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CN116173025A - Aerosol pharmaceutical composition containing glycopyrronium salt and indacaterol salt, and preparation method and application thereof - Google Patents

Aerosol pharmaceutical composition containing glycopyrronium salt and indacaterol salt, and preparation method and application thereof Download PDF

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CN116173025A
CN116173025A CN202310107966.4A CN202310107966A CN116173025A CN 116173025 A CN116173025 A CN 116173025A CN 202310107966 A CN202310107966 A CN 202310107966A CN 116173025 A CN116173025 A CN 116173025A
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pharmaceutical composition
salt
acid
indacaterol
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张春雨
秦践
李麒麟
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Sichuan Haisco Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics

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  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The present invention provides a propellant-free aerosol pharmaceutical composition comprising a pharmaceutically acceptable salt of glycopyrrolate, a pharmaceutically acceptable salt of indacaterol and water, the pharmaceutical composition comprising 0.045±0.001g to 0.090±0.001g, indacaterol 0.099±0.001g to 0.198±0.001g of glycopyrrolate per 100 mL; the pharmaceutical composition is particularly suitable for aerosol formation of active substances by means of a nebulizer for administration of active agents by inhalation in asthma and COPD symptoms.

Description

Aerosol pharmaceutical composition containing glycopyrronium salt and indacaterol salt, and preparation method and application thereof
The application is a divisional application of Chinese patent application with the application date of 2019, 7 month and 3 days, the application number of 201980023670.6 and the name of 'an aerosol pharmaceutical composition containing glycopyrronium salt and indacaterol salt, and a 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 indacaterol salt and a preparation method thereof, belonging to the field of pharmaceutical preparations.
Background
Chronic obstructive pulmonary disease (Chronic Obstructive Pulmonary Disease, COPD), abbreviated as chronic obstructive pulmonary disease, is a chronic respiratory disease characterized by sustained airflow limitation, which is a progressive development associated with chronic inflammatory reactions of the airways and lung tissue due to noxious gases and particulates. COPD has a high morbidity and mortality worldwide, and is increasingly highly valued by various countries and organizations.
Due to the complex pathogenesis of COPD, there is no specific therapeutic approach clinically available to reverse the disease process or significantly alter the decline of lung function, mostly symptomatic. There are many drugs used clinically for the treatment of COPD, such as bronchodilators, anti-inflammatory agents, expectorants, etc. The bronchodilator is a core medicine for COPD symptom management, is suitable for COPD treatment in each stage, and plays an important role in COPD drug treatment by regulating the tension of airway smooth muscle, dilating bronchi, and improving the airflow limitation degree. Commonly used bronchodilators include three classes: anticholinergic, theophylline, and β2 receptor agonists. Based on the low efficacy and high side effects of theophylline, it is generally not recommended to treat COPD, whereas long acting anticholinergic drugs (LAMA) and long acting β2 receptor agonists (LABA) are recommended by GOLD as first line bronchodilators for the treatment of slow-blocking lungs in stationary phase.
Glycopyrrolate (glycopyrrolate) is a long-acting quaternary ammonium anticholinergic agent with a long-acting toxic, and is usually used clinically in the form of its bromide salt (i.e. glycopyrrolate, glycopyrronium bromide) (structural formula shown in the following figures).
Figure SMS_1
Indacaterol (indacaterol) is a bronchodilator belonging to the class of long-acting inhaled β2 receptor agonists (LABA), usually in the form of its maleate salt (i.e. indacaterol maleate, indacaterol maleate), the structural formula of which is shown in the following figure, for clinical use.
Figure SMS_2
The glycopyrrolate-indacaterol maleate compound dry powder inhalation preparation is successfully developed by Nohua, switzerland, is used for relieving the symptoms of adult COPD patients for a long time by taking the preparation through a Breezhal dry powder inhaler 1 time a day.
The existing glycopyrronium bromide indacaterol maleate dry powder inhalation preparation mainly comprises lactose and magnesium stearate as auxiliary materials, wherein small particles in the lactose and the magnesium stearate are likely to be inhaled into the lung in the inhalation process, and the small particles are likely to be inhaled as foreign matters to cause adverse reactions; meanwhile, due to the characteristics of the inhalation powder spray formulation, the effective components which can be inhaled into the lung occupy a relatively low proportion, so that the glycopyrrolate and the indacaterol maleate can not exert the drug effect well.
