaceutical compositions

[0070] α-pinene, β-myrcene, p-cymene, β-phellandrene, and α-phellandrene were weighed respectively as shown in Tables 1 to 3, and the components were mixed uniformly at room temperature to obtain the corresponding pharmaceutical compositions, and the antiviral activity test was performed.

[0071] Table 1

[0072] The applicant explored the inhibitory effects of individual components and the synergistic effects of the four components on rhinoviruses and found that, when used as a single component, only α-pinene had a weak inhibitory effect. However, when the four components were used in combination, the anti-rhinovirus effect was significantly enhanced compared to the individual components. This effect was also related to the dosage of the four components. For example, when the dosage ratio of p-cymene in the pharmaceutical composition was reduced (Comparative Examples 1-3), β-phellandrene was not added (Comparative Examples 4-6), or the dosage ratio of myrcene was too high (Comparative Examples 7-9), the antiviral activity of the pharmaceutical composition was very low. Therefore, a pharmaceutical composition with a mass ratio of α-pinene, p-cymene, β-myrcene, and β-phellandrene controlled within (8-20):(1-10):(0.1-2):(0.1-1) exhibited a better anti-rhinovirus effect (SI index above 4).

[0073] On this basis, the applicant conducted further research on the dosage of each material component in order to obtain a composition with better effect, as shown in Table 2:

[0074] Table 2.

[0075] A pharmaceutical composition prepared with a mass ratio of α-pinene, p-cymene, β-myrcene and β-phellandrene of (10-16):(1-5):(0.3-0.9):(0.1-0.7) can further enhance the anti-rhinovirus effect (SI index is above 5); further, a pharmaceutical composition prepared with a mass ratio of α-pinene, p-cymene, β-myrcene and β-phellandrene of (10-14):(2-3):(0.5-0.7):(0.3-0.5) has a higher anti-rhinovirus effect, with an SI index of above 6.

[0076] The applicant further explored the antiviral effect of adding α-phellandrene (Table 3). The pharmaceutical composition with 0.2% to 0.6% α-phellandrene still maintained a high antiviral effect (SI index above 6).

[0077] Table 3

[0078] Example 2 Effects of the pharmaceutical composition on the behavior and mortality of mice infected with rhinovirus HRV-14

[0079] Test principle: Human rhinovirus (HRV-14) infects ICR mice and observes the behavior and mortality of the mice.

[0080] Test materials and methods:

[0081] For the drug administration group (drug composition 8 / 11 / 19), the drug composition was dissolved in a small amount of soybean oil and then prepared into an emulsion suspension with 0.9% saline;

[0082] ICR mice were provided by the Animal Center of Kanglong Chemical (Beijing) Pharmaceutical Technology Co., Ltd. The animals were randomly divided into a normal group, a model group, and a pharmaceutical composition preparation group, with 20 animals in each group. All mice, except the normal group, were lightly anesthetized with ether and then infected with the virus solution intranasally at 0.1 ml per mouse. The normal group received a 0.9% sodium chloride solution intranasally as a control. On the day of viral infection, the pharmaceutical composition group (8 / 11 / 19) and the ribavirin group were gavage-administered 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 consecutive days.

[0083] The mice were observed for 10 consecutive days starting from the day of infection, with their diet, mental state, and respiratory changes recorded daily. The mortality rate was calculated for 10 consecutive days starting from the day of model establishment. Mortality rate (%) = number of animals that died in the same group / experimental animals * 100%; life extension rate (%) = (average survival days of the experimental group - average survival days of the model group) / average survival days of the model group × 100%; average life days (d) = sum of the survival days of each animal in the same group / number of experimental animals. Statistical analysis of intergroup differences was performed using the SPSS software package. The experimental results are shown in Table 4:

[0084] Table 4 Effects of the pharmaceutical composition on the mortality rate and average life expectancy of mice infected with human rhinovirus (n=20)

[0085] Note: Compared with the model group, * indicates p ≤ 0.05.

