WO2020019953A1 - 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 glycopyrrolium salt, preparation method and application thereof Technical field

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

Background technique

Chronic obstructive pulmonary disease (Chronic, Obstructive, Disease, COPD), referred to as chronic obstructive pulmonary disease, is a feature of continuous airflow limitation, which develops progressively, and chronic inflammation caused by harmful gases and particles in the airway and lung tissue. Sexual response related to chronic respiratory diseases. The morbidity and mortality of COPD are relatively high globally, and they are increasingly valued by various countries and organizations. At present, COPD ranks fourth in the world as the cause of death. According to the prediction of the World Health Organization (WHO), by 2020, the disease will become the third leading cause of human death worldwide. In China, the prevention and treatment of COPD is also very serious, and the morbidity and mortality have increased year by year with various factors such as aging, smoking population, and the environment. The disease not only seriously threatens people's physical and mental health, but also causes a serious economic burden on the entire society. According to Globe's Forecast, Study forecast that by 2020, the economic burden of COPD will leap to the fifth place in the world, and China's economic burden of COPD will rise to the first place.

Due to the complicated pathogenesis of COPD, there are currently no clinically effective treatments that can reverse the course of the disease or significantly change the decline in lung function, mostly symptomatic treatment. There are many clinically used drugs for treating COPD, such as bronchodilators, anti-inflammatory drugs, expectorants and so on. Among them, bronchodilators are the core drugs for the management of COPD symptoms. They are applicable to the treatment of COPD at various stages. By adjusting the tension of airway smooth muscles, they relax the bronchi and improve the degree of airflow restriction. They play an important role in the medical treatment of COPD. Commonly used bronchodilators include three categories: anticholinergics, theophyllines, and β2 receptor agonists. Theophylline is generally not recommended for the treatment of COPD because of its low efficacy and high side effects. Long-acting anticholinergic drugs (LAMA) and long-acting β2 receptor agonists (LABA) are recommended as treatment by GOLD. First-line bronchodilators for stable COPD.

Glycommonium (glycopyrrolate) is a long-acting quaternary ammonium anticholinergic drug, which has a long-acting scopolamine receptor antagonist effect, usually in the form of its bromide salt (The structural formula is shown in the figure below) It is used in clinical development and successfully developed by Novartis, Switzerland. It is administered by Breezhaler dry powder inhaler once a day for long-term relief of symptoms in adult patients with COPD.

The existing glycopyrrolium bromide dry powder inhalation preparations are mainly supplemented with lactose and magnesium stearate. During inhalation of patients, small particles in lactose and magnesium stearate may be inhaled into the lungs, and they are used as foreign bodies. There is a risk of adverse reactions when inhaled. At the same time, due to the characteristics of inhaled powder formulations, it can be inhaled into the lungs with a relatively low amount of active ingredients, so that glycopyrrolate does not play a good role.

Summary of the Invention

In order to solve the shortcomings of the prior art, the present invention provides a glycopyrrolate aerosol pharmaceutical composition without a propellant 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 glycopyrrolium salts as an active substance. Based on the glycopyrrolium, the concentration is between 0.045 ± 0.001 g per 100 ml of the preparation and 0.090 ± 0.001 g per 100 ml of the preparation. Wherein one or more glycopyrrolium salts in the pharmaceutical preparation are present in a completely dissolved form;

Water is the sole solvent;

Adjust the pH with acid to between 2.8 and 3.05;

Chlorobenzyl ammonium as a pharmacologically acceptable preservative;

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

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

The above pharmaceutical composition according to the present invention preferably does not contain any other excipients other than water, glycopyrrolium ammonium, chlorobenzyl ammonium, disodium ethylenediamine tetraacetate, hydrochloric acid, and optionally sodium chloride. Agents and additives.

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

To achieve the best active substance distribution in the lungs, a propellant-free liquid formulation pharmaceutical composition is administered using a suitable inhaler. A particularly suitable inhaler is an aerosol pharmaceutical composition capable of nebulizing a small amount of a liquid preparation having a dose required for therapeutic purposes in a few seconds to form a therapeutic inhalation. Within the scope of the present invention, a preferred sprayer is an active substance liquid mist that is preferably capable of spraying in one or two shots, less than 100 microliters, preferably less than 50 microliters, and most preferably less than 20 microliters. 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.

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

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

The formulation pharmaceutical composition of the present invention is preferably an active substance that does not contain any other glycopyrronium-free active substance or a pharmaceutically acceptable salt thereof.

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

The pharmaceutical composition of the formulation according to the present invention preferably contains only a single glycopyrrolate salt, preferably glycopyrrolate. However, the pharmaceutical composition of such a formulation may also contain a mixture of different glycopyrrolium salts and solvates.

