TW202019397A - Aerosol pharmaceutical composition containing a glycopyrrolate salt, preparation method therefor, and uses thereof - Google Patents

Abstract

Provided is a propellant-free aerosol pharmaceutical composition comprising a pharmaceutical glycopyrrolate salt and water, wherein each 100 ml of the pharmaceutical composition contains from 0.045 ± 0.001g to 0.090 ± 0.001g of the glycopyrrolate. The pharmaceutical composition is particularly suitable for converting an active substance into an aerosol by means of atomization so as to ensure inhalation administration of a surfactant for treating asthma and COPD symptoms.

Description

Aerosol pharmaceutical composition containing glycopyrronium 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 a preparation method thereof, and belongs to the field of pharmaceutical preparations.

Chronic Obstructive Pulmonary Disease (COPD), referred to as chronic obstructive pulmonary disease, is a kind of chronic airflow and lung tissue caused by harmful gases and particles caused by chronic inflammation Related chronic respiratory diseases. The morbidity and mortality of COPD are high globally, and more and more are highly valued by various countries and organizations. At present, COPD ranks the fourth cause of death in the world. According to the prediction of the World Health Organization (WHO), the disease will become the third leading cause of human death in the world by 2020. In China, the prevention and treatment of COPD is also very serious, and the morbidity and mortality rates are increasing year by year with aging, smoking population, environment and other factors. The disease not only seriously threatens people's physical and mental health, but also poses a serious economic burden on the entire society. The Globe Burden of Disease Study predicts that by 2020, the economic burden of COPD will rank fifth in the world's disease economic burden, while China's COPD disease economic burden will leap to first place.

Due to the complicated pathogenesis of COPD, there is currently no clinically effective treatment for reversing the disease process or significantly changing the decline in lung function, mostly symptomatic treatment. There are many clinical drugs used to treat COPD, such as bronchodilators, anti-inflammatory drugs, and expectorants. Among them, bronchodilators are the core drugs for COPD symptom management. They are suitable for COPD treatment at various stages. By adjusting the tension of airway smooth muscle, bronchodilators are relaxed, and the degree of airflow limitation is improved. They play an important role in the treatment of COPD. Commonly used bronchodilators include three types: anticholinergic, theophylline, and β2 receptor agonist. Based on the characteristics of low theophylline efficacy and high side effects, 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 for COPD in stable phase.

Glycopyrrolate is a long-acting quaternary ammonium anticholinergic drug with long-acting muscarinic receptor antagonists, usually in the form of its bromide salt (ie glycopyrronium bromide) (The structural formula is shown in the figure below). It is used clinically and successfully developed by Swiss Novartis. It is used once a day by Breezhaler dry powder inhaler and is used to relieve symptoms of adult COPD patients for a long time.

Existing glycopyrrolate dry powder inhalation preparations, the auxiliary materials are mainly lactose and magnesium stearate. During the inhalation of patients, the small particles in lactose and magnesium stearate may be inhaled into the lungs, and they are inhaled as foreign bodies There is a risk of adverse reactions; at the same time, due to the characteristics of the inhaled powder aerosol dosage form, its active ingredients that can be inhaled into the lungs account for a relatively low amount, so that glycopyrronium bromide can not play a good effect.

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

The technical solution of the present invention is as follows:

The pharmaceutical composition provided by the present invention contains one or more glycopyrronium salts as the active substance. Based on glycopyrronium, 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, in which One or more glycopyrronium salts in the pharmaceutical preparation exist in a completely dissolved form;

Water is the only solvent;

Adjust the pH with acid to be between 2.8 and 3.05;

Benzalkonium chloride as a pharmacologically acceptable preservative;

5 mg to 20 mg of ethylenediaminetetraacetic acid or its pharmacologically acceptable salt per 100 ml of preparation is used as a pharmacologically acceptable complexing agent.

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

The above-mentioned pharmaceutical composition according to the present invention preferably contains no other excipients other than water, glycopyrronium salt, benzalkonium chloride, disodium edetate, hydrochloric acid, and optionally sodium chloride. Forms and additives.

The present invention relates to a liquid active substance preparation pharmaceutical composition of these compounds which is usually administered by inhalation, wherein the liquid preparation pharmaceutical composition according to the present invention meets high quality standards.

