BG65350B1 - Stable concentrate of formoterol - Google Patents

Abstract

The present invention relates to a storable formoterol-active substance concentrate in the form of a solution or suspension for use in inhalators for inhalation or nasal therapy.

Description

Field of application

The present invention relates to a stable concentrate of the active substance formoterol for administration in inhalers in inhalation or nasal therapy that does not contain propellant.

BACKGROUND OF THE INVENTION

Formoterol is an anilide of formula I, derived from adrenaline and used as a beta ₂ stimulant in the inhalation therapy of pulmonary diseases, in particular in the treatment of asthma bronchial. In patients with reversible obstructive airways, formoterol acts as a bronchodilator. The action occurs 1-3 min after inhalation and after 12 h the bronchodilator action is also significant. Formoterol suppresses the release of leukotrienes and other inflammatory mediators, such as. histamines. In addition, formoterol may have hyperglycemic activity.

formula 1

Liquid aerosol formulations of formoterol have been found not to be suitable for use in inhalers for outpatient inhalation treatment, since formoterol in solutions is not sufficiently stable and the pharmacological quality of the formulation cannot be guaranteed for a longer period. Therefore, inhalation therapy, formoterol is currently only used in powder form.

SUMMARY OF THE INVENTION

The present invention relates to a liquid concentrate of the active substance formoterol in the form of its freedom at the base or in the form of one of its pharmacologically tolerated salts or addition compounds (adducts). Formoterol-fumarate is particularly preferred as the salt and formoterol hydrate as the adduct. In the context of this specification, the term formoterol will be understood to mean both the free base of Formula 1 and salts of formoterol and other coupling compounds, unless otherwise indicated or clearly indicated in the text.

By dilution with a pharmacologically tolerable liquid, which optionally contains pharmacological auxiliaries and additives, a drug preparation (aerosol formulation) can be obtained from the concentrate of the active substance according to the invention, which can be converted into an inhaler aerosol using a nebulizer.

The invention therefore also relates to the use of such active substance concentrate in inhalation therapy.

The active substance concentrate according to the invention relates to solutions or suspensions in which formoterol is dissolved or suspended in high concentration in a pharmacologically suitable liquid and characterized in that the active substance formoterol may be stored therein for several months, possibly for many years without affecting the pharmacological quality.

The term "active substance concentrate" means a solution or suspension of an active substance in which formoterol is highly concentrated in a pharmacologically tolerable liquid in the form of a solution or suspension. Suspensions are preferred as they have proven to be particularly resistant to storage.

"Highly concentrated" means a concentration of the active substance which is usually too high and the corresponding solution or suspension cannot be administered by inhalation without dilution suitable for therapeutic purposes. According to the invention, the concentration of formoterol in the concentrate of the active substance is in the range between 10 mg / ml and 500 mg / ml. The minimum concentration is preferably at least 75 mg / ml. Preferred horse

65350 B1 concentrations are between 100 mg / ml to 400 mg / ml, in particular between 250 mg / ml and 350 mg / ml. Concentration values refer to mg of free formoterol base per ml of active concentrate. In the case of formoterol salts or its coupling compounds, the concentration values should be recalculated relative to the free base.

The term "pharmacologically acceptable liquid" within the meaning of the present invention is intended to mean a solvent or suspending agent which does not contain a propellant. Polar fluids, in particular proton fluids, are preferred.

Examples of polar solvents or suspending agents are e.g. dimethylsulfoxide or compounds containing hydroxyl groups or other polar groups, for example water or alcohols - in particular ethanol, isopropyl alcohol, glycols - in particular propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and esters nylenyl esters .

Examples of proton fluids that are the most preferred solvents, respectively. suspending agents in the context of the invention are water, aqueous saline solutions of one or more pharmacologically tolerable salt (s), ethanol or a mixture thereof.

In the case of water-ethanol mixtures, the ratio of ethanol to water, respectively. aqueous saline is 5:95 and 99: 1, preferably between 40:60 and 96: 4, and more particularly 75:25 and 96: 4. The particularly preferred ratio is between 40:60 and 60:40.

