TWI758617B - Aerosol pharmaceutical composition comprising glycopyrronium salt and indacaterol salt, its preparation method and use - Google Patents

Abstract

The present invention provides a propellant-free aerosol pharmaceutical composition, which comprises a pharmaceutically acceptable salt of glycopyrronium, a pharmaceutically acceptable salt of indacaterol and water, and each 100 mL of the pharmaceutical composition contains glycopyrronium 0.045 ± 0.001 g to 0.090 ± 0.001 g, indacaterol 0.099 ± 0.001 g to 0.198 ± 0.001 g; the pharmaceutical composition is particularly suitable for aerosolizing active substances by means of a nebulizer for asthma and COPD symptoms The active agent is administered by inhalation.

Description

Aerosol pharmaceutical composition comprising glycopyrronium salt and indacaterol salt, its preparation method and use

The invention relates to an aerosol pharmaceutical composition, in particular to an aerosol pharmaceutical composition containing glycopyrronium salt and indacaterol salt and a preparation method thereof, belonging to the field of pharmaceutical preparations.

Chronic Obstructive Pulmonary Disease (COPD), referred to as COPD, is a chronic obstructive pulmonary disease characterized by persistent airflow limitation, mostly progressive development, and chronic inflammatory reaction caused by harmful gases and particles in the airway and lung tissue. related chronic respiratory diseases. The morbidity and mortality of COPD are high worldwide, and more and more countries and organizations attach great importance to it. Currently, COPD ranks the fourth leading cause of death in the world, and according to the World Health Organization (WHO), by 2020, the disease will become the third leading cause of human death in the world. In China, the prevention and treatment of COPD is also very serious, and the morbidity and mortality are increasing year by year due to aging, smoking population, environment and other factors. The disease not only seriously threatens people's physical and mental health, but also imposes a serious economic burden on the entire society. According to the Globe Burden of Disease Study, the economic burden of COPD will jump to the fifth place in the world's economic burden of disease by 2020, and the economic burden of COPD disease in China will jump to the first place.

Due to the complex pathogenesis of COPD, there is currently no specific treatment method that can reverse the disease process or significantly change the decline of lung function in clinical practice, and most of them are symptomatic treatment. There are many drugs clinically used to treat COPD, such as bronchodilators, anti-inflammatory drugs, expectorants and so on. Among them, bronchodilators are the core drugs for COPD symptom management. They are suitable for COPD treatment at all stages. They play an important role in the drug treatment of COPD by regulating the tension of airway smooth muscle, dilating the bronchi, and improving the degree of airflow limitation. Commonly used bronchodilators include three classes: anticholinergic, theophylline, and beta2-receptor agonists. Based on the characteristics of low efficacy and high side effects of theophylline, theophylline is generally not recommended for the treatment of COPD, while long-acting anticholinergic drugs (LAMA) and long-acting β2-receptor agonists (LABA) are recommended by GOLD as treatment First-line bronchodilators in stable COPD.

Glycopyrrolate is a long-acting quaternary ammonium anticholinergic drug with long-acting muscarinic receptor antagonist action, usually in the form of its bromide salt (ie, glycopyrronium bromide) (The structural formula is shown in the figure below) for clinical use.

Indacaterol is a bronchodilator that belongs to the class of long-acting inhaled beta2-receptor agonists (LABA), usually in the form of its maleate (i.e., indacaterol maleate) ( The structural formula is shown in the figure below) for clinical use.

Glycopyrronium bromide maleate indacaterol compound dry powder inhalation preparation, successfully developed by Swiss Novartis, once a day through Breezhaler dry powder inhaler for long-term relief of symptoms in adult patients with COPD.

Existing glycopyrronium bromide indacaterol maleate dry powder inhalation preparation, its auxiliary materials are mainly lactose and magnesium stearate, in the process of inhalation, the small particles in lactose and magnesium stearate may be inhaled into the lungs, As a foreign body, it has the risk of adverse reactions if it is inhaled; at the same time, due to the characteristics of the inhaled powder aerosol formulation itself, the proportion of active ingredients that can be inhaled into the lungs is relatively low, so that glycopyrronium bromide, indate maleate Luo can't play the medicine well.

