CN112274497B

CN112274497B - Medicine for treating children bronchial asthma and preparation method thereof

Info

Publication number: CN112274497B
Application number: CN202011340736.5A
Authority: CN
Inventors: 于斌; 赵青; 曾鹏; 周洁
Original assignee: Qingdao Central Hospital
Current assignee: Qingdao Central Hospital
Priority date: 2020-11-25
Filing date: 2020-11-25
Publication date: 2022-04-15
Anticipated expiration: 2040-11-25
Also published as: CN112274497A

Abstract

The invention relates to a medicine for treating children bronchial asthma, which is characterized by containing salbutamol, budesonide and soybean lecithin. By reasonably designing the formula, the medicine for treating the infantile bronchial asthma has the advantages of good stability and uniform particle size, and the particle size distribution and the average particle size both meet the requirements of a lung inhalation preparation.

Description

Medicine for treating children bronchial asthma and preparation method thereof

Technical Field

The invention belongs to the technical field of medicinal preparations, and particularly relates to a medicament for treating children bronchial asthma and a preparation method thereof.

Background

Pediatric bronchial asthma, a heterogeneous disease characterized by chronic airway inflammation; a history of respiratory symptoms with wheezing, shortness of breath, chest tightness and coughing, with variable expiratory airflow limitation, which may vary in respiratory symptoms and intensity over time. Asthma can develop at any age, mostly starting before the age of 4-5 years. The vast majority of asthma is due to respiratory tract infections, with symptoms manifested as paroxysmal episodes of cough and wheezing, with severity at night and in the early morning. Nasal discharge, sneezing and chest distress may occur before the onset, dyspnea during the onset, prolonged expiratory phase with wheezing and wheezing. In severe cases, the patient is seated and breathed, feared, profuse sweat, cyanosis in the face, flapping of nasal wings, lips and nails, even cold sweat, and panic and restlessness in the face, which often indicates a critical state.

The earlier the asthma control treatment should be, the better. The principle of long-term, continuous, normative and individual treatment should be adhered to. The treatment comprises the following steps: acute attack stage: rapidly relieving symptoms, such as asthma and anti-inflammatory therapy; chronic duration and clinical remission: preventing exacerbation of symptoms and preventing relapse, such as avoidance of triggers, anti-inflammation, reduction of airway hyperreactivity, prevention of airway remodeling, and good self-management. The combination of the drug therapy and the non-drug therapy is emphasized, and the effects of the non-drug therapy such as asthma control education, allergen avoidance, treatment of psychological problems of children patients, improvement of life quality, pharmacogenomics and the like in the long-term management of asthma cannot be ignored.

β₂Receptor agonists are currently the most widely used bronchodilators in clinical applications. The medicine is divided into two categories of quick-acting and slow-acting according to the acting speed, and is divided into two categories of short-acting and long-acting according to the duration of the maintenance time. Inhalation type quick-acting beta₂The curative effect of the receptor stimulant can be maintained for 4-6 hours, the receptor stimulant is the first choice medicine for relieving the acute symptoms of asthma, the receptor stimulant can be inhaled 1 time every 20 minutes in the 1 hour of severe asthma attack, and can be inhaled repeatedly every 2-4 hours later. Salbutamol is a short-acting beta₂An adrenergic receptor agonist is used as antiasthmatic, and can effectively inhibit the release of allergic substances such as histamine and prevent bronchospasm. Is suitable for treating bronchial asthma, asthmatic bronchitis, bronchospasm, emphysema, etc. As a β 2 adrenergic receptor agonist, salbutamol has been used in acute hyperkalemia which stimulates potassium influx into cells, thereby reducing potassium in the blood, but due to this effect, it is stated in British national formulary that high doses or prolonged use may lead to hypokalemia, particularly in some patients with renal failure. In addition, salbutamol is dissolved in water, the solubility of the salbutamol in 1mol/l hydrochloric acid solution is 50mg/ml, and when the salbutamol is inhaled to administer the drug, part of the drug enters the stomach, so that the local concentration is too high, and side effects are caused. The combination of salbutamol with a carrier, or other active drug, effectively reduces this toxic side effect.

Inhaled glucocorticosteroids (ICS) are the first choice of drugs for long-term control of asthma and also the most effective anti-inflammatory drugs at present, and have the advantages that the drugs directly act on airway mucosa through inhalation, the local anti-inflammatory effect is strong, and the systemic adverse reactions are few. The long-term and standard inhalation is usually required to be 1-3 years for the prevention effect. Currently, commonly used inhaled glucocorticoids in clinic include budesonide, fluticasone propionate and beclomethasone dipropionate.

