KR20010080187A - Two chamber cartridge for atomizers - Google Patents

Abstract

The present invention relates to an active material in which the active material used for storage and the device in the form of a closed chamber and a container in the form of a two-chamber cartridge capable of separating and storing the active material and solvent until the device is used in the nebulizer is present in solution or suspension. Relates to a concentrate.

Description

Two chamber cartridge for atomizers

The present invention relates to a device comprising an airtight cap and container in the form of a two-chamber cartridge capable of separating and storing the active ingredient and solvent until the device is used as a nebulizer and a propellant in which the active ingredient is present in a highly concentrated form for storage. (propellant-free) relates to active substance concentrates. The cartridge according to the invention serves in particular as a container for drug formulation for use in aerosol preparation nebulizers, for inhalation or nasal application, in particular for use in propellant nebulizers.

International patent application WO 91/14468, entitled "Spraying apparatus and method", and also in Examples 6a and 6B and related specification description of WO 97/12687, describe the metered amounts of fluid drugs for inhalation applications. A device for administering no propellant is described. In such nebulizers, the drug solution is converted to an aerosol accessible to the lungs by high pressure and sprayed. For this type of application, it may be necessary to gradient filter a solution containing the active ingredient into the vessel so that only a small amount of air and gas residues are included. Suitable containers for this purpose are, for example, containers as described in International Patent Application No. PCT / EP95 / 03183, which is a reference for the present invention. The containers described in this document are described as being particularly suitable for drugs which can be stored for long periods in the form of aqueous or ethanol solutions.

In order to increase the shelf life of the active ingredient in a solution that decomposes only after several months, DE 196 15 422 describes a cartridge having a solvent and two chambers for separate storage of the active ingredient in powder or compressed tablet form. have. The cartridge is designed in such a way that when the cartridge is inserted into an aerosol preparation device (inhaler), the container containing the active ingredient penetrates into the inhaler by a cannula, so that the active ingredient is dissolved in contact with the solvent in the container. Although the cartridge for storage of the inhalation formulation in the container described above has many advantages, the cannula of the inhaler as described above can often be blocked when penetrating the chamber containing the active ingredient. For this reason, no drug suspension can be stored in the chamber described above. In addition, since the active ingredient formulated as a solid cannot be guaranteed to always dissolve quickly enough in the solvent, the concentration of the desired active ingredient can only be achieved over time. In this way, it is difficult to use the cartridge-mounted inhaler without any problem.

The above-mentioned problem and also known problems of the prior art are solved by the present invention which provides a novel two-chamber or multi-chamber cartridge (container) capable of storing two or more inhalation formulation components separately from one another.

In particular, the present invention relates to an apparatus comprising a closure cap and a container which can be used as a cartridge (container) for a nebulizer. Within this cartridge, one or more active ingredients specified for inhalation or nasal administration and one solvent of the therapeutic formulation may be stored separately until the cartridge is installed in the nebulizer as described above. High pressure nebulizers and in particular the nebulizers described in FIGS. 6A and 6B of WO 91/14468 and WO 97/12687 and the related specifications are particularly suitable as nebulizers. Here, the cartridges can be separated from the use of the cartridge in the inhaler and the stored components can be mixed with each other without causing cannula blockage and the drug formulation can be used within the shortest possible time, preferably minutes and possibly seconds Molded to be manufactured. Within the context of the present invention, it is not important whether the drug formulation to be applied is a solution or suspension, but it is important that the formulation to be applied is a fluid formulation which can be converted into an aerosol for inhalation or nasal administration using a nebulizer of the type described above. Is the point. However, for administration by inhalation using the inhaler described above, the formulation in solution form is generally preferred over the formulation in suspension form.

Within the scope of the present invention, the terms nebulizer, injector, inhaler and high pressure nebulizer, and also metering aerosol and aerosol, are used synonymously unless stated otherwise.

Detailed description of the invention

The invention is constructed in a manner analogous to the invention of the above-mentioned document DE 196 15 422, which is incorporated by reference in its entirety. As in DE 196 15 422, a cartridge according to the invention comprises a container comprising at least two possible ways of storing the formulation or components of the formulation, i.e. the cartridge and another chamber formed in the closure closure of the cartridge. Have Some components of the formulation to be administered are stored in the chamber until used, while the remaining components are stored in a container containing most of the liquid component. The main liquid component includes a solvent or suspending agent prepared for administration, or a majority thereof, preferably a solvent, and any other component which will be described more completely below. The term "most of these" refers to the portion of the formulation to be applied which is not formulated with the active substance in the chamber. In the following text, there are no differences between solvents and mixtures of solvents. That is, "solvent" includes mixtures of solvents, unless otherwise noted. However, in contrast, the mixture of solvents always comprises two or more fluids, which are chemically different components.

The active substance, especially the active ingredient which cannot be stored in a pharmaceutically stable manner in an ethanol solvent for the above-mentioned period of time, in a pharmaceutically stable manner for a very long time, for example for several months or possibly for several years, It can be stored in the chamber described above.

The chamber is preferably formed in a hermetic closure, but can be located anywhere in the cartridge, for example inside the container.

For clarity, the expression “chamber” herein refers to both a single chamber and multiple chambers of the same type located directly adjacent to each other, unless stated otherwise.

The chamber has one or more, preferably two openings. The closure closure is designed such that even if the closure closure tightly seals the container, the contents of the chamber can be conveyed into the interior of the chamber through an opening present in each case by external influences. This opening is hereinafter referred to as the inner opening.

In addition, the chamber may optionally have additional openings. Under the sealed conditions of the cartridge, the connection of the chamber to the external environment is made by such an opening, so that an object such as, for example, a plunger, stopper, cannula, capillary or rod can be introduced from the outside into the chamber. This opening is hereinafter referred to as outer opening. It should be emphasized that the terms "inner opening" and "outer opening" are differences in terminology and do not relate to the position or mutual arrangement of the openings. If necessary, the inner opening may take over the function of the outer opening.

In a preferred embodiment, the chamber is a tightly sealed opening that allows one or more openings (or only one opening, a variant of the present opening) to be moved into or out of the chamber by an external cannula or external rod to open the chamber. It is characterized in that it is connected to the plunger.

The inner opening of the chamber may be closed by a movable stopper, a permeable, easily broken membrane or other movable sealing component. Optionally provided outer openings tightly seal the chamber on the one hand, but on the other hand are sealed by a plunger having dimensions that can be moved into the chamber by force.

In some embodiments, the plunger has a hollow interior and has an opening. In this variant, the plunger can fill the entire chamber accurately, so that the active ingredient is located inside it. If necessary, the plunger is arranged such that the plunger tightly seals the outer and inner openings simultaneously and does not require any additional sealing components for tightly sealing and storing the active ingredient in the cavity of the plunger.

When the cartridge is inserted into the inhaler, the cannula or rod located in the inhaler penetrates the closure cap, thereby opening the sealing component of the inner opening directly or indirectly. This can be achieved, for example, by cannula rupture, penetration, opening or movement, preferably starting from an outside point of the chamber. If desired, the cannula may open the sealing component at the point in the chamber. The sealing component can be, for example, a sealing foil.

In addition, the cannula may be inserted into the chamber when the cartridge is inserted into the inhaler, for example, to open the inner opening such that the sealing component is directly penetrated, ruptured or opened by the plunger or opened by an overpressure formed in the chamber. Can be compressed into. In this case, the plunger is compressed directly into the chamber by the cannula until the plunger is lowered into the container through the inner opening or remains in the chamber in such a way that the plunger does not interfere with the recovery of the fluid through the cannula.

