WO2014054978A2 - Stable combined solution of fenoterol hydrobromide and ipratropium bromide - Google Patents

Description

 Stable combination solution of fenoterol hydrobromide and ipratropium bromide

Technical field

The invention relates to medicine and the pharmaceutical industry and relates to a solution of a highly effective pharmaceutical substance and excipients, which allows the formation of an aerosol of small particles with the aim of penetrating into the bronchi and alveoli of the lungs.

Bronchial asthma (BA) is one of the most common diseases of the respiratory system among people of all ages. In Russia, asthma affects 5 to 7% of the adult population. According to the severity of the disease: 30% of patients have a mild course of the disease, 50% have moderate severity and 20% have a severe form. AD is the cause of 0.4% of all cases of the appeal of the population for medical care, 1, 4% - hospitalizations. Chronic obstructive pulmonary disease (COPD) is another common chronic respiratory disease, which is accompanied by the presence of chronic recurrent inflammation of the bronchial wall. COPD is characterized by steady progression, when even without exacerbation there is an increase in bronchial obstruction, the addition of complications, and patients gradually lose their ability to work. According to some reports, there are more than 1 1 in Russia million people suffer from COPD. Thus, there is a significant need for drugs that are effective against respiratory diseases, especially for the treatment of asthma and chronic obstructive pulmonary disease.

 In the practice of treating respiratory diseases, three main methods of aerosol formation are used. These are drugs that are under pressure and sprayed with an auxiliary substance - a propellant, inhalation powders, activated, as a rule, by the inhalation of the patient, and solutions or suspensions sprayed with a special device - a nebulizer. Each of the methods has its own specific properties, making them preferred when used in different groups of patients, place of use, weather conditions, etc. The common feature of these methods is that the preparations should ensure the formation of a respirable fraction, i.e. form an aerosol cloud with a predominant particle size of from 0.5 to 5 microns.

State of the art

The specific properties of nebulizer therapy is the ability to assist patients with severe bronchial obstruction and respiratory failure, which leads to the inability of patients create an inspiratory flow and, as a result, drug delivery in two other ways. Nebulization may also be the only way to treat children. Spraying solutions for nebulization has a less irritating effect and reduces the cough effect.

 In medical practice, nebulizers of various designs are used, using the energy of compressed air, ultrasound or driven by mechanical devices. The most common compressor nebulizers. A general requirement for all types of nebulizers is the generation of an aerosol cloud with particle sizes from 0.5 μm to 10 μm, preferably from 0.5 μm to 5.0 μm, preferably from 0.5 μm to 3.0 μm. Such a narrow respirable fraction can be obtained only by spraying true solutions of medicinal substances. The measurement of the respirable fraction in the case of non-boiled preparations is possible both using impactors and directly measuring the size of particles in the air stream, in particular by laser diffraction. Measurements using impactors allows you to immediately get the mass distribution and does not depend on the shape of the particles.

When measuring the dispersion of an aerosol cloud during nebulization, it should be taken into account that part of the drug does not enter the respiratory system of patients, but disperses into atmosphere or deposited in a nebulizer. This is due to the fact that nebulization occurs continuously, and the breathing of patients is discrete. Using nebulizers with valves does not completely solve this problem. Therefore, when evaluating the effectiveness of drugs using impactors, the fraction of fine particles should be evaluated in comparison with the amount of the drug that “entered” the impactor.

 In addition to active pharmaceutical substances and solvents, the substances that ensure the stability of the solution during storage, such as acidity regulators, preservatives, and antioxidants, can be added to the composition of nebulization solutions. Flavor-correcting substances, aerosol particle size regulators, etc. may be added.

 Solvents and / or cosolvents are selected from the group of biologically acceptable liquids such as water, alcohols, glycols, etc. A preferred solvent is water.

For example, inhalation solutions are known, including for nebulization (application WO2008102128), containing beta-agonists as active substances, including the above excipients. This source does not discuss or investigate the effect of combinations of excipients on the size of the respirable fraction. Combined solutions of phenoterol and ipratropium are known for the treatment of obstructive pulmonary diseases, containing benzalkonium chloride as an excipient, a complexing agent such as EDTA.

