HRP20010255A2 - Storable active substance concentrate with formoterol - Google Patents

Description

The proposed invention relates to an active substance concentrate with formoeterol, which is suitable for storage, without pressure gas, for use in inhalers for inhalation or nasal therapy.

Formoterol is an anilide of formula I derived from adrenaline and is used as a β2 stimulator in the inhalation therapy of lung diseases, especially for the treatment of bronchial asthma.

In patients with reversible obstructive diseases of the respiratory tract, formoterol works by dilating the bronchi. The effect occurs already 1-3 minutes after inhalation, and the bronchodilator effect is still present to a significant extent even after 12 hours. Formoterol suppresses the release of leukotrienes and other substances that indicate inflammation, such as histamines. In addition, formoterol can cause hyperglycemic effects.

Formula 1

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Previously, it was assumed that liquid aerosol formulations of formoterol were not suitable for use in inhalers for ambulatory inhalation treatment, because formoterol in solution could not be stored stably enough to guarantee the pharmaceutical quality of the formulation even over a long period of time. For this reason, until now formoterol was used only in powder form in inhalation therapy.

DESCRIPTION

The proposed iz™ refers to a liquid concentrate of an active substance with formoterol™ as an active substance in the form of its free base or in the form of its pharmacologically tolerable salt or addition products (adducts). Formoterol fumarate is especially advantageously used as a salt, and formoterol hydrate is used as an addition product. In the following text of this description, the name formoterol is understood to mean both free bases in accordance with formula I, as well as formoterol salts and other addition products if not stated otherwise or if it can be concluded otherwise from the composition.

The concentrate of the active substance according to the invention can be converted into a drug preparation (aerosol formulation) by diluting it with a pharmacologically tolerable liquid, which liquid, if necessary, contains pharmaceutical auxiliaries and additional substances, which preparation is turned into an aerosol that can be inhaled using a device for creating a mist.

Therefore, iz™ also refers to the use of such active substance concentrates in inhalation therapy.

The active substance concentrate according to the invention refers to solutions or suspensions in which formoterol is dissolved or suspended in a suspended concentration in a pharmacologically suitable liquid and characterized by the fact that the active substance, formoterol, can be stored in them for a period of several months, if necessary up to more years, while pharmaceutical quality does not deteriorate.

The term "active substance concentrate" means a solution or suspension of an active substance, in which the active substance formoterol is present in a high concentration in a pharmacologically tolerable liquid as a solution or suspension. Preference is given to suspensions, because they are particularly stable during storage.

By high concentration of the active substance is meant a concentration that is usually too high for the corresponding solution or suspension to be used in a therapeutically useful manner for inhalation purposes without dilution. According to the invention, the concentration of formoterol in the active substance concentrate is between 10 mg/ml and 500 mg/ml. The minimum concentration is preferably at least 75 mg/ml. Preferred concentrations are between 100 mg/ml and 400 mg/ml, especially between 250 mg/ml and 350 mg/ml. The concentration information refers to the free base of formoterol per ml of the active substance concentrate. In the case of formoterol salts or their addition compounds, the data for the concentration have been appropriately converted to the free base.

The term "pharmacologically suitable liquid", in the sense of the proposed invention, means a solvent or suspending agent that is not a liquefied propellant gas. These are primarily polar liquids, and protonic liquids are particularly favorable.

Examples of polar solvents or suspending agents are, for example, dimethylsulfoxide or compounds containing hydroxyl groups or other polar groups, for example water or alcohols - especially ethanol, isopropyl alcohol, glycols - especially propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohol and polyoxyethylene-fatty acid ester, etc.

Examples of protonic liquids that are the most favorable solutions in terms of the invention, i.e. suspending agents, are water, aqueous solutions of salts with one or more pharmacologically tolerable salts, ethanol or their mixture.

In the case of aqueous ethanol mixtures, the volume ratio of ethanol to water, or to the aqueous salt solution, is between 5:95 and 99:1, preferably between 40:60 and 96:4, particularly preferably between 75:25 and 96:4. A particularly favorable ratio is between 40:60 and 60:40.