Instead of sealing the outer opening with a plunger, one or more other equivalents may be used to perform the plunger function. These include stoppers, balls, spikes, small plates or seals of various types such as, for example, sealing foils, clamp seals, plug seals or screw seals or the like.

The device according to the invention can be used as a cartridge for inhalers for both mono- or combination formulations. In the case of single-agents, the active ingredient is preferably stored in a stable formulation in the chamber, with the additional ingredients of the pharmaceutical formulation to be applied, which are mostly liquid ingredients, stored in a container. In the case of a combined formulation, the active ingredient may be stored as a stable formulation in one single chamber or in several chambers. If the active ingredients used have significantly different shelf lives, more sensitive active ingredients can be stored in the chamber as described above. Other, more stable active ingredients can be stored in a container with a solvent or suspending agent. Thus, a prerequisite for this is that the active ingredient must be stable in the solvent for the desired storage time of months or years.

Thus, the shelf life of such filled cartridges, compared to cartridges containing finished pharmaceutical formulations, can actually be extended by storing sensitive materials in a different formulation than the materials to be applied until the cartridge is inserted into the inhaler. The active substance may be stored in the chamber as a powder, granules, tablets, solutions or suspensions. In general, for the storage of a substance or substances in a chamber, it is desirable that the herbal formulations facilitate simple and rapid dissolution of the active ingredient in the solvent when the two substances are mixed with each other. Active substance concentrates are preferred and constitute a further aspect of the invention.

The active substance concentrates according to the invention can be administered by inhalation and preferably comprise one or more active substances which can be used for inhalation therapy. Thus, the present invention also relates to the use of this kind of active substance concentrate in inhalation therapy.

The active substance concentrates according to the invention can be converted into pharmaceutical formulations (aerosol formulations), which are converted into inhalable aerosols by nebulizers, optionally by dilution with pharmaceutically acceptable liquids comprising pharmaceutical excipients and additives. have. The diluent is preferably stored in the container 2 when the cartridge according to the invention is used. The pharmaceutical formulation to be administered with the active substance concentrate determines the exact composition of the diluent.

The active substance concentrates according to the invention are dissolved or suspended in highly concentrated form in an active pharmaceutical substance in a pharmaceutically suitable liquid, and the active substance is stored for several months to possibly several years without any alteration in pharmaceutical quality. It refers to a solution or suspension which can be characterized.

The term "active substance concentrate" refers to a solution or suspension of one or more active substances present in highly concentrated form in a pharmaceutically acceptable liquid, such as a solution or suspension. Preference is given to suspensions which have been found to be particularly stable upon storage.

The term “highly concentrated” refers to the concentration of the active substance which is too high to be inhalable for therapeutic purposes without diluting the corresponding solution or suspension. In active substance concentrates, the concentration of the active substance (or substances) may be 10 to 500 times, preferably 100 to 400 times, most preferably 250 to 350 times greater than the concentration of the pharmaceutical formulation administered. . According to the invention, the active substance concentration in the active substance concentrate in the suspension is 10 mg / ml to 1000 mg / ml, preferably 75 mg / ml to 1000 mg / ml, more preferably 75 mg / ml to 500 Mg / ml, most preferably 100 mg / ml to 400 mg / ml, most particularly preferably 250 mg / ml to 350 mg / ml. The range of concentration in the solution is preferably 10 mg / ml to 500 mg / ml, preferably 75 mg / ml to 500 mg / ml, more preferably 75 mg / ml to 200 mg / ml, most preferably Is 75 mg / ml to 150 mg / ml. Thus, as one embodiment of the formulation according to the invention the formoterol is from 10 mg / ml to 500 mg / ml, preferably from 75 mg / ml to 500 mg / ml, more preferably from 100 mg / ml to 400 mg. / Ml, most preferably 250 mg / ml to 350 mg / ml. For inhalation, the formulation should be diluted to a concentration of about 0.9 to 1.5 mg / ml. Concentration data is for debase formoterol (mg) per ml of active substance concentrate.

The active substance (s) are suitable for administration by inhalation and may be any substance that can be dissolved or suspended in the solvents or suspensions described above. Preferred active substances are, in particular, betamimetics, anticholiners, antiallergic agents, leukotriene antagonists and especially steroids and active ingredient combinations thereof.

Specific examples include tiotropium bromide, 3-[(hydroxydi-2-thienylacetyl) oxy] -8,8-dimethyl-, 8-azoniabicyclo [3.2.1] oct-6-ene-bromide ,

As beta-like agents:

Bambuterol bitolterol carbuterol formoterol

Crenbuterol Penoterol Hexoprelinin Procaterol

Ibuterol Pyrbuterol Salmeterol Turobuterol

Leproterol Sabutamol Suponeterol Terbutalin

1- (2-fluoro-4-hydroxyphenyl) -2- [4- (1-benzimidazolyl) -2-methyl-2-butylamino] ethanol, erythro-5'-hydroxy-8 ' -(1-hydroxy-2-isopropylaminobutyl) -2H-1,4-benzoxazin-3- (4H) -one, 1- (4-amino-3-chloro-5-trifluoromethylphenyl) 2-tert-butyl-amino) ethanol, 1- (4-ethoxycarbonylamino-3-cyano-5-fluorophenyl) -2- (tert-butylamino) ethanol.

As anticholinergic agents:

Ipratropium Bromide

Oxytropium bromide

Tropium Chloride

N-β-fluoroethylnortropin benzylate methobromide.

As an antiallergic agent:

Disodium chromoglycate

Nedochromil

Epine asstin.

As a steroid:

Flunisolid dexamethasone-21-isonicotinate

Ceraproast mycofenolate mofetil

Francaste Gilroyton

Butiksocort Budesonide

Delplazacort Budesonide

Fluticasone promedrol

Mometasone fluorate tipredan

Beclomethasone (or 17,21 dipropionate)

Beclomethasone, Douglas Icometason Enbutaate

Cycolmethasone Clofredol

Fluorocortinbutyl halomethasone

Deplazacort Acolmethasone

Cyclomethasone Isaktide

Prednicarbate Hydrocortisone Butyrate Propionate

Thixocortol pivalate acolmethasone dipropionate

Lotrisone Carnesten-HC

Deprodone Pulluticason Propionate

Methylprednisolone acenate halopredone acetate

Mometasone mometasone fluorate

Hydrocortisone acenate mometasone

Ulovetasol Propionate Aminoglutethiimide

Triamcinolone Hydrocortisone

Meprednisone Fluorometholone

Dexamethasone betamethasone

Medridone Fluclolone Acetonide

Fluorcinolone Acetonide Paramethasone Acetate

Deprodone Propionate Aristocortes Diacetate

Fluorinolide Marzipredon

Diflufredate Betamethasone Valerate

Dexamethasone isicotinate beclomethasone dipropionate

Fluorocortolone capronate formocotal

Triamcinolone Hexacetonide Clofredol

Formebolon Clobetasson

Endryone Pullun Solide

Halcinonon Fluazacort

Clobetasol Hydrocortisone 17-butyrate

Diflorason Fluorocortin

Amcinonin betamethasone dipropionate

Cortibazole Betamethasone Adamantate

Fluorexic Acid Trillostan

Budesonide clobetason

Demetex Trimashinone Benetonide

9-α-chloro-6-α-fluoro-11-β-dihydroxy-16-α-methyl-3-oxo-1,4-androstadiene-17-β-methylcarboxylate-17-pro Cypionate.

