CN114601866B - Composition for treating or preventing viral influenza and application thereof - Google Patents
Composition for treating or preventing viral influenza and application thereof Download PDFInfo
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- CN114601866B CN114601866B CN202011446487.8A CN202011446487A CN114601866B CN 114601866 B CN114601866 B CN 114601866B CN 202011446487 A CN202011446487 A CN 202011446487A CN 114601866 B CN114601866 B CN 114601866B
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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- Molecular Biology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
The invention provides application of a pharmaceutical composition for treating or preventing viral influenza in preparation of a medicament, wherein the pharmaceutical composition comprises eucalyptol, limonene and alpha-pinene. The pharmaceutical composition provided by the invention can effectively inhibit influenza A virus and relieve symptoms such as cough, expectoration and the like, and has the advantages of reasonable and simple formula, simple and convenient preparation process and contribution to production.
Description
Technical Field
The invention belongs to the field of biological medicines, and particularly relates to a pharmaceutical composition for treating or preventing cold or other complications caused by influenza viruses and application thereof, and more particularly relates to a eucalyptol and pinene preparation and pharmaceutical combination.
Background
The virus of the viral cold is the genuine virus which causes the cold, such as parainfluenza virus, respiratory syncytial virus, adenovirus, herpes simplex virus and the like, which are common viruses causing the cold. The onset of viral influenza is mostly hoarse voice or nasal obstruction, then the upper respiratory symptoms such as rhinorrhea, sneezing and cough become more and more serious, the general symptoms are slight, and fever can also occur, but the body temperature is not too high.
Influenza viruses are a representative species of orthomyxoviruses, and are causative agents of influenza, also known as influenza viruses. Influenza viruses are classified into types A, B and C, of which influenza A poses the greatest threat to humans. At present, most of highly pathogenic avian influenza viruses with serious harm are H5, H7 and H9 subtypes, namely H5N1, H7N7, H9N2 and the like, wherein the death rate of the H5N1 subtype is high. Human influenza viruses are, in turn, predominantly of the H1, H2 and H3 subtypes, of which H1 and H3 subtypes are susceptible to human infection. Influenza viruses have been prevalent in humans for over 300 years, with outbreaks occurring every few years, and with global influenza pandemics occurring for decades. Influenza epidemics can cause 25 to 50 million deaths per year, with 300 to 500 million cases, and about 5 to 15% of people worldwide are infected. For a global influenza pandemic, "vaccines and antiviral drugs are the most important countermeasures to reduce morbidity and mortality during the pandemic period. However, 3 hundred million people of trivalent influenza vaccine can be produced in the world at present, which is only enough for the prevention of influenza in western countries and cannot meet the requirements of global influenza pandemics, and the influenza virus has strong antigen variation capability, and the vaccine cannot be developed before new virus strains appear. Typically, the development and manufacture of a vaccine on a large scale takes at least six months, even then, many countries without production facilities will not use the vaccine during the 1 st pandemic due to limited global production capacity and the concentration of production facilities in developed countries. The protection rate that current vaccines can provide is not high. Anti-influenza virus drugs are not only late but also few clinical quick-acting and effective therapeutic drugs, belonging to small varieties of anti-infection drugs. Currently, there are two classes of anti-influenza virus drugs that are officially marketed as approved by the U.S. Food and Drug Administration (FDA): (1) M2 ion channel blockers represented by amantadine and rimantadine. The drugs only have the effects of preventing and treating influenza A virus, researches show that the drugs have toxic and side effects such as neurotoxicity and the like, and drug-resistant strains generally exist due to wide use, so the CDC recommends that the drugs are not used for preventing influenza virus infection any more. (2) Neuraminidase inhibitors, representative of such drugs are oseltamivir and zalamivir. Such drugs are effective against all known human influenza viruses and highly pathogenic avian influenza viruses, but there have been reports of drug-resistant strains of oseltamivir in recent years.
Therefore, there is a need for the development of a safe and non-side-effect drug that can effectively prevent and treat influenza a.
Disclosure of Invention
The present invention is directed to solving, at least in part, one of the technical problems in the related art.
In a first aspect of the invention, the invention proposes the use of a pharmaceutical composition for the manufacture of a medicament. According to an embodiment of the invention, the medicament is used for treating or preventing influenza virus cold caused by influenza A (H3) virus or complications thereof, and the pharmaceutical composition comprises eucalyptol, limonene and alpha-pinene. The pharmaceutical composition provided by the embodiment of the invention can effectively relieve influenza virus symptoms and inhibit influenza virus amplification, and is simple in formula, natural in three substances, easily available in raw materials, low in price, low in toxicity and high in safety.