According to the proportion of glycopyrronium in the final pharmaceutical preparation, the concentration of glycopyrrolium salt depends on the therapeutic effect to be achieved. For most conditions that are responsive to glycopyrrolate, glycopyrrolate concentrations range between 0.03 grams per 100 grams of preparation and 0.10 grams per 100 grams of preparation. Since the density of the formulation is 1 g / cm ³ , a 100 gram formulation corresponds to a volume of 100 ml. Within the scope of this specification, the expression "per 100 mL" or "/ 100 mL" is, unless stated differently, a preparation per 100 ml in each case. An amount of 0.035 g / 100 mL to 0.095 g / 100 mL is preferable, and an amount of 0.04 g / 100 mL to 0.09 g / 100 mL is more preferable. 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 aerosol pharmaceutical composition of the present invention has a pH 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 a pharmacologically acceptable acid.

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

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

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

According to the present invention, the aerosol pharmaceutical composition comprises ethylenediaminetetraacetic acid (EDTA) or one of its known salts, such as sodium ethylenediaminetetraacetate or disodium ethylenediaminetetraacetate dihydrate, as Stabilizer or complex forming agent. The use of disodium ethylenediamine tetraacetate is preferred.

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

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

It is noted that disodium ethylenediaminetetraacetate can be used similarly. Other additives, although not preferred compared to ethylenediaminetetraacetic acid or its salts, have complexing properties and can be used instead, such as nitrogen Acetic acid and its salts.

Within the scope of the present invention, the complexing agent preferably refers to a molecule capable of entering a coordination bond. Preferably, the cations are complexed by metal cations.

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

In this context, auxiliaries and additives refer to any pharmacologically acceptable and therapeutically useful substance, which is not an active substance, but can be formulated with the active substance in a pharmacologically suitable solvent to improve the preparation of the active substance. quality. Preferably, these substances have no pharmacological effect or do not have a comparable or at least no pharmacological effect in the desired therapeutic condition. These auxiliaries 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. This additive also contains pharmaceutically acceptable salts, such as sodium chloride.

Preferred auxiliaries include antioxidants, such as ascorbic acid, provided that they are not used to adjust pH, vitamin A, vitamin E, tocopherols and similar vitamins or vitamin precursors present in the human body.

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

The preferred formulation, in addition to the water solvent and the glycopyrrolium salt, contains only ammonium chlorobenzyl alkane, disodium ethylenediamine tetraacetate 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 the individual components.

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

The aerosol inhalation device shown in FIG. 1 is a piezoelectrically actuated droplet delivery device for delivering a medicinal solution as a jet of droplets to a patient's lung system. The device includes:

case;

A liquid storage tank, which is arranged in the housing or communicates with a liquid passage in the housing, and is used for storing a certain volume of medicinal liquid;

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

At least one pressure difference sensor disposed in the housing;

The differential pressure sensor activates the ejection mechanism when it senses a predetermined pressure change in the housing, thereby generating a stream of ejected droplets;

The spraying mechanism can generate a sprayed droplet flow, wherein at least about 70% of the droplets have an average sprayed droplet diameter of less than about 5 micrometers, so that at least about 70% of the sprayed droplet flow 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 all incorporated herein. Figure 1 provides a detailed view of an exemplary injector closing mechanism. Removing the housing top cover 152 exposes the ejector closing actuation mechanism 506, which includes a closing guide 508, a sliding seal plate 510, and a motor mechanism 512. When the motor mechanism 512 is activated, the motor mechanism 512 can open and close the sliding seal plate 510 . Any suitable micromotor mechanism can be used.

The aerosol inhalation device shown in FIG. 2 includes a base unit 100, an interface tube 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 receiving an interface pipe, and a key lock member 104; the interface pipe includes a first section 200a and a second section 200b, and the first section 200a includes an air inlet 201 and a side opening 202 for accommodating the spray generator, the first segment can be inserted into the groove of the base unit, and the second segment 200b includes a spray outlet 203; the spray head includes a spray generator 301, a liquid container 302, and a base unit The key lock member 303 is complementary to the key lock member 303; the base unit, the interface pipe, and the spray head can be connected to each other, so that when the key lock member is joined with the complementary member, the spray generator is inserted into the side opening of the interface pipe.

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

The glycopyrrolate aerosol pharmaceutical composition containing no propellant provided by the present invention not only solves the problem that the existing glycopyrrolate powder adjuvant is inhaled into the lungs, but also solves the problem of glycopyrrolate powder The problem that the active ingredients of the aerosol can reach the lungs is too small, which can reduce the product specifications, reduce the amount of glycopyrrolium raw materials, reduce the cost of medicines, and reduce the burden on patients; at the same time, due to the existing treatment of chronic obstructive lungs Most aerosols for diseases contain a propellant. On the one hand, the propellant destroys the ozone layer in the atmosphere and is not good for environmental protection. On the other hand, the aerosol has a short fogging time, which reduces the efficiency of the drug. The provided glycopyrrolium aerosol does not contain a propellant, and there is no problem that has an impact on environmental protection. At the same time, because it is used for a long time, it has greatly improved the efficiency of the drug.

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 the glycopyrrolium salt described above , Or one or more selected from the group consisting of ipratropium bromide, fenoterol hydrobromide, salbutamol sulfate, tiotropium bromide, odaterol hydrochloride, adibromide, and humidinium bromide Aerosol preparation.