Salbutamol, tiotropium and / or formoterol and salts thereof, in particular formoterol, are preferably formulated as concentrates as suspensions.

The term "pharmacologically suitable fluid" for the present invention means a solvent or suspending agent that is not a liquefied propellant gas. Polar fluids are preferred, particularly protic fluids.

Examples of polar solvents or suspending agents for active substance concentrates are, for example, dimethylsulfoxide or hydroxyl groups or water or alcohols, in particular ethanol, isopropyl alcohol, glycols, in particular propylene glycol, polyethylene glycol, polypropylene glycol, glycoethers. And other polar groups such as glycerol, polyoxyethylene alcohol and polyoxyethylene fatty acid esters.

Examples of polar liquids, which are the most preferred solvents or suspending agents within the scope of the present invention, include water, saline aqueous solutions comprising one or more pharmacologically acceptable salts, ethanol or mixtures thereof. In the case of an aqueous ethanol mixture, the volume ratio of ethanol to water or saline solution is 5:95 to 99: 1, preferably 40:60 to 96: 4, most preferably 75:25 to 96: 4. A particularly preferred ratio is 40:60 to 60:40.

In saline aqueous solutions, either as a solvent or suspending agent or as a component thereof, particularly suitable salts are those which exhibit some or only negligible pharmacological activity after administration. Preferably an aqueous saline solution is used in the suspension concentrate. To stabilize the suspended particles, the addition of salts significantly reduces the solubility of the active substance or substances in water. If necessary, saturated saline solution can be used. The amount of salt depends on the exact composition of the solvent or suspending agent and their ability to dissolve the active substance. For example, formoterol should be present in dissolved form in an aqueous formoterol suspension in the sense of the active substance concentrate according to the invention in an amount of less than 0.5% by weight, preferably less than 0.1% by weight, the amount being It is based on the total amount (weight) of moterol. However, if the amount of dissolved material is above the specified level, it can be reduced below this level by the addition of salts.

In general, solubility can be reduced to one half by adding salts, and in some cases to one fifth or less. Preference is given to aqueous saline solutions having a salt content of up to 50% by weight, in particular up to 20% by weight.

Both inorganic and organic salts can be used as salts. Preference is given to inorganic salts such as sodium chloride, alkali metal salts or ammonium halide salts. Sodium chloride is particularly preferred. Suitable organic salts are, for example, the sodium, potassium or ammonium salts of ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and / or propionic acid.

Cosolvents may be added to the solvent or suspending agent. Cosolvents are suitable for improving the solubility of additives and any active material (or materials). Preferred cosolvents are hydroxyl groups or other polar groups such as alcohols (especially isopropyl alcohol), glycols (especially propylene glycol, polyethylene glycol, polypropylene glycol, glycol ethers, if they have not already been used as solvents or suspending agents) Glycerol), polyoxyethylene alcohol and polyoxyethylene fatty acid esters.

Other excipients and additives may be added to the active substance concentrates according to the invention.

The term excipients and additives herein is not an active substance for enhancing the qualitative properties of the active substance concentrate or pharmaceutical formulation obtained by dilution for inhalation, but is a pharmacologically suitable solvent with the active substance (or substances). Or any pharmacologically suitable, therapeutically useful substance that can be formulated with a suspending agent. Preferably, such materials do not have any significant or undesirable degree of pharmacological activity within the scope of any pharmacological activity or desired treatment. Excipients and excipients include, for example, suspension-stabilizing surfactants, other stabilizers, complexing agents, antioxidants and / or preservatives, perfumes, vitamins known in the art to prolong the service life of the finished pharmaceutical formulation. And / or other additives.

Active substance concentrates as surfactants may include, for example, useful concentrations of sorbitan esters such as soy lecithin, oleic acid, sorbitan esters such as sorbitan trioleate or other surfactants. .

The addition of organic or inorganic acids, preferably in combination with complexing agents, improves the stability (save life) of some drugs, including ethanol as solvent, in particular drugs containing steroids. This applies in particular to drugs comprising formoterol, flunisolide or hydrates or hemihydrates or budenosides as active ingredients.

Examples of preferred inorganic acids for this application are hydrochloric acid, nitric acid, sulfuric acid and / or phosphoric acid. Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid, propionic acid and the like. Preferred acids are hydrochloric acid and / or fumaric acid.

The concentration of the acid is chosen such that the active substance concentrate has a pH of 2.0 to 7.0, preferably 4.0 to 6.0, most preferably 4.5 to 5.5.

Examples of complexing agents that can be used on their own or in combination with an acid include EDTA (ethylenediaminetetraacetic acid, or a salt thereof such as disodium salt), citric acid, nitrilotriacetic acid and salts thereof. Preferred complexing agent is EDTA.

Preservatives can be used to protect concentrates from infection by pathogenic bacteria. Preservatives known in the art are suitable, in particular benzalkonium chloride or benzoic acid, or benzoate such as sodium benzoate.

Suitable antioxidants are especially well known pharmacologically acceptable antioxidants present in the human body, ie vitamins such as ascorbic acid or vitamin E or provitamins.

If the active substance or substances are present as a suspension in the active substance concentrate according to the invention, the particles are preferably formulated to a particle size of 20 μm or less, preferably 10 μm or less, particularly preferably 5 μm or less. .

Preferred active substance concentrates comprise one or two active substances; Particular preference is given to active substance concentrates comprising one active substance.

Suspensions are most preferred as active substance concentrates.

The active substance concentrate according to the invention has the advantage that the active substance can be formulated in such a way that it remains stable for a fairly long time. Apart from the concentration of the active substance, there is no need for a concentrate corresponding to the composition of the finished pharmaceutical formulation. For example, if the pH of the concentrate ensures a more stable solution or suspension of the active substance, the pH of the concentrate may actually differ from the pH of the pharmaceutical formulation to be administered.

The active substance concentrates according to the invention are generally not suitable for direct medicinal use, especially for inhalation. As mentioned above, the use of active substance concentrates involves converting them into pharmaceutical formulations (aerosol formulations). The term "pharmaceutical formulation" refers to a formulation of a pharmaceutical substance suitable for inhalation in which a pharmaceutical substance or mixture of substances is required and / or can be administered at the recommended concentration.

The pharmaceutical preparations can preferably be administered by inhalation using a suitable nebulizer.

A preferred method of converting the active substance concentrate into a pharmaceutical formulation suitable for administration is to dilute the active substance concentrate according to the invention with a pharmacologically suitable solvent or suspending agent.

To obtain a pharmaceutical formulation for administration, the active substance concentrate is diluted until a pharmaceutical formulation is prepared which can be used directly for inhalation. The pharmaceutical formulation to be administered, together with the active substance concentrate in chamber 17, determines the exact dilution composition in container 2.

Examples of formulations suitable for administration are described in WO 97/01329, which is incorporated by reference. When such formulations are administered within the scope of the present invention, the active substance concentrates in the chamber 17 and the dilutions in the vessel 2 are similar to or according to the formulation of WO 97/01329 when they are mixed with each other. It must be prepared in dosage form.

In this type of formulation suitable for administration, the proportion of drug dissolved in the finished pharmaceutical formulation is generally from 0.001 to 5%, preferably from 0.05 to 3%, particularly preferably from 0.01 to 2%. Weight percent). For solutions such as finished pharmaceutical formulations, the maximum concentration of drug depends on the solubility and dosage in the solvent required to achieve the desired therapeutic effect.