In order to solve the deficiencies of the prior art, the present invention provides a propellant-free glycopyrronium salt, indacaterol salt aerosol pharmaceutical composition and a preparation method thereof.

The technical scheme of the present invention is as follows:

The pharmaceutical composition provided by the present invention uses glycopyrronium salt and indacaterol salt as active substances, based on glycopyrronium, and its concentration is between 0.045±0.001 g per 100 ml of preparation and 0.090±0.001 g per 100 ml of preparation between 0.099 ± 0.001 g per 100 ml of preparation and 0.198 ± 0.001 g per 100 ml of preparation based on indacaterol, wherein the glycopyrronium salt, indacaterol salt in the pharmaceutical preparation are exist in a completely dissolved form;

water is the only solvent;

Adjust pH with acid between 2.8 and 3.05;

benzalkonium chloride as a pharmacologically acceptable preservative;

Each 100 ml preparation contains 5 mg to 20 mg of ethylenediaminetetraacetic acid or a pharmacologically acceptable salt thereof as a pharmacologically acceptable complex agent.

According to the above-mentioned pharmaceutical composition of the present invention, preferably, the glycopyrronium salt is obtained from glycopyrronium and hydrobromic acid, hydrochloric acid, hydroiodic acid, monomethyl sulfate, methanesulfonic acid or p-toluenesulfonic acid. Formed salts; indacaterol salts are indacaterol salts formed with benzoic acid, maleic acid, succinic acid, fumaric acid or tartaric acid.

According to the above-mentioned pharmaceutical composition of the present invention, preferably, in addition to water, glycopyrronium salt, indacaterol salt, benzalkonium chloride, disodium EDTA, hydrochloric acid and optional sodium chloride , does not contain any other excipients and additives.

The present invention is concerned with liquid active substance formulation pharmaceutical compositions of these compounds usually administered by inhalation, wherein the liquid formulation pharmaceutical compositions according to the invention meet high quality standards.

To achieve optimal distribution of the active substance in the lungs, a suitable inhaler is used to administer the pharmaceutical composition in liquid formulation without propellant gas. Particularly suitable inhalers are aerosol pharmaceutical compositions capable of nebulizing in seconds a small amount of a liquid formulation having the dose required for therapeutic purposes to form aerosol pharmaceutical compositions suitable for therapeutic inhalation. Within the scope of the present invention, the preferred nebulizer is preferably capable of atomizing less than 100 μL, preferably less than 50 μL, and most preferably less than 20 μL of the active substance liquid in one or two sprays to form Aerosols with an average particle size of less than 20 microns, preferably less than 10 microns, such that the inhalable portion of the aerosol corresponds to a therapeutically effective amount.

According to the present invention, any pharmaceutically acceptable glycopyrronium salt, indacaterol salt can be used as a formulation. When glycopyrronium and indacaterol are used within the scope of the present invention, they are used as references for glycopyrronium and indacaterol. The reference for glycopyrronium corresponds to the cation of free ammonium. Glycopyrronium salts thus contain an anion as a counter ion. Glycopyrronium salts useful within the scope of the present invention preferably contain, in addition to glycopyrronium as a counter ion (anion), chloride ion, bromide ion, iodide ion, mesylate ion, p-toluenesulfonate ion and /or a compound of methyl sulfate ion. Indacaterol useful within the scope of the present invention is preferably a compound of benzoic acid, maleic acid, succinic acid, fumaric acid, tartrate ion.

In the context of the present invention glycopyrronium bromide is preferred, in the context of the present invention glycopyrronium bromide is generally understood to mean all possible amorphous and crystalline modified glycopyrronium bromide; preferably indene maleate Dacaterol, indacaterol maleate is generally understood in the context of the present invention as all possible amorphous and crystalline modified indacaterol maleate.

The formulation pharmaceutical composition of the present invention preferably does not contain any other active substances that do not contain glycopyrronium, indacaterol or a pharmaceutically acceptable salt thereof.

