CN111971034A

CN111971034A - Aerosol pharmaceutical composition containing glycopyrronium salt and preparation method and application thereof

Info

Publication number: CN111971034A
Application number: CN201980023568.6A
Authority: CN
Inventors: 张春雨; 秦践; 李麒麟
Original assignee: Sichuan Haisco Pharmaceutical Co Ltd
Current assignee: Sichuan Haisco Pharmaceutical Co Ltd
Priority date: 2018-07-26
Filing date: 2019-07-03
Publication date: 2020-11-20
Also published as: TW202019397A; WO2020019953A1; CN116196298A

Abstract

A propellant-free aerosol pharmaceutical composition comprising a pharmaceutically acceptable salt of glycopyrronium and water, said pharmaceutical composition comprising from 0.045 ± 0.001g to 0.090 ± 0.001g glycopyrronium per 100 mL; the pharmaceutical composition is particularly suitable for the aerosol formation of the active substance by means of a nebulizer for the administration of the active agent by inhalation in asthma and COPD symptoms.

Description

Aerosol pharmaceutical composition containing glycopyrronium salt and preparation method and application thereof

Technical Field

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

Background

Chronic Obstructive Pulmonary Disease (COPD), referred to as Chronic Obstructive Pulmonary Disease, is a Chronic respiratory Disease characterized by persistent airflow limitation, which is a progressive Disease related to Chronic inflammatory reactions of airways and lung tissues caused by harmful gases and particles. The morbidity and mortality of COPD is high worldwide and is increasingly being highly appreciated by various countries and organizations. COPD is currently the fourth leading cause of death worldwide and, as predicted by the World Health Organization (WHO), by 2020, will be the third leading cause of human death worldwide. In China, the prevention and treatment condition of COPD is very severe, and the morbidity and mortality rate rise year by year with aging, smoking population, environment and other factors. The disease not only seriously threatens the physical and psychological health of people, but also causes serious economic burden to the whole society. According to the prediction of Global Burden of Disease studio, the economic Burden of COPD will jump the fifth place of the economic Burden of world diseases by 2020, while the economic Burden of COPD in China will jump the first place.

Because the pathogenesis of COPD is complex, no specific treatment method which can reverse the disease process or remarkably change the decline of the lung function is clinically available at present, and the treatment is usually symptomatic treatment. Many drugs for clinically treating COPD are available, such as bronchodilators, anti-inflammatory drugs, expectorants, and the like. The bronchodilators are core drugs for COPD symptom management, are suitable for COPD treatment of various stages, and play an important role in the drug treatment of COPD by adjusting the tension of airway smooth muscle, dilating bronchus and improving the airflow limitation degree. Commonly used bronchodilators include three classes: anticholinergics, theophyllines, beta 2 receptor agonists. Theophylline is generally not recommended for the treatment of COPD based on its low efficacy and high side effects, whereas long-acting anticholinergic drugs (LAMA) and long-acting beta 2 receptor agonists (LABA) are recommended by GOLD as first-line bronchodilators for the treatment of stable chronic obstructive pulmonary disease.

Glycopyrrolate (glycopyrrolate) is a long-acting quaternary ammonium anticholinergic drug with long-acting toxic alkaloid receptor antagonist effect, is generally used clinically in the form of bromide salt (glycopyrrolate) with the structural formula shown in the figure below, is successfully developed by noval, switzerland, and is administered 1 time a day through a Breezhaler dry powder inhaler for long-term relief of symptoms in adult COPD patients.

In the existing glycopyrronium bromide dry powder inhalation preparation, the auxiliary materials mainly comprise lactose and magnesium stearate, and during the inhalation process of a patient, small particles in the lactose and the magnesium stearate have the possibility of being inhaled into the lung and are inhaled as foreign matters to cause the risk of adverse reaction; meanwhile, due to the characteristics of the formulation of the inhalation powder inhalation, the effective component of the inhalation powder inhalation can be inhaled into the lung in a lower proportion, so that the glycopyrronium bromide can not well exert the drug effect.