As mentioned above, aqueous saline solutions, preferably aqueous solutions which may comprise ethanol, are particularly preferred as solvents or suspending agents for finished pharmaceutical preparations, ie formulations suitable for inhalation or oral administration. 30% (v / v) ), Particularly preferably at least 50% (v / v) ethanol. Particular preference is given to solutions with an ethanol content of 95% (v / v). The concentration is% by volume (v / v) and the remainder is water or saline solution. Particular preference is given to ethanol comprising a small amount of water, for example 96% ethanol and 4% water (v / v), in order to be no longer hygroscopic and to azeotropically evaporate.

The pharmaceutical formulation applied with the active substance concentrate in chamber 17 determines the exact dilution composition in container 2.

Ready-to-use drug formulations are prepared only when the contents of the chamber 17 are mixed with the contents of the container 2 so that the cartridge is inserted only into the inhaler, where the contents of the individual components or diluents are It is important to note that it is defined as described above in connection with active substance concentrates that do not limit or otherwise mention the contents.

Preferred solvents or suspending agents for dilution are propellant liquids, preferably polar, more particularly protic liquids.

Particularly preferred diluents are water, saline aqueous solutions containing one or more pharmacologically acceptable salts, ethanol or mixtures thereof, with mixtures of water and ethanol being particularly preferred. For aqueous ethanol mixtures, the volume ratio of ethanol to water or saline solution is such that the inhalable pharmaceutical formulation has a formulation comprising at least 30% (v / v) ethanol, more preferably at least 50% (v / v) ethanol. It is the same rain as that. Particular preference is given to pharmaceutical preparations having an ethanol content of at least 95% (v / v). The concentration is given in volume ratio (v / v), the remainder being water or saline solution. Particular preference is given to ethanol which comprises a small amount of water, for example 96% ethanol, in order to be no longer hygroscopic and to azeotropically evaporate.

The diluent need not be identical or identical to the solvent or suspending agent of the active substance concentrate. If desired, the solvent or suspending agent of the active substance concentrate may comprise one or several diluent components.

It should be noted here that the above-mentioned cosolvents and / or excipients or additives and / or active substances associated with the active substance concentrates according to the invention may be dissolved or suspended in the diluent.

In a preferred embodiment the diluent comprises a preservative and / or a complexing agent.

Optionally, diluents may include buffering materials such as trisodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, Na-EDTA, EDTA, mixtures thereof and other materials known in the art. Preferred materials are sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium hydrogen phosphate, potassium dihydrogen phosphate, potassium hydrogen phosphate, tripotassium hydrogen phosphate, and mixtures thereof. The buffer material is of particular advantage when the pH of the active substance concentrate suitable for storage according to the invention is significantly different from the pH of the substance which is preferred for application, for example when the pH increases the stability of the active substance during storage. have. In this case, the buffer substance is preferably an aerosol formulation suitable for administration after mixing the active substance concentrate with the diluent, preferably at a pH of 2.0 to 7.0, particularly preferably 4.0 to 6.0, most preferably 4.5 to 5.5 It is present in the diluent at the same concentration as having.

In a preferred embodiment, the pharmaceutical formulation comprises a complexing agent preferably selected from the complexing agents described above in connection with the active substance concentrate. The amount of the complexing agent is 100 mg / 100 ml or less, preferably 50 mg / 100 ml or less. Preferred complexing agent is EDTA. Preferred pharmaceutical formulations include, for example, 1.667% by weight of pullunisolide, 0.01 mg / 100 ml of EDTA and ethanol (96% v / v) as a solvent in the pharmaceutical formulation to be administered. Acid (hydrochloric acid) is added to adjust the pH to 3.0 to 4.0, preferably 4.0.

If the diluent comprises one or more active substances, the diluent comprises as an stabilizer, in particular for drugs containing steroids, preferably organic or inorganic acids combined with complexing agents. This is especially true for pharmaceutical preparations comprising formoterol, flunisolide or hydrate or their hemihydrate or budesonide as active substances.

As mentioned above, the pharmaceutical formulation to be administered with the active substance concentrate determines the exact composition of the diluent.

Preferred pharmaceutical preparations comprise one or two kinds of active substances, with pharmaceutical preparations having one active substance being particularly preferred.

The active substance concentrates suitable for storage according to the invention or the pharmaceutical preparations for administration obtained by dilution do not contain any propellant.

Preferably, the mixing is carried out at ambient temperature and atmospheric pressure. One advantage of the active substance concentrate according to the present invention is that it can be diluted to be used in a therapeutically effective formulation and / or nebulizer in a very short time, for example in minutes or possibly seconds. It can be converted to a suitable material. In addition, mixing can also be accomplished by patients who generally lack pharmaceutical knowledge.

For inhalation, as described above, in the separation of the individual components of the pharmaceutical formulation to be administered, the active substance as a storeable solution or suspension, which preferably does not need to contain the pharmaceutical formulation to be administered, ) Can be stored. In this case, as described above, the concentration of the active substance corresponds to the concentration of the pharmaceutical formulation to be administered (± 10% by weight). The chamber 17 then contains other excipients and additives for preparing the pharmaceutical formulation to be administered, preferably those described above. They are then administered in the form of powders, tablets, suspensions or solutions.

For example, the active substance may be stored in the container 2 as a solution or suspension at a pH that is more acidic or more basic than the pH of the pharmaceutical formulation to be administered. In this case, chamber 17 may comprise a buffer, for example those as described above. When the cartridge is inserted into the inhaler, the preferred pH for administration is achieved by mixing the contents in the chamber 17 with the formulation in the container 2. For example, a liquid formulation containing tiotropium bromide as the active ingredient may be stored in the container 2 at a pH of less than 3.0. The chamber 17 has a buffer material such as, for example, sodium hydrogen phosphate and potassium hydrogen phosphate, having a pH of 3.0 to 7.0, preferably 3.0 to 4.0, when such buffer is mixed with the tiotropium formulation. Include in amounts to be These features are merely examples of possible formulations for tiotropium bromide and are not necessary for the other active materials described above. In addition, while the chamber 17 contains a pharmaceutically acceptable solvent, the active substance can be stored as a suspension in the container 2, so that a solution formulation is prepared when they are mixed with each other.

The preferred volume of formulation in chamber 17 and container 2 is strictly determined by the volume of chamber 17 and container 2. In a preferred embodiment the amount of active substance concentrate suitable for storage according to the invention for storage in the cartridge described above is selected corresponding to a volume of from 0.001 to about 0.05 ml, preferably from 0.001 to 0.02 ml.

The above examples indicate that two-chamber cartridges can be used to separately store different components of the active substance formulation until the cartridge is inserted into a suitable inhaler. Thus, there is no need to store the components for administration by themselves. Thus, to produce the desired formulations that can be directly administered, all of the requirements are that the stored ingredients are mixed with each other when the cartridge is inserted into a suitable inhaler.

Detailed description of the cartridge according to the invention

Hereinafter, the present invention will be described in more detail with reference to specific embodiments.

1 shows a longitudinal cross section of a cartridge 1 according to the invention comprising a container 2 for solvents and a closure closure which is actually only in sealed form. Further properties of the closure plug 3 are described in more detail in FIGS. 3 to 11 below.

FIG. 2 shows one embodiment of a closure plug 3 showing any sealing concept similar to that of FIG. 1 showing only the sealed form in detail. The container 2 is only marked.

FIG. 3 shows, in axial cross section, an aspect of a closure plug 3 having a chamber 17, a plunger 21 and a guide tube 16.

