WO2015065220A1 - Inhaled drug for the treatment of bronchial asthma and chronic obstructive pulmonary disease and method for producing same - Google Patents

Abstract

The invention relates to medicine and the pharmaceutical industry and concerns a dry powder drug containing two high-potency pharmaceutical substances, budesonide and formoterol fumarate dihydrate, in micronized form, which enables penetration into the bronchi and alveoli of the lungs, and specially prepared excipients, namely a mixture of lactose and sodium benzoate, which enable the effective dosing and disaggregation of the active ingredients.

Description

 Inhalation drug for the treatment of bronchial asthma and chronic obstructive pulmonary disease and method for its preparation

 The invention relates to medicine and the pharmaceutical industry, and relates to a dry powder preparation containing two highly effective pharmaceutical substances in microionized form, which allows penetration into the bronchi and alveoli of the lungs and specially prepared excipients that allow the dosage and disaggregation of active substances. State of the art

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 associated with the presence of chronic recurrent inflammation. 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, in Russia more than 1 1 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.

 The main place in the modern treatment of these diseases is inhalation therapy. When using inhalation methods, it is possible to create a high concentration of the drug substance directly in the bronchi and lungs, and the possibility of its systemic effect is reduced. This is due to the lack of binding to blood proteins, modifications in the liver, etc. drug before its action. The use of inhalation agents significantly reduces the total dose of the drug necessary to provide a therapeutic effect.

To achieve the effect of deep penetration into the lungs, it is necessary that the particle diameter of the biologically active substance does not exceed 5 - 10 microns. Finely dispersed (micronized) biologically active substances used for inhalation are characterized by a high specific surface area of the particles, which leads to a resulting distribution of interaction forces and, in turn, to an increase in the adhesion and cohesion of particles. Since the biologically active substance or mixture of substances is introduced by the patient using special devices, the drug should not linger in the specified device and not be lost when sprayed. That is, it is necessary to select such carriers that would ensure effective delivery of the drug when placed in an inhaled dosing device.

 Known inhalation composition for the treatment of bronchial asthma, containing drugs used in bronchial asthma, and sodium benzoate as a diluent. The sodium benzoate content in the composition is from 20 to 99.8%. The proposed composition does not cause side effects (for example, fungal diseases of the oral cavity) encountered when used as a diluent Sugars (RU 2054932 C1).

Also in the Russian Federation, a composition containing sodium benzoate as the only auxiliary substance is patented. The authors explain its use by the antifungal action of sodium benzoate (fungal lesions of the oral cavity with inhalation therapy, especially when glucocorticosteroids are used, are quite common (RF patent 2242972).

 However, because of the property of sodium benzoate, these compositions are easy to aggregate; they do not allow obtaining respirable fractions much more than 15 -17%. The introduction of benzoic or succinic acids into the preparation somewhat enhances the antifungal effect, but does not increase the respirable fraction.

 Lactose as carriers is used in almost all powder inhalation preparations. Its use is indicated in many foreign and Russian patents, for example, patents of the Russian Federation 2140260 and 2194497. However, as a rule, such a carrier does not provide a satisfactory fluidity of small particles, and therefore ease of penetration into the lungs.

 As the closest analogue, the Symbicort preparation of the company Astra Zeneca can be indicated in the Turbuhaler multi-dose dry powder inhaler (http://www.rlsnet.ru/tn_index_id_17658.htm).

 Composition of active substances: Budesonide + Formoterol fumarate dihydrate.

 Dosage:

I. 80 + 4.5 mcg / dose; II. 160 + 4.5 mcg / dose;

 III. 320 + 9 mcg dose.

 Excipient: lactose monohydrate - 491 mg / dose.

 The known composition does not provide a significant amount of respirable fraction, which determines the effectiveness of inhalation.

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 drug for inhalation administration containing micronized Budesonide and micronized Formoterol fumarate dihydrate as active substances, and lactose with an average particle size of 1 to 10 microns and sodium benzoate with a bulk density in the range of 0.30-0 as a carrier. 50 g / cm ³ , preferably 0.38-0.44 g / cm ³ , with the following components per dose:

 Budesonide 50 mcg - 800 mcg

 Formoterol fumarate dihydrate 4.5 mcg - 18 mcg

 Lactose 5 mg - 50 mg

Sodium benzoate 0.01 mg - 5 mg Effect: a higher percentage of respirable fraction of active substances and, accordingly, higher efficiency.