According to an embodiment of the invention, the causative agent of the influenza virus cold belongs to the H3N2 subtype of influenza a virus in orthomyxovirus;
according to an embodiment of the invention, the causative agent of the influenza virus cold belongs to a subtype A/Hanfang/359/95 of influenza A virus H3N2 in orthomyxoviruses.
According to an embodiment of the invention, the drug may inhibit amplification of the pathogen. The inventor surprisingly finds that the combination of three components of eucalyptol, limonene and alpha-pinene can effectively inhibit the amplification of influenza viruses, only a small amount of medicaments can achieve a strong inhibition effect on the influenza viruses, the difference between the half toxic concentration and the half effective concentration of the medicaments is large, the medicament selection index is high, the safety is high, and the medicament is beneficial to medicament use or combined medicament use.
According to an embodiment of the invention, the medicament has antitussive, expectorant and/or anti-inflammatory effects. According to the application of the embodiment of the invention, the medicine can effectively relieve cough, expectoration, inflammation reaction of red, swelling, heat, pain and functional injury, and alleviate influenza symptoms.
According to an embodiment of the invention, the medicament has at least one of the following effects: improve the movement of mucociliary of trachea, promote the secretion of glandular bodies in respiratory tract and increase the moving speed of mucus in respiratory tract. The inventor finds that the medicine can enhance the foreign matter removing capacity of respiratory mucosa and enhance the capacity of adhering foreign matters to the respiratory tract by improving the movement of respiratory cilia, thereby effectively removing the foreign matters in the respiratory tract and relieving the influenza symptom.
According to an embodiment of the invention, the patient with the influenza cold has at least one of the following symptoms: cough, expectoration, reduced ability to clear the respiratory mucosa, and reduced ability to adhere foreign bodies to the respiratory tract. According to the application of the embodiment of the invention, aiming at the patients, the pharmaceutical composition can relieve the influenza symptoms of the patients with the symptoms, relieve the pain of the patients, specifically inhibit the proliferation of pathogens, and further treat or prevent influenza and/or organ complications caused by the influenza A (H3) virus.
According to an embodiment of the invention, the drug has a selection index of not less than 4.6, the selection index being the quotient of the half toxic concentration of the drug to the cell and the half inhibitory concentration of the drug to the virus. According to an embodiment of the invention, the selection index of the drug is 4.6, 4.7, 7.4, 6.4, 6.1.
According to an embodiment of the invention, the pharmaceutical composition comprises: the pharmaceutical composition comprises: 20-40 parts of eucalyptol, 10-40 parts of limonene and 10-40 parts of alpha-pinene. The inventor obtains the better proportioning through a large amount of experiments, thereby obtaining better effects of inhibiting viruses and relieving symptoms, and other proportioning has no more excellent effect than the proportioning.
According to an embodiment of the invention, the pharmaceutical composition comprises: 25 parts by mass of eucalyptol, 25 parts by mass of limonene and 25 parts by mass of alpha-pinene.
According to an embodiment of the invention, the pharmaceutical composition comprises: 37 parts by mass of eucalyptol, 25 parts by mass of limonene and 13 parts by mass of alpha-pinene.
According to an embodiment of the invention, the pharmaceutical composition comprises: 25 parts by mass of eucalyptol, 13 parts by mass of limonene and 37 parts by mass of alpha-pinene.
According to an embodiment of the invention, the pharmaceutical composition comprises: 25 parts of eucalyptol, 37 parts of limonene and 13 parts of alpha-pinene.
According to an embodiment of the invention, the pharmaceutical composition comprises: 37 parts by mass of eucalyptol, 13 parts by mass of limonene and 25 parts by mass of alpha-pinene.
According to an embodiment of the invention, the pharmaceutical composition further comprises at least one pharmaceutical carrier. According to the embodiment of the invention, the drug carrier can enable the pharmaceutical composition to obtain better absorption characteristics, better adaptability, better stability and smaller side effects and adverse reactions.
According to the embodiment of the invention, the drug carrier is soybean oil, wherein the mass ratio of the drug composition to the soybean oil is (3-5): 1, preferably 3.
