CN105456201B - The preparation method of ambroxol salbutamol pellet - Google Patents

Abstract

This invention relates to ambroxol and salbutamol microcapsules, belonging to the field of pharmaceutical preparations. The microcapsules of this invention, with appropriate amounts of poloxamer 188, meglumine, and mannitol, can significantly improve the stability and bioavailability of ambroxol hydrochloride and salbutamol sulfate in the preparation, resulting in stable quality and significant efficacy, effectively treating respiratory diseases such as acute and chronic bronchitis and asthma.

Description

The preparation method of ambroxol albuterol pellets

technical field

The invention relates to the field of pharmaceutical preparations, in particular to ambroxoxalbutamol pellets and a preparation method thereof.

Background technique

Respiratory system disease is a common and frequently-occurring disease. The main lesions are in the trachea, bronchi, lungs, and chest cavity. Mild cases often cause coughing, chest pain, and respiratory problems. Severe cases have dyspnea, hypoxia, and even death due to respiratory failure. The death rate in the city is the third, while in the countryside it is the first. What should be paid more attention to is that due to air pollution, smoking, population aging and other factors, chronic obstructive pulmonary disease (referred to as COPD, including chronic bronchitis, emphysema, pulmonary heart disease), bronchial asthma, lung cancer, etc. , Pulmonary diffuse interstitial fibrosis, and the morbidity and mortality of diseases such as pulmonary infection are increasing.

According to the statistics of the top ten major causes of death in some cities and rural areas of the country in 2006, respiratory diseases (excluding lung cancer) accounted for the fourth (13.1%) of the causes of death in cities and the third (16.4%) in rural areas. %). Due to factors such as air pollution, smoking, the inhalation of physical and chemical factors and biological factors caused by the development of industrial economy, and the aging of the population, the incidence of respiratory diseases such as lung cancer and bronchial asthma has increased significantly in recent years, and chronic obstructive pulmonary disease has remained high. (more than 8% of those over 40). Although the incidence of tuberculosis has been controlled to some extent, it has been on the rise again in recent years. Pulmonary thromboembolism already constitutes a significant healthcare problem, and pulmonary hypertension has received increasing attention in recent years. The incidence of diseases such as pulmonary diffuse interstitial fibrosis and immunocompromised pulmonary infection is increasing day by day. The leading cause of death in AIDS is lung infection, especially Pneumocystis carinii pneumonia. Since the end of 2002, the infectious atypical pneumonia (severe acute respiratory syndrome, SARS) epidemic that broke out in my country and the world, because it mostly occurred in young and middle-aged people, it is highly contagious, has a high fatality rate, and lacks targeted measures. Drugs have thus caused panic among the masses and at the same time caused huge losses to the national economy. The fatality rate of human avian influenza in many countries exceeds 60%. The main target organ of the avian influenza virus invading the human body is also the lung. This just shows that respiratory diseases are still very harmful to the health of our people, and the task of prevention and treatment is arduous.

Ambroxol Hydrochloride (Ambroxol Hydrochloride) is also known as bromcyclohexyl hydrochloride, the chemical name is trans-4-[(2-amino 3,5-dibromobenzyl) amino] cyclohexanol hydrochloride, it is The active metabolite of the expectorant bromhexine (N-demethylation, cyclohexyl para-position introduces trans-hydroxyl), the toxicity is lower than that of bromhexine, but the activity is higher than that of bromhexine. Ambroxol hydrochloride is a mucolytic agent developed by Boehringer Ingelheim of Germany. The drug was first launched in Germany in the early 1980s, and then successively launched in France, Italy, Japan, Spain and many other countries. It is a new generation of mucolytic agent. Phlegm dissolving agent can improve expectoration, and has the effect of promoting pulmonary surfactant and airway secretion and cilia movement. Ambroxol hydrochloride can regulate mucus and mucus secretion clinically, activate cilia swing, easily dilute sputum, strengthen mucus outward transport, and be easy to discharge. It can also promote the synthesis of pulmonary surfactant to maintain alveolar tension and ensure lung Internal function indicators; promote antibiotic penetration into tissues to increase concentration and enhance bactericidal effect; anti-oxidation, reduce the release of inflammatory mediators to reduce inflammatory reactions; cooperate with bronchial antispasmodic substances to improve the curative effect of antispasmodic drugs. Therefore, the drug can be widely used clinically for acute and chronic respiratory diseases accompanied by abnormal secretion of the respiratory tract, especially for the expectorant treatment of chronic bronchitis, the adjuvant treatment of neonatal respiratory distress and lung surgery, and has low toxicity and high efficacy. It is one of the most commonly used expectorants due to its advantages of being precise and being able to produce good synergistic effects with antibiotics. In recent years, it has always been at the top of the drug rankings of key hospitals in major cities in my country.