[0086] The mice in the normal group were in good spirits, agile, breathing and eating normally, and their weight increased naturally. The mice in the model group showed no obvious symptoms after infection, but began to experience shortness of breath, slow movement, and decreased appetite on the third day, and began to die on the fourth day.

[0087] Drug compositions 8 and 19 began to show mortality on the 8th day, and the mortality time of mice was mainly concentrated between the 8th and 10th days; the mice in the drug composition 11 group began to show reduced activity, diet and weight loss on the 6th day of the observation period, and some mice were observed to die. On the 8th day, the mice were observed to begin to improve, their activity increased, and no more mice died.

[0088] In addition, gross lung lesions in each group of mice were observed visually. The lungs of mice in the normal group were pale pink, air-filled, and lacked areas of consolidation. The lungs of infected mice in the model group were enlarged, with most exhibiting consolidation covering one or more lobes, appearing dark red. Compared to the model group, the lung lesions in mice treated with pharmaceutical compositions 8, 11, and 19 were alleviated to varying degrees, demonstrating that the pharmaceutical compositions of this application have a certain effect in ameliorating pneumonia.

[0089] Example 3: Effect of pharmaceutical composition preparation on sulfur dioxide-induced cough in mice

[0090] Sixty Kunming mice, half male and half female, were randomly divided into a positive control group (given codeine) and a blank control group (given water). The drug-treated group was given (pharmaceutical composition 8 / 11 / 19) at a dose of 15 mg / kg in a volume of 20 ml / kg, administered once daily by gavage for 5 consecutive days. One hour after the last dose, each mouse was placed in a sulfur dioxide gas preparation device to induce coughing. The cough latency and the number of coughs within 60 seconds and 90 seconds were recorded and compared with the blank group. The results are shown in Table 5.

[0091] Table 5. Test results of the effect of the pharmaceutical composition on sulfur dioxide-induced cough in mice Note: Compared with the blank group, * indicates p≤0.05, ** indicates p≤0.01, *** indicates p≤0.001

[0092] The results showed that the cough latency of drug composition groups 8, 11, and 19 was significantly longer than that of the blank group. This suggests that intraperitoneal administration of the drug composition has a certain antitussive effect on sulfur dioxide-induced cough in mice. Furthermore, drug composition 19 outperformed the other drug-treated groups in terms of cough latency, number of coughs within 60 seconds, and number of coughs within 90 seconds.

[0093] Persistent cough is a common symptom in lower respiratory tract infections caused by rhinovirus. Given that the pharmaceutical composition described in this application has a good effect in improving cough, the pharmaceutical composition described in this application has a good effect in both antiviral infection and improving cough caused by rhinovirus infection.

[0094] Example 4 Preparation of Enteric-coated Capsules of Pharmaceutical Composition and Test of Influencing Factors

[0095] Contents: (1) Pharmaceutical composition 11: 14g α-pinene, 0.7g p-cymene, 2g β-myrcene and 0.5g β-phellandrene, soybean oil was added until the total weight of the contents reached 100g; (2) Pharmaceutical composition 19: 10g α-pinene, 0.5g p-cymene, 3g β-myrcene, 0.5g β-phellandrene and 0.6g α-phellandrene, soybean oil was added until the total weight of the contents reached 100g;

[0096] The capsule shell formula is: 100g gelatin, 120g water, 40g glycerin;

[0097] Coating materials: 6g polyacrylic acid resin II, 12g polyacrylic acid resin III, 4.3g castor oil, 4.4g polyethylene phthalate, 2g Tween 80, 1.2g polyethylene glycol 6000.

[0098] After the contents are compressed, shaped, and washed, a one-time molded high-molecular enteric coating material is directly coated on the outside of the capsule shell to prepare the product.

