CN115068549B

CN115068549B - Atomized product for treating acute bronchitis cough of children and preparation method thereof

Info

Publication number: CN115068549B
Application number: CN202210948081.2A
Authority: CN
Inventors: 晁恩祥; 晁燕; 张朝鸥
Original assignee: Beijing Oriental Fortune Technology Development Co ltd
Current assignee: Beijing Dongfang Yunjia Pharmaceutical Co ltd
Priority date: 2022-08-09
Filing date: 2022-08-09
Publication date: 2023-06-20
Anticipated expiration: 2042-08-09
Also published as: CN115068549A

Abstract

The invention relates to a new formulation product for treating acute bronchitis cough in children and a preparation method thereof. The product is prepared from radix Scutellariae, rhizoma Fagopyri Dibotryis, folium Eriobotryae, bulbus Fritillariae Thunbergii, rhizoma Polygoni Cuspidati and radix Glycyrrhrizae as raw materials, has excellent cough relieving performance, quick action, safety, no irritation, and is suitable for children.

Description

Atomized product for treating acute bronchitis cough of children and preparation method thereof

Technical Field

The invention relates to the field of traditional Chinese medicines, in particular to an atomized product for treating children acute bronchitis cough.

Background

Acute bronchitis in children is a common respiratory disease of children, often secondary to upper respiratory tract infection or early manifestation of pneumonia, and also an early symptom or complication of acute infectious diseases in children such as measles, pertussis, typhoid fever, scarlet fever, etc. The children suffering from acute bronchitis often have long cough time, and the activities of catching cold, inhaling cold air or stimulating gas, running and jumping and the like can aggravate or induce the cough; cough is also often more pronounced in the morning or at night. Nausea, vomiting and chest and abdomen muscle pains can be caused when the cough is severe, for example, bronchospasm can be caused, wheezing, shortness of breath and other symptoms can also occur, and the infants are greatly injured in mind and body.

The inventor of the application provides a pharmaceutical composition for treating the cough-relieving symptoms caused by the heat-phlegm-resistance of the lung and lung failure of dispersing and descending of the lung of children for many years, and the pharmaceutical composition is used for treating the cough caused by the acute bronchitis of children. When the decoction is taken with difficulty, the decoction is prepared into a soft capsule dosage form, so that the oral administration of children is facilitated, but in the practical process, the situation that part of infants still have dysphagia or conflict with swallowing for oral administration medicines is found, so that the efficacy is difficult to realize.

The western medicine can reduce the cough degree by adopting the mode of ultrasonic atomization and inhalation of medicines such as budesonide, salbutamol, terbutaline and the like when treating the pediatric acute bronchitis and adopting the methods of diluting sputum and dilating trachea, the administration mode has quick effect, no foreign body sensation and higher acceptance for infants; however, the medicines are not suitable for single use for a long time, are easy to cause medicine dependence, and have adverse reactions such as dry mouth, palpitation, hypokalemia and the like. Therefore, the inventor actively explores, when considering the adjustment of the administration mode, the advantage of atomization administration is intended to be utilized, and the existing pediatric gold soft capsule product is adjusted to be an atomization product, so that a new variety is added to the children cough relieving administration, and the application is proposed.

Disclosure of Invention

The invention provides an atomized product for treating children acute bronchitis cough and a preparation method thereof.

The atomized product for treating the children acute bronchitis cough comprises the following raw material medicaments:

4-18 parts of radix scutellariae, 4-16 parts of wild buckwheat, 4-16 parts of loquat leaves (stir-baked with honey), 3-12 parts of fritillary bulb, 3-12 parts of giant knotweed and 1-6 parts of liquorice.

Preferably, the bulk drugs are: 9 parts of baical skullcap root, 8 parts of wild buckwheat rhizome, 8 parts of loquat leaf (stir-baked with honey), 6 parts of thunberg fritillary bulb, 6 parts of giant knotweed rhizome and 3 parts of liquoric root.

