HRP20010874A2 - Special steel canister for propellant-operated dosing aerosols - Google Patents

Description

description of the invention

The proposed invention relates to a corrosion-resistant stainless steel container for propellant-containing aerosol formulations used in propellant gas inhalers.

Background of the invention

In inhalers that work on a propellant, the active substances are deposited together with the propellant in containers similar to cartridges. As a rule, these containers consist of an aluminum container that is closed with an aluminum valve cap in which the valve is inserted. Such a container can then be introduced into the inhaler as a cartridge and remain there permanently or be replaced with a new one after use. Already at the beginning of the nineties, at a conference in Rio de Janeiro, hydrocarbons containing fluorine and chlorine (FCKW, CFC) were condemned due to their ozone-depleting properties, so the search began to replace the use of hydrocarbons containing fluorine (FKW, HFA) as of propellants in inhalers that work on a propellant. So far, the most promising are TG 134a (1,1,2,2-tetrafluoroethane) and TG 227 (1,1,1,2,3,3,3-heptafluoropropane). Accordingly, the existing application systems must be reworked for inhalation therapy with propellants that do not contain CFCs, and it is necessary to develop new application systems and new formulations of active substances.

Surprisingly, it turned out that aluminum containers are not always resistant to drug formulations that contain fluorocarbons as a suppressant, but depending on the composition of the formulation, show a high risk of corrosion. This is especially true for formulations in which electrolytes and/or free ions, especially free halides, are present. In these cases, the aluminum is corroded so that aluminum cannot be used as a tank jacket material. Similar instabilities of aluminum tanks are observed when using hydrofluorocarbons as suppressants if the formulations contain acidic or basic ingredients, for example in the form of active substances, additives, as stabilizers, surfactants, flavor enhancers, antioxidants and the like.

Description of the invention

One of the tasks of the proposed invention is to create a container for inhalers with a propellant that is resistant to corrosion of the active substances of the formulation for inhalation therapy, and which formulation contains hydrofluorocarbon as a propellant, and a container that has sufficient compressive and breaking strength necessary for processing and use and which ensures the quality of the formulation stored in it and with which the shortcomings known from the state of the art are overcome.

A further task of the invention is to create a container for inhalers that work on a pressure medium, the container of which consists of a single and structurally homogeneous material.

It has surprisingly been found that this task is solved according to the invention with a container consisting of a container and a valve cap with a valve, wherein at least the container is made of certain noble steel alloys. These alloys include chromium (Cr), nickel (Ni), molybdenum (Mo), iron (Fe) and carbon (C). Such alloys may additionally contain copper (Cu), manganese (Mn) and silicon (Si). The container is primarily made from one of the alloys described below.

The invention also relates to the use of such a vessel, or container, and to a valve cap with a valve in devices for dosing aerosols (inhalers) that work on a propellant and to the process for its production.

The invention will be explained in more detail below with the help of figures 1 and 2.

Figure 1 shows a cross-section of a container consisting of a container (2), a valve cap (8) and a valve (9).

Figure 2 shows in cross-section a further design of the valve cap (8) and valve (9).

Figure 1 shows a section of the container (1) according to the invention. The container (1) consists of a container (2) for receiving the drug formulation and a valve cap (8) with a valve (9). The shape and dimensions of the container correspond to aluminum containers known from the state of the art.

The vessel (2) according to the invention is made of an alloy with the following composition:

iron: from 40.0-53.0%,

nickel: 23.0-28.0%,

chromium: 19.0-23.0%,

molybdenum: 4.0-5.0%,

manganese: 0.0-2.0%,

copper: 1.0-2.0%,

silicon: 0.0-1.0%,

phosphorus: 0.0-0.045%,

sulfur: 0.0-0.035% i

carbon: 0.0-0.020%.

This alloy is an alloy that has the material number 1.4539 in the steel-iron list of the Association of German Iron Casters (Verein deutscher Eisenhüttenleute).

The leading alloy of this type has the following composition:

iron: 19.0-21.0%,

nickel: 24.0 - 26.0%,

molybdenum: 4.0-5.0%,

copper: 1.0-2.0%,

manganese: up to 2.0%,

silicon: up to 0.5% i

carbon: up to 0.02%,

with the rest being mostly iron.