 The drug is intended for the treatment of respiratory diseases - bronchial asthma and chronic obstructive pulmonary disease.

 The patented composition is a powder containing budesonide and formoterol fumarate as active substances, which have different mechanisms of action and exhibit an additive effect, and lactose and sodium benzoate as auxiliary substances.

 Local action glucocorticosteroid budesonide - with an inhalation procedure, it has a powerful anti-inflammatory effect in the bronchi, reducing the severity of symptoms and the frequency of exacerbations of bronchial asthma.

 The selective agonist of p-adrenergic receptors formoterol has a bronchodilatory effect in patients with airway obstruction. The effect of the drug occurs within 3 minutes and lasts up to 12 hours after inhalation.

The drug can be placed in gelatin capsules and used using a special device - a single dose dry powder inhaler, for example Inhaler CDM, from Qualitec Industria, or a multi-dose inhaler container, for example Cyclohaler, Pulmed.

 For inhalation purposes in lung diseases, micronized substances are used (see the prior art) with an average particle size of from 0.1 μm to 10 μm. Preferably the proportion of particles of the active component with a size

0.5-5 microns is at least 95%, even more preferably 99% by weight.

 Another object of the invention is a method for producing the drug.

A method of obtaining a preparation for inhalation administration is characterized in that the substances of the active substances are micronized in a planetary mill, sieved through a sieve of lactose with an average particle size of 100-120 μm, followed by micronization to an average particle size of 1 to 10 μm, sieved with sodium benzoate to obtain a bulk density in the range of 0.30-0.50 g / cm ³ , preferably 0.38-0.44 g / cm ³ , preformed formoterol fumarate with micronized lactose in a ratio of 1: 16.6 -35.6, added to the resulting mixture micronized bud esonide and mix thoroughly, then injected into the mixture of sodium benzoate and the remaining amount lactose, stirred at a speed of 40-45 rpm for 12-15 minutes

 If necessary, produce the preparation of the drug. Depending on the type of inhaler used, the packaging is carried out either in hard gelatin capsules, or in containers of multi-dose inhalers, or in other devices for inhalation.

Tests

The drug obtained by the above technology and the control drug were tested in accordance with the requirements established for powders for inhalation of the European Pharmacopoeia. Of particular importance for inhaled preparations is the fraction of fine particles of active substances, measured in μg / dose or percentage 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 and up to 10 and 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 it 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. According to the test results of various drugs for respirable fraction and the results of the effectiveness of the use of these drugs in medical practice, we can estimate the size of the respirable fraction: 15% - satisfactory, 25% - good, 35% and higher - excellent (however, the pharmacological properties of the active substances must be taken into account ) This assessment is conditional since depends on the apparatus on which the study was conducted, selection and analysis techniques, calculation methods.

When studying mixtures of acceptable carriers, it was found that a mixture of lactose and sodium benzoate prepared by the above method, when tested on an Andersen impactor using an Inhaler CDM inhaler (pumped air volume 4 l, flow rate 28.3 l / min), has a higher percentage respirable fraction of active substances than a similar drug containing as a carrier only lactose. The specific values of the respirable fractions (measured by budesonide, steps 2-7 and filter) are given in the examples. A preparation containing a mixture of lactose and sodium benzoate was easily dosed into capsules and containers, and it can also be expected that sodium benzoate will exhibit its antifungal properties.

 The uniformity of the released dose was within the requirements of the European Pharmacopoeia. The best example of carrying out the invention

 Example 1

 Budesonide 50 mcg;

 Formoterol fumarate 4.5 mcg;

 Lactose 10 mg;

 Sodium benzoate 0.01 mg

 Respiratory fraction 30.1%

 The technology of preparation:

 The micronization of the active substances is carried out in a planetary mill, for example, Retsch, PM 400. Achieve that the proportion of particles with sizes of 0.5-5 microns was at least 99% by weight. The preparation of excipients is as follows ..

Lactose with an average particle size of 100-120 μm (e.g. Inhalac® 100, Meggle, Lactohale®, Domo or any other that meets the requirements of the European or American Pharmacopoeia) is sieved through a sieve with 200 μm cells. Lactose is micronized to particle sizes from 1 to 10 microns in a mill or purchased from manufacturers with the required particle sizes. Sodium benzoate is sieved through a 400 μm sieve loaded with stainless steel balls on a sieve machine with intense vertical vibrations, for example Model AS 200 basic, Retsch (Germany). For each analytical sieve with a mesh size of 400 μm, 2 kg of balls are placed, made of stainless steel with a diameter of 9 mm, and sodium benzoate is loaded. The technological mode of operation of the sieve analyzer is established: the sifting time is 10 minutes, the oscillation amplitude is 2.5-3 mm. The bulk density of sieved sodium benzoate was obtained in the range of 0.30-0.50 g / cm.