The preparation method of the atomized product comprises the following steps:

(1) Collecting radix Scutellariae, rhizoma Fagopyri Dibotryis, folium Eriobotryae, bulbus Fritillariae Thunbergii and radix Glycyrrhrizae, collecting the primary distillate by steam distillation, adding distilled water and small amount of glycerol into the distillate, redistilling, collecting the distillate, and storing the residue;

(2) Mixing rhizoma Polygoni Cuspidati with the above residues, soaking in water, filtering decoction, mixing filtrates, centrifuging, collecting supernatant, and concentrating to relative density of 1.30-1.32 (80deg.C) to obtain extract;

(3) Precipitating the extract with ethanol for three times, adding ethanol to make ethanol content in the solution reach 30%, 75% and 50%, standing for 12 hr each time, concentrating under reduced pressure, filtering, adding the above distillate, stirring, adding active carbon at a ratio of 2g/100ml, heating in water bath for 1 hr, cooling, collecting supernatant, recovering ethanol until no ethanol smell, concentrating to half volume, centrifuging at high speed, filtering, and ultrafiltering to 2-5 um.

Specifically, in the step (1), the amount of glycerol is 1-3% of the volume of the primary distillation liquid, the amount of distilled water added is 30-50% of the volume of the primary distillation liquid, and the distillation liquid with the volume of 30-50% of the volume of the primary distillation liquid is collected after double distillation. Preferably, distilled water accounting for 30% of the volume of the primary distillation liquid and glycerol accounting for 2% of the volume of the primary distillation liquid are added into the distillation liquid.

Specifically, in the step (3), the amount of activated carbon added is 1-2g/100ml of the liquid volume.

The atomized product of the invention is based on the existing pediatric gold product, and the effective components are concentrated by the efficient and simple extraction and refining technology, so that the impurities are removed, the large particle impurities easily appearing in the atomized product of the traditional Chinese medicine are well eliminated, the compliance of the pediatric patient is greatly improved on the basis of keeping the excellent cough relieving effect of the product, and the atomized product has excellent cough relieving effect on pediatric acute bronchitis cough, and has quick effect and high safety.

Detailed Description

The atomized product needs to be changed into small particles by an ultrasonic atomizer or an air compression atomizing pump, and the small particles are output in the form of aerosol and act with the respiratory airflow entering the respiratory tract. The traditional Chinese medicine atomization inhalation therapy is also similar, and the traditional Chinese medicine liquid is changed into tiny fog particles or fog drops through an atomization device and is suspended in inhaled gas, so that the airway is humidified, the traditional Chinese medicine liquid enters the respiratory tract, and the respiratory tract mucosa is reached, and the medicine effect is exerted.

The current practice finds that if the traditional Chinese medicine decoction, oral liquid or even the traditional Chinese medicine injection is directly used as an atomized product, the effect cannot be well exerted, for a plurality of reasons. For example, the purity factor is that the water decoction and the oral liquid are mostly clear liquid, but the purity requirement is higher for the atomized medicine, if the atomized agent contains large-particle impurities, the patient can inhale and choking cough, pulmonary discomfort and other symptoms, if the fog drops are too small and too light, the fog drops are difficult to attach to the airway along with the movement of the airflow of the exhales, and the atomized product needs to be developed specifically; component factors, because of high concentration of aerosol inhalation local medicine, if the product contains some components which can induce asthma attack by inhalation, there is a great risk that preservatives such as nitrite and the like possibly contained in injection, and the aerosol product needs to be developed specifically, and the safety of the aerosol product is especially confirmed; the concentration factor, aerosol inhalation does not need to pass through the gastrointestinal tract to directly reach focus, has quick effect and direct action, and needs to determine proper concentration to play an excellent effect under the condition of ensuring safety.

Therefore, the team of the present inventors has made various researches and efforts to propose the technical solution of the present invention, and through experiments, the safety and effectiveness of the product of the present invention have been confirmed. Because of the many factors that need to be considered, and the repetition of the screening process, only a portion of the experimental results are provided below to confirm the effectiveness of the present protocol.