In an almost identical alternative alloy, the molybdenum content is limited to 4.5-5.0%.

In an alternative embodiment, the container (2) according to the invention is made of material number 1.4404 from the steel-iron list of the Association of German Iron Casters.

The composition of the alloy is:

iron: from 60.0-72.0%,

nickel: 9.0-13.0%,

chromium: 17.0 - 21.0%,

molybdenum: 2.0 - 3.0%,

manganese: 0.0-1.5%,

silicon: 0.0-1.5%,

phosphorus: 0.0-0.04%,

sulfur: 0.0-0.04% i

carbon 0-0.03%.

In a further embodiment, the container is made of an alloy with the following composition:

chromium: 16.5-18.5%,

nickel: 11.0-14.0%,

molybdenum: 2.0-2.5%,

carbon: maximum 0.03%

and iron as the rest of the composition.

These alloys are of a type that is resistant to corrosion by various liquefied fluorocarbons such as TG 134a (1,1,1,3-tetrafluorocarbon) and TG 227 (1,1,1,2,3,3,3-heptafluoropropane). In addition, propellant formulations with appropriate active agents, surfactants, co-solvents, stabilizers, complexing agents, flavor enhancers, antioxidants, salts, acids, bases or electrolytes are also contemplated, such as, for example, hydroxide ions, cyanide ions and/or halide anions such as fluoride, chloride, bromide or iodide, which formulations are suitable for inhalation therapy.

The container (2) is made of a jacket made of the alloy described above. The vessel (2) has four distinct zones: a flat or concave bottom (3) that is curved inwards, a cylindrical area (4) that in the upper third passes into a narrowing throat (5) and finally ends in a bulge (6) that goes around the opening (7) containers.

The thickness of the wall of the container (2) in the preferred form of performance is between 0.15 and 0.35 mm, and in particular, approx. 0.19 to 3.0 mm.

In a preferred embodiment, the container (2) withstands a burst pressure greater than 30,000 hPa, preferably more than 100,000 hPa, and most especially preferably more than 200,000 hPa. The weight of the container (2) in the preferred embodiment is 5-15 g, and in the second 7-10 g, and again in a further preferred embodiment 7.9-8.7 g. In the preferred embodiment, the container (2 ) has a volume of 5 to 50 ml. The second container has a volume of 10 to 20 ml, and also in a further favorable form of approx. 15–18 ml.

In the closed state, the container (2) is tightly closed with the valve cap (8) after filling with the drug formulation and the propellant.

In one embodiment, the valve cap (8) is also made of corrosion-resistant material. In this case, it is primarily the alloy described above for the container and/or polymeric materials of appropriate pharmaceutical quality.

In another embodiment, the valve cap (8) is made of aluminum. In this case, the seal (10) and/or the valve (9) are made so that the cap (8) of the valve itself does not come into contact with the liquid inside the container.

The preferred embodiment of the valve cap (8) is that according to GB 2324121, which is therefore taken into account here in its entirety.

When the container is closed, the valve cap (8) covers the container (2) on its neck (6). In the preferred embodiment, there is a gasket (10) between the cap (8) of the valve and the neck (8). At the same time, this seal can be ring-shaped or plate-shaped. Plate shape is preferred. It can be made from materials known from the state of the art, which are suitable for use in drug formulations with fluorocarbons as propellants. Suitable for this are, for example, thermoplastics, elastomers, materials such as neoprene, isobutylene, isoprene, butyl rubber, buna rubber, nitrile rubber, copolymers of ethylene and propylene, terpolymers of ethylene, propylene and a single diene, for example butadiene, or fluorinated polymers. Preferred materials are ethylene/propylene diene terpolymers (EPDM).

On the side of the valve cap (8) facing the inside of the container, a valve (9) is made so that the basic part (12) of the valve goes through the valve cap (8) all the way to the other side. The valve (9) sits snugly in the center opening of the gasket (10). In doing so, the seal (10) and the valve (9) together seal the cap (8) of the valve towards the inside of the container so that it cannot come into contact with the liquid in the container (2).