4A-4G show various aspects of the plunger 21 in an axial cross section.

FIG. 5 shows, in axial cross section, an embodiment of a closure plug 3 with a hollow plunger 21 for receiving the active ingredient.

6 shows in a axial cross section a further aspect of a closure plug 3 with a hollow plunger 21.

FIG. 7 shows in a axial cross section a further embodiment of a closure plug 3 with a hollow plunger 21.

8 shows in a axial cross section a further embodiment of a closure plug 3 with a hollow plunger 21.

FIG. 9 shows, in axial cross section, an aspect of a closure plug 3 having a plunger 21, a guide tube 16 and a chamber 17 divided into two compartments.

FIG. 10 shows, in axial cross-section, an aspect of a closed stopper 3 without a guide track for a correctly fitted cannula 15.

FIG. 11 shows an embodiment of a closure plug 3 with only one opening in which the chamber 17 is sealed with a plunger 21.

FIG. 12 shows one embodiment with a chamber 17 that can rupture at the connecting part 7.

1 shows a cartridge 1 according to the invention, comprising a solvent chamber 2 and a closure plug 3, in an axial cross section along the longitudinal axis. This figure shows one of the properties of the closure closure 3 necessary for sealing the container 2. Additional properties of the closure plug 3 are described in more detail in the following figure.

The container 2 according to the invention comprises a "jacket" 4 and an inner bag 5 which can be easily deformed. The inner bag 5 is aligned with the inner wall of the jacket 4 but is not secured to the jacket 4 except for the neck of the container and the metal plate 6. The advantage of the deformable inner bag attached in this way is that the low pressure, which can be generated by further extraction, does not cause the inner bag to develop or unfavorably collapse the inner bag during removal of the fluid, thereby allowing the inner fluid to flow through the cannula. It can be extracted from the bag. In the following text, in particular in the following claims, there is no difference between "container 2", jacket 4 and "inner bag 5", rather the term "container 2" is used exclusively.

The closure plug 3 has a device-in the form of a connecting piece 7 which is immersed here-in which part of the contents is conveyed from the container 2 during the sealing process. If the connecting part 7 is tightly sealed by the closure 3, the connecting part 7 preferably has a gas or fluid inside the container 2 along the connecting part 7. It is not in contact with the neck of the container 2 so that it can be discharged from it, or so that a gap is formed between the connecting portion 7 and the inner surface of the container 2. In addition, the connecting portion 7 may have (not shown) at its surface one or more vertical notches (s) through which the gas or fluid may flow out of the vessel 2 during its closure process. In this case, the outer diameter of the connecting part 7 may correspond to the inner diameter of the neck of the container. In the closed state, the closure 3 tightly seals the container 2 such that no further gas or fluid can flow out of the inside of the container 2.

The circumferential convex face 8 located inside the lower edge of the closure stopper 3 head is connected to a sealed position below the cylindrical cylinder ring 9 located outside the container neck. In the sealed state, the sealing ring 11 is filled in the intermediate space between the flat portion of the closure stopper 3 which is provided with the circumferential lip 10 for better sealing and the upper edge of the container neck, in this way The interior of the container 2 is sealed. The inner diameter of the sealing ring 11 is suitably chosen to lie firmly with the connecting part 7. Due to the closure method, the medium (gas, air or fluid) spilled from the interior of the container 2 can be discharged through one or more outlets 12 in the head of the closure closure 3. The outlet or opening 12 may be placed at another point of the cartridge, for example, the side in the circumferential portion of the stopper.

2 shows a side view of one embodiment in which the closure plug 3 is sealed by a corrugated aluminum sleeve 13. In addition, this feature of the closure plug 3 necessary for sealing the container 2 is only shown in the figure. All other properties of the closure plug 3 are described in more detail in the following figures. The container 2 represents only a portion.

The sleeve 13 has a central opening 14 for the cannula 15 to pass through. The continuation of the central opening 14 of the guide tube 16 for cannula through the closure plug 3 shows only a portion.

The central opening 14 may be sealed with a source seal or with a septum to protect it from dust and other impurities. Such sealing methods are known, for example, in ampoules for injection. A source seal of this kind can be formed in the closure plug according to FIG. 1.

3 to 11 below, various embodiments of the closure plug 3 are shown in axial cross section. The chamber 17 is shown as an essential component of the connecting portion 7. All figures show a closure closure with a sealing system as shown in FIG. 1. In addition, although similar embodiments may have a sealing system according to FIG. 2, they are not shown.

3 shows one embodiment of the closure plug 3 in an axial cross section. The central component of the closure plug 3 is the chamber 17 which terminates at the footrest of the connecting portion 7, which chamber 17 is, for example, a concentrated solution or suspension, powder, granules, or any of the other forms described above. It includes the active ingredient (s) 22 described above, which may be one or more active substances, excipients, and additives that may be in one form. Preferably, the chamber comprises a concentrate of the active substance described above. The chamber 17 has two openings 18 and 19. Material may enter the chamber 17 from the outside through the opening 18 and the contents of the chamber 17 may exit the chamber 2 through the opening 19. The opening 19 is sealed with the separating component 20 attached thereon and is firmly attached to the connecting portion 7. The opening 18 is sealed by the plunger 21. From the top end of the closure plug 3, a guide tube 16 for capillary or cannula 15 for extracting fluid is connected to the plunger 21. A diaphragm or o-ring seal 23 can be supplied in the guide tube.

The position of the separating component 20 or the plunger 21 can vary widely over the range inside the connecting portion 7, but preferably by the separating component 20 or the separating component 20 and the plunger 21. The internal space formed is arranged to function to adjust the amount of active ingredient 22 such that it contains no minimum possible volume of gas (air), preferably no gas at all.

Separation component 20 may be a foil that may be ruptured by pressure, for example, or may be easily ruptured and opened by a sharp or pointed object. Preference is given to heat sealed sealing foils which are impermeable to diffusion. Such a kind of sealing foil is, for example, an aluminum layer. In one embodiment, the separating component 20 may have a weak point attached to the side wall of the connecting portion 7 so that it breaks at a weak point when a pressure or force is applied thereto. As an alternative to the sealing foil, the opening 19 can be sealed (not shown) by a stopper or plunger.

The plunger 21 is made of a material that is too rigid to penetrate the round cannula, or is so inelastic that it does not adhere to the cannula even when the cannula firmly presses the plunger. Preferred materials are elastomers, soft plastics and / or plastics such as polyethylene, silicone, EPDM (ethylene-propylene-diene-copolymer).

The shape of the plunger 21 may be cylindrical, for example. In any case, the form of the plunger is such that it tightly seals the opening provided with the plunger. Preferably the plunger 21 has a length longer than the diameter of the plunger, for example, factor 1.2 to 2, preferably factor 1.5. In this way, the plunger 21 is guided along its outer surface upon movement and canting is prevented. 4A-4G show additional aspects of the plunger 21 in which one or more spikes or one side is cut (FIG. 4C) are provided with cutting edges or the plunger 21 is tapered to one point (FIG. 4D). . The provided spikes or cut edges may have a very small diameter (μm to mm) and are in the starting position of the plunger 21, ie the position before the plunger 21 is moved by the cannula 15. ) Can barely or almost reach.