Budesonide is a glucocorticoid with highly effective local anti-inflammatory action, which can enhance the stability of endothelial cells, smooth muscle cells and lysosome membranes, inhibit immune reaction and reduce antibody synthesis, thereby reducing the release and activity of allergic active mediators such as histamine, etc., relieving the enzymatic process triggered by antigen-antibody binding, inhibiting the synthesis and release of bronchoconstrictor substances and relieving the contraction reaction of smooth muscle. Is clinically used for patients with glucocorticoid dependent or independent bronchial asthma and asthmatic chronic bronchitis.

The active drugs salbutamol and the insoluble corticosteroid budesonide have been reported to be combined clinically for treating chronic obstructive pulmonary diseases such as bronchitis, bronchial asthma and the like. However, budesonide has a technical problem of poor solubility, and combining the budesonide and the budesonide to prepare an inhalant has technical problems of non-uniform powder particle size and easy caking of the powder during storage.

Disclosure of Invention

The invention aims to provide a medicament for treating the bronchial asthma of children, which has good stability and uniform particle size, meets the requirement of a lung inhalation preparation, and can improve the solubility of budesonide. Specifically, in order to achieve the purpose of the present invention, the following technical solutions are proposed:

the invention relates to a medicine for treating children bronchial asthma, which is characterized by containing salbutamol, budesonide and soybean lecithin. The soybean lecithin is added, so that the solubility of the budesonide is improved, the average particle size of the medicine is reduced, and the particle size distribution uniformity is improved.

In a preferred embodiment of the invention, the ratio of salbutamol: budesonide: the molar ratio of the soybean lecithin is 1-5: 0.1 to 0.5.

In a preferred embodiment of the present invention, the medicament further comprises polylactic acid. The invention improves the stability of the medicament while reducing the average grain diameter of the medicament through the synergistic action of the polylactic acid and the soybean lecithin.

In a preferred embodiment of the invention, the ratio of salbutamol: the molar ratio of the polylactic acid is 1-5: 0.5-1.

In a preferred embodiment of the invention, the medicament is an inhalant.

In another preferred embodiment of the present invention, the average particle size of the drug is 3 to 4 μm; preferably, more than 80% of the particles in the medicament have a particle size between 3 and 4 μm.

In another preferred embodiment of the present invention, the drug substance has a mean particle size change of not more than 3% when stored at room temperature for one month; preferably not more than 2.5%.

The invention also relates to a preparation method of the medicine, which is characterized by comprising the following steps: the components with the formula amount are dissolved in ethanol water solution, stirred and ultrasonically treated, and then spray drying is carried out to obtain the medicine.

The invention also relates to application of the medicine in preparing a medicine for treating the infantile bronchial asthma.

Advantageous effects

By reasonably designing the formula, the medicine for treating the infantile bronchial asthma has the advantages of good stability and uniform particle size, and the particle size distribution and the average particle size both meet the requirements of a lung inhalation preparation.

Drawings

FIG. 1 is a graph showing the particle size distribution of the drug substance prepared in example 1.

Fig. 2 is a graph showing the particle size distribution of the drug substance prepared in example 2.

Fig. 3 is a graph showing the particle size distribution of the drug substance prepared in example 3.

FIG. 4 is a graph showing the particle size distribution of the drug prepared in comparative example 1.

Detailed Description

In order to further understand the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

Unless otherwise specified, the reagents involved in the examples of the present invention are all commercially available products, and all of them are commercially available.

Example 1:

adding salbutamol: budesonide: polylactic acid: soybean lecithin was added at a ratio of 1: 1: dissolving the mixture in 90% ethanol water solution in a molar ratio of 0.5:0.1, stirring for 1 hour, performing ultrasonic treatment at 40KHz and 40 ℃ for 1 hour, and performing spray drying under the following spray conditions: drying gas: nitrogen, suction rate: 100%, inlet temperature of 60-90 ℃, outlet temperature: 40-50 ℃, cooling temperature: -17 ℃, feed rate: 5% -12% (1.5ml/min-3.6 ml.min).

Example 2:

adding salbutamol: budesonide: polylactic acid: soybean lecithin was added at a ratio of 2: 1: dissolving the mixture in 90% ethanol water solution in a molar ratio of 0.5:0.1, stirring for 1 hour, performing ultrasonic treatment at 40KHz and 40 ℃ for 1 hour, and performing spray drying under the following spray conditions: drying gas: nitrogen, suction rate: 100%, inlet temperature of 60-90 ℃, outlet temperature: 40-50 ℃, cooling temperature: -17 ℃, feed rate: 5% -12% (1.5ml/min-3.6 ml.min).