Disclosure of Invention

In order to solve the defects of the prior art, the invention provides a glycopyrronium salt aerosol pharmaceutical composition without a propellant and a preparation method thereof.

The technical scheme of the invention is as follows:

the present invention provides pharmaceutical compositions comprising one or more glycopyrronium salts as active substance in a concentration of between 0.045 ± 0.001g per 100ml of formulation and 0.090 ± 0.001g per 100ml of formulation, based on glycopyrronium salt, wherein the one or more glycopyrronium salts are present in the pharmaceutical formulation in fully dissolved form;

water is the only solvent;

adjusting the pH value to between 2.8 and 3.05 with an acid;

benzalkonium chloride as a pharmacologically acceptable preservative;

5mg to 20mg of ethylenediamine tetraacetic acid or a pharmacologically acceptable salt thereof per 100ml of the preparation is used as a pharmacologically acceptable complexing agent.

According to the above pharmaceutical composition of the present invention, preferably, the glycopyrronium salt is a salt of glycopyrronium with hydrobromic acid, hydrochloric acid, hydroiodic acid, monomethyl sulfate, methanesulfonic acid or p-toluenesulfonic acid.

The above-mentioned pharmaceutical composition according to the present invention preferably does not comprise any other excipients and additives other than water, glycopyrronium salt, benzalkonium chloride, disodium edetate, hydrochloric acid and optionally sodium chloride.

The invention relates to liquid active agent formulation pharmaceutical compositions of these compounds for administration by inhalation in general, wherein the liquid formulation pharmaceutical compositions according to the invention meet high quality standards.

To achieve an optimal active substance distribution of the active substance in the lungs, pharmaceutical compositions in liquid preparation without propellant gas are administered using a suitable inhaler. A particularly suitable inhaler is one that is capable of aerosolizing a small quantity of a liquid formulation having the dose required for therapeutic purposes within a few seconds to form an aerosol pharmaceutical composition suitable for therapeutic inhalation. Within the scope of the present invention, a preferred nebulizer is one that is preferably capable of nebulizing less than 100 microliters, preferably less than 50 microliters, most preferably less than 20 microliters of liquid active substance in one or two puffs to form an aerosol having an average particle size of less than 20 micrometers, preferably less than 10 micrometers, such that the respirable fraction of the aerosol corresponds to a therapeutically effective amount.

Any pharmaceutically acceptable glycopyrronium salt can be used as a formulation according to the invention. The term glycopyrronium is used within the scope of the present invention as a reference to glycopyrronium species. The glycopyrronium reference corresponds to the cation of the free ammonium. The glycopyrronium salt thus comprises an anion as the counterion. Glycopyrronium salts which can be used in the context of the present invention are preferably compounds which, in addition to glycopyrronium, also contain chloride, bromide, iodide, methanesulfonate, p-toluenesulfonate and/or methosulfate as counter-ions (anions).

Glycopyrronium bromide is preferred within the scope of the invention. Reference to glycopyrronium bromide within the scope of the invention is generally understood to be a reference to all possible amorphous and crystalline modified glycopyrronium bromide.

The pharmaceutical composition of the formulation of the invention is preferably free of any other glycopyrronium-free active substance or pharmaceutically acceptable salt thereof.

One or more glycopyrronium salts of the pharmaceutical composition are dissolved in water. No other solvent was used. In particular, such formulations are devoid of propellant gas.

The pharmaceutical composition of the formulation according to the invention preferably contains only a single glycopyrronium salt, preferably glycopyrronium bromide. However, such pharmaceutical compositions may also contain mixtures of different glycopyrronium salts and solvates.

Depending on the glycopyrronium ratio of the final pharmaceutical preparation, the concentration of glycopyrronium salt is determined by the therapeutic effect to be achieved. For most conditions responsive to glycopyrronium, the concentration of glycopyrronium is between 0.03 grams per 100 grams of formulation and 0.10 grams per 100 grams of formulation. Because the density of the preparation is 1g/cm³A 100 gram formulation corresponds to a volume of 100 ml. Within the context of the present description, the expression "per 100 mL" or "/100 mL" is, unless stated otherwise, in each case a formulation per 100 mL. Preferably 0.035g/100mL to 0.095g/100mL, more preferably 0.04g/100mL to 0.09g/100 mL. The optimal amount is 0.045 +/-0.001 g per 100ml of the preparation to 0.090 +/-0.001 g per 100ml of the 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, and most preferably 2.9.

