CN116196298A

CN116196298A - Aerosol pharmaceutical composition containing glycopyrronium salt and preparation method and application thereof

Info

Publication number: CN116196298A
Application number: CN202310253443.0A
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: 2023-06-02
Also published as: CN111971034A; WO2020019953A1; TW202019397A

Abstract

The present invention provides a propellant-free aerosol pharmaceutical composition comprising a pharmaceutically acceptable salt of glycopyrrolate and water, the pharmaceutical composition comprising 0.045±0.001g to 0.090±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 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 201980023568.6 and the name of 'an aerosol pharmaceutical composition containing glycopyrronium salt, 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 a preparation method thereof, and belongs 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. COPD is currently the fourth leading cause of death worldwide, and by the World Health Organization (WHO) predicts that by 2020, the disease will be the third leading illness to death in humans worldwide. In China, the prevention and treatment conditions of COPD are also very severe, and the morbidity and mortality rate rise year by year with various factors such as aging, smoking population, environment and the like. The disease not only seriously threatens the physical and mental health of people, but also causes serious economic burden to the whole society. According to Globe Burden of Disease Study, it is predicted that by 2020 the economic burden of COPD will jump to the fifth place of the economic burden of the world disease, whereas the economic burden of chinese COPD disease will jump to the first place.

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 base receptor antagonist, usually in the form of its bromide salt (i.e. glycopyrrolate, glycopyrronium bromide) for clinical use, developed successfully by the company of northwest, switzerland, 1 time daily, administered by a brezhaler dry powder inhaler for long-term relief of symptoms in adult COPD patients.

In the existing glycopyrronium bromide dry powder inhalation preparation, auxiliary materials mainly comprise lactose and magnesium stearate, small particles in the lactose and the magnesium stearate are likely to be inhaled into the lung in the inhalation process of a patient, 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 cannot exert the drug effect well.

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 as active substance one or more glycopyrronium salts in a concentration of between 0.045±0.001 gram per 100ml of formulation and 0.090±0.001 gram per 100ml of formulation, based on glycopyrronium, wherein the one or more glycopyrronium salts in the pharmaceutical formulation are present in a fully 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;

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.

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

The above-described pharmaceutical composition according to the present invention preferably does not contain any other excipients and additives other than water, glycopyrronium 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 glycopyrronium salt may be used as a formulation according to the present invention. The term glycopyrrolate, when used within the scope of the present invention, is intended to be a reference to glycopyrrolate. 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).

Glycopyrronium bromide is preferred within the scope of the present invention. References to glycopyrrolate within the scope of the present invention are generally understood to be references to all possible amorphous and crystalline modified glycopyrrolate.

The pharmaceutical compositions of the formulation of the present invention are preferably free of any other glycopyrrolate-free active substance or its pharmaceutically acceptable salts.

One or more of the glycopyrronium 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 only a single glycopyrronium salt, preferably glycopyrronium bromide. However, such formulated pharmaceutical compositions may also contain mixtures of salts and solvates of different formats Long An.

Depending on the proportion of glycopyrronium salt of the final pharmaceutical formulation, the concentration of glycopyrronium salt will depend on the therapeutic effect to be achieved. For most conditions that respond to glycopyrrolate, the concentration of glycopyrrolate 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/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, more preferably in an amount of 0.04g/100mL to 0.09g/100 mL. The optimal amount is 0.045+ -0.001 g per 100ml formulation to 0.090+ -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 aerosol pharmaceutical compositions of the present invention can 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 patent publication CN103785086A, CN104010685A, CN104271187A, CN107929894a, et al, which is incorporated herein in its entirety.

The glycopyrronium salt aerosol pharmaceutical composition without the propellant solves the problem that the existing glycopyrronium bromide powder aerosol auxiliary materials are inhaled into the lung to generate side effects, and solves the problem that the active ingredients of the glycopyrronium bromide powder aerosol can actually reach less quantity of the lung, so that the product specification can be reduced, the consumption of glycopyrronium raw materials is reduced, the cost of medicines 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 an 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, and the glycopyrronium salt aerosol provided by the invention does not contain propellant, has no problem of influence on environmental protection, and simultaneously, the efficiency of the drug action is greatly improved due to long mist time when the glycopyrronium salt aerosol is used.