Example 3:

adding salbutamol: budesonide: soybean lecithin was added at a ratio of 1: 1: dissolving 0.1 mol ratio in 90% ethanol water solution, stirring for 1 hr, performing ultrasonic treatment at 40KHz and 40 deg.C for 1 hr, and spray drying under the following conditions: drying gas: nitrogen, suction rate: 100%, inlet temperature of 60-90 ℃, outlet temperature: 40-50 ℃, cooling temperature: -17 ℃, feed rate: 5% -12% (1.5ml/min-3.6 ml.min).

Comparative example 1:

adding salbutamol: budesonide: the polylactic acid is prepared from 1: 1: dissolving 0.5 mol ratio in 90% ethanol water solution, stirring for 1 hr, performing ultrasonic treatment at 40KHz and 40 deg.C for 1 hr, and spray drying under the following conditions: drying gas: nitrogen, suction rate: 100%, inlet temperature of 60-90 ℃, outlet temperature: 40-50 ℃, cooling temperature: -17 ℃, feed rate: 5% -12% (1.5ml/min-3.6 ml.min).

The drug prepared in the above example was subjected to particle size distribution test using a malvern laser particle sizer (Mastersizer3000 Aero-S), light-shielding rate: 0.5% -5%, sample introduction speed: 75% -80%, air pressure: 3.5bar-4bar, the test results are shown in FIGS. 1-4. As can be seen from FIGS. 1-4, the particle size distribution of examples 1-3 is relatively uniform (especially the uniformity of the particle size distribution of the drug of example 3 is the best), and the most frequent particle size is about 3 μm, which satisfies the requirement of inhalant for particle size, while the particle size distribution of comparative example 1 is relatively wide, and the most frequent particle size exceeds 5 μm, which is not suitable for the requirement of children's bronchus patients for inhalant.

The above drugs were charged into a closed container, stored at room temperature for one month, and the average particle size was again measured, and the results are shown in table 1.

From the above experimental results, the addition of polylactic acid helps to maintain the stability of the particle size, and the addition of lecithin helps to reduce the particle size, so that it meets the requirements of the inhalant for the particle size. The synergistic effect of polylactic acid and lecithin is preferred because it helps to maintain particle size stability at lower particle sizes.

The pharmaceutical preparations prepared in examples 1-3 and comparative example 1 were left for 12 months at a temperature of 25. + -.2 ℃ and a relative humidity of 60. + -.10%, and sampled for 3, 6, 9 and 12 months, respectively, to determine the contents of albuterol and budesonide in relation to the initial formulation, and the results are shown in Table 2.

Based on the experiments, the main drug salbutamol in the preparation has better stability, particularly, the preparation containing polylactic acid can effectively improve the stability of the salbutamol, and the preparation containing soybean lecithin can effectively improve the stability of budesonide.

The foregoing describes preferred embodiments of the present invention, but is not intended to limit the invention thereto. Modifications and variations of the embodiments disclosed herein may be made by those skilled in the art without departing from the scope and spirit of the invention.

Claims

1. A medicament for treating infantile bronchial asthma is characterized by comprising salbutamol, budesonide and soybean lecithin; the ratio of salbutamol in the medicine is: budesonide: the molar ratio of the soybean lecithin is 1-5: 0.1 to 0.5; the medicament also comprises polylactic acid; the ratio of salbutamol in the medicine is: the molar ratio of the polylactic acid is 1-5: 0.5-1; the medicine is prepared by a preparation method comprising the following steps: the components with the formula amount are dissolved in ethanol water solution, stirred and ultrasonically treated, and then spray drying is carried out to obtain the medicine.

2. The medicament of claim 1, wherein the medicament is an inhalant.

3. The drug substance according to claim 2, wherein the average particle size of the drug substance is 3 to 4 μm.

4. The medicament of claim 3, which has a mean particle size change of no more than 3% when stored at room temperature for one month.

5. The medicament of claim 3, which has a mean particle size change of no more than 2.5% when stored at room temperature for one month.

6. A process for the preparation of a medicament according to any one of claims 1 to 5, characterized in that it comprises the following steps: the components with the formula amount are dissolved in ethanol water solution, stirred and ultrasonically treated, and then spray drying is carried out to obtain the medicine.

7. Use of a medicament according to any one of claims 1 to 5 in the manufacture of a medicament for the treatment of childhood bronchial asthma.