A further preferred embodiment of the plunger 21 is shown in FIG. 4E. The plunger has a recess 28 in the form of a hollow space with one side open. The opening of the recess 28 is in the direction of the head of the closure plug 3, ie in the direction of the capillary or cannula 15. The inner diameter of the opening or recess 28 is larger than the outer diameter of the cannula 15. In the cross sectional view, the plunger 21 is in the shape of a U having a corner with any angle. At the bottom of the recess 28 is formed a point on the plunger 21 that allows the cannula 15 to compress the plunger 21 into the chamber 17. The advantage of this shape and arrangement is that the plunger 21 is facilitated by the pressure of the cannula 15 on the bottom of the recess 28 at the opposite end, ie the face of the plunger 21 which directly seals the opening 18. Can be tapered. That is, due to the pressure exerted by the cannula 15, the shape of the plunger 21 in the cross section changes from a U shape to a nearly V shape. This allows the plunger 21 to pass through the opening 18 more easily. A further advantage of this shape change of the plunger 21 generated by the pressure from the cannula 15 is that the plunger 21 can be moved by the cannula 15 without quenching, even if a firmly fitted plunger 21 is provided. The pressure of the plunger 21 on the wall to be reduced is reduced. This embodiment is particularly advantageous when the plunger 21 seals the chamber 17 with respect to the opening 18, as shown in FIG. 3.

FIG. 4F shows exactly or almost exactly the plunger 21 with the hollow space 24 filling the entire chamber 17 along its length and width. In this regard, the term “exactly” indicates that the width of the plunger 21 may have the same outer dimensions as the interior of the chamber 21 or may be 5% or less wider than the chamber 17. The term "almost exactly" means that the plunger 21 is slightly smaller than the dimensions and / or length inside the chamber 17. The plunger 21 is preferably manufactured as a plunger that fits correctly. Such a variant may be advantageous when filling the closure plug 3 as well as when the plunger is moved through the chamber 17 by the cannula 15. Here, if the plunger 21 is embedded too deep into the chamber, the opening of the hollow space 24 is sealed by the separating component 20 (FIG. 5), or the opening of the hollow space 24 is the side wall of the chamber 17. It is firmly sealed by (FIG. 6). A variant 4g shows another embodiment in the form of an axial cross section in the form of a plunger 21 shown in FIG. 4F in which the hollow space 24 is separated into two chambers by fractions for separating and filling different components in the chamber 17. will be. Here, the separating component 20 likewise seals the plunger on its opening face. The openings of the plungers 21 according to FIGS. 4F and 4G can extend over their entire width (shown) or a portion (not shown).

In order to prevent the plunger 21 from tilting, guide means such as, for example, guide rails or guide ribs (not shown) may be provided on the side walls of the plunger and / or chamber 17. In order to improve the sliding of the plunger 21 through the opening 18 and the chamber 17, the wall of the plunger 21 or the chamber 17 can be coated with a pharmaceutically-acceptable lubricant. Such lubricants are known in the art and include sorbitan esters, sorbitan trioleates, oleic acid, lecithin and other fatty acids, fatty alcohols, esters of fatty acids and the like thereof.

The cannula or capillary guide tube 16 may be designed such that the capillary 15 that fits correctly is tightly sealed to the connecting portion 7 when it is pushed into the connecting portion 7. If necessary, the guide tube 16 is tapered as its length extends from the head of the closure plug 3. Alternatively or in addition, the permeable diaphragm or elastic O-ring seal 23 may be located at a desired position within the guide tube 16. For the sake of simplicity, the "diaphragm 23" is now used for both the permeable diaphragm and the elastic O-ring seal 23. As the name implies, the guide tube 16 serves to guide the cannula or capillary 15 along the passageway through the predetermined closure plug 3 without any complexity.

In terms of opening the head end inwards, the guide tube 16 may have a source seal or shield from impurities. This function may optionally be performed by the diaphragm 23.

In a preferred embodiment, the chamber 17 has a constant inner diameter along its entire longitudinal axis. The opening 18 and the opening 19 lie perpendicular to the longitudinal axis on the upper or lower side of the chamber 17. Both openings extend over the entire diameter of the chamber 17. In particular when the plunger is in its sealed position in the chamber 17, the plunger 21 has an outer diameter slightly larger than the inner diameter of the chamber 17 (FIG. 3). In this way, a better seal of the opening 18 is achieved. In addition, the plunger 21 has the advantage of completely emptying the chamber 17 when the plunger 21 is compressed through the chamber 17.

As already mentioned, an embodiment with a hollow plunger 21 in which the active ingredient or components 22 are stored in the hollow region 24 of the plunger instead of being stored directly in the chamber 17 is shown in FIGS. 5 and 6. have. In this embodiment, the cannula 15 pushes the plunger 21 through the chamber 17 until it is pushed down into the plunger vessel 2, the contents 22 of the plunger 21 being the solvent in the container 2. Dissolved or suspended by

Such a variant may be designed (not shown) such that the plunger cannot be compressed directly through the chamber 17, but only enough to cause the active ingredient 22 to be injected into the container 2. In this case, the guide rails and / or detents are located on the outer wall of the plunger 21 and / or the inner wall of the chamber 17 to prevent the plunger from fully compressing through the chamber 17 ( Not shown). In such a case, the side wall of the chamber 17 may also have an opening that is kept sealed by the plunger 21 until the plunger 21 is moved by the cannula 15. Here, the opening is designed so that the ready-to-use aerosol formulation can be removed through the opening by the cannula 15. Here, the plunger 21, chamber 17, cannula 15 and guide rail and / or detent are designed such that the plunger 21 cannot block the cannula 15 after the plunger is pushed to its distal position by the cannula. . If necessary, the cannula 15 may cause initial movement of the plunger 21 through the chamber 17 after the plunger 21 is pushed down to its detent in its distal position by, for example, gravity or other mechanism. . This prevents the plunger 21 from blocking the cannula 15.

FIG. 7 shows a further variant with a hollow plunger 21 which completely fills the chamber 17. A plunger 21 having its own opening is a stopper similar to the stopper provided in the connecting portion 7, which holds the plunger 21 in the chamber 17 and at the same time tightly seals the opening of the plunger 21. Is inserted into In this variant, the opening of the plunger 21 is designed such that only a part of the side wall is opened. The guide tube 16 serves for the cannula 15 to squeeze the plunger 21 from the portion where the injection portion 27 is mounted in the closed portion of the side wall of the plunger 21 to be compressed into the container 2. To a closed portion of the side wall of the plunger 21. In addition, the plunger 21 may have several openings in the connecting portion 7 which are sealed by a plurality of stoppers-like injection parts 27 (FIG. 8).

In this variant, although this may be the case, the inner opening 19 need not be sealed by the separating component 20 (not shown).

FIG. 9 shows an embodiment of a closure plug 3 similar to FIG. 3 in which the chamber 17 is divided into two compartments by the separating component 25. Separation component 25 is easy to open or remove in a manner similar to separation component 20. Each part serves to separate and store two or more active ingredients or additives. In a similar manner, more than two compartments may be provided (not shown).

In one embodiment, in an embodiment where the chamber 17 has two or more compartments, pharmacologically acceptable solvents having very good solubility for the active ingredient are, for example, compartments that are not sealed by the separation component 20 ( Storage in one compartment (upper compartment). Such a solvent may be a solvent of the type described above or another solvent known in the art, for example pure ethanol.

In this aspect, the plunger 21 is provided with one or more spikes or cut edges. In a two-stage mechanism, the separated component 25 is first opened, so that the solvent flows from the upper compartment to the lower compartment, thereby dispensing or suspending the plunger 21 to dissolve or suspend the active ingredient 22 located in the lower compartment. Compress enough into. In a second step, the plunger 21 may be further moved to open the separation component 20 to allow the dissolved or suspended active component to flow into the chamber 2.