In a second aspect of the invention, the invention provides a eucalyptol and pinene formulation for use in the treatment or prevention of influenza a virus cold or complications thereof. According to an embodiment of the invention, the active ingredients of the preparation are eucalyptol, limonene and alpha-pinene, wherein the eucalyptus oil20 to 40 parts of essence, 10 to 40 parts of limonene and 10 to 40 parts of alpha-pinene. The inventor is proved through a great deal of theoretical research and experiments that the effect of treating influenza disease or inhibiting virus is not better than that of the formula by changing one to two components in the preparation, and in addition, the inventor is proved through TC 50 (half toxic concentration of drug to cell), IC 50 Analysis of data of half inhibitory concentration of the drug to the virus and SI (selective index) shows that the cytotoxicity of the single-component drug in the formula is stronger than that of the preparation of the invention, and the antiviral effect is not as good as that of the preparation of the invention. In the long run, the preparation is easier to prepare.
The inventor evaluates the inhibitory effect of the preparation of the invention on paramyxovirus, such as parainfluenza virus HPIV, and finds that the preparation of the invention has no inhibitory effect on the virus, which indicates that the preparation of the invention has strong specificity on orthomyxoinfluenza virus causing influenza, can specifically inhibit the proliferation of influenza A virus and relieve clinical symptoms caused by influenza virus.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Detailed Description
The following detailed description of embodiments of the invention is intended to be illustrative of the invention and is not to be construed as limiting the invention.
The terms "first", "second" and "first" are used for descriptive purposes only and are not to be construed as indicating or implying relative importance or implicitly indicating the number of technical features indicated. Thus, a feature defined as "first" or "second" may explicitly or implicitly include at least one such feature. In the description of the present invention, "a plurality" means at least two, e.g., two, three, etc., unless explicitly specified otherwise.
Pharmaceutical use
In a first aspect of the invention, the invention proposes the use of a pharmaceutical composition for the manufacture of a medicament. According to an embodiment of the present invention, the medicament is for treating or preventing viral influenza, and the pharmaceutical composition comprises eucalyptol, limonene and alpha-pinene.
The term "treating" any disease or condition, as used herein, means all that can slow, halt, arrest, control or halt the progression of the disease or condition, but does not necessarily mean that all the symptoms of the disease or condition have disappeared, and also includes prophylactic treatment of the symptoms, particularly in patients susceptible to such disease or disorder. In some embodiments, refers to ameliorating a disease or disorder (i.e., slowing or arresting or reducing the development of the disease or at least one clinical symptom thereof), such as clinical symptoms of cough, expectoration, and the like. In other embodiments, "treating" or "treatment" refers to mitigating or improving at least one physical parameter, including physical parameters that may not be perceptible to the patient, such as viral content in the patient, or the like. In other embodiments, "treating" or "treatment" refers to modulating the disease or disorder, either physically (e.g., stabilizing a perceptible symptom) or physiologically (e.g., stabilizing a parameter of the body), or both. In other embodiments, "treating" or "treatment" refers to preventing or delaying the onset, occurrence, or worsening of a disease or disorder.
The term "composition" as used herein refers to a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. The meaning of such terms with respect to pharmaceutical compositions includes a product comprising the active ingredient(s) and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention include any composition prepared by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
Eucalyptus and pinene preparation
The invention provides a eucalyptol and limonene pine preparation which is used for treating or preventing influenza or complications thereof caused by influenza viruses. According to the embodiment of the invention, the active ingredients of the preparation are eucalyptol, limonene and alpha-pinene, wherein the eucalyptol accounts for 20-40 parts by mass, the limonene accounts for 10-40 parts by mass and the alpha-pinene accounts for 10-40 parts by mass.
According to an embodiment of the invention, the formulation further comprises a pharmaceutically acceptable excipient, and suitable pharmaceutically acceptable excipients will vary depending on the particular dosage form selected. In addition, pharmaceutically acceptable excipients may be selected for their specific function in the composition. For example, certain pharmaceutically acceptable excipients may be selected that can aid in the production of a uniform dosage form. Certain pharmaceutically acceptable excipients may be selected to aid in the production of stable dosage forms. Certain pharmaceutically acceptable excipients may be selected to facilitate carrying or transporting the disclosed compositions from one organ or portion of the body to another organ or portion of the body when administered to a patient. Certain pharmaceutically acceptable excipients may be selected that enhance patient compliance.
