RU2519653C1 - Aerosol preparation of ipratropium bromide for treating respiratory diseases - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: inhalation formulation in the form of aerosol for treating bronchial asthma and chronic obstructive pulmonary disease containing ipratropium bromide monohydrate as an active ingredient, ethanol absolute as a solvent, an aerosol particle size regulator as an adjuvant consisting of triethyl citrate and an acid specified in a group: citric acid, hydrochloric acid, orthophosphoric acid, 1,1,1,4-tetrafluoroethane (HFA-134a) and/or 1,1,1,2,3,3,3-heptafluoropropane (HFA-227ea) as a propellant in certain proportions.

EFFECT: increasing the respirable fraction and obtaining an optimised particle size distribution profile.

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Description

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

In the treatment of bronchial asthma, an important point in the implementation of successful therapy is the delivery of a drug in the form of an aerosol to the site of inflammation in the bronchi. In the practice of treating respiratory diseases, three main methods of aerosol formation are used. These are: drugs under pressure and sprayed with an auxiliary substance - a propellant, also called metered-dose aerosols, inhalation powders, activated, as a rule, by inhalation of the patient, and solutions or suspensions sprayed with a special device - a nebulizer. Each of the methods has its own specific properties, which make them preferred when used in different groups of patients, place of use, weather conditions, etc. Common to these methods, preparations should ensure the formation of a respirable fraction, i.e. to form an aerosol cloud with a particle size of not more than 10 microns, preferably not more than 5.0 microns. The presence of particles with a size of less than 0.5 microns is useless, because they are not deposited in the lungs and are excreted upon exhalation.

State of the art

The advantages of aerosol preparations for the treatment of respiratory diseases are their portability and ease of use.

Aerosol preparations for the treatment of respiratory organs have been used since the mid 50s of the last century. The first aerosol preparations were suspensions in liquefied gases - propellants. Chlorine-containing freons, inert and non-toxic compounds were used as propellants, however, as it turned out, they have the property to destroy the ozone layer of the planet. Because of this, their use was prohibited and preparations began to be developed with new propellants - hydrofluoroalkanes. The most acceptable of these are tetrafluoroethane (HFA-134a propellant) and heptafluoropropane (HFA-227ea propellant). The use of these propellants has fundamentally changed the production technology of aerosol preparations and the compositions of the preparations themselves. To reduce the vapor pressure, auxiliary substances began to be used, the most acceptable was ethyl alcohol. The use of ethyl alcohol made it possible to obtain preparations under pressure in the form of true solutions, and this, in turn, made it possible to eliminate such a complex stage of the technology as micronization of powders, and made it possible to obtain a stably high respirable fraction upon inhalation. To form aerosol particles during inhalation with respirable sizes, it is necessary to add excipients selected from the group of biologically acceptable liquids to the solution. These should be heavy, non-volatile liquids, preferably miscible with the propellant.

A known pharmaceutical composition for use in metered-dose aerosol inhalers containing the active ingredient is ipratropium bromide, hydrofluoroalkane, co-solvent ethyl alcohol and glycerin (US2003157028 (A1), publ. 2003-08-21). The composition is not stable enough.

Known liquid pharmaceutical composition in the form of an aerosol containing the active substance, for example, ipratropium in the form of bromide, at least one organic solvent, at least one partially fluorinated hydrocarbon as a propellant, at least one inorganic or organic acid (RU 2126248 C1, publ. 02.20.1999). The introduction of acid in this solution ensures the stability of the active component, but does not solve the problem of improving the particle size distribution, which affects respiration.

As the closest analogue of the claimed drug can be called the dosed aerosol Atrovent-N (number of registration certificate P N014363 / 01, dated 14.03.2008), having the composition for one dose:

Ipratropium bromide monohydrate 0.021 mcg Ethanol 8.415 mg Purified water 0.281 mg Citric Acid 0.002 mg HFA-134a Up to 56 mg

A well-known drug is not effective enough, since a large number of small particles are formed due to the lack of a particle size regulator.

The present invention is to develop an effective inhalation composition for the treatment of bronchial asthma and chronic obstructive pulmonary disease.

This problem is solved by a new composition in the form of an aerosol for the treatment of bronchial asthma and chronic obstructive pulmonary disease, containing ipratropium bromide monohydrate ((endo, syn) - (±) -3 - (3-hydroxy-1-oxo-2- phenylpropoxy) -8-methyl-8- (1-methylethyl) -8-azoniabicyclo [3.2.1] octane bromide monohydrate), absolute ethyl alcohol as a solvent, aerosol particle size regulator consisting of triethyl citrate and an acid selected from the group: citric acid, hydrochloric acid, phosphoric slots, as a propellant - 1,1,1,4-tetrafluoroethane (HFA-134a) and / or 1,1,1,2,3,3,3-heptafluoropropane (HFA-227ea) in the following ratio of components, mg /dose:

Ipratropium bromide monohydrate 0.010-0.030 Citric Acid 0.002-0.050 or Hydrochloric acid 0.002-0.005 or Phosphoric acid 0.002-0.005 Triethyl citrate 0,025-2,000 Ethanol anhydrous 9,000-20,000 HFA-134a and / or HFA-227ea to the mass of the dose of the metering valve

Typically, the valve dose mass of the inhalation device is 54-65 mg.

Ipratropium bromide is a well-known m-cholinergic blocker, a bronchodilator. Due to the instability of ipratropium in a neutral environment, an acidifier must be added to the drug. According to the invention, it is proposed to use hydrochloric, phosphoric and citric acid, which contribute not only to the stability of the active principle, but also affect the particle size in the preparation.