One or more glycopyrronium salts, indacaterol salts in the pharmaceutical composition according to the present invention are dissolved in water. No other solvents are used. In particular, this formulation has no propellant gas.

The preparation pharmaceutical composition according to the present invention preferably contains glycopyrronium salt and indacaterol salt, preferably glycopyrronium bromide and indacaterol maleate. However, such formulated pharmaceutical compositions may also contain mixtures of different glycopyrronium salts, indacaterol salts and solvates.

According to the ratio of glycopyrronium and indacaterol in the final pharmaceutical preparation, the concentration of glycopyrronium salt and indacaterol salt is determined by the desired therapeutic effect. For most of the conditions corresponding to glycopyrronium and indacaterol, the concentration of glycopyrronium is between 0.03 g per 100 g preparation and 0.10 g per 100 g preparation, and the concentration of indacaterol is between 0.033 g per 100 g preparation and between 0.22 grams per 100 grams of preparation. Since the density of the formulation is 1 g/ ^cm3 , 100 grams of formulation corresponds to a volume of 100 ml. Within the scope of this specification, the expression "per 100 mL" or "/100 mL", unless stated otherwise, is in each case per 100 mL of the formulation. Preferably it contains glycopyrronium 0.035g/100mL to 0.095g/100mL, indacaterol 0.077g/100mL to 0.209g/100mL, more preferably glycopyrronium 0.04g/100mL to 0.09g/100mL, Indacaterol in an amount of 0.088 g/100 mL to 0.198 g/100 mL. The optimum amounts are glycopyrronium 0.045±0.001 g per 100 ml preparation to 0.090±0.001 g per 100 ml preparation, and indacaterol 0.099±0.001 g per 100 ml preparation 0.198±0.001 g per 100 ml preparation.

The pH of the aerosol pharmaceutical composition of the present invention is between 2.7 and 3.1, preferably between 2.8 and 3.05, more preferably between 2.80 and 3.0, most preferably 2.9.

The pH is adjusted by adding a pharmacologically acceptable acid.

Examples of preferred inorganic acids for this purpose also include: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and/or phosphoric acid. Examples of particularly suitable organic acids are ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid and the like. The preferred inorganic acids are hydrochloric acid and sulfuric acid. It is also possible to use acids which form acid addition salts with the active substances. Among the organic acids, ascorbic acid, fumaric acid and citric acid are preferred, and citric acid is the most preferred. If desired, mixtures of the abovementioned acids can also be used, especially in the case of acids which have properties in addition to acidifying properties, for example acids as flavouring agents or antioxidants, such as citric acid and ascorbic acid.

Of the acids mentioned above, hydrochloric acid and citric acid are clearly indicated as being particularly preferred.

When necessary, pharmacologically acceptable bases can be used to accurately titrate pH. Suitable bases include, for example, alkali metal hydroxides and alkali metal carbonates. The preferred alkali metal ion is sodium. If such bases are used, care must be taken to ensure that the final salt contained in the final pharmaceutical formulation is pharmacologically compatible with the aforementioned acids.

According to the present invention, the aerosol pharmaceutical composition comprises ethylenediaminetetraacetic acid (EDTA) or one of its known salts, such as sodium EDTA or disodium EDTA dihydrate, as stable agent or complex forming agent. It is preferable to use disodium EDTA.

According to the content of disodium EDTA is between 5 mg per 100 ml preparation and 20 mg per 100 ml preparation, preferably between 5 mg per 100 ml preparation and 15 mg per 100 ml preparation, More preferably it is between 8 mg per 100 ml of formulation and 12 mg per 100 ml of formulation, most preferably 10 mg per 100 ml of formulation.

If a different EDTA salt or acid thereof is used, a similar amount of complexing agent is used.

It is noted that in relation to disodium EDTA, other additives, although less preferred than those of EDTA or its salts, can be similarly used, but which have complex properties and can be used instead, such as nitrogen Triacetic acid and its salts.