1. Early test

The Chinese medicinal decoction is the most common product form, the formula of the invention is also prepared into soft capsules in the prior method, and the Chinese medicinal decoction of the formula of the invention can be obtained by dissolving the extract form of the Chinese medicinal decoction in distilled water and then filtering the extract form. However, when the above-mentioned Chinese medicinal liquid was administered to acute bronchitis model mice, it was found that although cough state of most of the atomized administration mice can be significantly reduced in a short time as compared with that of the gavage mice, the ratio of adverse reactions such as apparent choking, craving and the like of the atomized mice is higher than that of the gavage mice, and the administration is stopped due to the blockage of the atomizer by large particles in the middle course, indicating that the conversion of the existing aqueous extract product into an atomized product is advantageous for cough symptoms of acute bronchitis, but the problems of operability, safety and tolerance of the preparation still need to be considered, and a preparation and purification method suitable for the atomized product needs to be proposed.

2. Determination of the method

1. Safety test

1.1 test article

Sample 1 is the preparation method of the atomized liquid: taking medicinal materials except giant knotweed according to the proportion, collecting a primary distillate by a steam distillation method, adding distilled water accounting for 30% of the volume of the primary distillate and glycerol accounting for 2% of the volume of the primary distillate into the distillate, redistilling, collecting the distillate for later use, and storing dregs; mixing rhizoma Polygoni Cuspidati with the above residues, soaking in water, filtering decoction, mixing filtrates, centrifuging, collecting supernatant, and concentrating to relative density of 1.30-1.32 (80deg.C) to obtain extract; precipitating the extract with ethanol for three times, adding ethanol to make ethanol content in the solution reach 30%, 75% and 50%, standing for 12 hr each time, concentrating under reduced pressure, filtering, adding the above distillate, stirring, adding active carbon at a ratio of 2g/100ml, heating in water bath for 1 hr, cooling, collecting supernatant, recovering ethanol until no ethanol smell, concentrating to half volume, centrifuging at high speed, filtering, and ultrafiltering to 2-5um to obtain sample 1.

Sample 2 preparation method: mixing all the materials, soaking in water, decocting for three times, filtering decoction, mixing filtrates, centrifuging, collecting supernatant, and concentrating to relative density of 1.30-1.32 (80deg.C) to obtain extract; precipitating the extract with ethanol for three times, adding ethanol to make ethanol content in the solution reach 30%, 75% and 50%, standing for 12 hr each time, concentrating under reduced pressure, filtering, adding the above distillate, stirring, adding active carbon at a ratio of 2g/100ml, heating in water bath for 1 hr, cooling, collecting supernatant, recovering ethanol until no ethanol smell, concentrating to half volume, centrifuging at high speed, filtering, and ultrafiltering to 2-5um to obtain sample 2.

Preparation method of sample 3 was prepared by the steps of the method other than steam distillation of all the medicinal materials, such as sample 1.

Preparation method of sample 4 was prepared by the other method steps like sample 1 except that all the medicinal materials were subjected to steam distillation and no glycerol was added in the double distillation step.

Preparation of sample 5 was prepared by other method steps, such as sample 1, except that no glycerol was added in the double distillation step.

Preparation method of sample 6 was prepared by other method steps such as sample 1 except that polyethylene glycol 200 was added instead of glycerol in the double distillation step.

Preparation method of sample 7-9 except that the range of the medicinal materials distilled by steam is determined as that of all medicinal materials except for radix Scutellariae, all medicinal materials except for folium Eriobotryae, all medicinal materials except for rhizoma Fagopyri Dibotryis, and the excluded medicinal materials and the residue are combined and decocted, other method steps are as sample 1, and sample 7-9 is prepared.

1.2 vehicle: laboratory animal drinking water (laboratory self-made distilled water).

1.3 preparation method of administration preparation

The samples were taken separately, diluted 10-fold with distilled water, and prepared on the day of administration, as it is.

1.4 test subjects

Variety strain: SD rats.

Sex and number of mice: 100 male and female halves are combined.

Age of mice: 21 days of age at the time of the infusion, and 22 days of age at the time of the administration (corresponding to 3-year-old children).

