Pharmaceutical composition and application thereof

Abstract

The invention provides a pharmaceutical composition and application thereof, and the pharmaceutical composition comprises alpha-pinene, p-cymene, beta-myrcene and beta-phellandrene. The pharmaceutical composition has good inhibitory activity on rhinoviruses and can be used for relieving cough symptoms.

Description

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) has no envelope and is approximately round in shape with a diameter of about 27 to 30 nm. Its viral structure mainly includes the outer capsid and the internal nucleic acid. The HRV capsid is symmetrical and is composed of four structural proteins, vp1, vp2, vp3 and vp4, arranged in a certain pattern. The genome structures of different types of HRV are similar, all of which are single-stranded positive-sense RNA with a total length of about 7200 bp.

[0003] In recent years, it has been found that HRV infection can cause lower respiratory tract infections such as bronchiolitis and pneumonia, and is closely related to severe respiratory diseases such as acute wheezing, asthma exacerbation, persistent cough, dyspnea in children, and chronic obstructive pulmonary disease in adults. In addition, HRV can also cause co-infection 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 series of diseases such as otitis media, sinusitis and pharyngitis. HRV can infect people of all ages, and infants, the elderly and people with weakened immune systems are more susceptible to infection and their condition is relatively serious.

[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 drug against rhinovirus infection. 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 as described above in the preparation of a medicament for preventing and / or treating human rhinovirus infection.

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

[0009] The positive and progressive effects of the present invention are: The present application provides a pharmaceutical composition that has a good inhibitory effect on rhinovirus (each component exhibits a synergistic effect), and can improve the diet, mental state, respiratory and lung changes and mortality caused by rhinovirus infection.

[0010] The pharmaceutical composition of the present application is expected to further improve cough symptoms, including cough caused by human rhinovirus infection.

[0011] The pharmaceutical composition of the present application can be further prepared into an enteric-coated capsule preparation or an emulsion. The appearance and related substances of the prepared preparation are generally stable under high temperature conditions, and the preparation has good prospects for drug development. DETAILED DESCRIPTION

[0012] 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 in the range of 1-10. The ratio of any value (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10) of β-myrcene to any value between 0.1 and 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 between 0.1 and 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 the like.

[0013] 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) 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).

[0014] In a specific embodiment, the pharmaceutical composition may further include one or more other ingredients, wherein the other ingredients refer to substances that do not interfere with the biological activity of the pharmaceutical composition.

[0015] In a specific embodiment, the pharmaceutical composition may further comprise α-phellandrene.

[0016] 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).

[0017] 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 in the range of 8-20 of α-pinene (for example, 9.5, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20) and any point value in the range of 1-10 of p-cymene (for example, 1, 2, 3, 4, 5, 6, 7 , 8, 9, 10) and any point value between 0.1 and 2 of β-myrcene (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 between 0.1 and 1 of β-phellandrene (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 between 0.1 and 1 of α-phellandrene (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 of α-pinene, p-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, and the like.

[0018] 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).

[0019] 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).

[0020] In a specific embodiment, the pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

[0021] The term "pharmaceutically acceptable excipient" as used in this application refers to an excipient that does not cause significant stimulation to an organism and does not interfere with the biological activity and properties of the administered active ingredient (such as the pharmaceutical composition described in this application). Pharmaceutically acceptable excipients can be selected specifically according to the specific functions in the composition. Pharmaceutically acceptable excipients include, but are not limited to: diluents, fillers, binders, disintegrants, lubricants, glidants, granulators, wetting agents, solvents, cosolvents, suspending agents, emulsifiers, sweeteners, flavoring agents, masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, tackifiers, antioxidants, preservatives, stabilizers, surfactants and buffers.

[0022] The pharmaceutical composition of the present invention can be formulated into a dosage form suitable for administration to a patient via a desired route. For example, (1) oral administration, such as tablets, capsules (such as soft capsules, gelatin capsules, 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; (3) inhalation, such as sprays, aerosols, solutions and dry powders.

[0023] 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 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 cellulose, cross-linked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium starch glycolate, colloidal silicon dioxide, nonionic surfactants and osmotic pressure regulators.

[0024] In a specific embodiment, the pharmaceutical composition described above can be prepared into capsules, such as soft capsules, soft capsules, hard capsules; preferably soft capsules.

[0025] In a specific embodiment, the soft capsule can be further prepared into an enteric-coated capsule.