Salts which, after administration, have no pharmacological action or are negligible, are particularly suitable as solvents or suspending agents for saline solution or as an ingredient thereof. Saline solutions are preferred over suspension concentrates. The addition of salt significantly reduces the ability of water to dissolve formoterol so that the effect of stabilizing the suspended particles is achieved. Saturated saline solutions may optionally be used. The amount of salt depends on the exact composition of the solvent or suspending agent and their corresponding ability to dissolve the active substance. In aqueous suspensions within the meaning of the active substance concentrate of the invention, the dissolved formoterol should be less than 0.5%, preferably less than 0.1% relative to the total amount / weight / formoterol. If the dissolved amount is still above the given values, then it may be reduced to them by the addition of salt. As a rule, the addition of salt can halve the solubility by half, in some cases to one-fifth or more.

Salt solutions with a salt content of up to 50% by weight are preferred. and in particular up to 20 wt. %.

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

Co-solvents may be added to the solvent or suspending agent. Co-solvents are suitable for enhancing the solubility of adjuvants as well as possibly formoterol.

Preferred co-solvents are those which contain hydroxyl groups or other polar groups, e.g. alcohols, in particular isopropyl alcohol, glycols, in particular propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters, insofar as the above are not the solvent or suspending agent itself.

Excipients and additives may also be added to the active substance concentrate of the invention.

In this context, excipients and excipients are understood to mean any pharmacologically tolerable and therapeutically relevant substance which is not an active substance but which, together with formoterol, may be formulated in pharmacologically suitable solutions

65350 Bl wire or suspending agent for improving the performance of the active substance concentrate or inhalation drugs obtained by dilution. Preferably, these substances do not exhibit pharmacological action or, if they have any in the context of therapy, it is insignificant or at least not undesirable pharmacologically. Auxiliaries and extras are, for example. surfactants for stabilizing suspensions, any stabilizers, complexing agents, antioxidants and / or preservatives that prolong the suitability for use of formulations, flavor enhancers, vitamins, antioxidants and / or any other additives known in the art.

The active substance concentrate may contain as surfactants e.g. soya lecithin, oleic acid, sorbitanester, as well as sorbitan trioleate or other known surfactants in conventional concentrations.

The addition of an organic or inorganic acid, preferably in combination with a complexing agent, has been found to improve the stability / storage stability / of formoterol-containing solutions or suspensions, especially if they contain ethanol as a solvent.

Examples of such preferred inorganic acids are: hydrochloric acid, nitric acid, sulfuric acid and / or phosphoric acid.

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

The acid concentration is chosen so that the active substance concentrate is at a pH of 2.0 to 7.0, preferably between 4.0 and 6.0, and the most preferred pH is between 4.5 and 5 , 5.

As complexing agents can be used e.g. EDTA / ethylenediaminetetraacetic acid, respectively. its salt, e.g. disodium salt), citric acid, nitrilotriacetic acid and its salts. EDTA is preferred.

Preservatives may be added to protect the concentrate from contamination with pathogenic microbes. Suitable preservatives are those known in the art, in particular benzalkonium chloride or benzoic acid, respectively. benzoates such as sodium benzoate.

Suitable and pharmacologically tolerated antioxidants, especially vitamins or provitamins as they are found in the human body, e.g. ascorbic acid or vitamin E.

If formoterol is in suspension in the active substance concentrate of the invention, the formulated particle size is preferably 20 micrometer, preferably up to 10 micrometer and more particularly up to 5 micrometer.

The most preferred form of active substance concentrate is suspensions.

The concentrate according to the invention may optionally contain one or more active substances from the group of betamimetics, anticholinergics, antiallergics, leukotriene antagonists, and in particular steroids.

The active substance concentrate of the invention gives the advantage that formoterol can be formulated so as to remain stable for a longer time. However, the concentrate, regardless of the concentration of the active substance in its composition, does not need to be consistent with the finished drug. For example, the pH value of the concentrate may be significantly different from that of the dosage form, if this results in more stable storage of formoterol.

The active substance concentrate according to the invention is generally not suitable for direct medical use, especially for inhalation. As described, the application of the concentrate to the active substance is to convert it

65350 Bl in medicine (aerosol formulation). The term " drug " is understood to mean a formulation of a drug that is suitable for inhalation administration and in which a drug or mixture of drugs can be administered at the required and / or recommended concentration.