Body weight of mice: 44-60 g of male mice and 44-57 g of female mice when the mice are transferred.

1.5 test method: the experiment is divided into 10 groups, a solvent control group and 1-9 groups, 100 SD rats with the age of 22 days are used, each group of male and female rats is half, the administration is carried out by atomizing at a dose equivalent to 50g/kg of crude drug for 2 times a day, the administration volume is 20 ml/kg/time, each time interval is 4 hours, feed is added after 1-2 hours after the 2 nd administration, and the observation period is 14 days. Observing animal appearance, behavior, secretion, excretion, etc.; recording animal toxic response conditions including toxic symptoms, toxic occurrence time, duration, recovery time and animal death time; weighing before and after D0 administration, D1, D4, D7, D10 and D14 respectively; all animals were dissected and observed for changes in volume, color, texture, etc. in the major viscera.

1.6 evaluation of results: and at the end of the test, the animal does not die, internal organs are not abnormal after the animal is killed and dissected, the animal moves normally and the weight is increased normally during the test, and the administration sample is considered to pass the acute toxicity test, so that the safety requirement is met. If death or other abnormality occurs, it is undesirable.

1.7 test results: under the test condition, the administration of one rat in the sample 4 group shows obvious choking cough, the individual rats in the sample 3 group show dysphoria, reduced drinking water, occasional asthma, slightly fluffy hair and no abnormality in main organs of autopsy. The remaining groups of rats had normal activity, normal weight gain and no abnormality in internal organs after dissection during the test period.

1.8 discussion: after determining the administration mode, the inventor performs acute toxicity tests on the administration of products prepared by various methods through the atomization route because the atomization administration mode has higher requirements on the safety of the medicament compared with oral administration. The above test results are not the initial test process, and in the whole research process, the safety is not problematic but the efficacy test is not ideal, the efficacy test is good but the results are simultaneously expressed with appetite change and the like, so the above test results are recorded for showing the safety condition between the product of the invention and the products of other methods. The safety test shows that the administration of part of volatile oil components of the medicinal material in an atomization mode has a certain hidden trouble for the low-age animals, and care needs to be taken.

2. Test of efficacy

2.1 test study of cough relieving and phlegm eliminating effects

2.1.1 animals: CD mice, SPF animals, 16-18 g, 120 animals, male and female animals, 21 days old when transferred, 22 days old when dosed.

2.1.2 test methods

The test was divided into 12 groups, blank group, vehicle control group, samples 1-9 groups and soft capsule product group, and 120 CD mice were used, 10 male and female mice each, and the weights were randomly divided. The soft capsule product group is infused with the stomach to be given with the tested sample according to the ratio of 4.5g/kg twice a day; the other groups were each given by nebulization, 1 time per day, samples 1 to 9 groups were each diluted 5-fold with distilled water, and the vehicle control group was given by nebulization in the same manner for 3 consecutive days with a nebulization of 0.2ml per minute. After 1 hour of the last administration, the mice were placed in a sealed bell jar (5000 ml), and 20ml SO was injected ₂ And (3) gas. Immediately, the time for stimulation was 3 minutes, and the time for the mice to start cough was counted as cough latency. The mice were removed and placed in a beaker for continued observation for 20 minutes and the cough count of the mice was recorded for 0-10, 10-20 minutes. The mean and SD are calculated for each group, SPSS10.0 for windows is used for data statistical analysis, the values are expressed by X+ -SD, ANOVA analysis is adopted for comparison among groups, LSD is adopted for variance alignment, dunnetcs T3 is adopted for variance alignment, and P < 0.05 is the difference with statistical significance.

2.1.3 test results are shown in the following table.

Note that: * Represents P < 0.05,0.01 compared to model group

2.1.4 analysis of results

The administration group can obviously reduce SO ₂ The times of cough of mice are caused, the incubation period of the cough is prolonged, and compared with a blank group and a solvent control group, the mice have obvious difference, and the sample groups are indicated to have the effects of preventing cough and relieving cough. The effects of the samples 1, 3 and 4 are better than those of other samples, and are slightly better than those of oral administration groups, so that the effect of the product can be improved effectively by adding a steam distillation step to enrich the effective components; however, considering that young mice are sensitive to medicines, the product obtained by the extraction mode of the sample 1 group is more suitable for the young mice by combining acute toxicity test results.