[0099] Referring to the method of the guidance principles for stability testing of pharmaceutical preparations in Part IV of the 2020 edition of the Chinese Pharmacopoeia, the above-mentioned enteric-coated capsules containing the pharmaceutical composition were placed under high temperature (60°C) conditions, and samples were taken on 5 days to observe the appearance of the samples and compare them with the appearance on day 0, and the content of the pharmaceutical composition in the samples was detected. The test results are shown in Table 6.

[0100] Table 6. Test results of drug component content in enteric-coated capsule preparations of the pharmaceutical composition at 0 days and at high temperature for 5 days

[0101] The appearance of the two groups of pharmaceutical compositions did not change after 5 days of high temperature. As shown in Table 6, the enteric-coated capsules of pharmaceutical compositions 11 and 19 had good content stability under high temperature conditions, with the change values ​​both below 4.0%, indicating that the enteric-coated capsules of the pharmaceutical compositions had good stability.

[0102] Example 5 Preparation of pharmaceutical composition emulsion and test of its influencing factors

[0103] 35 g of the pharmaceutical composition (pharmaceutical composition 11 / 19) was added to 15 g of soybean oil and mixed evenly. The mixture was stirred at a speed of 50 rpm in a constant temperature water bath at 30°C for 1 hour to obtain the drug-containing oil; 20 g of emulsifier Tween 80 and 6 g of co-emulsifier 1,2-propylene glycol were added to the above-mentioned drug-containing oil, and stirred at a speed of 50 rpm in a constant temperature water bath at 30°C for 2 hours to completely mix them; the mixed oil phase was dropped into 300 g of purified water under stirring, and then sheared at a speed of 10,000 r / min for 10 minutes under a high-speed shearing machine. After the shearing was completed, homogenization was performed and homogenized at a pressure of 20 bar for 3 minutes to obtain an emulsion of the pharmaceutical composition, which was divided into suitable oral solution bottles.

[0104] Referring to the method of the guidance principles for stability testing of pharmaceutical preparations in Part IV of the 2020 edition of the Chinese Pharmacopoeia, the oral solutions containing the above-mentioned pharmaceutical compositions were placed under high temperature (60°C) conditions, and samples were taken on 5 days to observe the appearance uniformity of the oral solutions and compare them with those on day 0. At the same time, the content of the pharmaceutical composition in the samples was detected. The content test results are shown in Table 7.

[0105] Table 7 Test results of drug component content of oral solution of pharmaceutical composition at 0 day and at high temperature for 5 days

[0106] The emulsions of pharmaceutical compositions 11 and 19 showed no stratification and no significant change in uniformity after 5 days of high temperature. As shown in Table 6, the content of each substance in the oral solutions of pharmaceutical compositions 11 and 19 was basically stable under high temperature conditions, with the change value within 10%.

[0107] Although the embodiments of the present invention have been shown and described above, it will be understood that the above embodiments are illustrative and are not to be construed as limitations on the present invention. A person skilled in the art may change, modify, replace and modify the above embodiments within the scope of the present invention.

Claims

1. A pharmaceutical composition, characterized in that the pharmaceutical composition comprises α-pinene, p-cymene, β-myrcene, and β-phellandrene; wherein, The mass ratio of α-pinene, p-cymene, β-myrcene and β-phellandrene is (8-20):(1-10):(0.1-2):(0.1-1).

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

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

4. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition further comprises α-phellandrene.

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

6. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

7. The pharmaceutical composition according to claim 6, characterized in that The pharmaceutical composition is prepared into soft capsules or emulsions.

8. The pharmaceutical composition according to claim 7, characterized in that When prepared into soft capsules, the pharmaceutically acceptable excipients include edible oil; or, When prepared into emulsions, the pharmaceutically acceptable excipients include oils, water, emulsifiers and co-emulsifiers.

9. Use of the pharmaceutical composition according to any one of claims 1 to 8 in the preparation of a medicament for preventing and / or treating human rhinovirus infection.

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

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

12. The use according to claim 11, characterized in that The pharmaceutical composition is used in preparing medicines for preventing and / or treating pneumonia, bronchitis and sinusitis caused by human rhinovirus infection.