The valve (9) is made so that every element that can come into contact with the liquid inside the container (2) is made of corrosion-resistant material. These elements include, for example, the spring or springs (11), the valve base (12) that protrudes from the inside to the outside through the opening (17) of the valve cap (8), the dosing chamber (13) and the valve body (14). . The spring (11) is made of steel, preferably stainless steel. Further elements of the valve (9) can be, for example, made of steel, the alloys described above and/or made of plastic. Elements (12), (13) and (14) are preferably made of plastic, especially preferably made of polyester, and very particularly preferably made of polybutylene terephthalate.

As shown in Figure 1, one or more seals can be made, for example seals (15) and/or (16), which prevent the escape of liquid or gas from the inside of the container to the outside. At the same time, the seal)e) can be placed so that the liquid inside the vessel, apart from the seal(s), comes into contact only with the shell of the vessel and the valve.

The gasket (15) seals the base part of the valve, which is movable in the vertical direction, as needed, at the point where it pierces the cap (8) of the valve. The seal (16) seals the basic part of the valve (12) inside the valve against the valve body (14) and/or towards the dosing chamber (13). Thus, the seals (15) and (16) prevent liquid or gas from escaping from the inside of the container along the outer shell of the basic part of the valve from the container, i.e. from coming into contact with the valve cap. The seals (15) and (16) can be made of the same material as the seal (10), that is, preferably of ethylene/propylene-diene-terpolymer.

In one embodiment, with the valve cap (8), which is not made of aluminum but made of one of the corrosion-resistant materials described above, it is not necessary for the seal (10) together with the valve (9) to completely isolate the valve cap from the inside of the container. Therefore, in this case, it is also not necessary that the seal (10) and the valve (9) touch each other sealingly. If necessary, there is a gap between the seal (10) and the valve (9). In such a case, the gasket (10) sits, for example, directly on the underside of the valve cap (8) and seals the edge of the valve cap (8) towards the neck (8) of the container. Then the gasket (15) seals the opening (17) in the cap (8) of the valve towards the inside of the container.

Figure 2 shows a further embodiment of the valve cap (8) with an inserted valve (9). This embodiment is largely and entirely identical to the one shown in Figure 1. The essential difference is that the seal (10) and seal (16) of the embodiment from Figure 1 are included together in one seal (18). The seal (18) goes on the lower side of the cap (8) of the valve. It is made so that the body (14) of the valve is located in the gasket. The basic part (12) of the valve passes past the seal through the opening (19) located directly below the opening (17) of the cap (8) of the valve. The opening (19) has such dimensions that the basic part (12) of the valve seals against the cap (8) of the valve. The material for making the seal (18) is the same as that described for the seal (10).

The production of the container (2) according to the invention is carried out analogously to the procedures known from the state of the art, among others for the production of aluminum containers, which can be used to produce containers from sheet metal of the appropriate material, that is, the appropriate alloy. According to the proposed invention, the vessel (2) is stamped from the above-described alloy of chromium (Cr), nickel (Ni), molybdenum (Mo), iron (Fe) and carbon, or from an alloy that additionally contains copper (Cu), manganese (Mn). and silicon (Si).

The container according to the invention (2), i.e. the container consisting of the container (2) and the valve cap (8) with a valve is particularly suitable for the use of propellant gas formulations containing hydrofluorocarbon. Propellant gas formulations which may be advantageously used in conjunction with the invention are described in WO 94/13262, which is hereby incorporated by reference in its entirety. Of these, ethanol and/or acid-stabilized propellant formulations containing 1,1,2,2-tetrafluoroethane (TG 134a) and/or 1,1,1,2,3,3,3 -hepta-fluoropropane (TG 227) and especially those that contain ipatropium bromide, oxytropium bromide, albuterol, tiotropium bromide or fenoterol as active substances.

Depending on the active substance, inorganic and organic acids are suitable for stabilization. Examples of inorganic acids include, apart from halogen acids and other mineral acids: sulfuric acid, hydrochloric acid, nitric acid or phosphoric acid, and examples of organic acids include ascorbic acid or citric acid. In the case of salts of active substances, those acids whose anions are identical to the anions of the salt of the active substance are preferred. For all active substances and salts of active substances, citric acid is generally suitable and is also given the highest preference.