Salbutamol Sulfate (Salbutamol Sulfate), also known as albuterol, its main component is salbutamol, chemical name 1-(4-hydroxy-3-hydroxymethylphenyl)-2-(tert-butylamino)ethanol, is a high choice Sexual stimulation of bronchial smooth muscle β-adrenergic receptor stimulants, bronchial smooth muscle relaxation, thereby relieving bronchial smooth muscle spasm. It has a stronger effect on bronchiectasis, but a weaker effect on the β1-receptor of the heart. It is currently the safest and most commonly used anti-asthma drug. It is suitable for the prevention and treatment of bronchospasm in patients with bronchial asthma, asthmatic bronchitis and emphysema, and relieves symptoms such as dyspnea caused by airway obstructive diseases such as bronchial asthma, chronic bronchitis and emphysema. Its advantage is that it works quickly , can quickly improve the patient's symptoms, relieve spasm, relieve asthma, and eliminate phlegm. Beta-agonist desensitization and even resistance to asthma treatment.

There are dosage forms such as solutions and granules containing ambroxol hydrochloride and salbutamol sulfate in the prior art, but there is no report of pellets.

In addition, albuterol sulfate and ambroxol hydrochloride are the active ingredients in the same minimum preparation unit. During long-term storage, due to possible chemical compatibility changes between the ingredients, by-products are likely to be produced, which will reduce the effect or increase side effects. Product stability Not ideal.

Contents of the invention

Considering the synergistic effect of ambroxol hydrochloride and salbutamol sulfate, the purpose of the present invention is to provide a safe and effective, stable quality, strong patient adaptability, remarkable effect, effective treatment of respiratory diseases such as acute and chronic bronchitis and asthma Ambroxol albuterol pellets.

In the research, we unexpectedly found that adding poloxamer 188, meglumine and mannitol in an appropriate amount during the preparation of the preparation can significantly improve the stability and bioavailability of ambroxol hydrochloride and salbutamol sulfate in the preparation, It is of great significance for the clinical use of medicines.

The technical scheme that the present invention solves this technical problem is:

A kind of ambroxoxalbutamol pellet, is made up of the component of following weight:

Salbutamol sulfate: 8-10g;

Ambroxol hydrochloride: 15-20g;

Poloxamer 188:8-10g;

Meglumine: 6-8g;

Mannitol: 2-4g;

Filler: 200-400g;

Disintegrant: 10-20g;

Adhesive: Appropriate amount.

The preferred prescription is:

Salbutamol sulfate: 10g;

Ambroxol hydrochloride: 20g;

Poloxamer 188: 8g;

Meglumine: 8g;

Mannitol: 4g;

Filler: 400g;

Disintegrant: 20g;

Adhesive: Appropriate amount.

The filler is selected from one or more of starch, lactose, dextrin, compressible starch and powdered sugar.

The disintegrating agent is selected from one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, cross-linked sodium carboxymethyl cellulose and sodium alginate.

The binder is selected from one or more of starch, pregelatinized starch, hypromellose, hypromellose and povidone.