The pH is adjusted by the addition of a pharmacologically acceptable acid.

Preferred examples of 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. Preferred inorganic acids are hydrochloric acid and sulfuric acid. It is also possible to use acids which form acid addition salts with the active substance. Among the organic acids, ascorbic acid, fumaric acid and citric acid are preferred, and citric acid is most preferred. Mixtures of the above acids may also be used, if desired, especially in the case of acids which have other properties in addition to their acidifying properties, for example as flavoring agents or antioxidants, such as citric acid and ascorbic acid.

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

If necessary, a pharmacologically acceptable base can be used to precisely titrate the 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 above-mentioned acids.

According to the present invention, the aerosol pharmaceutical composition comprises ethylenediaminetetraacetic acid (EDTA) or one of its known salts, such as sodium ethylenediaminetetraacetate or disodium ethylenediaminetetraacetate dihydrate, as a stabilizer or a complex former. Disodium edetate is preferably used.

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

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

It is noted that other additives, which are less preferred than ethylenediaminetetraacetic acid or a salt thereof, but which have complexing properties such as nitrilotriacetic acid and salts thereof, may similarly be used in relation to disodium ethylenediaminetetraacetate.

In the context of the present invention, complexing agents preferably mean molecules which are capable of entering into a coordinate bond. Preferably, the complexation is performed by cations of these compounds, most preferably metal cations.

According to the invention, other pharmacologically acceptable auxiliary agents can also be added to the aerosol pharmaceutical composition.

Auxiliaries and additives in this context mean any pharmacologically acceptable, therapeutically useful substance which is not an active substance but which can be formulated together with the active substance in a pharmacologically suitable solvent in order to improve the quality of the active substance preparation. Preferably, these substances have no pharmacological effect or have no equivalent or at least no desired pharmacological effect under the desired therapeutic conditions. Such adjuvants and additives may include, for example, other stabilizers, complexing agents, antioxidants, and/or preservatives, flavoring agents, vitamins, and/or other additives known in the art that may prolong the shelf life of the final pharmaceutical formulation. Such additives also include pharmaceutically acceptable salts, such as sodium chloride.

Preferred adjuvants include antioxidants, such as ascorbic acid, but with the proviso that they are not used to adjust the pH, vitamin a, vitamin E, tocopherol and similar vitamins or vitamin precursors present in the human body.

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

Preferred formulations contain, in addition to the aqueous solvent and the glycopyrronium salt, only benzalkonium chloride, disodium edetate and the acid required to adjust the pH, preferably hydrochloric acid.

The glycopyrronium salt aerosol pharmaceutical compositions of the invention can be prepared by mixing the individual components.

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

The aerosol inhalation device of figure 1 is a piezo-electrically actuated droplet delivery device for delivering a medical fluid as a stream of ejected droplets to the pulmonary system of a patient, the device comprising:

a housing;

the liquid storage bin is arranged in the shell or is communicated with a liquid passage in the shell and is used for storing liquid medicine with a certain volume;

an ejection mechanism in fluid communication with the reservoir, the ejection mechanism including a piezoelectric actuator and an orifice plate, the orifice plate having a plurality of openings, the piezoelectric actuator oscillating the orifice plate at a frequency to produce a stream of ejected droplets;

at least one differential pressure sensor disposed within the housing;

the differential pressure sensor activates the spray mechanism upon sensing a predetermined pressure change within the housing, thereby producing a stream of sprayed droplets;

the ejection mechanism may generate an ejected stream of droplets in which at least about 70% of the droplets have an average ejected droplet diameter of less than about 5 microns, such that at least about 70% of the ejected stream of droplets is delivered to the lungs of the patient.