Suitable pharmaceutically acceptable excipients include the following types of excipients: diluents, fillers, binders, disintegrants, lubricants, glidants, granulating agents, coating agents, wetting agents, solvents, co-solvents, suspending agents, emulsifiers, sweeteners, flavoring agents, taste masking agents, colorants, anti-caking agents, humectants, chelating agents, plasticizers, viscosity increasing agents, antioxidants, preservatives, stabilizers, surfactants and buffers. The skilled artisan will recognize that certain pharmaceutically acceptable excipients may provide more than one function, and provide alternative functions, depending on how many such excipients are present in the formulation and those other excipients are present in the formulation.
The formulations disclosed herein are generally formulated in a dosage form suitable for administration to a patient by a desired route. For example, dosage forms include those suitable for the following routes of administration: (1) Oral administration, such as tablets, capsules, caplets, pills, troches, powders, syrups, elixirs, suspensions, solutions, emulsions, sachets and cachets; (2) Parenteral administration, such as sterile solutions, suspensions, and reconstituted powders; (3) inhalation, such as aerosols, solutions and dry powders.
The invention will now be described with reference to specific examples, which are intended to be illustrative only and not to be limiting in any way.
EXAMPLE 1 preparation of formulations
1. Preparing single components such as eucalyptol, limonene, alpha-pinene and the like:
rectifying eucalyptus oil (crude oil) to obtain eucalyptol with content of above 80%; squeezing lemon peel of plant of Citrus of Rutaceae, distilling with steam to obtain lemon oil (crude oil), and rectifying to obtain limonene with content of above 93%; the alpha-pinene is obtained by distilling and refining oleoresin exuded from Pinus massoniana of Pinaceae with steam, and the content is more than 90%. The three single components are provided by Beijing Yuandajiu and pharmaceutical Co.
2. Preparation of a eucalyptus and limonene mixture:
the eucalyptus and limonene mixture consists of eucalyptol, limonene and alpha-pinene, and the total weight is 3kg. On the basis of the same proportion of the components, the proportion of the components in the eucalyptus and limonene mixture is tried to be changed, and the eucalyptus and limonene mixture for inhibiting influenza viruses and improving the influenza viruses is prepared, wherein the weight percentage of the components is 16% -50%. The eucalyptus and limonene mixture and the soybean oil are mixed according to a weight ratio of 3.
The preparation method of the eucalyptus and lemon pinene mixed oil comprises the following steps:
the preparation method comprises the following steps:
weighing eucalyptol, limonene and alpha-pinene according to the composition and proportion of the pharmaceutical composition, placing 1.0kg of soybean oil in a stainless steel barrel, stirring at room temperature until the mixture is completely mixed, and filtering to obtain eucalyptol and limonene mixed oil;
example 2 antiviral in vitro assay
In order to verify that the eucalyptol and pinene medicinal composition has inhibitory activity on influenza virus, the following experiments are carried out:
and (3) testing items: anti-H3N 2 influenza A virus-A/Hanfang/359/95 Activity Screen
The test principle is as follows: MDCK (dog kidney) cells are taken as virus hosts, and the degree of cytopathic effect (CPE) caused by virus inhibition of the samples is determined.
Test materials and methods:
1) Virus strain: influenza A/Hanfang/359/95 (H3N 2), culturing in chick embryo allantoic cavity for passage (2018.3), and storing at-80 deg.C.
2) Sample treatment: samples were prepared into stock solution with DMSO just before use, and then diluted 3-fold with culture medium at 8 dilutions, and each sample was tested in three groups in parallel.
3) Blank control: soybean oil (supplied by Beijing Yuanjiu & pharmaceutical Co., ltd., from Guangzhou Baiyunshan prescription modern pharmaceutical Co., ltd.).
4) The test method comprises the following steps: inoculation of MDCK cells into 96-well culture plates, setting up to 5% CO 2 And cultured at 37 ℃. Infection with influenza virus 1/3 10 after 24 hours -5 Adsorbing for 2 hr, discarding virus solution, adding maintenance solution containing samples of different dilutions and positive control drug, setting cell control well and virus control well simultaneously, 5% 2 And cultured at 37 ℃. Observing the pathological change degree (CPE) of each group of cells when the pathological change degree (CPE) of the virus control group reaches 4+, and respectively calculating the half Toxic Concentration (TC) of the sample to the cells by using a Reed-Muench method 50 ) And half maximal Inhibitory Concentration (IC) against virus 50 )。
The test results are shown in table 1.