Pre-mix formoterol fumarate with micronized lactose in a ratio of 1: 17.8. Micronized budesonide is added to this mixture and mixed thoroughly. This procedure ensures that the ratios of active substances in the drug are unchanged. Then sodium benzoate is charged, followed by the remaining amount of lactose. Mixing is switched on at a speed of 42 rpm and driven for 14 minutes. Depending on the type of inhaler used, the packing is carried out either in hard gelatin capsules, or in containers of multi-dose inhalers, or in other devices for inhalation.

Example 2

 Budesonide 80 mcg;

 Formoterol fumarate 4.5 mcg;

 Lactose 10 mg;

 Sodium Benzoate 5 mg

 Respiratory fraction 33.1%

Example 3

 Budesonide 160 mcg;

 Formoterol fumarate 9 mcg;

 Lactose 50 mg;

 Sodium benzoate 2 mg

 Respiratory fraction 42.5%

The drug is obtained as in example 1. Pre-mixing formoterol fumarate with micronized lactose in a ratio of 1: 35.6. Stirring at a speed of 40 rpm and lead it for 15 minutes Example 4

 Budesonide 200 mcg;

 Formoterol fumarate 18 mcg;

 Lactose 10 mg;

 Sodium benzoate 2 mg

 Respiratory fraction 37.5%

Example 5

 Budesonide 400 mcg;

 Formoterol fumarate 9 mcg;

 Lactose 25 mg;

 Sodium Benzoate 5 mg

 Respiratory fraction 39.9%

 The drug is obtained as in example 1. Pre-mixing formoterol fumarate with micronized lactose in a ratio of 1: 16.6. The bulk density of sifted sodium benzoate was obtained in the range of 0.38-0.44 g / cm.

Example 6

 Budesonide 800 mcg;

 Formoterol fumarate 9 mcg;

 Lactose 10 mg;

 Sodium benzoate 1 mg

Respiratory fraction 38.1% Example 7

 Budesonide 800 mcg;

 Formoterol fumarate 4.5 mcg;

 Lactose 12.5 mg;

 Sodium benzoate 2.5 mg

 Respiratory fraction 38.7%

Example 8

 Budesonide 80 mcg;

 Formoterol fumarate 4.5 mcg;

 Lactose 10 mg;

 Respiratory fraction 12.3%

Industrial applicability

 The invention is applicable in the field of medicine and the pharmaceutical industry and relates to an effective inhalation composition for the treatment of bronchial asthma and COPD.

Claims

CLAIM 1. Inhalation preparation for the treatment of bronchial asthma and chronic obstructive pulmonary disease, containing micronized budesonide and micronized formoterol fumarate dihydrate as active substances, characterized in that it contains lactose with an average particle size of 1 to 10 microns and sodium benzoate with bulk density in the range of 0.30-0.50 g / cm ³ , with the following content of components per dose of the drug:  Budesonide 50 mcg - 800 mcg  Formoterol fumarate dihydrate 4.5 mcg - 18 mcg  Lactose 5 mg - 50 mg  Sodium benzoate 0.01 mg - 5 mg  2. The drug according to claim 1, characterized in that the proportion of micronized particles of the active component with a size of 0.5-5 microns is at least 95% by weight. 3. A preparation according to claim 1, characterized in that the bulk density of the sodium benzoate is in the range 0,38-0,44 g / cm ^3. 4. A method of obtaining an inhalation preparation according to any one of claims 1 to 3, characterized in that the substances of the active substances are micronized in a planetary mill, sieved through a sieve lactose with an average particle size of 100-120 μm with their subsequent micronization to an average particle size of 1 to 10 μm, sieved with sodium benzoate to obtain a bulk density in the range of 0.30-0.50 g / cm ³ pre-mixed formoterol micronized lactose fumarate in proportion 1: 16.6-35.6, micronized budesonide is added to the resulting mixture and thoroughly mixed, then sodium benzoate and the remaining amount of lactose are added to the mixture, stirred at a speed of 40-45 rpm for 12-15 minutes.