In order to achieve the best active substance distribution in the lungs, a suitable inhaler is used to administer the liquid pharmaceutical composition without propellant gas. A particularly suitable inhaler is an aerosol pharmaceutical composition capable of nebulizing a small amount of liquid preparation having a dosage required for therapeutic purposes within a few seconds. Within the scope of the present invention, the preferred atomizer is preferably capable of atomizing less than 100 μL, preferably less than 50 μL, and most preferably less than 20 μL of 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, so that the inhalable portion of the aerosol corresponds to a therapeutically effective amount.

According to the present invention, any pharmaceutically acceptable glycopyrronium salt can be used as a formulation. When the term glycopyrronium is used within the scope of the present invention, it is used as a reference for glycopyrronium. The glycopyrronium reference corresponds to the free ammonium cation. The glycopyrronium salt therefore contains an anion as a counter ion. The glycopyrronium salts that can be used within the scope of the present invention preferably include, in addition to glycopyrronium, as the counter ion (anion), chloride ion, bromide ion, iodide ion, methanesulfonate ion, p-toluenesulfonate ion and And/or methyl sulfate ion compounds.

Within the scope of the present invention glycopyrrolate is preferred. Glycopyrronium bromide is generally understood to mean all possible amorphous and crystalline modifications of glycopyrronium bromide within the scope of the present invention.

The preparation pharmaceutical composition of the present invention is preferably an active substance that does not contain any other active substance without glycopyrronium or a pharmaceutically acceptable salt thereof.

One or more glycopyrronium 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 only a single glycopyrronium salt, more preferably glycopyrrolate. However, this pharmaceutical composition may also contain a mixture of different glycopyrronium salts and solvates.

According to the proportion of glycopyrrolate in the final pharmaceutical preparation, the concentration of glycopyrronium salt depends on the therapeutic effect to be achieved. For most conditions corresponding 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. Since the density of the preparation is 1 g/cm ³ , a 100-gram preparation corresponds to a volume of 100 ml. Within the scope of this specification, the expression "per 100 mL" or "100 mL", unless stated differently, is the formulation per 100 mL in each case. The amount is preferably 0.035 g/100 mL to 0.095 g/100 mL, and more preferably 0.04 g/100 mL to 0.09 g/100 mL. The optimal amount is 0.045±0.001 g per 100 ml of preparation to 0.090±0.001 g per 100 ml of preparation.

The pH value 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 adding pharmacologically acceptable acids.

Examples of preferred inorganic acids suitable 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 the most preferred. If necessary, a mixture of the above-mentioned acids can also be used, especially in the case of acids having other properties in addition to acidifying properties, for example, acids as flavoring agents or antioxidants, such as citric acid and ascorbic acid.

Among the above-mentioned acids, it is clearly indicated that hydrochloric acid and citric acid are particularly preferred.

When necessary, pharmacologically acceptable bases can be used to accurately 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 preparation is pharmacologically compatible with the above 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 edetate dihydrate, as a stabilizer Agent or complex forming agent. The use of disodium edetate is preferred.

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

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

Note that involving disodium ethylenediaminetetraacetic acid, other additives similar to ethylenediaminetetraacetic acid or its salts can also be used similarly, but it has a mismatching property and can be used instead, such as nitrogen Triacetic acid and its salts.

Within the scope of the present invention, a complexing agent preferably refers to a molecule capable of entering a coordinate bond. Preferably, the complexation of these compound cations is preferably a metal cation.

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

Adjuvants and additives herein refer to any pharmacologically acceptable and 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 no equivalent or at least no desired pharmacological effect under the desired treatment conditions. 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 that extend the shelf life of the final pharmaceutical formulation. Such additives also contain pharmacologically acceptable salts, such as sodium chloride.

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

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

The preferred formulation contains, in addition to the water solvent and glycopyrronium salt, only benzalkonium chloride, disodium edetate, and the acid required to adjust the pH, preferably hydrochloric acid.

The glycopyrrolate aerosol pharmaceutical composition of the present invention can be prepared by mixing a single composition, that is, by mixing individual components of the composition.

The glycopyrrolate aerosol pharmaceutical composition of the present invention can be used in combination with Respimat aerosol inhalation device, or with the aerosol inhalation device shown in FIG. 1 or FIG. 2.