Small therapeutic doses of ipratropium and low concentrations in the alcohol - propellant solution determine the special role of the particle size regulator. Tests of a number of biologically inert compounds have shown that triethyl citrate is the most promising compound.

Triethyl citrate (E 1505) - an oily liquid, used in food and pharmaceutical industries, described in the European Pharmacopoeia, allowable daily intake of 20 mg / kg body weight (Guidelines for the safety of the use of excipients in medicines, Federal State Institution NCESMP, Ministry of Health and Social Development of the Russian Federation, Moscow, 2004).

Thus, the safety of triethyl citrate is not in doubt.

It was found that increasing the content of triethyl citrate in the preparation to 0.25% increases the respirable fraction by 1.8 times, and the distribution profile has a maximum in the range from 1.5 to 2.0 μm. A further increase in the content of triethyl citrate to 1.0% has little effect on the respirable fraction, but makes the maximum wider.

As the propellant, 1,1,1,4-tetrafluoroethane (HFA-134a) and / or 1,1,1,2,3,3,3-heptafluoropropane (HFA-227ea) were used. It should be noted that the respirable fraction depends on the correctly selected metering valve, atomizer and their combinations.

The technical result of the use of the composition is an increase in the respirable fraction to 35-40% and obtaining the optimal particle distribution profile.

Preparation of the drug

You can get the drug both in two-stage and in one-stage technology.

In the first case, a solution of the acid in absolute ethanol is prepared, the active substance, triethyl citrate is introduced into it, the solution is dosed into aerosol containers, the containers are covered with metering valves and evacuated, the valves are crimped. Then, through the valve, propellant is dosed into the cylinders.

According to a one-stage technology, a solution of an acid in absolute ethanol is prepared in a mixing vessel operating under pressure, the active substance, triethyl citrate and propellant are added to the solution, the solution is mixed. Dosing valves are placed on aerosol cans, the cylinders are evacuated, the valves are crimped. The dosage of the solution of the active substance in the propellant occurs through the valve.

In both cases, the solutions are filtered through membrane filters with a pore size of 0.2 μm.

The invention is illustrated by examples, which cannot be construed as limiting the variation of compositions. The number of components per dose of the drug is given. In the examples for ipratropium bromide, a dosage of 20 μg was selected.

To determine the respirable fraction, it is possible to use several devices described in pharmacopeias. The most commonly used is the 8-stage Andersen impactor, which allows not only to determine the respirable fraction, but also to evaluate the particle size distribution profile.

We determined the respirable fraction using the Andersen impactor, at an air flow rate of 28.3 l / min, while passing 4 l of air. The ratio of the mass of small particles (2-7 cascades and filter) to the mass of all particles included in the impactor was taken.

Example 1

Ipratropium bromide monohydrate 0.020 mg Citric Acid 0.005 mg Triethyl citrate 0.160 mg Ethanol anhydrous 10,000 mg HFA-134a up to 65 mg

The result is a respirable fraction of 35.9%.

Example 2

Ipratropium bromide monohydrate 0.020 mg Hydrochloric acid 0.002 mg Triethyl citrate 0.025 mg Ethanol anhydrous 12,000 mg HFA-134a up to 65 mg

The result is a respirable fraction of 23.2%.

Example 3

Ipratropium bromide monohydrate 0.020 mg Phosphoric acid 0.002 mg Triethyl citrate 0.070 mg Ethanol anhydrous 9,000 mg HFA-134a up to 65 mg

The result is a respirable fraction of 28.0%.

Example 4

Ipratropium bromide monohydrate 0.020 mg Citric Acid 0.005 mg Triethyl citrate 0.330 mg Ethanol anhydrous 10,000 mg HFA-134a up to 65 mg

The result is a respirable fraction of 28.0%.

Example 5

Ipratropium bromide monohydrate 0.020 mg Citric Acid 0.005 mg Triethyl citrate 0.650 mg Ethanol anhydrous 10,000 mg HFA-134a up to 65 mg

The result is a respirable fraction of 36.2%.

Example 6 comparative

Ipratropium bromide monohydrate 0.020 mg Citric Acid 0.005 mg Ethanol anhydrous 10,000 mg HFA-134a up to 65 mg

The result is a respirable fraction of 18.0%.

Example 7 Comparative

Ipratropium bromide monohydrate 0.021 mg Ethanol Absolute 8.415 mg Purified water 0.281 mg Citric Acid 0.002 mg HFA-134a Up to 56 mg

The result is a respirable fraction of 23%.

Thus, a new form of the drug ipratropium bromide in the form of a metered-dose aerosol has been developed and obtained, which allows to eliminate the disadvantages of the known forms and can be effectively used in therapeutic practice for the treatment of diseases of the respiratory system.

Claims (1)

An inhalation composition in the form of an aerosol for the treatment of bronchial asthma and chronic obstructive pulmonary disease, containing ipratropium bromide monohydrate, solvent, adjuvant and propellant, characterized in that it contains absolute ethyl alcohol as a solvent, and, as an adjuvant, an aerosol particle size regulator consisting of triethyl citrate and an acid selected from the group: citric acid, hydrochloric acid, phosphoric acid, 1,1,1,4-tetrafluoroethane (HFA-134a) and / or 1,1,1,2,3,3 as propellant, 3-heptafluoro Rop (HFA-227ea) in the following ratios, mg / dose:
Ipratropium bromide monohydrate 0.010-0.030 Citric Acid 0.002-0.050 or Hydrochloric acid 0.002-0.005 or Phosphoric acid 0.002-0.005 Triethyl citrate 0,025-2,000 Ethanol anhydrous 9,000-20,000 HFA-134a and / or HFA-227ea up to 54-65