In this case, the permeable membrane can likewise be provided at the position of the plunger 21. In this case, the dimensions of the guide tube 16 and the upper part are designed such that the cannula 15 can only penetrate or rupture open the separating component 25 so that the solvent flows into the lower component, dissolving the active ingredient. Or suspend. The separating component 20 is then connected to the connecting portion 20 in such a way that the solvent breaks the bond between the connecting portion 7 and the separating component 20 such that a solution or suspension of the active ingredient flows without being disturbed into the vessel 2. ) Is combined. The modification described last is advantageous when the active ingredient in the chamber 17 is a solid that does not dissolve or suspend sufficiently quickly in a solvent provided for pharmaceutical formulation.

In addition, the mixing of the solvent in the upper portion with the contents 22 in the lower portion can take place directly, for example, by the user compressing the closure plug 3 against the container 2 before mounting the cartridge into the inhaler. This is done with the first step of the mechanism by a suitable device. This type of mechanism can be applied regardless of the number of compartments in the chamber 17. That is, only one compartment may be provided to the chamber 17 if necessary.

FIG. 10 shows an embodiment similar to that of FIG. 3 in which a wide guide tube 26 is provided in the closure plug 3, instead of the guide tube 16 for the capillary 15 that fits correctly. In this embodiment, the plunger 21 is located on the surface on which the permeable diaphragm or elastic O-ring seal 23 lies in the head direction of the closure stopper 3. In this case, too, the guide tube 26 may be sealed by a shield from the seal or impurities from the substance at its opening end in the head of the closure cap.

In another embodiment, no guide tube 16 or tube 26 is provided. In this case, the diaphragm or elastic O-ring seal 23 is fused into the upper face of the closure stopper 3 below where the plunger 21 or chamber 17 is located directly. Although this embodiment is not shown, a very similar embodiment is shown in FIG. 10.

In the embodiments of FIGS. 3-10 described so far, the chamber 17, the opening 18, the opening 19, and the plunger 21 are capillary 15, although the plunger 21 tightly seals the opening 18. It is dimensioned to allow complete compression of the chamber 17 and the opening 19 by the pressure on it. In the case of the embodiments of FIGS. 3-6 and 9-10, the separation component 20 is opened as the plunger 21 moves into the chamber 17 by force applied through the capillary or cannula 15. That is, for example, it bursts as pressure increases inside the chamber 17 and / or penetrates by one or more spikes or cutting edges supplied to the plunger 21. The contents of the chamber 17 enter the container 2 containing the solvent upon opening of the separation component 20. The shape and arrangement of the components included in the method is such that the cannula 15 does not contact the contents of the chamber before or after the contents of the container 2 and the contents of the chamber are mixed. In this way, clogging of the cannula 15 is prevented.

Another embodiment is shown in FIG. 11, where the interior of the connecting portion 7 is actually hollow, thus forming the chamber 17. The guide tube 16 is held by the lower sidewall of the chamber 17 from the head of the closure closure 3 through the chamber 17, and the plunger 21 which tightly seals the chamber 17 and the guide tube 16. It leads to. The plunger 21 simultaneously seals the guide tube 16 opposite the chamber 17. The diaphragm 23 is located in the guide tube. The plunger 21 is designed such that it can be pressed into the container 2 by a cannula or capillary 15. If necessary, the chamber 17 can be divided into several compartments by fractions (not shown) provided parallel to the longitudinal axis of the connecting portion (all fractions are sealed (not shown) by the plunger 21).

FIG. 12 shows a hermetic closure provided with a guide tube 16 having a permeable diaphragm 23 at the connecting portion 7. The guide tube 16 extends to the bottom of the connecting portion 7 where the chamber 17 is held by a precisely manufactured weak point 29. In this embodiment, the opening 19 is parallel to the longitudinal axis of the connecting portion 7 and tightly sealed with the separating component 20. The separating component 20 extends over the opening 19, at which point it is fixedly connected to the connecting portion 7. When the capillary 15 penetrates the diaphragm 23 to compress the chamber 17, the weak point 29 ruptures first. Subsequently, the inherent weight of the chamber 17 or the additional through the cannula 15, such that the separating component 20 remains connected to the connecting portion 7, but the chamber 17 itself falls into the container 2. The pressure causes the separation component 20 on the opening 19 to burst open. If desired, the weak point 29 may be made of something such as an easily rupturable foil or adhesive strip that connects the chamber 17 to the connecting portion 7 in the opposing separating component 20.

In addition, the chamber 17 can be connected solely with the connecting portion 7 via the separating component 20. In this case, the weak point 29 is not provided.

When the active ingredient is administered as a solution and stored in the chamber 17 as a suspension, the embodiment according to FIGS. 3, 4, 9 and 10 is particularly preferred, in which the separation component 20 is designed in the form of an aluminum coated sealing foil. This embodiment ruptures the separation component 20 by the pressure of the plunger 21 such that overpressure in the chamber 17 causes the suspension to flow from the chamber to the vessel under pressure and quickly dissolve in the solvent in the vessel 2. Has the advantage of being formed from

Containers and closure closures are generally made of deformable plastics. The walls of the containers are made such that they can withstand or shrink sufficiently even when the fluid is removed. Separation component 20 generally consists of a thin plastic foil. Separation component 20 preferably comprises a thin aluminum foil.

According to the invention, cartridges for inhalers containing drug formulations must have a long shelf life. To this end, it is essential that the solvent in the container 2 cannot be diffused into the chamber 17 containing the active ingredient before use. Apart from chambers with walls of sufficient thickness, an additional aluminum sheath can be applied to the outer or inner surface of the chamber 17.

Preferably the cartridge is sized for insertion into an inhaler, for example as described above. The preferred volume of the container 2 is about 5 ml, the volume of the chamber 17 is 0.001 ml to 0.5 ml, preferably 0.001 ml to 0.2 ml, more preferably 0.001 ml to 0.05 ml, most preferably 0.001 Ml to 0.03 ml.

Suitable plastics such as, for example, polystyrene (PS), polycarbonate (PC), polymethylmethacrylate (PMMA), acrylonitrile / butadiene / styrene copolymer (ABS), polyethylene terephthalate (PET) and other plastics Can be used for the production of such containers and also for the manufacture of closed caps.

It should be emphasized that if a patient uses the present cartridge having a chamber 17 in the inhaler, it must be required to be able to use it in the same way as a conventional cartridge.

Examples of Active Material Concentrates According to the Invention

In accordance with the methods of the Examples, data on concentrations or amounts of individual formulations are shown below. However, this example only shows those selected from possible combinations of the formulations described above.

Example 1

5 mg of formoterol (particle size: 5 μm) is metered into the chamber 17 in a suspension containing 0.015 mL of water. The pH is adjusted to 5.0 using fumaric acid. The concentration of formoterol is 333 mg / ml.

4.5 ml of water / ethanol 1: 1 (v / v) solution are charged to the vessel 2. This solution contains 0.45 mg of benzalkonium chloride and 2.25 mg of Na-EDTA and the pH value is adjusted to 5.0 using HCl.

After mixing, the formoterol concentration of the formulation to be administered is about 1.1 mg / ml.

Example 2

5 mg of formoterol (particle size: 5 μm) is metered into the chamber 17 with a suspension containing 0.015 mL of 20% by weight aqueous NaCl solution. Adjust pH to 5.0 with HCl.