The acid content is such that the pH value of the formulation is between 1.0 and 7.0, preferably between 2.0 and 5.0, and especially preferably approx. 3.5. In the case of inorganic acids, the preferred acid content is in the range of approx. 0.00002 to 0.01 N. In the case of ascorbic acid, a favorable content is approx. in the range from 0.0045 to 5.0 mg/ml, and in the case of citric acid in the range from 0.0039 to 27.7 mg/ml.

The formulations may further contain ethanol as well as co-solvents. The preferred amount is 1.0 to 50.0 wt. % formulation.

Listed below are examples of preferred formulations that can be placed in a container of the type described above.

Example 1

Ipatropium bromide monohydrate 0.001-2.5 wt. %

ethanol, absolute 0.001-50 wt. %

TG 134a 50.0-99.0 wt. %

inorganic acid 0.01-0.00002 normal

water 0.0-5.0 wt. %.

Example 2

Ipatropium bromide monohydrate 0.001-2.5 wt. %

ethanol, absolute 0.001-50 wt. %

TG 134a 50.0-99.0 wt. %

ascorbic acid 0.00015-5.0 mg/ml

water (purified) 0.0-5.0 wt. %.

Example 3

Ipatropium bromide monohydrate 0.0187 wt. %

ethanol, absolute 15.0000 wt. %

TG 134a 84.4773 wt. %

citric acid 0.0040 wt. %

water (purified) 0.5000 wt. %.

a total of 100.0000 wt. %

Example 4

Ipatropium bromide monohydrate 0.0374 wt. %

ethanol, absolute 15.0000 wt. %

TG134a 84.4586 wt. %

citric acid 0.0040 wt. %

water (purified) 0.5000 wt. %.

a total of 100.0000 wt. %.

Example 5

Ipatropium bromide monohydrate 0.0748 wt. %

ethanol, absolute 15.0000 wt. %

TG134a 84.4212 wt. %

citric acid 0.0040 wt. %

water (purified) 0.5000 wt. %

a total of 100.0000 wt. %.

Example 6

Fenoterol hydrobromide 0.192 wt. %

ethanol, absolute 30,000 wt. %

TG 134a 67,806 wt. %

citric acid 0.002 wt. %

water (purified) 2,000 wt. %.

a total of 100.0000 wt. %.

The procedure for filling the container with the appropriate formulation can be for example "Dual Stage Pressure Fill Method", "Single Stage Cold Fill-Method" or "Single Stage Pressure Fill-Method". ” (pressure filling in one stage).

Claims (26)