The aerosol inhalation device shown in FIG. 1 is a piezoelectric brake droplet delivery device, which is used to deliver the medical fluid as a jetted droplet flow to the lung system of a patient. The device includes:

case;

Liquid storage bin, set in the housing or communicating with the liquid passage in the housing, used to store a certain volume of liquid medicine;

An injection mechanism communicating with the liquid in the liquid storage bin 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, thereby generating a jetted droplet flow;

At least one differential pressure sensor is provided in the housing;

The differential pressure sensor activates the spray mechanism when it senses a predetermined pressure change in the housing, thereby generating a sprayed droplet flow;

The jetting mechanism can generate jets of droplets in which at least about 70% of the droplets have an average jetting droplet diameter of less than about 5 microns, so that the jetted droplets flow at least about 70% to the lungs of the patient.

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, CN109475709A and other patents, all of which are incorporated herein by reference. Figure 1 provides a detailed view of an exemplary injector closure mechanism. Removal of the housing top cover 152 exposes the ejector closing brake mechanism 506, which includes the closing guide 508, the sliding seal plate 510, and the motor mechanism 512, which can open and close the sliding seal plate 510 when the motor mechanism 512 is activated. Any suitable micromotor mechanism can 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 groove 103 for accommodating an interface tube, and a keying member 104; the interface tube includes a first segment 200a and a second segment 200b, and the first segment 200a includes an 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 a spray outlet 203; the spray head includes a spray generator 301, a liquid container 302, and a base unit The keying member 303 is complementary to 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 patent publications such as CN103785086A, CN104010685A, CN104271187A, CN107929894A, all of which are incorporated herein by reference.

The glycopyrrolate aerosol pharmaceutical composition without propellant provided by the present invention not only solves the problem of side effects caused by the inhalation of existing glycopyrrolate powder aerosol adjuvants, but also solves the glycopyrronium bromide powder mist The amount of active ingredients that can actually reach the lungs is relatively small, which can reduce product specifications, reduce the amount of glycopyrronium raw materials, reduce the cost of drugs, and reduce the burden on patients; at the same time, due to the existing treatment of chronic obstructive pulmonary disease Most aerosols contain propellants. On the one hand, the propellant will destroy the ozone layer in the atmosphere, which is not conducive to environmental protection. On the other hand, this aerosol has a short fogging time, which reduces the efficiency of the drug. The invention provides The glycopyrrolate aerosol contains no propellant and does not have the problem of having an impact on environmental protection. At the same time, because of its long fogging time when used, the efficiency of the drug's function is greatly improved.

The present invention also provides a pharmaceutical combination system comprising an aerosol pharmaceutical composition and an aerosolized inhalation device for treating COPD, the aerosol pharmaceutical composition is selected from the aerosol formulations containing glycopyrronium salt, or An aerosol formulation selected from one or more of ipratropium bromide, fenoterol hydrobromide, salbutamol sulfate, tiotropium bromide, octaterol hydrochloride, aclidinium bromide, and budesonium bromide.

In one embodiment, the aerosol inhalation device processes the aerosol pharmaceutical composition by the aerosol inhalation device, and the aerosol inhalation device processes a unit dose volume of 10 to 50 μL.

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

The present invention will be further described in conjunction with the following examples, so that those of ordinary skill in the art can more fully understand the present invention, but do not limit the present invention in any way. Example 1-6 :

Each 100ml glycopyrrolate aerosol pharmaceutical composition contains:

The remaining components are purified water or water for injection at a temperature of 15-31°C and a density of 1.00g/cm ^3. They are all prepared by mixing a single composition. After sterilization by filtration, they are canned in the pill 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 powder aerosol was measured by a new-generation impactor (NGI). The results are as follows:

The above FPF value is the FPF value of the active ingredient glycopyrrolate in the powder or aerosol generated by the inhalation preparation product after passing through the corresponding inhalation device, which are measured by a new generation impactor (NGI). Novartis' glycopyrrolate inhalation powder mist The inhalation device corresponding to the agent is Breezhaler (that is, 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 Embodiment 6 of the present invention is shown in FIG. 2 Inhalation device.

Comparing the results in the above table, it can be seen that the lung deposition rate of the glycopyrrolate aerosol of the present invention is much higher than that of the glycopyrrolate inhalation powder commercially available from Novartis, which significantly improves the glycopyrronium bromide aerosol. usage efficiency.