4.5 ml of water / ethanol 1: 1 (v / v) solution are charged to the vessel 2. This solution contains 0.45 mg of benzalkonium chloride and 2.25 mg of Na-EDTA and the pH value is adjusted to 5.0 using HCl.

The same cartridge is prepared containing formoterol as the active ingredient, the content of formoterol is preferably 100 to 400 mg / ml, most preferably 250 to 350 mg / ml.

Example 3

In the vessel 2, 0.1% by weight tiotropium bromide, 0.01% by weight benzalkonium chloride and 0.05% by weight EDTA are formulated in 4.5 ml of water as a solvent. The pH is adjusted to 3.0 using hydrochloric acid. Chamber 17 contains 10 mg tablets comprising 0.5 mg of buffer material Na ₂ HPO ₂ × 2H ₂ O and 9.5 mg of NaCl. When the cartridge is inserted into the inhaler, the buffer material of the chamber 17 is mixed with the solution in the container 2 to obtain a pH of 3.5.

Similarly, cartridges are prepared in which the content of tiotropium bromide, including tiotropium bromide as the active substance, is preferably between 0.002 and 0.4% by weight, most preferably between 0.0005 and 0.2% by weight. Before mixing with the buffer in the chamber 17, the pH of the solution of the container 2 is in this case not more than 4.0, more preferably 2.0 to 3.0, in particular 2.5 to 3.0.

Claims (30)

The closure stopper 3 is characterized in that the chamber 2 comprises at least one opening which is rigidly connected or integrated with the connecting portion 7 and which is tightly sealed by the movable plunger 21. Separate storage of the active ingredient and the pharmacologically acceptable liquid, including the closure cap 3 and the container 2, having a connecting portion 7 which moves a portion of the contents of the container when compressed over the neck of Device in the form of a cartridge for 2. The device according to claim 1, wherein the permeable diaphragm is located in a hermetic plug between the plunger and the external environment. Device according to claim 1 or 2, characterized in that a guide tube (16) is provided in the closure stopper for passing the capillary or cannula (15) through the closure stopper (3). The device according to claim 1, wherein a permeable diaphragm or an elastic O-ring seal (23) is formed in the guide tube (16). The device as claimed in claim 1, wherein the chamber further has an opening sealed by a permeable, tearable or mobile separating component. 6. Device according to claim 5, characterized in that the separation component (20) is formed as a sealing foil. 7. The chamber 17 according to any one of the preceding claims, wherein the chamber 17 has two or more compartments arranged one on top of the other, each sealed to each other by a permeable, tearable or mobile separation component 25. Sealing stopper, characterized in that. 8. A closure closure according to any one of the preceding claims, wherein the plunger (21) is cylindrical having a length to diameter ratio of 1.2 to 2.0. The surface according to any one of claims 1 to 8, wherein the face of the plunger 21 in contact with the chamber 17 is inclined, tapered to one point and / or oriented in the direction of the chamber 17. A closure cap, characterized in that it has more than one spike (s) or cutting edge (s). 10. The device according to claim 1, wherein the chamber (17) is filled with a correctly fitted plunger (21) comprising a hollow space (24) having an opening on one side. Device according to one of the preceding claims, characterized in that the opening of the hollow space (24) is sealed by the separating component (20) or by the side wall of the chamber (17). 12. The hollow space (24) according to claim 11, wherein the hollow space (24) is separated by a partition wall into two or more compartments tightly sealed to each other, each compartment being formed on the side wall of the separation component (20) or the chamber (17). And is sealed by means of a device. 13. A device according to any one of the preceding claims, characterized in that a recess (28) is formed in the plunger (21) oriented in the direction of the head of the closure closure (3) having an opening. 14. The plunger 21 and / or wall of the chamber 17 comprises a pharmacologically acceptable lubricant, preferably oleic acid, lecithin, or sorbitan trioleate. Apparatus characterized in that the coating is covered by a sorbitan ester. The method according to any one of claims 1, 2, 3, 4, 8, 9, 10, 11, 12, 13 and 14, The chamber 17 has only one opening 19 at the lower end of the connecting portion 7, which is tightly sealed by the plunger 21, and a capillary or guide tube 16 for cannula is passed through the chamber 17. Device characterized in that it leads to the plunger (21). 16. The device according to claim 15, wherein the chamber is divided into a plurality of compartments in such a way that all compartments are sealed by the plunger (21). The plunger 21 according to any one of claims 10, 11, 12, 13, 14, 15 and 16, wherein the plunger 21 having the hollow space 24 is connected to the connecting portion 7. And through one or more openings of the plunger (21) by means of one or more stoppers (27) similar to the ones formed in (6). 18. The device according to any one of the preceding claims, wherein the width of the plunger (21) is 5% or less wider than the opening that is closed. 19. The chamber according to claim 1, wherein the chamber 17 is in an aqueous solution comprising a pharmacologically acceptable propellant liquid, preferably water, a pharmacologically acceptable salt, ethanol or mixtures thereof. A device comprising a pharmaceutical concentrate, preferably a suspension or solution, most preferably a suspension, together with one or more active substances, in particular the active substance or active substances suitable for inhalation therapy. 20. The device of claim 19, wherein the active agent (s) is selected from the group consisting of betamimetics, anticholiners, antiallergic agents, leukotriene antagonists and / or steroids. The device according to claim 19 or 20, wherein the active substance (forms) is formoterol, tiotropium and / or salbutamol and / or salts thereof. The active substance according to any one of claims 19 to 21, wherein the concentration of the active substance is 75 mg / ml to 1000 mg / ml, more preferably 75 mg / ml to 500 mg / ml, most preferably 100 mg / ml. Apparatus characterized in that from ml to 400mg / ml. 23. The chamber 17 according to claim 21 or 22, wherein the chamber 17 provides a suspension of formoterol from 75 mg / ml to 500 mg / ml, preferably from 100 mg / ml to 400 mg / ml, most preferably 250 mg. / Ml to 350mg / ㎖ concentration device. The device according to any one of the preceding claims, characterized in that the active substance concentrate in the chamber (17) comprises an acid, a preservative and / or a complexing agent. The pharmacologically acceptable propellant liquid, preferably water, according to claim 1, wherein the vessel 2 optionally comprises an acid, a complexing agent, a preservative, a surfactant and / or a buffer. , Saline solution, ethanol or a mixture thereof. The device of claim 25, wherein the solution or suspending agent preferably comprises one or more agents selected from the group consisting of beta-like agents, anticholiners, antiallergic agents, leukotriene antagonists and / or steroids. 27. The chamber according to claim 25 or 26, wherein the chamber 17 comprises a buffer material, preferably sodium dihydrogen phosphate or potassium dihydrogen phosphate and / or disodium hydrogen phosphate or dipotassium hydrogen phosphate and / or mixtures thereof. Characterized in that the device. 28. The method according to any one of claims 19 to 27, wherein the vessel comprises from 0.002 to 0.4% by weight, preferably from 2.0 to 4.0, preferably from 2.0 to 4.0, preferably from 2.0 to 3.0, most preferably 2.8, of a thiotropium bromide solution. Is in an amount of 0.0005 to 0.2% by weight, most preferably 0.1% by weight. 29. The device according to any one of the preceding claims, characterized in that the closure cap (3) together with the container (2) forms a cartridge for the nebulizer. Use of the device according to any one of claims 1 to 29 as a container for liquid drug formulation of an inhaler for producing an aerosol suitable for drug treatment, in particular inhalation therapy.