Table 1: test results
Note:
(1) In the table "-" indicates that the sample had no anti-viral activity at the maximum non-toxic dose;
(2)TC 50 : half toxic concentration of drug; IC (integrated circuit) 50 : the median inhibitory concentration of the drug on the virus; and (6) SI: selection index, SI = TC 50 /IC 50 。
And (4) conclusion:
the eucalyptus and limonene mixed oil has certain inhibitory activity on viruses, wherein the eucalyptus and limonene mixed oil which is divided into a first group, a second group, a fourth group, a sixth group and a seventh group and has the eucalyptol proportion of 33% and 50% has stronger inhibitory activity on the viruses compared with other groups, the four groups have the best effect, and the contribution sequence of each component on the antiviral activity is as follows: eucalyptol is stronger than alpha-pinene than limonene.
TC for mixed oil of single active ingredient and eucalyptus and pinene 50 、IC 50 And SI numerical analysis shows that: under the test condition, the limonene has no anti-virus activity in the detected sample under the detected concentration; under the condition that one component of the three components, namely limonene has no anti-virus activity, compared with single active components of eucalyptol and alpha-pinene, any combination of the three components has smaller cytotoxicity and stronger anti-virus effect, which shows that the three components have more excellent drug selection property after being compounded.
Influenza virus attacks target the mucosal epithelial cells of the respiratory tract, causing degeneration, necrosis and even shedding of host cells, resulting in mucosal congestion, edema and increased secretions, resulting in nasal congestion, runny nose, sore throat, dry cough and other symptoms of upper respiratory tract infections, and when the virus spreads to the lower respiratory tract, bronchiolitis and interstitial pneumonia may result.
The virus-based animal in vivo infection experiments do not easily show clinical symptoms, and the inventor selects an experimental animal model of the clinical symptoms to perform experiments so as to explore the relieving effect of the composition on the clinical symptoms of the influenza.
Experimental example 3 phlegm reducing action of eucalyptol, limonene and pinene medicinal composition on rats
(rat capillary sputum excretion method)
1. Materials:
(1): sample preparation: the tested medicine, namely the eucalyptol and pinene medicine composition, is prepared by Beijing Yangdangjiu and pharmaceutical industry Co Ltd, 1.5kg of eucalyptol, 0.5kg of limonene, 1kg of alpha-pinene and 1.0kg of soybean oil are put into a stainless steel barrel, stirred at room temperature until the mixture is completely mixed, and filtered to obtain the eucalyptol and pinene content. After solubilizing with a little Tween-80, the mixture is prepared into 21.5mg/ml,13.5mg/ml and 105mg/ml emulsion suspension by using normal saline.
(2): the known medicine ammonium chloride is used as a positive control medicine, and is prepared into a 10% solution by normal saline after a little tween-80 is used for assisting dissolution.
(3): tool medicine: uratan, prepared into 11% solution with normal saline.
(4): animals: healthy white rats of 200 to 250g weight were provided from the animal center of the military medical academy of sciences.
(5): capillary (4-5 cm long, 0.6mm internal diameter), electronic scale, syringe, thin plastic tube, dissecting scissors, hemostatic forceps, ophthalmic forceps, surgical scissors, rat fixing plate, and cotton thread.
2. The method comprises the following steps:
selecting healthy rats, fasting for 16 hours, anesthetizing with 1.1g/kg of urethane, fixing in a supine position, flatly placing, cutting a neck skin separation trachea, pricking a small hole between two cartilages at the center of the lower edge of the thyroid cartilage by using an injection needle, inserting a glass capillary tube, inserting the glass capillary tube into the small hole, changing the capillary tube into a position just contacting the inner wall of the tube, when the capillary tube is filled with secretion liquid, taking the weight (mg) of the liquid in the capillary tube as an evaluation result (after one hour of postoperative rest, inserting the glass capillary tube, if the administration is gastric lavage, inserting a thin plastic tube into the mouth through the esophagus immediately for gastric lavage and using the tube immediately when the rats are anesthetized), collecting the tracheal secretion liquid for two hours before administration, taking the gastric lavage for one hour after rest, then collecting the secretion liquid for two hours, comparing whether the average secretion liquid amount per hour after administration is increased compared with that before administration, judging the strength of the phlegm eliminating effect of the average secretion amount per hour after administration is 170% of the average secretion amount per hour after the normal amount per hour before administration, or the highest secretion amount is 200% of the normal amount before administration, and considering that the phlegm eliminating effect is achieved. (results are shown in Table 2)
Table 2: the result of the detection
And (4) conclusion: the eucalyptus and lemon pinene medicinal composition has the function of eliminating phlegm.