In the context of the present invention, a complexing agent preferably refers to a molecule capable of entering a coordinate bond. Preferably, the complexation is carried out by these compound cations, most preferably metal cations.

According to the present invention, other pharmacologically acceptable adjuvants may also be added to the aerosol pharmaceutical composition.

In this context adjuvant and additive refer to any pharmacologically acceptable, therapeutically useful substance which is not an active substance but can be formulated together with the active substance in a pharmacologically suitable solvent to improve the quality of the active substance preparation . Preferably, these substances have no pharmacological effect or have no comparable or at least no desired pharmacological effect in the desired therapeutic situation. These adjuvants and additives include, for example, other stabilizers, complexing agents, antioxidants, and/or preservatives, flavoring agents, vitamins, and/or other additives known in the art to extend the shelf life of the final pharmaceutical formulation. This additive also contains pharmacologically acceptable salts such as sodium chloride.

Preferred adjuvants include antioxidants such as ascorbic acid, provided that they are not used to adjust pH, vitamin A, vitamin E, tocopherol and similar vitamins or vitamin precursors that are present in humans.

Preservatives may be added to protect the formulation from contamination by pathogenic bacteria. Suitable preservatives are known in the art, in particular benzalkonium chloride, or benzoic acid, or benzoates, such as sodium benzoate, in concentrations known in the art. Preferably, according to the present invention, the preparation is mixed with benzalkonium chloride. The amount of benzalkonium chloride is between 5 mg per 100 ml preparation and 20 mg per 100 ml preparation, preferably between 5 mg per 100 ml preparation and 15 mg per 100 ml preparation, more preferably between Between 8 mg per 100 ml of formulation and 12 mg per 100 ml of formulation, with 10 mg per 100 ml of formulation being optimal.

A preferred formulation contains only benzalkonium chloride, disodium EDTA and acid required for pH adjustment, preferably hydrochloric acid, in addition to water solvent and glycopyrronium salt.

The glycopyrronium salt and indacaterol salt aerosol pharmaceutical compositions of the present invention can be prepared by mixing the individual components, ie, by mixing the individual components of the composition.

The glycopyrronium salt aerosol pharmaceutical composition of the present invention can be used with the Respimat aerosol inhalation device, and can also be used with the aerosol inhalation device shown in FIG. 1 or FIG. 2 .

The aerosol inhalation device shown in FIG. 1 is a piezoelectrically actuated droplet delivery device for delivering a medical fluid as a jet of droplets to a patient's pulmonary system, the device comprising:

case;

The liquid storage bin is arranged in the shell or communicated with the liquid passage in the shell, and is used to store a certain volume of medicinal liquid;

The ejection mechanism communicated with the liquid storage tank includes a piezoelectric actuator and an orifice plate, the orifice plate has a plurality of openings, and the piezoelectric actuator can oscillate the orifice plate at a certain frequency to generate ejected droplets flow;

at least one differential pressure sensor, arranged in the casing;

The differential pressure sensor activates the jetting mechanism when sensing a predetermined pressure change in the housing, thereby generating a jetted stream of droplets;

The jetting mechanism can produce a jetted stream of droplets, wherein at least about 70% of the droplets have an average jetted droplet diameter of less than about 5 microns, such that at least about 70% of the jetted stream of droplets is delivered to the patient's lungs.

The detailed structure and function of the aerosol inhalation device shown in Fig. 1 can be found in WO2017192767A1, US20170319796A1, WO2017192773A1, WO2017192774A1, WO2017192778A1, WO2017192782A1, CN109475707A, CN109414178A, CN109414178A, etc. FIG. 1 provides a detailed view of an exemplary injector closure mechanism. Removal of housing top cover 152 exposes injector closure actuation mechanism 506, which includes closure guide 508, sliding seal plate 510, and motor mechanism 512 that can open and close sliding seal plate 510 when motor mechanism 512 is activated . Any suitable micromotor mechanism may be used.