[0026] When prepared into capsules, the pharmaceutical composition is used as the content of the capsules (e.g., soft capsules). When used as the content, the pharmaceutical composition further includes edible oil. Further, 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, grape seed oil, walnut oil, peony seed oil, etc. The edible oil can be used specifically as a carrier.

[0027] In a specific embodiment, the pharmaceutical composition is placed as a content in a soft capsule pill press and pressed into a soft capsule.

[0028] 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 enteric-coated capsules.

[0029] 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 diethyl phthalate, Tween 80, and polyethylene glycol 6000.

[0030] 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.

[0031] 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.

[0032] In some specific embodiments, when the pharmaceutical composition as described above is prepared into a soft capsule (such as an enteric-coated capsule), the weight percentage of α-pinene in the content is 7% to 15% (it can be any value between 7% and 15%, for example, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% or 15%).

[0033] In a specific embodiment, the pharmaceutical composition as described above may be prepared as an emulsion.

[0034] 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.

[0035] In a specific embodiment, the emulsion is an oil-in-water emulsion.

[0036] In a specific embodiment, when the pharmaceutical composition as described above is prepared into an emulsion, the pharmaceutical composition further comprises oil and water. Further, the oil is selected from one or more of edible oil, medium chain triglyceride 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, grape seed oil, walnut oil, peony seed oil, etc.

[0037] 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.

[0038] 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.

[0039] 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.

[0040] 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.

[0041] In a specific embodiment, the emulsion comprises: 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, Aqueous phase: The aqueous phase is water or composite water. The composite water refers to composite water obtained by optionally adding one or more substances selected from flavoring agents, preservatives, and stabilizers into water.

[0042] 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, mixing evenly, to obtain the drug emulsion.

[0043] In a specific embodiment, the human rhinovirus is selected from human rhinovirus type 14.

[0044]

[0013] The recitation of numerical ranges by endpoints herein includes all values ​​subsumed within the range as well as the recited endpoints.

[0045] In the present invention, the mass ratio of each substance represents the ratio of the mass of each component, and the range of the corresponding ratio includes all mass ratios that fall within the ratio range of the present invention after multiplying or dividing by any coefficient, and they all belong to the protection scope of the present invention. For example, when the mass ratio of α-pinene, p-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 the coefficient 2 is also within the protection scope of the present application.

[0046] Additional aspects and advantages of the present invention will be given in part in the following description and in part will be obvious from the following description, or will be learned through practice of the present invention.

[0047] Unless otherwise stated, the various embodiments or embodiments of different preferred levels described in this application can be arbitrarily combined.

[0048] The scheme of the present invention will be explained below in conjunction with the embodiments. Those skilled in the art will understand that the following embodiments 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 embodiments, the techniques or conditions described in the literature in the field or the product instructions are used. The reagents or instruments used without indicating the manufacturer are all conventional products that can be purchased commercially. In this example, α-Pinene was purchased from Shanghai MacLean Biochemical Technology Co., Ltd.

[0049] β-Myrcene was purchased from Jiangsu Aikang Biopharmaceutical Research and Development Co., Ltd.

[0050] p-Cymene was purchased from Shanghai MacLean Biochemical Technology Co., Ltd.

[0051] α-Pheretene was purchased from Jiangsu Aikang Biopharmaceutical Research and Development Co., Ltd.

[0052] β-Pheretene was purchased from Shanghai Sai Ke Rui Biotechnology Co., Ltd. Example

[0053] Example 1 Preparation of pharmaceutical composition and testing of anti-rhinovirus activity Antiviral activity test method: Test principle: Using H1-Hela cells as virus hosts, the degree of inhibition of virus-induced cytopathic effect (CPE) by single components and drug combinations is determined.

[0054] Test Materials and Methods: 1) Virus strain: Human rhinovirus 14 (strain 1059), provided by ATCC. Cultured and passaged in cells and stored at -80°C.

[0055] 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.

[0056] 3) Positive control drug: Ribavirin (RBV), Shanghai Wellcome Pharmaceutical Co., Ltd.

[0057] 4) Test method: H1 Hela cells were inoculated into 96-well culture plates and placed in 5% CO 2 , cultured at 37°C. After 24 hours, 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 5% CO 2 , cultured at 37°C. 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 samples to cells was calculated by the Reed-Muench method. 50 ) and the half inhibitory concentration (IC 50 ), and calculate the selection index SI, SI = TC 50 / IC 50 .

[0058] Preparation and activity testing of pharmaceutical compositions

[0059] 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 composition, and the antiviral activity test was performed.