The drug is preferably in the form of an inhalable sprayable device.

A preferred way of converting an active substance concentrate into a useful drug is to dilute the active substance concentrate of the invention with a pharmacologically suitable solvent or suspending agent.

To obtain the applicable formulation, the concentrate of the active substance formoterol is diluted with the diluent, e.g., 0.9 mg / ml to 1.5 mg / ml.

Preferred solvents or suspending agents are propellant-free liquids and are predominantly polar, in particular proton fluids. It should be noted here that the individual constituents or substances contained in the diluent are defined as given in relation to the concentrate of the active substance, insofar as those ingredients or contained substances are described therein and unless otherwise stated.

Particularly preferred diluents are water, aqueous salt solutions with one or more pharmacologically tolerated salts, with ethanol or a mixture thereof. In the case of water-ethanol mixtures, the ratio of volumes of ethanol to water, respectively. aqueous saline is between 5:95 and 99: 1, preferably between 40:60 and 96: 4, and in particular between 75:25 and 96: 4. The particularly preferred ratio is between 40:60 and 60:40.

The diluent need not be identical to the solvent or suspending agent of the active substance concentrate. The latter may optionally contain one or not very similar ingredients to the diluent.

The diluents and / or excipients and / or excipients and / or other active substances mentioned in connection with the concentrate of the active substance according to the invention may also be dissolved or suspended also or only in the diluent.

The diluent forms preferred in the embodiment contain preservatives and / or complexing agents.

The diluent may optionally contain one buffer salt such as e.g. trisodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, Na-EDTA, EDTA, mixtures thereof and other known substances. Preferred are sodium dihydrogen phosphate, disodium hydrogen phosphate, trisodium hydrogen phosphate, potassium dihydrogen phosphate, potassium hydrogen phosphate, tricalcium hydrogen phosphate and mixtures thereof. Buffering agents are particularly advantageous when the ready-to-store concentrate of the active substance of the invention has a H-value that is significantly different from the desired pH value in the application, e.g. this increases storage stability. In this case, the buffer substance in the diluent is at such a concentration that, after mixing the active concentrate with the diluent, an aerosol formulation of the desired pH value is preferably obtained, preferably between 2.0 and 7.0, especially preferably between 4.0 and 6.0 and in particular between 4.5 and 5.5.

In a preferred embodiment, the medicament comprises a complexing agent, preferably selected from the complexing agents mentioned in connection with the concentrate of the active substance. The amount of complexing agent is up to 100 mg / 100 ml, preferably up to 50 mg / 100 ml. A preferred complexing agent is EDTA.

The exact composition of the diluent is determined depending on the drug to be administered and the concentrate of the active substance.

Neither the storage-resistant concentrate of the active substance of the invention nor the dilution drug for administration contains propellant.

Preferably, mixing is carried out at room temperature and normal pressure. One thing

65350 B1 The advantage of the active substance concentrate of the invention is that for a very short time, e.g. within minutes, or possibly a few seconds, it may be obtained by dilution to form a therapeutic effect and / or a formulation for administration in a nebulizer. Mixing can also be done by patients who do not have pharmaceutical preparation as a rule.

For use in inhalation therapy, it is preferable to dilute the active concentrate according to the invention with a suitable nebulizer before first use and to spray the resulting drug through a nebulizer.

In this context, suitable atomizers are those that can spray liquid non-propellant formulations. Preferred atomizers are e.g. high pressure inhalers or dispensers as published in WO 1991/014468 "Atomizing Device and Methods" or in WO 1997/012687, and in particular those described therein by Figures 6a and 6b, which are fully taken into account here. In such nebulizers, the solutions of the medicaments for administration are generally preferred over the suspensions.