The aerosol inhalation device shown in FIG. 2 includes a base unit 100 , a mouthpiece 200 , a spray head 300 and a screw cap 304 . The base unit includes an air inlet 101, an air outlet 102, a slot 103 for accommodating a mouthpiece, and a keying member 104; the mouthpiece includes a first section 200a and a second section 200b, the first section 200a including the air inlet 201 and a side opening 202 for accommodating the spray generator, the first section can be inserted into the groove of the base unit, the second section 200b includes the spray outlet 203; the spray head includes the spray generator 301, the liquid container 302 and the base unit The complementary keying member 303 of the keying member; the base unit, the mouthpiece and the spray head can be connected to each other so that when the keying member is engaged with the complementary member, the spray generator is inserted into the side opening of the mouthpiece.

The detailed structure and function of the aerosol inhalation device shown in FIG. 2 can be found in patents such as CN103785086A, CN104010685A, CN104271187A, CN107929894A, etc., all of which are incorporated herein.

The propellant-free glycopyrronium salt indacaterol salt aerosol pharmaceutical composition provided by the invention not only solves the problem that the existing glycopyrronium salt indacaterol salt powder aerosol auxiliary material is inhaled into the lungs and causes side effects , and solved the problem that the actual amount of active ingredients of glycopyrronium salt indacaterol powder aerosol that can actually reach the lungs is too small, so that the product specification can be reduced and the consumption of glycopyrronium salt and indacaterol salt raw materials can be reduced. , reducing the cost of drugs and reducing the burden on patients; at the same time, because most of the existing aerosols for the treatment of chronic obstructive pulmonary disease contain propellants, on the one hand, propellants will destroy the ozone layer in the atmosphere and are not conducive to environmental protection. Due to the short fog time of the aerosol, the efficiency of the drug is reduced, and the glycopyrronium salt indacaterol salt aerosol provided by the present invention does not contain propellants and does not have the problem of having an impact on environmental protection. When used, it is foggy for a long time, which greatly improves the efficiency of the medicine.

The present invention also provides a pharmaceutical combination system, comprising an aerosol pharmaceutical composition and an aerosol inhalation device for treating COPD, wherein the aerosol pharmaceutical composition is selected from the above-mentioned glycopyrronium salts and indacaterol salts The aerosol preparation, or selected from the group consisting of ipratropium bromide, fenoterol hydrobromide, salbutamol sulfate, tiotropium bromide, odaterol hydrochloride, aclidinium bromide, umeclidinium bromide, or Various aerosol formulations.

In one embodiment, the pharmaceutical combination system treats the aerosol pharmaceutical composition by the nebulizing inhalation device to nebulize it, and the nebulizing inhalation device handles a unit dose volume of 10 to 50 μL.

In one embodiment, the aerosol inhalation device in the drug combination system is as shown in FIG. 1 or as shown in FIG. 2 .

The present invention will be further described below in conjunction with the examples, so that those skilled in the art can understand the present invention more comprehensively, but do not limit the present invention in any way. Embodiment 1-6 :

Per 100 ml of glycopyrronium and indacaterol aerosol pharmaceutical composition contains:

The remaining components are purified water, or water for injection with a temperature of 15-31°C and a density of 1.00g/ ^cm3 , which are prepared by mixing individual components, sterilized by filtration, and canned in the medicine box of the atomization device. . Comparative example

The lung deposition rate (FPF value) of the product of the present invention and the commercial product of glycopyrronium bromide indacaterol maleate powder aerosol was measured by a new generation impactor (NGI), and the results are as follows:

The above FPF values are the FPF values of the two active ingredients in the powder mist or aerosol generated by the inhalation preparation products after passing through the corresponding inhalation device, all measured by a new generation impactor (NGI). The inhalation device is Breezhaler (that is, the commercially available device of the product), the inhalation device used for the product of Example 1 of the present invention is the inhalation device shown in Figure 1, and the inhalation device used for the product of Example 6 of the present invention is the inhalation device shown in Figure 2.

Comparing the results in the above table, it can be seen that the lung deposition rate of glycopyrronium bromide indacaterol maleate aerosol of the present invention is much higher than the commercially available glycopyrronium bromide indacaterol maleate indacaterol of Novartis. Inhalation of the powder aerosol significantly improved the utilization efficiency of glycopyrronium bromide and indacaterol.