Example 4 Effect of Eucalyptus Carpini pharmaceutical composition on ciliary movement
The purpose of the test is as follows: the effect of eucalyptol pinene pharmaceutical compositions and import thinning mucins on respiratory tract ciliary movement was observed and compared.
The tested medicine is as follows: the medicine is prepared by self-made by Beijing Yangdangjiu and pharmaceutical industry Co Ltd, 1.5kg of eucalyptol, 0.5kg of limonene, 1kg of alpha-pinene and 1.0kg of soybean oil are taken and put in a stainless steel barrel, stirred at room temperature until the mixture is completely mixed, and filtered to obtain the eucalyptus citrapinum content. The diluted mucins are commercially available.
Experimental animals: the ducklings have female and male bodies with the weight of 120-160 g, and are provided by the duck farm of the pharmaceutical plant institute of Chinese synergetic medical university of Chinese medical academy of sciences.
Selecting a test method: ink assay.
The test mainly comprises the following steps: the test is divided into five groups of the medicine and the diluted mucin, wherein the two groups of the medicine and the diluted mucin respectively have two doses (0.4 g/kg and 0.2 g/kg), each group has eight animals, and the animals are fasted without water prohibition before the test. Weighing, injecting Uratan (1.8 mg/kg) by ip injection, anesthetizing pentobarbital (27 mg/kg) [7], fixing animals, performing intragastric administration after stabilizing for 1 hour of exposed trachea (operation), injecting 5 μ l India ink from the upper part of trachea wall after 10 minutes in the control group, observing the moving speed of ink to head end, and measuring the moving distance (cm) of ink along 0.5, 1, 2, 5 and 10 minutes by using a stopwatch and two-foot gauges. (results are shown in Table 3)
Table 3: data and statistical processing
Compared to the blank control group: * P is less than 0.05; * P < 0.0.1; * P < 0.001
And (4) conclusion: the experiment proves that the medicine and the diluted mucin can improve the ciliary activity of the tracheal mucosa, promote the secretion of the respiratory tract glandular body, obviously increase the moving speed of mucus, and have no obvious difference compared with the medicine and the diluted mucin.
Example 5 cough test by chemical stimulation
1. Materials:
1) Sample preparation: EXAMPLE 1 four groups of the pharmaceutical preparations were solubilized with a little Tween-80, and made into a suspension of 43mg/ml, 21.5mg/ml, 10.5mg/ml with physiological saline.
2) The known drug codeine is formulated to 0.6%.
3) Tool chemical (concentrated ammonia C.P), beijing chemical plant, with NH 3 Counting: 25 to 28 percent of NH 4 OH。
4) The animals are provided by animal center of medical hospital, 20-22 g healthy Kunming male mice. Equipment:
A. medical electric suction apparatus (with medical vacuum meter).
B. 402 ultrasonic nebulizer.
C. Animal container (glass tube 4 cm in diameter and 10 cm in length).
D. A waste ammonia water container.
E. Syringes, stopwatches.
2. The operation method comprises the following steps:
before the experiment, concentrated ammonia water (25-28%) is filled into a 402 ultrasonic atomizer, 1 mouse is placed into an animal container, the ammonia water atomizer and an electric suction apparatus (a medical vacuum pump points to 0.01 Mpa) are started to enable the mouse to receive ammonia water stimulation to reach the preset time, the suction apparatus is closed, the mouse is immediately taken out, and the cough frequency within 1min is observed. If more than three typical cough actions (contraction of abdominal muscles or chest contraction, and mouth enlargement, sometimes with cough) occur within 1min, the patient is counted as "having cough", otherwise, the patient is counted as "not having cough". Setting five groups of positive medicine (codeine) and negative normal saline control group, 430mg/kg, 215mg/kg and 105mg/kg of the medicine oil, carrying out intragastric administration for 1 hour in each group, starting to receive strong ammonia aerosol stimulation, changing the time of each mouse receiving the spray according to the principle of statistically calculating half effective amount by the upper and lower methods, observing whether cough occurs or not, and recording.