For a salt solution, as a solvent or suspending agent, or as an ingredient thereof, those salts which do not develop any pharmacological effect after application or which are negligible are particularly favorable.

Salt solutions are primarily used for suspension concentrates. The addition of salt significantly reduces the possibility of dissolving formoterol in water, so that the effect of stabilizing suspended particles is achieved.

If necessary, saturated salt solutions can also be used. The amount of salt depends on the exact composition of the solution or suspending agent and its capabilities as a solvent for the active substance. In aqueous suspensions, in terms of the concentrate of the active substance according to the invention, formoterol must be dissolved in an amount of less than 0.5%, preferably less than 0.1%, whereby the information refers to the total amount (mass) of formoterol. If the dissolved amount is still higher than the specified values, it can be reduced below these values by adding salt. As a rule, by adding salt, the solubility can be reduced to half, in many cases to a fifth or even lower.

Salt solutions with a salt content of 50 wt. %, especially favorable up to 20 wt. %.

Both inorganic and organic salts can be used as salts. Inorganic salts such as sodium chloride, alkaline or ammonium halogen salts are preferred. Sodium chloride is particularly beneficial. Suitable organic salts are, for example, sodium, potassium or ammonium salts of the following acids: ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid.

Co-solvents can be added to solvents or suspending agents. Co-solvents are suitable for increasing the solubility of excipients and, if necessary, formoterol.

Favorable co-solvents are those containing hydroxyl groups or other polar groups, for example alcohols - especially isopropyl alcohol, glycols - especially propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohol and polyoxyethylene fatty acid ester, if they are not already present as a solvent or suspending agent.

Further auxiliaries and additional substances can also be added to the active substance concentrate according to the invention.

In this text, auxiliary and additional substances mean any pharmacologically tolerable and therapeutically meaningful substance, which is not an active substance, but can be formulated together with formoterol in pharmacologically suitable solvents or suspending agents to improve the qualitative properties of the active substance concentrate or drug preparation to be administered. can be obtained by dilution and is suitable for inhalation application. First of all, these substances do not develop any, or in terms of the desired therapy, no noticeable or at least no undesirable pharmacological action. Auxiliary and additional substances include, for example, surface-active substances for stabilizing suspensions, other stabilizers, complex-forming agents, antioxidants and/or preservatives, which extend the useful life of the finished drug formulation, flavor enhancers, vitamins, antioxidants and/or other additives known from the state of the art.

As surface-active substances, the active substance concentrate may contain, for example, soy lecithin, oleic acids, sorbitan ester, such as sorbitan trioleate or other surface-active substances (surfactants) known from the state of the art in the usual concentration.

The addition of an organic or inorganic acid, preferably in combination with a complexing agent, has been shown to improve the stability (storage stability) of a solution or suspension containing formoterol, especially if it contains ethanol as a solvent.

Examples of inorganic acids which are preferred in this respect are: hydrochloric acid, nitric acid, sulfuric acid and/or phosphoric acid.

Examples of particularly favorable organic acids are ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid and others. Preferred acids are hydrochloric acid and/or fumaric acid.

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

For example, EDTA (ethylenediaminetetraacetic acid or its salts, such as the disodium salt), citric acid, nitrilotriacetic acid and its salts can be used as complex forming agents. EDTA is preferred.

Preservatives can be used to protect the concentrate from contamination with pathogenic germs. Suitable preservatives are agents known from the state of the art, especially benzalkonium chloride or benzoic acid, or benzoates such as sodium benzoate.

Known pharmacologically tolerable antioxidants are suitable as antioxidants, especially vitamins or provitamins that are found in the human body, for example ascorbic acid or vitamin E.

If the formoterol in the active substance concentrate according to the invention is present as a suspension, the particles are preferably formulated with a size of up to 20 μm, preferably up to 10 μm, and especially preferably up to 5 μm.

The biggest preference is given to the suspension as a concentrate of the active substance.

The active substance concentrate according to the invention may, if necessary, contain one or more further active substances from the group of betamimetics, anticholinergics, antiallergics, leukotriene antagonists and especially steroids.