1. A container (1) for an aerosol inhaler operating on a propellant and consisting of a container (2) and a valve cap (8) with an inserted valve (9), characterized in that the container is made of an alloy containing 40.0 -53.0% iron, 23.0-28.0% nickel, 19.0-23.0% chromium, 4.0-5.0% molybdenum, 0.0-2.0% manganese, 1.0 -2.0% copper, 0.0-1.0% silicon, 0.0-0.045% phosphorus, 0.0-0.035% sulfur and 0.0-0.020% carbon. 2. Container according to claim 1, characterized in that the container (2) is made of an alloy with the following composition: chromium 19.0-21.0%, nickel 24.0-26.0%, molybdenum 4.0-5.0 %, copper 1.0-2.0%, manganese up to 2.0%, silicon up to 0.5% and carbon up to 0.02%, and the rest is mainly iron. 3. Container (1) for an aerosol inhaler that works on a pressure medium and which consists of a container (2) and a valve cap (8) with an inserted valve (9), characterized by the fact that the container is made of an alloy having the following composition: iron 60.0-72.0%, nickel 9.0-13.0%, chromium 17.0-21.0%, molybdenum 2.0-3.0%, manganese 0.0-1.5%, silicon 0.0-1.5%, phosphorus 0.0-0.04%, sulfur 0.0-0.04% and carbon 0-0.03%. 4. Container (1) for an aerosol inhaler working on a pressure medium and consisting of a container (2) and a valve cap (8) with an inserted valve (9), characterized in that the container is made of an alloy containing 16.5 -18.5% chromium, 11.0-14.0% nickel, 2.0-2.5% molybdenum, maximum 0.03% carbon and the rest is iron. 5. Container according to any of claims 1 to 4, characterized in that the valve cap (8) is made of aluminum and is closed with a seal (10) and/or (18) towards the inner space of the container. 6. Container according to any of claims 1 to 5, characterized in that the valve (9) has one or more stainless steel springs (11), a valve base (12), a dosing chamber (13) and a valve body (14). , wherein the main part (12) of the valve, the chamber for (13) dosing and/or the body (14) of the valve are made of steel, steel alloy according to any of claims 1 to 3 and/or plastic. 7. Container according to any of claims 1 to 6, characterized in that the spring(s) is made of stainless steel, and the basic part (12) of the valve, the chamber (13) for dosing and the body (14) of the valve are made of polybutylene- terephthalate. 8. Container according to any of claims 1 to 7, characterized in that the basic part (12) of the valve is sealed with a seal (15) or (18) to the cap (8) of the valve. 9. Container according to any of claims 1 to 8, characterized in that the seal (10) and/or seal (15) and/or seal (18) is made of ethylene/propylene-diene terpolymer. 10. Container according to any of claims 1 to 9, characterized in that the valve cap (8) is made of the same alloy as the container (2). 11. Container according to any of claims 1 to 10, characterized in that the container withstands a burst pressure greater than 30,000 hPa, preferably greater than 100,000 hPa. 12. A container according to any one of claims 1 to 11, characterized in that the container withstands a burst pressure greater than 200,000 bPa. 13. Container according to any of claims 1 to 12, characterized in that the container has a wall thickness of 0.1 to 0.5 mm, preferably 0.15 to 0.35 mm. 14. Container according to any of claims 1 to 13, characterized in that the container has a wall thickness of 0.19 to 3.0 mm. 15. Container container (1) for a propellant aerosol inhaler, characterized in that the container is made of an alloy according to any of claims 1 to 4. 16. Container according to claim 15, characterized in that this container withstands a burst pressure greater than 30,000 hPa, preferably greater than 100,000 hPa. 17. A vessel according to claim 15, characterized in that the vessel withstands a burst pressure greater than 200,000 hPa. 18. A container according to any of claims 15 to 17, characterized in that the container has a wall thickness of 0.1 to 0.5 mm, preferably 0.15 to 0.35 mm. 19. A container according to any of claims 15 to 18, characterized in that the container has a wall thickness of 0.19 to 3.0 mm. 20. The use of a container according to any of claims 1 to 14 or a container according to any of claims 15 to 19, characterized by the fact that he or she is used in an inhaler and/or for storing a formulation of an active substance that contains 1.1 as a suppressant, 2,2-tetrafluoroethane and/or 1,1,1,2,3,3,3-heptafluoropropane. 21. Use according to claim 20 of a container according to any of claims 1 to 14 or a container according to any of claims 15 to 19, characterized in that the formulation contains acid for stabilization, ethanol as a co-solvent and ipatropium bromide, oxytropium bromide, tiotropium bromide, albuterol or fenoterol as an active substance. 22. Use according to claim 20 or 21 of a container according to any claim 1 to 14 or a container according to any claim 15 to 19, characterized in that the formulation contains acid for stabilization, ethanol and ipatropium bromide, oxytropium bromide or tiotropium bromide as an active substance. 23. Use according to claim 20, 21 or 22 of a container according to any of claims 1 to 14 or a container according to any of claims 15 to 19, characterized in that the formulation contains citric acid. 24. Use according to claim 20, 21 or 22 of a container according to any of claims 1 to 14 or a container according to any of claims 15 to 19, characterized in that the formulation contains a mineral acid. 25. Use according to claim 20, 21 or 22 of a container according to any of claims 1 to 14 or a container according to any of claims 15 to 19, characterized in that the formulation contains hydrochloric acid. 26. Method for the production of a container (2) or container (1) consisting of a container (2) and a valve cap (8) with an inserted valve (9) for aerosol inhalers that work on a pressure medium, characterized in that the container ( 2) made by stamping from sheet metal having an alloy composition according to any requirement from 1 to 4.