100: base unit 101, 201: air inlet 102: outlet 103: slot 104, 303: key lock member 152: top cover 154: mouthpiece tube 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 ejection outlet 506: brake mechanism 508: closed guide 510: sliding seal plate 512: Motor mechanism 514: screw

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

152: top cover

154: mouthpiece tube

504: ejector ejection outlet

506: brake mechanism

508: closed guide

510: sliding seal plate

512: Motor mechanism

514: screw

Claims (19)

An aerosol pharmaceutical composition without propellant, characterized in that the pharmaceutical composition includes glycopyrronium salt, preservative benzalkonium chloride, complexing agent ethylenediaminetetraacetic acid or a pharmaceutically acceptable salt thereof , Water, water in the pharmaceutical composition is the only solvent, in which glycopyrronium salt exists in a completely dissolved form; based on glycopyrronium and ethylenediaminetetraacetic acid, the pharmaceutical composition contains glycopyrronium per 100 mL 0.045±0.001g to 0.090±0.001g, ethylenediaminetetraacetic acid 5mg to 20mg; the pH of the pharmaceutical composition is between 2.8 and 3.05. The pharmaceutical composition according to item 1 of the patent application range, wherein the glycopyrronium salt is glycopyrronium and hydrobromic acid, hydrochloric acid, hydroiodic acid, monomethyl sulfate, methanesulfonic acid or Salts formed by p-toluenesulfonic acid. The pharmaceutical composition according to item 2 of the patent application range, wherein the glycopyrronium salt is glycopyrronium bromide. The pharmaceutical composition according to any one of items 1 to 3 of the patent application range, characterized in that the complexing agent is disodium ethylenediaminetetraacetic acid, based on ethylenediaminetetraacetic acid, per 100 mL of the pharmaceutical combination The substance contains 8-12mg of ethylenediaminetetraacetic acid. The pharmaceutical composition according to any one of items 1 to 4 of the patent application range, characterized in that the pharmaceutical composition contains the preservative 5 mg to 20 mg of benzalkonium chloride per 100 mL of the pharmaceutical composition. The pharmaceutical composition according to any one of items 1 to 5 of the patent application range, characterized in that the pH is between 2.8 and 3.0. The pharmaceutical composition according to item 6 of the patent application range, wherein the pH value is 2.9. The pharmaceutical composition according to any one of items 1 to 7 of the patent application range, characterized in that the pH value is adjusted with an inorganic acid. The pharmaceutical composition according to item 8 of the patent application range, wherein the inorganic acid is hydrochloric acid. The pharmaceutical composition according to any one of items 1 to 9 of the patent application range, characterized in that in addition to water, glycopyrronium salt, benzalkonium chloride, disodium ethylenediaminetetraacetic acid, hydrochloric acid and optional chlorine In addition to sodium hydroxide, the pharmaceutical composition does not contain any other excipients and additives. A use of the pharmaceutical composition according to any one of items 1-10 of the patent application range, characterized in that the pharmaceutical composition is used for nebulization in an inhaler. The use according to item 11 of the patent application range is characterized in that the volume of the unit dose is 10 to 50 μL. Use of the pharmaceutical composition according to any one of the items 1-10 of the patent application scope in the preparation of a medicament for treating COPD. A method for preparing a pharmaceutical composition according to any one of items 1 to 10 of the patent application range, characterized in that it is carried out by mixing a single composition. An application of the pharmaceutical composition according to any one of items 1-10 of the patent application scope in the aerosol device shown in FIG. 1. An application of the pharmaceutical composition according to any one of items 1-10 of the patent application scope in the aerosol device shown in FIG. 2. A medicine combination system, comprising an aerosol medicine composition and an aerosolized inhalation device for treating COPD, the aerosol medicine composition is selected from the medicine according to any one of items 1-10 of the patent application The composition, or one or more selected from the group consisting of ipratropium bromide, fenoterol hydrobromide, salbutamol sulfate, tiotropium bromide, octaterol hydrochloride, aclidinium bromide, and wudedinium bromide Aerosol preparation. The medicine combination system according to item 17 of the patent application range, characterized in that the aerosol pharmaceutical composition is processed by the atomization inhalation device to be atomized, and the unit dose volume processed by the atomization inhalation device 10 to 50 μL. The medicine combination system according to item 18 of the patent application range, wherein the atomization inhalation device is shown in FIG. 1 or shown in FIG. 2.

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