The active substance concentrate according to the invention has the advantage that formoterol can be formulated so that it remains stable over a longer period of time. At the same time, it is not necessary that the concentrate, regardless of the concentration of the active substance, corresponds in its composition to the finished drug preparation. For example, the pH value of the concentrate may deviate significantly from the pH value of the preparation to be applied if this enables a more stable storage of formoterol.

The active substance concentrate according to the invention as such is usually not suitable directly for medical use, especially for application by inhalation.

As already described, the use of the active substance concentrate consists in testing the drug preparation (aerosol formulation). In this case, the term "drug preparation" means a drug formulation that is suitable for application by inhalation and with which a drug or a mixture of drugs of the required and/or recommended concentration can be administered.

Preference is given to such a drug preparation which can be administered by inhalation using a suitable nebulizer.

A favorable method for testing the active substance concentrate in the preparation that can be applied is the dilution of the active substance concentrate according to the invention with a pharmacologically suitable solvent or with a suspending agent.

To obtain an administrable formulation, the formoterol active ingredient concentrate is diluted to, for example, 0.9 mg/ml to 1.5 mg/ml with a diluent.

For the purpose of dilution, favorable solvents or suspending agents are liquids that do not contain a propellant, preferably polar, especially protosinic liquids. It may be noted at this point that the individual components or ingredients of the diluent are defined as stated in relation to the active substance concentrate, unless those components or ingredients described therein are otherwise described or indicated therein.

Particularly favorable diluents are water, aqueous solutions of salts with one or more pharmacologically tolerable salts, ethanol or a mixture thereof. In the case of an aqueous ethanol mixture, the volume ratio of ethanol to water, or to the aqueous salt solution, is between 5:95 and 99:1, preferably between 40:60 and 96:4, particularly preferably between 75:25 and 96:4. A particularly favorable ratio is between 40:60 and 60:40.

Of course, it is not necessary for the diluent to be the same as the solvent or the suspending agent. The latter may also contain only one or several components of the diluent, if necessary.

At this point it should be expressly emphasized that the co-solvents and/or auxiliary or additional substances and/or further active substances, which have already been mentioned in connection with the composition of the active substance concentrate according to the invention, can also be present dissolved or suspended only in the diluent .

Advantageous embodiments of the diluent contain a preservative and/or a complexing agent.

If necessary, a powder substance such as trisodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, Na-EDTA, EDTA, their mixture and other substances known from the state of the art may be present in the diluent. Preferred are sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium hydrogen phosphate, potassium dihydrogen phosphate, potassium hydrogen phosphate, tripotassium hydrogen phosphate and their mixture. Special preference is given to buffers if the storage-stable active substance concentrate according to the invention has a pH value that clearly deviates from the value desired for the application, for example, if it increases the stability of the active substance during storage. In this case, the buffer concentration in the diluting agent is such that after mixing the active substance concentrate with the diluting agent, an aerosol formulation for application with the desired pH value is obtained, preferably between 2.0 and 7.0, especially preferably between 4.0 and 6 ,0, and quite favorably between 4.5 and 5.5.

In preferred embodiments, the drug preparation contains a complexing agent that is selected primarily from among the complexing agents listed in connection with the active substance concentrate. The amount of complex forming agent is up to 100 mg/100 ml, preferably up to 50 mg/100 ml. A favorable agent for complex formation is EDTA.

The preparation of the drug for application together with the active substance concentrate determines the exact composition of the diluent.

Neither the concentrate of the active substance according to the invention, which is stable during storage, nor the drug preparation for application obtained with dilution contains a suppressant.

Mixing is preferably done at ambient temperature and under normal pressure. The advantage of the active substance concentrate according to the invention is that it can be converted into a therapeutically effective formulation and/or into a formulation suitable for use with a mist generating device by diluting it in a very short time, for example in less than a few minutes or if necessary a few seconds. At the same time, mixing can also be performed by a patient who, as a rule, does not have any pharmaceutical knowledge.