The invention also provides a pharmaceutical combination system comprising an aerosol pharmaceutical composition selected from the aerosol formulation comprising glycopyrronium salt as described above or from one or more of ipratropium bromide, fenoterol hydrobromide, salbutamol sulphate, tiotropium bromide, odaterol hydrochloride, aclidinium bromide, and turnip bromide 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 glycopyrronium salt aerosol pharmaceutical composition comprises per 100 milliliters:

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 lung deposition rate (FPF value) of the product of the invention and glycopyrrolate powder mist commercial product was measured by a New Generation Impactor (NGI) and the results are as follows:

the above-mentioned FPF value is the FPF value of glycopyrrolate as an active ingredient 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 of Impactors (NGI), the inhalation device corresponding to the inhalation of glycopyrrolate by 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 aerosol of the present invention is much higher than that of glycopyrrolate inhalation powder aerosol sold by Nohua corporation, and the utilization efficiency of glycopyrrolate is remarkably improved.

Claims

1. A propellant-free aerosol pharmaceutical composition comprising a glycopyrronium salt, a preservative benzalkonium chloride, a complexing agent ethylenediamine tetraacetic acid or a pharmaceutically acceptable salt thereof, water, wherein water is the only solvent in the pharmaceutical composition, and wherein the glycopyrronium salt is present in a fully dissolved form; 0.045+ -0.001 g to 0.090+ -0.001 g, 5mg to 20mg of ethylenediamine tetraacetic acid per 100mL of the pharmaceutical composition based on glycopyrronium and ethylenediamine tetraacetic acid; the pH of the pharmaceutical composition was 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 glycopyrronium salt is glycopyrronium bromide.

4. A pharmaceutical composition according to any one of claims 1-3, characterized in that the complexing agent is disodium edetate, in an amount of 8-12mg of edetate per 100mL of the pharmaceutical composition calculated as edetic acid.

5. Pharmaceutical composition according to any one of claims 1-4, characterized in that the preservative benzalkonium chloride is comprised between 5mg and 20mg per 100mL of the pharmaceutical composition.

6. Pharmaceutical composition according to any one of claims 1 to 5, characterized in that the pH value is 2.8-3.0.

7. The pharmaceutical composition according to claim 6, wherein the pH is 2.9.

8. Pharmaceutical composition according to any one of claims 1 to 7, characterized in that the pH is adjusted with a mineral acid.

9. The pharmaceutical composition according to claim 8, characterized in that the mineral acid is hydrochloric acid.

10. Pharmaceutical composition according to any one of claims 1-9, characterized in that the pharmaceutical composition does not comprise any other excipients and additives than water, glycopyrronium salt, benzalkonium chloride, disodium edetate, hydrochloric acid and optionally sodium chloride.

11. Use of a pharmaceutical composition according to any one of claims 1-10, characterized in that the pharmaceutical composition is for nebulization in an inhaler.

12. Use according to claim 11, characterized in that the unit dose has a volume of 10 to 50 microliters.

13. 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.

14. 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.

15. Use of a pharmaceutical composition according to any one of claims 1 to 10 in an aerosol device as shown in figure 1.

16. Use of a pharmaceutical composition according to any one of claims 1 to 10 in an aerosol device as shown in figure 2.

17. A pharmaceutical combination comprising an aerosol pharmaceutical composition selected from the pharmaceutical composition of any one of claims 1-10, 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.

18. The pharmaceutical combination system of claim 17, wherein the aerosol pharmaceutical composition is aerosolized by treatment with the aerosolization inhalation device in a unit dose volume of 10 to 50 microliters.

19. The pharmaceutical combination according to claim 18, wherein the aerosolized inhalation device is as shown in fig. 1 or as shown in fig. 2.