[0060] Table 1

[0061] The applicant explored the inhibitory effects of a single component and four components on rhinovirus in a synergistic manner, and found that when a single component was used, only α-pinene had a weak inhibitory effect. However, when the four components were used in combination, the anti-rhinovirus effect could be significantly increased compared to the single component, and it 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 much (Comparative Examples 7-9), the antiviral activity of the pharmaceutical composition was very low. Therefore, the pharmaceutical composition with a mass ratio of α-pinene, p-cymene, β-myrcene and β-phellandrene controlled at (8~20): (1~10): (0.1~2): (0.1~1) showed a good anti-rhinovirus effect (SI index was above 4).

[0062] On this basis, the applicant further studied the dosage of each material component in order to obtain a composition with better effect, as shown in Table 2: Table 2

[0063] The pharmaceutical composition prepared with the mass ratio of α-pinene, p-cymene, β-myrcene and β-phellandrene as (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, the pharmaceutical composition prepared with the mass ratio of α-pinene, p-cymene, β-myrcene and β-phellandrene as (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.

[0064] The applicant further explored the antiviral effect after adding α-phellandrene (Table 3). The pharmaceutical composition with 0.2% to 0.6% α-phellandrene still maintained a high antiviral effect (SI index was above 6).

[0065] Table 3

[0066] Example 2 Effects of the pharmaceutical composition on the behavior and mortality of mice infected with rhinovirus HRV-14 Test principle: Human rhinovirus (HRV-14) infects ICR mice and observes the behavior and mortality rate of the mice.

[0067] Test Materials and Methods: In the drug administration group (drug composition 8 / 11 / 19), the drug composition was dissolved with a small amount of soybean oil and then prepared into an emulsion suspension with 0.9% saline; The ICR mice used in the experiment were provided by the Animal Center of Kanglong Chemical (Beijing) New Drug Technology Co., Ltd. The experimental animals were randomly divided into a normal group, a model group and a drug composition preparation group, with 20 animals in each group. Except for the normal group, the mice in other groups were lightly anesthetized with ether and then infected with virus drops in the nose, 0.1 ml / mouse. The normal group was controlled by 0.9% sodium chloride solution drops in the nose. The drug composition 8 / 11 / 19 group and the ribavirin group were given oral administration on the day after virus infection, 0.2 ml / mouse / d, and the normal group and the model group were given an equal amount of 0.9% sodium chloride solution, and the administration was continued for 7 days.

[0068] The mice were observed continuously for 10 days from the day of infection, and the diet, mental state, and respiratory changes of the mice were observed and recorded daily; the animals were observed continuously for 10 days from the day of modeling, and the mortality rate of the animals was calculated. 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. The SPSS software package was used to perform statistical tests on the differences between the groups. The experimental results are shown in Table 4: Table 4 Effects of the drug combination preparation on the mortality rate and average life span of mice infected with human rhinovirus (n=20)

[0069] Note: Compared with the model group, * indicates p≤0.05.

[0070] The mice in the normal group were in good spirits, agile, breathing and eating normally, and their body weight increased naturally. The mice in the model group showed no obvious symptoms after infection with the virus, but began to show symptoms such as shortness of breath, slow movement and reduced diet on the third day, and began to die on the fourth day.

[0071] Drug compositions 8 and 19 began to show mortality on the 8th day, and the mortality of mice was mainly concentrated between the 8th and 10th days. Drug composition 11 group of mice began to show reduced movement, 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.

[0072] In addition, by visually observing the gross lung lesions of mice in each group, the lungs of mice in the normal group were light pink, contained air, and had no consolidation area. In the model group, the lung volume of infected mice increased, and most of them had more than one lobe of consolidation area, showing a dark red appearance, and the lung lesions of mice in the drug composition 8, 11, and 19 groups were alleviated to varying degrees compared with the model group.

[0073] Example 3 Effect of the pharmaceutical composition on sulfur dioxide-induced cough in mice

[0074] 60 Kunming mice, half male and half female, were randomly divided into a positive control group (give codeine), a blank control group given water, and a drug group given (drug composition 8 / 11 / 19), with a dose of 15 mg / kg, a volume of 20 ml / kg, and oral administration once a day for 5 consecutive days. 1 hour after the last administration, each mouse was placed in a sulfur dioxide gas preparation device to induce coughing by sulfur dioxide. The cough latency and the number of coughs within 60s and 90s were recorded, and compared with the blank group. The results are shown in Table 5.