2.2 dosing test

2.2.1 animals: CD mice, SPF animals, 16-18 g, 70 animals, male and female animals, 21 days old when transferred, 22 days old when dosed.

2.2.2 test methods

Mice were randomly divided into 5 groups of 14 mice each. Model group, example 1 product group (high dose group), example 1 product diluted 5-fold (medium dose group) and 10-fold diluted (small dose group), budesonide suspension 1mg (2 ml) group (positive group); all are administrated by an atomization mode, the mist output is 0.2ml every minute, the administration is carried out for 10 minutes, and the administration is carried out once a day for three days continuously. After 1 hour of the last administration, the mice were placed in a sealed bell jar (5000 ml), and 20ml SO was injected ₂ And (3) gas. Immediately, the time for stimulation was 3 minutes, and the time for the mice to start cough was counted as cough latency. The mice were removed and placed in a beaker for continued observation for 20 minutes and the cough count of the mice was recorded for 0-10, 10-20 minutes. Each group calculates mean, SD, and data statistics analysis was performed using SPSS10.0 for windows.

2.1.3 test results are shown in the following table.

Note that: * Represents P < 0.05,0.01 compared to model group

2.1.4 analysis of results

The large dosage group of the medicine can obtain the effect very similar to that of the positive group, and can obviously reduce the times of cough, which indicates that the medicine has obvious cough relieving effect. The product also has good cough relieving effect in the medium and low dosage groups, and has little influence on the effect even if the atomization is stopped in a short time or terminated in advance in the atomization process.

3. Clinical trial

3.1 test method: 100 cases were included according to the following case inclusion criteria, and were randomized into treatment and control groups (50 cases per group) for nebulized administration. The treatment group was administered with the product prepared in example 1, diluted 5 times, and nebulized for 10 minutes at a dose of 0.5 ml/min, and nebulized for 1 branch (2 ml) of budesonide was administered once daily, and the control group was administered with physiological saline at a dose of 0.5 ml/min, nebulized for 10 minutes at a dose of once daily for 5 days as a treatment course.

3.2 case inclusion criteria

Diagnostic criteria: meets the therapeutic effect standard of pediatric disease diagnosis, and is used for diagnosing acute bronchitis cough and combining clinical determination.

Inclusion criteria: meets the above diagnostic criteria, and the course of disease is 2-10 days. Excluding those under 1 year and over 14 years of age; there are serious complications or convalescence cases; patients with severe malnutrition or serious systemic diseases accompanied with cardiovascular, liver, kidney, hematopoietic system, etc. and allergic patients to the present medicine.

3.3 therapeutic efficacy criterion

And (3) healing: the clinical symptoms such as cough with excessive phlegm disappear, if fever occurs, the body temperature is recovered to be normal, the tongue pulse condition is recovered to be normal, and the blood routine review is recovered to be normal.

The effect is shown: the clinical symptoms such as cough with excessive phlegm are basically disappeared, if fever occurs, the body temperature is basically recovered to be normal, the tongue pulse is basically normal, and the routine blood review is obviously improved.

The method is effective: the clinical symptoms such as cough with excessive phlegm are relieved, the body temperature is reduced if fever occurs, the tongue pulse is good, and the blood routine review is good.

Invalidation: the clinical symptoms such as cough and excessive phlegm, body temperature, tongue pulse condition and blood routine re-examination are not improved or aggravated.

3.4 the results are given in the following table.