Disclosure of Invention
In order to solve the defects of the prior art, the invention provides a glycopyrronium salt and indacaterol salt aerosol pharmaceutical composition without propellant and a preparation method thereof.
The technical scheme of the invention is as follows:
the invention provides a pharmaceutical composition, which takes glycopyrronium salt and indacaterol salt as active substances, the concentration of the glycopyrronium salt and the indacaterol salt is between 0.045+/-0.001 gram and 0.090+/-0.001 gram of each 100ml of preparation, and the concentration of the indacaterol salt and the indacaterol salt is between 0.099+/-0.001 gram and 0.198+/-0.001 gram of each 100ml of preparation, wherein the glycopyrronium salt and the indacaterol salt in the pharmaceutical preparation exist in a completely dissolved form;
water is the only solvent;
adjusting the pH value to be between 2.8 and 3.05 by acid;
benzalkonium chloride as a pharmacologically acceptable preservative;
each 100ml of the preparation contains 5mg to 20mg of ethylenediamine tetraacetic acid or a pharmacologically acceptable salt thereof as a pharmacologically acceptable complexing agent.
The above pharmaceutical composition according to the present invention, preferably, the glycopyrronium salt is a salt of glycopyrronium and hydrobromic acid, hydrochloric acid, hydroiodic acid, monomethyl sulfate, methanesulfonic acid or p-toluenesulfonic acid; the indacaterol salt is a salt formed by indacaterol and benzoic acid, maleic acid, succinic acid, fumaric acid or tartaric acid.
The above-described pharmaceutical composition according to the present invention preferably does not comprise any other excipients and additives other than water, glycopyrronium salt, indacaterol salt, benzalkonium chloride, disodium edetate, hydrochloric acid and optionally sodium chloride.
The present invention relates to liquid active substance preparation pharmaceutical compositions of these compounds, which are usually administered by inhalation, wherein the liquid preparation pharmaceutical compositions according to the invention meet high quality standards.
To achieve optimal active substance distribution in the lungs, liquid formulation pharmaceutical compositions without propellant gas are administered using a suitable inhaler. Particularly suitable inhalers are those capable of nebulizing a small amount of a liquid formulation having a 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 preferably capable of atomizing less than 100 microliters, preferably less than 50 microliters, and most preferably less than 20 microliters of an active liquid in one or two puffs to form an aerosol having 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.
Any pharmaceutically acceptable salt of glycopyrronium, indacaterol, can be used as a formulation according to the present invention. Glycopyrrolate, indacaterol, are used as references to glycopyrrolate, indacaterol, when used within the scope of the present invention. The glycopyrronium reference corresponds to the free ammonium cation. The glycopyrronium salt thus comprises an anion as counter ion. The glycopyrronium salts which can be used within the scope of the present invention are preferably compounds which comprise, in addition to glycopyrronium, also chloride, bromide, iodide, methanesulfonate, p-toluenesulfonate and/or methylsulfate ions as counter ions (anions). Indacaterol which can be used within the scope of the present invention is preferably a compound of the benzoic, maleic, succinic, fumaric, tartaric ion.
Glycopyrrolate is preferred within the scope of the present invention, reference to glycopyrrolate within the scope of the present invention generally being understood as reference to all possible amorphous and crystalline modified glycopyrrolate; the preferred indacaterol maleate reference within the scope of the present invention is generally understood to be a reference to all possible amorphous and crystalline modifications of indacaterol maleate.
The pharmaceutical compositions of the formulation of the present invention are preferably free of any other active substance which does not contain glycopyrronium, indacaterol or a pharmaceutically acceptable salt thereof.
One or more of the glycopyrronium salts, indacaterol salts in the pharmaceutical composition of the formulation according to the present invention are dissolved in water. No other solvents were used. In particular, such formulations are free of propellant gas.
The pharmaceutical composition of the formulation according to the invention preferably contains a glycopyrronium salt, an indacaterol salt, preferably glycopyrronium bromide with indacaterol maleate. However, such formulated pharmaceutical compositions may also contain mixtures of different glycopyrronium salts, indacaterol salts and solvates.