A series of sprays arranged in equal ratios of 12.6s, 15.9s, 20.0s, 25.1s, 31.6s, 39.8s, 50.1s, 63.1s were set forth as followsFog time (difference between the logarithms of two adjacent times is 0.1). In the experiment, mice were sprayed at a certain spray time, and when a cough reaction occurred, the next animal was sprayed at a lower time. If, on the other hand, no cough response has occurred, the next dose is sprayed one higher. Filling the results in a pre-prepared table, where the score for a cough is "+"; and the negative indicates that the spray time does not cause cough, and the spray time ET required by half of mice to cause cough in the administration group and the control group is calculated according to a formula 50 (EDT 50 )，ET 50 = Log-1c/n. Where n is the number of animals, c is the sum of the rx values and r is the number of animals per dose group. x is the logarithm of the dose (spray time). The results show that R value is generally adopted to evaluate whether the medicine has the effect of relieving cough and the action strength, and the medicine is primarily considered to have the effect of relieving cough when the R value is more than 130 percent, and the medicine is considered to have the obvious effect of relieving cough when the R value is more than 150 percent. (results are shown in Table 4)
TABLE 4
And (4) conclusion: the medicine has cough relieving effect in three dosage groups, and the cough relieving effect is enhanced with the dosage increase.
Example 6 anti-inflammatory action of Eucalyptus Carpini pharmaceutical compositions
Swelling of mouse ear
1. Materials:
1) Sample preparation: : EXAMPLE 1 four groups of the pharmaceutical preparations were solubilized with a little Tween-80, and made into 79.4mg/ml, 61.5mg/ml, 49.2mg/ml, 34.0mg/ml of emulsion suspension with physiological saline.
2) The known drugs are: prednisone, sold by general ginseng medicine split charging factories, as a positive control drug, with the preparation method as in (1), 1.5mg/ml.
3) Tool medicine: the croton oil mixed inflammation causing agent is mixed inflammation causing liquid prepared from 0.2ml croton oil, 2ml absolute ethyl alcohol and 7.8ml diethyl ether.
4) Animals: 25-28 g of male mice were provided by the animal center of the hospital of medicine.
5) Equipment: a corneal trephine of 8mm diameter, forceps, electronic scale and syringe (1 ml, 0.25 ml).
2. The method comprises the following steps: mice fasted for 16 hours were weighed and randomly divided into six groups, four dose groups of the drug, 794mg/kg, 615mg/kg, 492mg/kg, 340mg/kg.
The known medicines are: prednisone 15mg/kg as positive control group, all administered by intragastric administration once. The blank control group was gavaged once at 10ml/kg (NS). After 1 hour of gastric administration, 0.05ml of croton oil mixed inflammation-causing liquid is coated on the front and back surfaces of the left ear of each mouse, the animals are killed after 4 hours of inflammation, the left and right ear disks of the mice are taken down by a corneal trephine and weighed, the weight of the left ear is subtracted from the weight of the right ear to obtain the swelling degree, and the administration group and a blank control group are treated. (the results are shown in Table 5)
TABLE 5
And (4) conclusion: shown in table 5: the medicament has obvious inhibition effect on the swelling of mouse ears, and the inhibition effect of the medicament is dose dependent.
3. Ip administration was performed in the same manner
The medicinal oil is 193mg/kg, 103mg/kg and 30.8mg/kg.
The positive drug, hydrocortisone, is 10mg/kg.
Blank control group, 10ml/kg physiological saline.
The five groups are all administrated ip once, and 0.05ml of croton oil mixed solution is used for causing inflammation in the left ear of each mouse after half an hour, and the following steps are all administrated with PO. (the results are shown in Table 6)
TABLE 6
And (4) conclusion: from table 6: the drug has obvious anti-inflammatory effect when being administrated in ip, and the anti-inflammatory effect of the drug is increased along with the increase of the dosage.
Comparative example 1 parainfluenza Virus resistance experiment
And (3) testing items: anti-parainfluenza virus (HPIV) activity screening.
The test principle is as follows: h1hela (human cervical carcinoma cell) cells are taken as virus hosts, and the degree of cytopathic effect (CPE) caused by the inhibition of the sample to the virus is determined.
Test materials and methods:
1. virus strain: parainfluenza virus 3 (HPIV-3) is provided by ATCC.