For use in inhalation therapy, the active substance concentrate according to the invention is preferably diluted before the first application using a suitable nebulizer and the resulting drug preparation is then sprayed with a nebulizer.

In this respect, those fogging devices that can turn liquid formulations that do not contain a propellant into a mist are suitable. Favorable nebulizing devices are, for example, inhalers or high-pressure nebulizers such as those described in WO91/14468 "Atomizing Device and Methods" or in WO 97/12687, and shown therein in Figures 6a and 6b, which thereby fully taken into account here. In such devices for creating a mist for application, as a rule, certain drug preparations that are available as solutions are more favorable than suspensions.

The active substance concentrate according to the invention and the diluent are conveniently stored separately in a container suitable for inhalers, which is designed so that both components are automatically mixed with each other when the container is inserted into the nebulizer or immediately before the first application - quasi in situ -. In this regard, the containers described for example in PCT/EP 95/03183, in WO 97/39831, and especially those shown there in figures 1, 2, 2a or 3b or in the German patent application having file number 198 are advantageous. 47 968.9 and especially those shown there in figures 1 to 11, especially the cartouche shown in figure 3, which is thereby fully taken into account here. These containers are particularly suitable for use in high-pressure sprayers of the type described above.

In such a container, two or more separate chambers can be made, where at least one chamber contains the concentrate of the active substance according to the invention, and the diluent is stored in the second chamber. The container is made so that both separately stored components can be mixed with each other by inserting it into the corresponding inhaler. In doing so, the amount of the two components is measured so that after mixing the two components, an aerosol formulation is created in which one or more active substances are present in such a concentration that with one or several activations of the appropriate device for generating the mist, the recommended individual therapeutic dose can be released. Within the scope of the proposed description, such or a similar process for the production of an aerosol formulation for application can be designated as "in situ", i.e. as "quasi in situ", if no procedure is associated with the user beyond the normal procedure for turning on the inhaler and using the aerosol formulation using inhaler.

For the purpose of storage in the above-mentioned cartridges in preferred embodiments, the amount of the active substance concentrate according to the invention, which can be stored, is selected so that it corresponds to a volume of 0.001 to approx. 0.05 ml, preferably from 0.001 to 0.02 ml.

Apart from the containers described for storing the formulations according to the invention, other containers can also be used.

Of course, dilution with a pharmacologically acceptable diluent can also be done differently, for example by mixing the diluent in an open container with an active substance concentrate or a different type and in a different way.

EXAMPLES

Example 1

5 mg of formoterol (particle size: 5 μm) is formulated as a suspension with 0.015 ml of storage water. The pH value is adjusted to 5.0 with fumaric acid. Production of a drug preparation that can be administered by inhalation:

For inhalation use, the suspension is diluted with 4.5 ml of a 1:1 water/ethanol (v/v) solution, wherein the dilution solution contains 0.45 mg of benzalkonium chloride and 2.25 mg of Na-EDTA and is adjusted to pH with HCl value 5.0.

The concentration of the active substance concentrate is approximately 300 times higher than the concentration of the solution to be applied.

Example 2

5 mg of formoterol (particle size: 5 μm) is formulated with 0.015 ml of 20% aqueous NaCl solution as a storage suspension. The pH value is adjusted to 5.0 with 5 fumaric acid.

Production of a drug preparation that can be administered by inhalation:

For inhalation use, the suspension is diluted with 4.5 ml of a 1:1 water/ethanol (v/v) solution, wherein the dilution solution contains 0.45 mg of benzalkonium chloride and 2.25 mg of Na-EDTA and is adjusted to pH with HCl value 5.0.

The concentration of the active substance concentrate is approximately 300 times higher than the concentration of the solution to be applied.

Example 3

In an aqueous solution, which has a pH value of 5.0, 10% of formoterol decomposes at 40°C within 3 months. No decomposition can be observed in a comparable suspension after 6 months of storage at 40°C.