Glycopyrronium, indac, according to the final pharmaceutical formulationThe concentrations of the glycopyrronium salt and indacaterol salt of te Luo Bili depend on the therapeutic effect to be achieved. For the most part, the conditions responsive to glycopyrrolate, indacaterol, the concentration of glycopyrrolate is between 0.03 g per 100 g of formulation and 0.10 g per 100 g of formulation, and the concentration of indacaterol is between 0.033 g per 100 g of formulation and 0.22 g per 100 g of formulation. Because the density of the preparation is 1g/cm 3 100 grams of the formulation corresponds to a volume of 100 ml. Within the scope of the present specification, the expression "per 100mL" or "/100mL" is, unless stated differently, in each case per 100mL of formulation. Preferably in an amount of 0.035g/100mL to 0.095g/100mL, indacaterol 0.077g/100mL to 0.209g/100mL, more preferably in an amount of 0.04g/100mL to 0.09g/100mL, indacaterol 0.088g/100mL to 0.198g/100 mL. The optimal amounts are 0.045+ -0.001 g glycopyrronium per 100ml formulation to 0.090+ -0.001 g, indacaterol 0.099+ -0.001 g to 0.198+ -0.001 g per 100ml formulation.
The aerosol pharmaceutical composition of the present invention has a pH of 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 mineral acids preferred 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, etc. Preferred mineral 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, with citric acid being most preferred. If desired, mixtures of the above-mentioned acids can also be used, in particular in the case of acids having other properties in addition to the acidifying properties, for example acids 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 particularly preferred.
If necessary, a pharmacologically acceptable base may 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 salts contained in the final pharmaceutical formulation are pharmacologically compatible with the acids described above.
According to the invention, the aerosol pharmaceutical composition comprises ethylenediamine tetraacetic acid (EDTA) or one of its known salts, such as sodium ethylenediamine tetraacetate or disodium ethylenediamine tetraacetate dihydrate, as a stabilizer or complex former. Disodium ethylenediamine tetraacetate is preferably used.
According to the disodium edetate content 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.
If a different salt of ethylenediamine tetraacetic acid or acid thereof is used, a similar amount of complexing agent is used.
It is noted that other additives, although less preferred than ethylenediamine tetraacetic acid or its salts, may be similarly used in relation to disodium ethylenediamine tetraacetic acid, but with complexing properties may be substituted for, for example, nitrilotriacetic acid and its salts.
Complexing agent in the context of the present invention preferably means a molecule capable of entering into a coordinative bond. Preferably, the complexing is carried out by means of cations, preferably metal cations, of these compounds.
According to the invention, other pharmacologically acceptable auxiliaries can also be added to the aerosol pharmaceutical composition.
Adjuvants and additives in this context mean any pharmacologically acceptable, therapeutically useful substance which is not an active substance but which can be formulated with the active substance in a pharmacologically suitable solvent in order to improve the quality of the active substance formulation. Preferably, these substances have no pharmacological effect or no equivalent or at least no desired pharmacological effect in the desired therapeutic situation. Such 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 that can extend 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 provided that they are not used to adjust 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 in the art, in particular benzalkonium chloride, or benzoic acid, or benzoate salts, for example sodium benzoate, in concentrations known in the art. Preferably, according to the invention, benzalkonium chloride is mixed in the formulation. 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 comprise, apart from the aqueous solvent and the glycopyrronium salt, only chlorobenzylammonium, disodium ethylenediamine tetraacetate and the acid required for pH adjustment, preferably hydrochloric acid.
The glycopyrronium salt and indacaterol salt aerosol pharmaceutical compositions of the present invention may be prepared by mixing the individual components.
The glycopyrronium salt aerosol pharmaceutical composition of the present invention may be used in conjunction with a Respimat aerosol inhalation device or with an aerosol inhalation device as shown in fig. 1 or 2.
The aerosol inhalation device of fig. 1 is a piezo-actuated droplet delivery device for delivering a medical fluid as a jet of droplets to the pulmonary system of a patient, the device comprising:
a housing;
the liquid storage bin is arranged in the shell or communicated with the liquid passage in the shell and is used for storing a certain volume of liquid medicine;
an ejection mechanism in fluid communication with the reservoir, the ejection mechanism comprising a piezoelectric actuator and an orifice plate, the orifice plate having a plurality of openings, the piezoelectric actuator being operable to oscillate 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 jetting mechanism upon sensing a predetermined pressure change within the housing, thereby producing a jet of droplets;
the ejection mechanism can produce a stream of ejected 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 droplet stream is delivered to the patient's lungs.