The detailed structure and function of the aerosol inhalation device shown in figure 1 can be found in patents such as WO2017192767a1, US20170319796a1, WO2017192773a1, WO2017192774a1, WO2017192778a1, WO2017192782a1, CN109475707A, CN109414178A, CN109475709A, etc., which are incorporated herein in their entirety. FIG. 1 provides a detailed view of an exemplary injector closure mechanism. Removal of the housing cap 152 exposes an injector closure actuation mechanism 506, which includes a closure guide 508, a sliding seal plate 510, and a motor mechanism 512, which motor mechanism 512 can open and close the sliding seal plate 510 when the motor mechanism 512 is activated. Any suitable micro-motor mechanism may be used.

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

The detailed structure and function of the aerosol inhalation device shown in figure 2 can be found in patent publications CN103785086A, CN104010685A, CN104271187A, CN107929894A, etc., which are incorporated herein in their entirety.

The glycopyrronium salt aerosol pharmaceutical composition without the propellant solves the problem that the auxiliary material of the existing glycopyrronium bromide powder aerosol is inhaled into the lung to generate side effect and also solves the problem that the amount of the active ingredient of the glycopyrronium bromide powder aerosol actually reaching the lung is less, thereby reducing the product specification, reducing the dosage of the glycopyrronium salt raw material, reducing the drug cost and lightening the burden of patients; meanwhile, most of the existing aerosol for treating chronic obstructive pulmonary disease contains propellant, on one hand, the propellant can destroy the ozone layer in the atmosphere and is not beneficial to environmental protection, on the other hand, the aerosol has short fogging time and reduces the efficiency of the drug to play, but the glycopyrronium salt aerosol provided by the invention does not contain the propellant and has no influence on environmental protection, and meanwhile, the aerosol has long fogging time when in use, so that the efficiency of the drug to play is greatly improved.

The present invention also provides a pharmaceutical combination system comprising an aerosol pharmaceutical composition selected from the aerosol formulations comprising glycopyrronium salts described above, or selected from the aerosol formulations comprising one or more of ipratropium bromide, fenoterol hydrobromide, salbutamol sulphate, tiotropium bromide, odaterol hydrochloride, aclidinium bromide, umeclidinium bromide, and an aerosol inhalation device for the treatment of COPD.

In one embodiment, the pharmaceutical combination system is adapted to treat the aerosol pharmaceutical composition to aerosolize it by the aerosolization inhalation device, the aerosolization inhalation device being adapted to treat a unit dose volume of from 10 to 50 microliters.

In one embodiment, the medicinal combination system is an aerosol inhalation device as shown in figure 1 or figure 2.

Drawings

Fig. 1 is a schematic diagram of an aerosol inhalation device related to patents such as WO2017192767a1, US20170319796a1, WO2017192773a1, WO2017192774a1, WO2017192778a1, WO2017192782a1, CN109475707A, CN109414178A, CN109475709A, etc.

Fig. 2 is a schematic view of an aerosol inhalation device according to patents CN103785086A, CN104010685A, CN104271187A, and CN 107929894A.

Detailed Description

The present invention is further described below in connection with examples, which will enable those skilled in the art to more fully understand the present invention, but which are not intended to limit the invention in any way.

Examples 1 to 6:

an aerosol pharmaceutical composition comprising per 100ml of glycopyrronium salt:

the rest component is purified water, or purified water with a temperature of 15-31 deg.C and a density of 1.00g/cm³The water for injection of (1) is prepared by mixing the individual components,after filtration sterilization, the mixture is canned in a medicine box of an atomizing device.

Comparative example

The lung deposition rate (FPF value) of the product of the invention and a commercial glycopyrrolate aerosol was determined by means of a New Generation Impactor (NGI) and the results were as follows:

the above FPF values are FPF values for the active ingredient glycopyrronium bromide in the powder mist or aerosol produced after the inhalation formulation product passes through the corresponding inhalation device, both measured by the New Generation Impactor (NGI), where the inhalation device for inhalation of glycopyrronium bromide by nova corporation is Breezhaler (i.e. a commercially available device for this product), the inhalation device used for the product of example 1 of the present invention is the inhalation device shown in fig. 1, and the inhalation device used for the product of example 6 of the present invention is the inhalation device shown in fig. 2.