Group of

Healing of the wound

Has obvious effect

Effective and effective

Invalidation of

Cure rate

Display efficiency

Total effective rate

Treatment group

28

19

3

0

56％

94％

100％

Control group

22

24

1

3

44％

92％

94％

The clinical application results show that after one treatment course, the product can obviously improve the clinical main symptoms of cough, excessive phlegm and the like of children patients, greatly improve the daily life quality of diet, exercise and the like of infants, and the effect basically reaches and exceeds the effect of the western medicine budesonide. The control group makes ineffective judgment by interrupting the treatment in the middle of the reaction of individual patients to the drug such as rash, crying and the like. Therefore, the product of the invention has good treatment effect on acute bronchitis cough of children, and is easy to accept by children in the process of drug administration, and is worth popularizing as another optional dosage form product.

Examples

The present invention is further illustrated by the following examples, but the contents of which are not limiting.

Example 1

Taking 900g of radix scutellariae, 800g of wild buckwheat rhizome, 800g of loquat leaf (stir-baked with honey), 600g of fritillary bulb, 600g of giant knotweed and 300g of liquorice. Collecting the first distillate except rhizoma Polygoni Cuspidati by steam distillation, adding distilled water 30% of the first distillate and glycerol 2% of the first distillate, redistilling, collecting the distillate, and storing residues; mixing rhizoma Polygoni Cuspidati with the above residues, soaking in water, filtering decoction, mixing filtrates, centrifuging, collecting supernatant, and concentrating to relative density of 1.30-1.32 (80deg.C) to obtain extract; precipitating the extract with ethanol for three times, adding ethanol to make ethanol content in the solution reach 30%, 75% and 50%, standing for 12 hr each time, concentrating under reduced pressure, filtering, adding the above distillate, stirring, adding active carbon at a ratio of 2g/100ml, heating in water bath for 1 hr, cooling, collecting supernatant, recovering ethanol until no ethanol smell, concentrating to half volume, centrifuging at high speed, filtering, and ultrafiltering to 2-5 um.

Claims

1. An atomized product for treating children acute bronchitis cough, wherein the atomized product comprises the following raw materials:

4-18 parts of radix scutellariae, 4-16 parts of wild buckwheat rhizome, 4-16 parts of honey-fried loquat leaf, 3-12 parts of fritillary bulb, 3-12 parts of giant knotweed and 1-6 parts of liquorice;

the atomized product is prepared by the following preparation method:

(1) Collecting radix Scutellariae, rhizoma Fagopyri Dibotryis, folium Eriobotryae, bulbus Fritillariae Thunbergii and radix Glycyrrhrizae, collecting the primary distillate by steam distillation, adding distilled water and small amount of glycerol into the distillate, redistilling, collecting the distillate, and storing the residue; the glycerol accounts for 1-3% of the volume of the primary distilled liquid, distilled water accounts for 30-50% of the volume of the primary distilled liquid, and distilled liquid accounting for 30-50% of the volume of the primary distilled liquid is collected after double distillation;

(2) Mixing rhizoma Polygoni Cuspidati with the above residues, soaking in water, filtering decoction, mixing filtrates, centrifuging, collecting supernatant, concentrating to 80deg.C, and measuring relative density to 1.30-1.32 to obtain extract;

(3) Precipitating the extract with ethanol for three times, adding ethanol to make ethanol content in the solution reach 30%, 75% and 50%, standing for 12 hr each time, concentrating under reduced pressure, filtering, adding the above distillate, stirring, adding active carbon at a ratio of 2g/100mL, heating in water bath for 1 hr, cooling, collecting supernatant, recovering ethanol until no ethanol smell, concentrating to half volume, centrifuging at high speed, filtering, and ultrafiltering to 2-5 μm.

2. The atomized product of claim 1 wherein the drug substance is: 9 parts of radix scutellariae, 8 parts of wild buckwheat rhizome, 8 parts of honey-fried loquat leaf, 6 parts of fritillary bulb, 6 parts of giant knotweed and 3 parts of liquorice.

3. The atomized product of claim 1 wherein in step (1), distilled water in an amount of 30% of the volume of the primary distillation liquid and glycerol in an amount of 2% of the volume of the primary distillation liquid are added to the distillation liquid.

4. The atomized product of claim 1 wherein in step (3) the activated carbon is added in an amount of 1-2g/100mL of liquid volume.