The detailed construction and function of the aerosol inhalation device shown in fig. 1 can be found in WO2017192767A1, US20170319796A1, WO2017192773A1, WO2017192774A1, WO2017192778A1, WO2017192782A1, CN109475707A, CN109414178A, CN109475709A, etc. patents, which are incorporated herein in their entirety. FIG. 1 provides a detailed view of an exemplary injector closing mechanism. Removing the housing top cover 152 exposes the injector seal actuation mechanism 506, which includes a seal guide 508, a sliding seal plate 510, and a motor mechanism 512, the motor mechanism 512 opening and closing 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 key lock 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 key member 303 complementary to the key member of the base unit; the base unit, mouthpiece and spray head can be connected to each other such that when the key lock 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 CN103785086A, CN104010685A, CN104271187A, CN107929894a et al, which is incorporated herein in its entirety.
The glycopyrronium salt indacaterol salt aerosol pharmaceutical composition without the propellant provided by the invention solves the problem that the existing glycopyrronium salt indacaterol salt aerosol auxiliary material is inhaled into the lung to generate side effects, and solves the problem that the active ingredient of the glycopyrronium salt indacaterol salt aerosol can actually reach the lung in a small amount, so that the product specification can be reduced, the consumption of the glycopyrronium salt and indacaterol salt raw materials is reduced, the cost of the medicine is reduced, and the burden of patients is lightened; meanwhile, as most of the existing aerosols for treating chronic obstructive pulmonary diseases contain propellant, on one hand, the propellant can destroy the ozone layer in the atmosphere, which is unfavorable for environmental protection, and on the other hand, the aerosol reduces the efficiency of the drug action due to short mist time, while the glycopyrronium salt indacaterol salt aerosol provided by the invention does not contain propellant, has no problem of influence on environmental protection, and meanwhile, because the aerosol takes long mist time during use, the efficiency of the drug action is greatly improved.
The invention also provides a pharmaceutical combination system comprising an aerosol pharmaceutical composition selected from the aerosol formulation comprising glycopyrronium salt and indacaterol salt as described above or from one or more of ipratropium bromide, fenoterol hydrobromide, salbutamol sulphate, tiotropium bromide, odaterol hydrochloride, aclidinium bromide, turnip bromide and an aerosol formulation comprising one or more of the foregoing and an aerosol inhalation device for the treatment of COPD.
In one embodiment, the pharmaceutical combination system is configured to aerosolize the aerosol pharmaceutical composition by treatment with the aerosolization inhalation device in a unit dose volume of 10 to 50 microliters.
In one embodiment, the aerosol inhalation device in the pharmaceutical combination system is as shown in fig. 1 or as shown in fig. 2.
Drawings
FIG. 1 is a schematic diagram of an aerosol inhalation device according to the patent WO2017192767A1, US20170319796A1, WO2017192773A1, WO2017192774A1, WO2017192778A1, WO2017192782A1, CN109475707A, CN109414178A, CN109475709A, etc.
Fig. 2 is a schematic view of an aerosol inhalation device according to CN103785086A, CN104010685A, CN104271187A, CN107929894a and the like.
Detailed Description
The invention will be further illustrated by the following examples, which will allow a person skilled in the art to more fully understand the invention, but which are not intended to limit the invention in any way.
Examples 1 to 6:
the pharmaceutical composition of the glycopyrronium salt and the indacaterol salt aerosol comprises per 100 milliliters of the pharmaceutical composition:
Figure SMS_3
Figure SMS_4
the rest components are purified water, or water with a temperature of 15-31deg.C and a density of 1.00g/cm 3 All the water for injection are prepared by mixing the components, and are filled in a medicine box of an atomization device after being sterilized by filtration.
Comparative example
The pulmonary deposition rate (FPF value) of the product of the invention with a commercial product of glycopyrrolate-indendamterol maleate powder mist was measured by a New Generation Impactor (NGI) and the results were as follows:
Figure SMS_5
the above-mentioned FPF values are the FPF values of two active ingredients in the powder mist or the aerosol produced after the inhalation formulation product passes through the corresponding inhalation device, and all the FPF values are measured by a New Generation Impactor (NGI), the inhalation device corresponding to the glycopyrrolate inhalation powder mist of the nowa company is brezhaler (i.e. the commercial device of the product), the inhalation device adopted for the product of the embodiment 1 of the present invention is the inhalation device shown in fig. 1, and the inhalation device adopted for the product of the embodiment 6 of the present invention is the inhalation device shown in fig. 2.