Its preparation method is:

1) Weigh the raw and auxiliary materials of the prescription amount, pass through 80-120 mesh sieve respectively for subsequent use;

2) Take the sieved adhesive and add distilled water to make an adhesive solution;

3) Mix the sieved albuterol sulfate, ambroxol hydrochloride, poloxamer 188, meglumine, mannitol, fillers and disintegrants in equal increments, and add the above binder solution to prepare soft material;

4) Prepare pellets by extrusion spheronization technology, dry at 50-70°C for 20-40min, sieve and pack.

Instantly.

The preferred preparation method is:

1) Weigh the raw and auxiliary materials of the prescription amount, pass through a 100-mesh sieve for subsequent use;

2) Take the sieved adhesive and add distilled water to make an adhesive solution;

3) Mix the sieved albuterol sulfate, ambroxol hydrochloride, poloxamer 188, meglumine, mannitol, fillers and disintegrants in equal increments, and add the above binder solution to prepare soft material;

4) Prepare pellets by extrusion spheronization technology, dry at 60°C for 30 minutes, sieve and pack.

The beneficial effect of the present invention is that the active ingredient content of the ambroxol albuterol pellets is significantly increased; the stability is greatly improved; therefore, the quality is stable and the effect is remarkable, and can effectively treat respiratory diseases such as acute and chronic bronchitis and asthma.

Detailed ways

Below in conjunction with specific embodiment, further illustrate the present invention. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. For the experimental methods without specific conditions indicated in the following examples, usually follow the conventional conditions or the conditions suggested by the manufacturer. All percentages, ratios, proportions or parts are by weight unless otherwise indicated.

Unless otherwise defined, all professional and scientific terms used herein have the same meanings as commonly understood by those skilled in the art. In addition, any methods and materials similar or equivalent to those described can be applied to the method of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

Example 1

prescription:

Salbutamol sulfate: 8g;

Ambroxol hydrochloride: 15g;

Poloxamer 188: 8g;

Meglumine: 8g;

Mannitol: 4g;

Lactose: 400g;

Sodium carboxymethyl starch: 20g;

Hypromellose: Appropriate amount.

The preparation method is:

1) Weigh the raw and auxiliary materials of the prescription amount, pass through a 100-mesh sieve for subsequent use;

2) Take the sieved hypromellose and add distilled water to make a binder solution;

3) Mix the sieved salbutamol sulfate, ambroxol hydrochloride, poloxamer 188, meglumine, mannitol, lactose and carboxymethyl starch sodium in equal increments, and add the above adhesive solution to prepare into soft material;

4) Prepare pellets by extrusion spheronization technology, dry at 60°C for 30 minutes, sieve and pack.

Example 2

prescription:

Salbutamol sulfate: 10g;

Ambroxol hydrochloride: 20g;

Poloxamer 188: 8g;

Meglumine: 6g;

Mannitol: 2g;

Lactose: 300g;

Low-substituted hydroxypropyl cellulose: 10g;

Hydroxypropyl Cellulose: Appropriate amount.

Preparation:

1) Weigh the raw and auxiliary materials of the prescription amount, and pass through 80 mesh sieves respectively for subsequent use;

2) Take the sieved hydroxypropyl cellulose and add distilled water to make a binder solution;

3) Mix the sieved salbutamol sulfate, ambroxol hydrochloride, poloxamer 188, meglumine, mannitol, lactose and low-substituted hydroxypropyl cellulose in equal increments, and add the above-mentioned binder The solution is made into a soft material;

4) Prepare pellets by extrusion spheronization technology, dry at 50°C for 30 minutes, sieve and pack.

Example 3

prescription:

Salbutamol sulfate: 8g;

Ambroxol hydrochloride: 18g;

Poloxamer 188: 10g;

Meglumine: 6g;

Mannitol: 4g;

Starch: 400g;

Microcrystalline cellulose: 15g;

Povidone: Appropriate amount.