Comparing the results in the above table, it can be seen that the lung deposition rate of the glycopyrronium bromide aerosol of the invention is much higher than that of the glycopyrronium bromide inhalation powder aerosol sold by Nowa company, and the utilization efficiency of glycopyrronium bromide is remarkably improved.

Claims

A propellant-free pharmaceutical aerosol composition comprising a glycopyrronium salt, a preservative benzalkonium chloride, a complexing agent ethylenediaminetetraacetic acid or a pharmaceutically acceptable salt thereof, water, wherein water is the sole solvent in the pharmaceutical composition, wherein the glycopyrronium salt is present in fully dissolved form; the pharmaceutical composition contains 0.045 +/-0.001 g to 0.090 +/-0.001 g of glycopyrronium and 5mg to 20mg of ethylenediamine tetraacetic acid per 100mL of glycopyrronium and ethylenediamine tetraacetic acid; the pH of the pharmaceutical composition was 2.8 and 3.05.
The pharmaceutical composition according to claim 1, characterized in that the glycopyrronium salt is a salt of glycopyrronium and hydrobromic acid, hydrochloric acid, hydroiodic acid, monomethyl sulfate, methanesulfonic acid or p-toluenesulfonic acid.
The pharmaceutical composition according to claim 2, characterized in that the glycopyrronium salt is glycopyrronium bromide.
The pharmaceutical composition of any one of claims 1-3, wherein the complexing agent is disodium edetate and comprises 8-12mg of edetic acid per 100mL of the pharmaceutical composition, calculated as edetic acid.
The pharmaceutical composition according to any one of claims 1-4, characterized in that the preservative benzalkonium chloride is comprised between 5 and 20mg per 100mL of said pharmaceutical composition.
Pharmaceutical composition according to any one of claims 1 to 5, characterized in that the pH value is between 2.8 and 3.0.
The pharmaceutical composition according to claim 6, characterized in that the pH value is 2.9.
Pharmaceutical composition according to any one of claims 1 to 7, characterized in that the pH is adjusted with a mineral acid.
The pharmaceutical composition according to claim 8, characterized in that the mineral acid is hydrochloric acid.
Pharmaceutical composition according to any one of claims 1 to 9, characterized in that it does not comprise any other excipients and additives than water, glycopyrronium salt, benzalkonium chloride, disodium edetate, hydrochloric acid and optionally sodium chloride.
Use of a pharmaceutical composition according to any one of claims 1 to 10, characterized in that the pharmaceutical composition is used for nebulization in an inhaler.
Use according to claim 11, characterized in that the volume of the unit dose is between 10 and 50 microliters.
Use of a pharmaceutical composition according to any one of claims 1 to 10 in the manufacture of a medicament for the treatment of COPD.
A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 10, characterized in that it is carried out by mixing the individual components.
Use of a pharmaceutical composition according to any one of claims 1 to 10 in an aerosol device as shown in figure 1.
Use of a pharmaceutical composition according to any one of claims 1 to 10 in an aerosol device as shown in figure 2.
A pharmaceutical combination system comprising an aerosol pharmaceutical composition selected from a pharmaceutical composition according to any one of claims 1 to 10, or an aerosol formulation comprising one or more of ipratropium bromide, fenoterol hydrobromide, salbutamol sulphate, tiotropium bromide, odaterol hydrochloride, aclidinium bromide, umeclidinium bromide, and an aerosol inhalation device for the treatment of COPD.
The pharmaceutical combination according to claim 17, wherein the aerosol pharmaceutical composition is aerosolized by treatment with the aerosol inhalation device having a unit dose volume of 10 to 50 microliters.
A pharmaceutical combination according to claim 18, wherein the aerosol inhalation device is as shown in figure 1 or as shown in figure 2.