In one embodiment, the drug combination system processes the aerosol pharmaceutical composition through the atomizing inhalation device to make it atomize, and the unit dose volume processed by the atomizing inhalation device is 10 to 50 microliters .

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

BRIEF DESCRIPTION OF THE DRAWINGS

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

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

detailed description

The following further describes the present invention with reference to the embodiments, so that those skilled in the art can more fully understand the present invention, but does not limit the present invention in any way.

Examples 1-6:

Each 100 milliliters of a 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 , which are prepared by mixing individual components. After filtering and sterilizing, they are canned in a pill box of an atomizing device. .

Comparative example

The lung deposition rate (FPF value) of the product of the present invention and the commercially available glycopyrrolate powder was measured by a new generation impactor (NGI), and the results are as follows:

The above FPF value is the FPF value of the active ingredient glycopyrronium bromide in the powder or aerosol generated after passing through the corresponding inhalation device of the inhalation preparation product, all measured by the new generation impactor (NGI), Novartis glycopyrrolate inhalation powder The inhalation device corresponding to the aerosol is Breezhaler (that is, a commercially available device of the product). The inhalation device used for the product of Example 1 of the present invention is the inhalation device shown in FIG. 1, and the inhalation device used for the product of Example 6 of the present invention is shown in FIG. 2. Shows the inhalation device.

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

Claims (19)

1. A propellant-free aerosol pharmaceutical composition, characterized in that the pharmaceutical composition comprises a glycopyrrolium salt, a preservative chlorobenzylammonium, a complexing agent, ethylenediaminetetraacetic acid, or a pharmaceutically acceptable agent thereof. Water, the only solvent in the pharmaceutical composition, wherein the glycopyrrolium salt exists in a completely dissolved form; based on glycopyrrolate and ethylenediaminetetraacetic acid, the pharmaceutical composition contains per 100mL Ammonium 0.045 ± 0.001g to 0.090 ± 0.001g, ethylenediaminetetraacetic acid 5mg to 20mg; the pH of the pharmaceutical composition is 2.8 and 3.05.
2. The pharmaceutical composition according to claim 1, wherein the glycopyrrolium salt is glycopyrrolate and hydrobromic acid, hydrochloric acid, hydroiodic acid, monomethyl sulfate, methanesulfonic acid, or p-toluenesulfonic acid. Salts formed by acids.
3. The pharmaceutical composition according to claim 2, wherein the glycopyrrolate is glycopyrrolate.
4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that the complexing agent is disodium ethylenediamine tetraacetate, and based on ethylenediamine tetraacetic acid, each 100mL of the pharmaceutical composition contains 8-12 mg of ethylenediamine tetraacetic acid.
5. The pharmaceutical composition according to any one of claims 1 to 4, characterized in that the pharmaceutical composition contains 5 to 20 mg of the preservative chlorobenzyl ammonium per 100 mL of the pharmaceutical composition.
6. The pharmaceutical composition according to any one of claims 1 to 5, characterized in that the pH value is 2.8 to 3.0.
7. The pharmaceutical composition according to claim 6, wherein the pH value is 2.9.
8. The pharmaceutical composition according to any one of claims 1 to 7, characterized in that the pH value is adjusted with an inorganic acid.
9. The pharmaceutical composition according to claim 8, wherein the inorganic acid is hydrochloric acid.
10. The pharmaceutical composition according to any one of claims 1 to 9, characterized in that in addition to water, glycopyrrolate, chlorobenzyl ammonium, disodium ethylenediamine tetraacetate, hydrochloric acid, and optionally sodium chloride In addition, the pharmaceutical composition does not contain any other excipients and additives.
11. The use of the pharmaceutical composition according to any one of claims 1 to 10, characterized in that the pharmaceutical composition is used for atomization in an inhaler.
12. Use according to claim 11, characterized in that the volume of the unit dose is 10 to 50 microliters.
13. Use of the pharmaceutical composition according to any one of claims 1 to 10 in the manufacture of a medicament for treating COPD.
14. A method for preparing a pharmaceutical composition according to any one of claims 1 to 10, characterized in that it is performed by mixing individual components.
15. Use of the pharmaceutical composition according to any one of claims 1 to 10 in the aerosol device shown in Fig. 1.
16. Use of the pharmaceutical composition according to any one of claims 1 to 10 in the aerosol device shown in FIG. 2.
17. A drug combination system comprising an aerosol drug composition and an atomizing inhalation device for treating COPD, the aerosol drug composition is selected from the drug combination according to any one of claims 1-10 Or one or more selected from the group consisting of ipratropium bromide, fenoterol hydrobromide, salbutamol sulfate, tiotropium bromide, odadrolol hydrochloride, adibromide, and humidinium bromide Aerosol preparation.
18. The pharmaceutical combination system according to claim 17, wherein the aerosol pharmaceutical composition is processed and atomized by the atomizing inhalation device, and the unit dose volume processed by the atomizing inhalation device is 10 to 50 μl.
19. The drug combination system according to claim 18, wherein the atomized inhalation device is shown in FIG. 1 or shown in FIG. 2.

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