[0075] Table 5. Test results of the effect of the drug composition on sulfur dioxide-induced cough in mice

[0076] Note: Compared with the blank group, * indicates p≤0.05, ** indicates p≤0.01, *** indicates p≤0.001 The results showed that the cough latency of drug composition groups 8, 11, and 19 was longer than that of the blank group, and the difference was significant. This indicated that after intraperitoneal administration of the drug composition, it had a certain antitussive effect on sulfur dioxide-induced cough in mice. In addition, drug composition 19 was superior to other drug administration groups in cough latency, cough times within 60s and 90s.

[0077] Persistent cough is a common symptom in lower respiratory tract infections caused by rhinovirus. Given the good effect of the pharmaceutical composition described in the present application in improving cough, the pharmaceutical composition described in the present application has good effects in both antiviral infection and improving cough caused by rhinovirus infection.

[0078] Example 4 Preparation of Enteric-coated Capsules of Pharmaceutical Composition and Experiment on Influencing Factors

[0079] Contents: (1) Pharmaceutical composition 11: 14g α-pinene, 0.7g p-cymene, 2g β-myrcene and 0.5g β-phellandrene, add soybean oil until the total weight of the contents is 100g; (2) Pharmaceutical composition 19: 10g α-pinene, 0.5g p-cymene, 3g β-myrcene, 0.5g β-phellandrene and 0.6g α-phellandrene, add soybean oil until the total weight of the contents is 100g; The capsule shell prescription is: 100g gelatin, 120g water, 40g glycerin; Coating materials: 6g polyacrylic acid resin II, 12g polyacrylic acid resin III, 4.3g castor oil, 4.4g polyethylene phthalate, 2g Tween 80, and 1.2g polyethylene glycol 6000.

[0080] After the contents are compressed, shaped, and washed, a one-time formed high molecular enteric coating material is directly coated on the outside of the capsule shell to prepare the product.

[0081] Referring to the method of the guidance principles for stability testing of drug preparations in Part IV of the 2020 edition of the Chinese Pharmacopoeia, the above-mentioned enteric-coated capsules containing the drug 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 drug composition in the samples was detected. The test results are shown in Table 6.

[0082] Table 6. Drug component content test results of the enteric-coated preparation of the drug composition at 0 day and at high temperature for 5 days

[0083] 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 have good content stability under high temperature conditions, and the change values ​​are all less than 4.0%, indicating that the enteric-coated capsules of the pharmaceutical compositions have good stability.

[0084] Example 5 Preparation of pharmaceutical composition emulsion and test of its influencing factors

[0085] Add 35g of the drug composition (drug composition 11 / 19) to 15g of soybean oil and mix well. Stir at a speed of 50rpm in a constant temperature water bath at 30°C for 1 hour to obtain the drug-containing oil; add 20g of emulsifier Tween 80 and 6g of auxiliary emulsifier 1,2-propylene glycol to the above-mentioned drug-containing oil, stir at a speed of 50rpm in a constant temperature water bath at 30°C for 2 hours to completely mix them; drop the mixed oil phase into 300g of purified water under stirring, and then shear at a speed of 10000r / min for 10 minutes under a high-speed shearing machine. After the shearing is completed, homogenize and homogenize at a pressure of 20bar for 3 minutes to obtain an emulsion of the drug composition, which is divided into suitable oral solution bottles.

[0086] Referring to the method of the guidance principles for stability testing of drug preparations in Part IV of the 2020 edition of the Chinese Pharmacopoeia, the oral solutions containing the above-mentioned drug compositions were placed under high temperature (60°C) conditions, and samples were taken on 5 days to observe the uniformity of the appearance of the oral solutions and compared with that on 0 days. At the same time, the content of the drug composition in the samples was detected. The content test results are shown in Table 7.

[0087] Table 7 Test results of drug component content of oral solution of drug composition at 0 day and at high temperature for 5 days

[0088] The emulsions of pharmaceutical compositions 11 and 19 did not stratify after 5 days of high temperature, and the uniformity did not change significantly. As shown in Table 6, the oral solutions of pharmaceutical compositions 11 and 19 were basically stable under high temperature conditions, and the change value was within 10%.

[0089] Although the embodiments of the present invention have been shown and described above, it is to be understood that the above embodiments are exemplary and are not to be construed as limitations of the present invention. A person skilled in the art may change, modify, replace and vary 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; in, 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, It is 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, It is 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, It is characterized in that The pharmaceutical composition further comprises α-phellandrene.

5. The pharmaceutical composition according to claim 4, It is 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, It is characterized in that The pharmaceutical composition further comprises one or more pharmaceutically acceptable excipients.

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

8. The pharmaceutical composition according to claim 7, It is 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.

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