As can be seen from comparing the results in the table, the lung deposition rate of the glycopyrrolate-indendaterol maleate aerosol is greatly higher than that of the glycopyrrolate-indendaterol maleate inhalation powder aerosol sold by Nohua company, and the utilization efficiency of glycopyrrolate and indacaterol is remarkably improved.

Claims (21)

1. An aerosol pharmaceutical composition without propellant, characterized in that the pharmaceutical composition comprises glycopyrronium salt, indacaterol salt, preservative benzalkonium chloride, complexing agent ethylenediamine tetraacetic acid or pharmaceutically acceptable salts thereof, water, wherein the water is the only solvent in the pharmaceutical composition, and the glycopyrronium salt and indacaterol salt exist in a completely dissolved form; each 100mL of the pharmaceutical composition contains 0.045+/-0.001 g to 0.090+/-0.001 g of glycopyrronium, 0.099+/-0.001 g to 0.198+/-0.001 g of indacaterol and 5mg to 20mg of ethylenediamine tetraacetic acid; the pH of the pharmaceutical composition is between 2.8 and 3.05.
2. 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.
3. Pharmaceutical composition according to claim 2, characterized in that the glycopyrrolate salt is glycopyrrolate.
4. Pharmaceutical composition according to claim 1, characterized in that the indacaterol salt is a salt of indacaterol with benzoic acid, maleic acid, succinic acid, fumaric acid, tartaric acid.
5. The pharmaceutical composition according to claim 4, wherein the indacaterol salt is indacaterol maleate.
6. Pharmaceutical composition according to any one of claims 1 to 5, characterized in that the complexing agent is disodium edetate, in terms of ethylenediamine tetraacetic acid, in an amount of 8-12mg per 100mL of the pharmaceutical composition.
7. Pharmaceutical composition according to any one of claims 1-6, characterized in that it contains 5mg to 20mg of the preservative benzalkonium chloride per 100mL of the pharmaceutical composition.
8. Pharmaceutical composition according to any one of claims 1 to 7, characterized in that the pH value is between 2.8 and 3.0.
9. The pharmaceutical composition according to claim 8, characterized in that the pH value is 2.9.
10. Pharmaceutical composition according to any one of claims 1 to 9, characterized in that the pH is adjusted with a mineral acid.
11. The pharmaceutical composition according to claim 10, characterized in that the mineral acid is hydrochloric acid.
12. Pharmaceutical composition according to any one of claims 1-11, characterized in that it does not contain any other excipients and additives other than water, glycopyrronium salt, indacaterol salt, benzalkonium chloride, disodium edetate, hydrochloric acid and sodium chloride.
13. Use of a pharmaceutical composition according to any one of claims 1-12, characterized in that the pharmaceutical composition is for nebulization in an inhaler.
14. Use according to claim 13, characterized in that the unit dose has a volume of 10 to 50 microliters.
15. Use of a pharmaceutical composition according to any one of claims 1 to 12 in the manufacture of a medicament for the treatment of asthma and/or COPD.
16. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 12, characterized in that it is carried out by mixing the individual components.
17. Use of a pharmaceutical composition according to any one of claims 1 to 12 in an aerosol device as shown in figure 1.
18. Use of a pharmaceutical composition according to any one of claims 1 to 12 in an aerosol device as shown in figure 2.
19. A pharmaceutical combination comprising an aerosol pharmaceutical composition selected from the pharmaceutical composition of any one of claims 1-12, or from an aerosol formulation comprising one or more of ipratropium bromide, fenoterol hydrobromide, salbutamol sulphate, tiotropium bromide, odaterol hydrochloride, aclidinium bromide, turnip bromide, and an aerosol inhalation device for the treatment of COPD.
20. The pharmaceutical combination system of claim 19, wherein the aerosol pharmaceutical composition is aerosolized by treatment with the aerosolization inhalation device in a unit dose volume of 10 to 50 microliters.
21. The pharmaceutical combination system according to claim 20, wherein the aerosolized inhalation device is as shown in fig. 1 or as shown in fig. 2.
CN202310107966.4A 2018-07-26 2019-07-03 Aerosol pharmaceutical composition containing glycopyrronium salt and indacaterol salt, and preparation method and application thereof Pending CN116173025A (en)

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