100: base unit 101, 201: Air intake 102: Air outlet 103: Groove 104, 303: key lock member 152: top cover 154: mouthpiece 200: Interface tube 200a: First segment 200b: Second segment 202: side opening 203: Spray outlet 300: Spray head 301: Spray Generator 302: Liquid container 304: Screw cap 504: Ejector jet outlet 506: Brake mechanism 508: Closed guide 510: Sliding seal plate 512: Motor mechanism 514: Screw

1 is a schematic diagram of aerosol inhalation devices related to patents such as WO2017192767A1, US20170319796A1, WO2017192773A1, WO2017192774A1, WO2017192778A1, WO2017192782A1, CN109475707A, CN109414178A, CN109475709A, etc.

Fig. 2 is a schematic diagram of the aerosol inhalation device involved in patents such as CN103785086A, CN104010685A, CN104271187A, CN107929894A and the like.

152: top cover

154: mouthpiece

504: Ejector jet outlet

506: Brake mechanism

508: Closed guide

510: Sliding seal plate

512: Motor mechanism

514: Screw

Claims (12)

A propellant-free aerosol pharmaceutical composition, characterized in that the pharmaceutical composition comprises glycopyrronium salt, indacaterol salt, preservative benzalkonium chloride, complex agent ethylenediaminetetraacetic acid or its Pharmaceutically acceptable salt, water, water is the only solvent in the pharmaceutical composition, wherein glycopyrronium salt, indacaterol salt exist in a completely dissolved form; with glycopyrronium, indacaterol and ethyl acetate In terms of diaminetetraacetic acid, each 100 mL of the pharmaceutical composition contains glycopyrronium 0.045±0.001g to 0.090±0.001g, indacaterol 0.099±0.001g to 0.198±0.001g, and ethylenediaminetetraacetic acid 5mg to 20mg; The pH value of the pharmaceutical composition is between 2.8 and 3.05; the glycopyrronium salt is glycopyrronium bromide, and the indacaterol salt is indacaterol maleate. The pharmaceutical composition according to item 1 of the claimed scope, characterized in that the complexing agent is disodium EDTA, calculated as EDTA, and every 100 mL of the pharmaceutical composition contains EDTA Acetic acid 8-12 mg. The pharmaceutical composition according to item 1 or 2 of the patent application scope is characterized in that each 100 mL of the pharmaceutical composition contains 5 mg to 20 mg of the preservative benzalkonium chloride. The pharmaceutical composition according to item 1 of the claimed scope, characterized in that the pH value is between 2.8 and 3.0. The pharmaceutical composition according to item 4 of the claimed scope is characterized in that the pH value is 2.9. The pharmaceutical composition according to claim 1 of the claimed scope is characterized in that the pH value is adjusted with an inorganic acid. The pharmaceutical composition according to item 6 of the patent application scope is characterized in that the inorganic acid is hydrochloric acid. The pharmaceutical composition according to item 1 of the scope of the application is characterized in that in addition to water, glycopyrronium salt, indacaterol salt, benzalkonium chloride, disodium EDTA, hydrochloric acid and sodium chloride Besides, it does not contain any other excipients and additives. A use of the pharmaceutical composition described in any one of items 1 to 8 of the scope of application in the preparation of a medicament for the treatment of asthma and/or COPD, characterized in that the pharmaceutical composition is used in an inhaler for Atomize. Use according to claim 9, characterized in that the volume of the unit dose is 10 to 50 μL. A drug combination system, comprising an aerosol pharmaceutical composition and a nebulized inhalation device for treating COPD, wherein the aerosol pharmaceutical composition is selected from the drugs described in any one of items 1 to 8 of the patent application scope combination. The pharmaceutical combination system according to claim 11, wherein the aerosol pharmaceutical composition is processed by the nebulizing inhalation device to be atomized, and the unit dose volume processed by the nebulizing inhalation device 10 to 50 μL.

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