 As the closest analogue of the claimed drug can be called a solution for inhalation Berodual (Beringer Ingelheim Pharma GmbH), having the composition:

 Fenoterol hydrobromide 0.5 mg / ml;

 Ipratropium bromide monohydrate 0.261 mg / ml

(Corresponds to 0.25 mg / ml ipratropium bromide);

 Benzalkonium chloride 0.1 mg / ml;

 Disodium edetate dihydrate 0.5 mg / ml;

 Hydrochloric acid 1H 0.0946 mg / ml;

 Purified water to 1 ml.

 The respirable fraction of the active substance was measured on an Andersen 8-stage impactor (air flow 28.5 l / min, discrete injection of 4 l after 5 s), the drug was sprayed on an M2000 nebulizer, manufactured by Marcos-Mifar, Italy. The respirable fraction calculated as the ratio of the mass of small particles to the mass of the "included in the impactor" is a fairly large value - about 70%, or 30% of the inhaled drug.

There is evidence that benzalkonium chloride can cause allergic reactions, especially in children. Disclosure of invention

 The present invention is to develop an effective inhalation composition for the treatment of bronchial asthma and COPD.

 This problem is solved by a new solution for the preparation for inhalation administration containing hydrobromide and ipratropium bromide as active substances of phenoterol, and benzoate as an excipient, an acidity regulator, which is a food grade organic acid and purified water with the following components in mg / ml :

 Fenoterol hydrobromide 1, 0 - 1, 1

 Ipratropium bromide monohydrate 0.2 - 2.0

 Sodium benzoate 0.2 - 2.0

 Organic acid 1, 3 - 1, 9

 The water purified is the rest, provided that the pH is 3.2 - 3.4.

 Sodium hydroxide can be used as a pH regulator.

Technical result: a higher percentage of the respirable fraction of the active substance and, accordingly, higher efficiency. The combined preparation containing fenoterol and ipratropium is in many cases more preferable than the use of monopreparations.

 Fenoterol is an L2 agonist of selective action. The bronchodilating effect of L2 agonists is ensured by stimulation of L2 receptors of smooth muscle cells. The effect occurs after 2 to 3 minutes and lasts up to 6 hours.

 Ipratropium is an anticholinergic drug that has a bronchodilator effect due to the blockade of M-cholinergic receptors and can help improve patency in the peripheral parts of the bronchopulmonary system by limiting the secretion of bronchial mucus. Its bronchodilator effect develops 3 (10 min after inhalation. The combined use of phenoterol and ipratropium provides a mutually reinforcing effect of these drugs and has a pronounced bronchodilator effect, especially in moderate to severe asthma, as well as in patients with concomitant chronic obstructive bronchitis.

 Indications: bronchial asthma, chronic obstructive bronchitis and a combination of these diseases in a patient.

The proposed composition contains sodium benzoate in concentrations from 0.2 mg to 2.0 mg per ml of solution. Sodium benzoate is especially effective in acidic solutions with a pH of 4.5 or lower and is especially effective against molds, the defeat of which often accompanies respiratory diseases. In this case, the amount of benzalkonium can be significantly reduced or its use can be completely abandoned. In particular, the solution may contain up to 0.05 mg / ml benzalkonium chloride. The stability check showed that phenoterol hydrobromide solutions are stable at pH 3.2 - 3.4; preferably pH 3.2-3.3. As a regulator of acidity, we propose using food-grade organic acids, such as malic, citric, tartaric, benzoic, salicylic, succinic, especially preferably citric acid. Tests have shown that the required amount of acid to achieve the desired pH is preferably about 1.5 mg / ml.

It is also possible in the particular case of the invention to add to the solution a complexing agent, preferably ethylenediaminetetraacetic acid, in the form of disodium salt dihydrate (EDTA). EDTA is a low-toxic substance with a permissible daily intake of 2.5 mg per kg of body weight (Methodological recommendations for the safety of the use of excipients in medicines, Federal State Institution Scientific Center for Health and Safety, Ministry of Health and Social Development of the Russian Federation, Moscow, 2004). We determined the concentration of the effective use of EDTA is from 0.1 mg / ml to 1.0 mg / ml. Organoleptic tests of such a solution confirmed the absence of a cough effect.