Preparation:

1) Weigh the raw and auxiliary materials of the prescription amount, and pass through 80 mesh sieves respectively for subsequent use;

2) Take the sieved povidone and add distilled water to make a binder solution;

3) Mix the sieved albuterol sulfate, ambroxol hydrochloride, poloxamer 188, meglumine, mannitol, starch and microcrystalline cellulose in equal increments, and add the above binder solution to prepare soft material;

4) Prepare pellets by extrusion spheronization technology, dry at 50°C for 30 minutes, sieve and pack.

Embodiment 4 stability test

Comparative example 1 adopts preparation method identical with embodiment; Prescription is as follows:

Salbutamol sulfate: 8g;

Ambroxol hydrochloride: 15g;

Lactose: 400g;

Sodium carboxymethyl starch: 20g;

Hypromellose: Appropriate amount.

Comparative example 2 adopts preparation method identical with embodiment; Prescription is as follows:

Salbutamol sulfate: 8g;

Ambroxol hydrochloride: 15g;

Poloxamer 188: 8g;

Lactose: 400g;

Sodium carboxymethyl starch: 20g;

Hypromellose: Appropriate amount.

1. Accelerated stability test

Embodiment 1, comparative example 1 and comparative example 2 gained ambroxol albuterol pellets were placed under the condition of light intensity 4500lx respectively for 10 days, respectively at the 0th, 5th, and 10th day sampling, detection content, related substances and other quality indicators , the results are shown in Table 1.

Table 1 Ambroxol albuterol pellets influencing factors test results

The results show that: the ambroxoxalbuterol pellets prepared by the present invention have no obvious change in the content of each component under strong light conditions, and the stability is obviously better than that of the comparative example. The reason is that the common excipients in the comparative example cannot support and stabilize the active ingredients well, which may lead to chemical compatibility changes between the ingredients and easily produce by-products; and because the content of the active ingredients is greater than that of ordinary The current state of the art has resulted in a greater reduction in stability.

2. Accelerated test

Ambroxol albuterol pellets obtained in Example 1 were placed in a constant temperature and humidity chamber of 40°C and RH20% for 6 months, and samples were taken in the 0, 1, 2, 3, and 6 months respectively to measure content and related substances. And other quality indicators, the results are shown in Table 2.

Table 2 Ambroxol albuterol pellets accelerated test results

The results showed that: Ambroxol albuterol pellets were placed under the conditions of 40°C and RH20% for 6 months. Compared with 0 months, except for a slight increase in related substances, other quality indicators had no significant changes, and the quality was stable and reliable. ,Compliance.

The above description is only a preferred embodiment of the present invention, and is not intended to limit the scope of the essential technical content of the present invention. The essential technical content of the present invention is broadly defined in the scope of the claims of the application, and any technical entity completed by others or method, if it is exactly the same as that defined in the scope of the claims of the application, or an equivalent change, it will be deemed to be included in the scope of the claims.

Claims (1)

1. a preparation method of ambroxol albuterol pellets, made of the following weight components: Salbutamol sulfate: 8-10g; Ambroxol hydrochloride: 15-20g; Poloxamer 188:8-10g; Meglumine: 6-8g; Mannitol: 2-4g; Filler: 200-400g; Disintegrant: 10-20g; Adhesive: Appropriate amount The preparation method is: 1) Weigh the raw and auxiliary materials of the prescription amount, pass through 80-120 mesh sieve respectively for subsequent use; 2) Take the sieved adhesive and add distilled water to make an adhesive solution; 3) Mix the sieved albuterol sulfate, ambroxol hydrochloride, poloxamer 188, meglumine, mannitol, fillers and disintegrants in equal increments, and add the above binder solution to prepare soft material; 4) Prepare pellets by extrusion spheronization technology, dry at 50-70°C for 20-40min, sieve and pack; The filler is selected from one or more of starch, lactose, dextrin and powdered sugar; The disintegrant is selected from one or more of sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, microcrystalline cellulose, croscarmellose sodium and sodium alginate; The binder is selected from one or more of starch, pregelatinized starch, hypromellose, hypromellose and povidone.