Claims (19)

1. Concentrate of an active substance, which can be stored and does not contain a propellant, for the production of an aerosol formulation without a propellant, characterized by the fact that the active substance contains formoterol in the form of its free base, its pharmacologically tolerable salt or its addition product in a pharmacological a tolerable solvent or suspending agent, wherein the formoterol concentration is between 75 mg/ml and 500 mg/ml. 2. Active substance concentrate according to claim 1, characterized in that the concentration of formoterol is between 100 mg/ml and 400 mg/ml. 3. Active substance concentrate according to claim 1, characterized in that the concentration of formoterol is between 250 mg/ml and 350 mg/ml. 4. Active substance concentrate according to any preceding claim, characterized in that the solvent or suspending agent is a polar, preferably protonic liquid. 5. Active substance concentrate according to any preceding claim, characterized in that the solvent or suspending agent is water, aqueous salt solution, preferably sodium chloride solution, ethanol or their mixture. 6. Active substance concentrate according to any preceding claim 1 to 5, characterized in that the formoterol is dissolved. 7. Active substance concentrate according to any preceding claim 1 to 5, characterized in that formoterol is suspended in water or in an aqueous salt solution. 8. Active substance concentrate according to any preceding claim 1 to 7, characterized in that the formulation contains a surface-active substance, for example sorbitan ester, preferably sorbitan trioleate, oleic acid and/or lecithin. 9. Active substance concentrate according to any preceding claim 1 to 8, characterized in that the active substance concentrate contains a pharmacologically tolerable acid, such as, for example, hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, ascorbic acid, citric acid, malic acid acid, tartaric acid, maleic acid, fumaric acid, succinic acid, acetic acid, formic acid and/or propionic acid, preferably hydrochloric acid and/or fumaric acid. 10. The active substance concentrate according to any preceding claim 1 to 9, characterized in that the pH value of the active substance concentrate is between 2.0 and 7.0, preferably between 4.0 and 6.0, and particularly preferably between 4.5 and 5.5. 11. Active substance concentrate according to any preceding claim 1 to 10, characterized in that the active substance concentrate contains a preservative, an antioxidant and/or a complex forming agent. 12. Active substance concentrate according to any preceding claim 1 to 11, characterized in that the formulation contains one or more inhaled active substances, preferably from the group of betamimetics, anticholinergics, antiallergics, leukotriene antagonists and/or steroids. 13. An active substance concentrate with formoterol as an active substance, which can be stored, characterized by the fact that the formoterol is present as a suspension in water at a concentration between 250 mg/ml and 350 mg/ml and that the active substance concentrate is adjusted to a pH value of 4, 5 to 5.5 and, if necessary, contains a pharmacologically tolerable salt in such an amount that the dissolved formoterol is present in an amount less than 0.5 wt. %, preferably less than 0.1 wt. %. 14. The use of the concentrate of the active ingredient formoterol according to any of the previous claims 1 to 13 for application by inhalation, characterized in that the formulation is diluted before application with a pharmacologically acceptable diluent, which does not contain a propellant gas, so that the concentration of formoferol is between 0.9 and 1.5 mg/ml. 15. Use of the concentrate of the active ingredient formoterol according to claim 14, characterized in that the diluent is water, an aqueous salt solution, ethanol or a mixture thereof. 16. The use of the concentrate of the active ingredient formoterol according to claim 14, characterized by the fact that the formoterol formulation is the formulation according to claim 13 and that the diluting agent is a mixture of water and ethanol containing a preservative and Na-EDTA and that the pH value is set between 4.5 and 5.5. 17. A solution formulation for inhalation therapy, characterized in that it contains a solvent mixture of water and ethanol adjusted to a pH value of approx. 4.5 to 5.5, dissolved formoterol with a concentration of approx. 0.9 to 1.5 mg/ml relative to formoterol, a pharmacologically tolerable amount of preservative and a pharmacologically tolerable amount of Na-EDTA. 18. The use of a concentrate of the active ingredient formoterol according to any one of claims 1 to 13, characterized in that it is used for the production of an aerosol formulation containing formoterol for use by inhalation. 19. The use of the concentrate of the active substance formoterol according to any of claims 1 to 13 and 17, characterized in that it is used in inhalers for inhalation therapy.