2. A sample to be tested: eucalyptol, limonene, alpha-pinene and four groups of example 2;
3. the sample treatment, blank and test methods were the same as in example 2.
And (4) conclusion: the four groups of formulations of example 2 tested had no inhibitory activity against parainfluenza virus (HPIV) under the same assay conditions as example 2.
The embodiment and the comparative example 1 show that the preparation is a compound synergistic preparation taking limonene, eucalyptol and alpha-pinene as active ingredients, has a good inhibition effect on influenza A viruses in orthomyxoviruses, can relieve clinical symptoms caused by subtype pathogens of influenza A viruses H3N2, is not a simple combination of limonene, eucalyptol and alpha-pinene, has no obvious inhibition activity on paramyxoviruses causing common cold, such as parainfluenza virus HPIV, and shows that the preparation formula has an important role in preparing influenza A virus medicaments by drug compounding and specifically has a significantly enhanced inhibition effect on influenza A viruses causing influenza.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.
Claims (9)
1. The application of the pharmaceutical composition in preparation of the medicine is characterized in that the medicine is used for treating or preventing influenza caused by the influenza A H3 virus, and the active ingredients of the pharmaceutical composition are eucalyptol, limonene and alpha-pinene, wherein 20 to 40 parts by mass of the eucalyptol, 10 to 40 parts by mass of the limonene and 10 to 40 parts by mass of the alpha-pinene are.
2. Use according to claim 1, characterized in that the influenza a H3 virus is selected from influenza a H3N2 viruses.
3. Use according to claim 2, wherein the influenza a H3N2 virus is selected from a/hanfang/359/95.
4. The use according to claim 2, wherein the medicament inhibits pathogen amplification.
5. The use according to claim 1, wherein the drug has a selectivity index of not less than 4.6, the selectivity index being the quotient of the half-toxic concentration of the drug to cells and the half-inhibitory concentration of the drug to viruses.
6. The use according to claim 1, characterized in that the pharmaceutical composition active ingredients are:
37 parts by mass of eucalyptol, 13 parts by mass of limonene and 25 parts by mass of alpha-pinene; or
25 parts by mass of eucalyptol, 25 parts by mass of limonene and 25 parts by mass of alpha-pinene; or
37 parts by mass of eucalyptol, 25 parts by mass of limonene and 13 parts by mass of alpha-pinene; or
25 parts by mass of eucalyptol, 13 parts by mass of limonene and 37 parts by mass of alpha-pinene; or
25 parts by mass of eucalyptol, 37 parts by mass of limonene and 13 parts by mass of alpha-pinene.
7. The use according to claim 1, wherein the pharmaceutical composition further comprises at least one pharmaceutical carrier.
8. The use according to claim 7, wherein the pharmaceutical carrier is soybean oil, and the mass ratio of the pharmaceutical composition to the soybean oil is (3 to 5): 1.
9. the use according to claim 8, wherein the mass ratio of the pharmaceutical composition to the soybean oil is 3.
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| CN1228048C (en) * | 2003-04-28 | 2005-11-23 | 浙江大学 | Medicine composition containing alpha-pinene and 1,8-eucalyptol fever-tree oil and use thereof |
| CN1660343A (en) * | 2005-01-11 | 2005-08-31 | 北京九和药业有限公司 | Combination of medication of containing eucalyptol, limonene and alpha pinene and application |
| CN101590033B (en) * | 2009-07-01 | 2012-05-09 | 北京九和药业有限公司 | Medicinal composition fat emulsion injection containing eucalyptol, limonene and alpha-pinene and preparation method |
| CN102697980B (en) * | 2012-07-09 | 2013-12-18 | 西南大学 | Composition and preparation for treating upper respiratory tract infection, as well as preparation method and application thereof |
| CN105362283B (en) * | 2014-08-07 | 2018-07-27 | 富力 | Forsythin/phillygenol composition is preparing the application in alleviating or/and treating the drug or health products of viral disease |
| CN108078975A (en) * | 2017-12-29 | 2018-05-29 | 北京九和药业有限公司 | Application of the pharmaceutical composition containing eucalyptol, limonene and australene in the drug for preparing treatment upper respiratory tract bacterium infection |
| CN110075092A (en) * | 2019-06-12 | 2019-08-02 | 颇黎芳香医药科技（上海）有限公司 | A kind of respiratory system conditioning essential oil |
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