 The preparation of the combined solution of phenoterol hydrobromide and ipratropium bromide was as follows:

In a vessel, in the purified water, the calculated amount of sodium benzoate and the complexing agent (if this is included in the recipe) are dissolved. The solution was adjusted to pH 3.2-3.3 by adding a 1% solution of organic acid in purified water. With stirring, the required amount of fenoterol hydrobromide and ipratropium bromide monohydrate are introduced into the solution sequentially, after complete dissolution of the previous one. Since the solution will be diluted with physiological saline before inhalation, depending on the indication and size of the nebulizer chamber, the calculation of the number of active substances is based on the need to obtain a 0.1% solution of phenoterol hydrobromide and a 0.0261% ipratropium bromide monohydrate solution. After complete dissolution, the pH values are monitored again and adjusted if necessary. The finished solution is filtered through a sterilizing membrane filter with a pore size of 0.22 μm and poured into sterile glass dropper bottles. The best example of carrying out the invention

 The invention is illustrated by examples, which cannot be construed as limiting the variation of compositions.

 Example 1

 Fenoterol hydrobromide - 2.521 g

 Ipratropium bromide monohydrate 0.614 g

 Benzalkonium chloride 0.1 g

 Sodium benzoate - 1, 179 g

 Citric acid - 4.08 g

 Water for injection - up to 2350 ml

 pH 3.2

Example 2

 Fenoterol hydrobromide - 2.521 g

 Ipratropium bromide monohydrate 0.614 g

 Sodium benzoate - 1, 179 g

 Citric acid - 4.08 g

 Water for injection - up to 2350 ml

 pH 3.2

Example 3

 Fenoterol hydrobromide - 2.521 g

 Ipratropium bromide monohydrate 0.614 g

 Sodium benzoate - 1.178 g

EDTA - 1.175 g Citric acid - 4.08 g

 Water for injection - up to 2350 ml

 pH - 3.21

 The solutions were poured into glass dropper bottles of 21-22 ml.

Test

The drug obtained by the above technology and the control drug were tested in accordance with the requirements established for solutions for inhalation of the European Pharmacopoeia. Of particular importance for inhaled preparations is the fraction of fine particles of active substances, measured in grams or percent and determined during aerodynamic tests. The value of this fraction, also called respirable, determines the effectiveness of the inhalation preparations intended for the treatment of respiratory organs. The determination of the respirable fraction is carried out using the devices described in the European and American Pharmacopoeias. The most commonly used is the eight-stage Andersen impactor (apparatus D of the European Pharmacopoeia), because it makes it possible to study in more detail the dispersed composition in the range from 0.5 microns to 10 or more microns. The European Pharmacopoeia establishes the conditions for the analysis - the volume of air pumped is 4 l, the flow rate is 28.3 l / min, although Allows the use of other speeds. However, each specific Andersen impactor model is designed for a specific air flow rate and cannot be used on another.

 For solutions, the respirable fractions were determined using the Andersen impactor using the above examples. They ranged from 84 to 91%. That is significantly higher than that of the prototype.

 The analytical determination of fenoterol hydrobromide and ipratropium bromide yielded a deviation value below the standard average. Thus, the uniformity of the released dose is very high.

 High stability of solutions is confirmed under accelerated aging.

Industrial applicability

 The invention is applicable in the field of medicine and the pharmaceutical industry and relates to a solution of highly effective pharmaceutical substance and excipients, which allows the formation of an aerosol of small particles with the aim of penetrating into the bronchi and alveoli of the lungs.

Claims

CLAIM 1. A solution for producing a preparation for inhalation administration containing hydrobromide and ipratropium bromide, purified water and excipients as active substances, characterized in that it contains sodium benzoate and a regulator as excipients. acidity, which is a food grade organic acid, with the following components in mg / ml:  Fenoterol hydrobromide 1, 0 - 1, 1  Ipratropium bromide monohydrate 0.2 - 2.0  Sodium benzoate 0.2 - 2.0  Organic acid 1, 3 - 1, 9  purified water provided that the pH is 3.2 to 3.4.  2. The solution according to claim 1, characterized in that as a food grade organic acid citric acid is contained in an amount of 1.5 mg / ml of solution.  3. The solution according to claim 1 or claim 2, characterized in that the pH is 3.2-3.3. 4. The solution according to claim 1 or claim 2, characterized in that it further comprises a complexing agent, preferably ethylenediaminetetraacetic acid in the form of disodium salt dihydrate. 5. The solution according to claim 4, characterized in that it contains ethylenediaminetetraacetic acid in the form of disodium salt dihydrate in an amount of from 0.1 mg to 1.0 mg per ml of solution.  6. The solution according to claim 1 or claim 2, characterized in that it further comprises benzalkonium chloride in an amount up to 0.05 mg per ml of solution.