It is preferred that the concentrate of the active substance according to the invention and the diluent be stored separately in one inhaler tank designed so that the two ingredients are mixed quasi in situ when placed in the nebulizer or immediately before the first application. Preferred reservoirs in this connection are published, e.g. in PCT / EP 1995/003183, in WO 1997/039831, and in particular those described in Figures 1, 2, 2a or 36, or in DE 198 47 968.9 specifically described in Figures 1 to 11, in particular by the cartridges of Figure 3. These tanks are particularly suitable for use in a high pressure atomizer of the type described above. Such a reservoir may contain two or more separate chambers, at least one of which stores the concentrate of the active substance according to the invention, and in another chamber the diluent. The tank is so arranged that the two individually stored ingredients can be mixed by placing the tank in the inhaler as defined. In this case, the amount of the two constituents is so sized that, after mixing, an aerosol formulation is obtained in which the concentration of the active substance (s) is such that it can be dispensed with one or more applications of the respective atomizer. the recommended single therapeutic dose. Within the scope of the present specification, such or a similar method of producing an aerosol formulation for administration may be termed "in situ" peen, "quasi in situ" if it does not require the user to operate beyond the normal manipulations of using an inhaler or using an inhaler. aerosol formulation using an inhaler.

In preferred embodiments for storage in the aforementioned chamber, the amount of the storage-resistant concentrate of the active substance according to the invention is selected so that it corresponds to a volume of 0.001 to about 0.05 ml, preferably 0.001 to 0.02 ml.

Other tanks than those described may be used to store the formulation according to the invention.

Dilution with a pharmacologically tolerable diluent may also be made in a different way, e.g. mixing the concentrate of the active substance with the diluent in an open container or otherwise.

Examples of carrying out the invention

Example 1. 5 mg of formoterol (particle size: 5 [mu] m) and 0.015 ml of water were formulated as a suspension for storage. A pH value of 5.0 was adjusted with fumaric acid.

Preparation of inhalable dosage formulation: For inhalation administration, the suspension is diluted with 4.5 ml of 1: 1 (v / v) solution of water and ethanol, wherein the diluent contains 0.45 mg benzalkonium chloride and 2.25 mg Na -EDTA and has a pH value of 5.0 corrected for HCl.

The concentration of the active substance concentrate is about 300 times the concentration of the solution for administration.

Example 2. 5 mg formoterol (particle size: 5 µm) and 0.015 ml aqueous

65350 Bl wt. A% NaCl solution is formulated as a storage suspension. Adjust to pH 5.0 with fumaric acid.

Preparation of inhalable dosage formulation: For inhalation administration, the suspension is diluted with 4.5 ml of 1: 1 (v / v) solution of water and ethanol, wherein the diluent contains 0.45 mg benzalkonium chloride and 2.25 mg Na -EDTA and has a pH value of 5.0 corrected for HCl.

The concentration of the active substance concentrate is about 300 times the concentration of the solution for administration.

Example 3. For 3 months at 40 ° C, formoterol in aqueous solution at pH 5.0 was destructured to 10%. In a comparable suspension, no decomposition may be observed after 6 months of storage at 40 ° C.

Claims (19)

Claims A stable, propellant-free concentrate of an active substance for the preparation of a propellant-free aerosol formulation, comprising formoterol in the form of its free base, one of its pharmacologically tolerated salts or one of its pharmacologically acceptable addition products a tolerable solvent or suspending agent wherein the concentration of formoterol is between 75 mg / ml and 500 mg / ml. Active substance concentrate according to claim 1, characterized in that the concentration of formoterol is between 100 mg / ml and 400 mg / ml. Active substance concentrate according to claim 1, characterized in that the formoterol concentration is between 250 mg / ml and 350 mg / ml. Active substance concentrate according to one of the preceding claims, characterized in that the solvent or suspending agent is a polar, preferably proton fluid. Active substance concentrate according to one of the preceding claims, characterized in that the solvent or suspending agent is water, aqueous saline solution, preferably sodium chloride solution, ethanol or a mixture thereof. Active substance concentrate according to one of the preceding claims 1 to 5, characterized in that formoterol is dissolved. Active substance concentrate according to one of the preceding claims 1 to 5, characterized in that formoterol is suspended in water or aqueous saline solution. Active substance concentrate according to one of the preceding claims 1 to 7, characterized in that the formulation contains a surfactant, such as e.g. sorbitanester, preferably sorbitan trioleate, oleic acid and / or lecithin. Active substance concentrate according to one of the preceding claims 1 to 8, characterized in that the active substance concentrate contains a pharmacologically tolerable acid, such as e.g. hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, fumaric acid, succinic acid, acetic acid, formic acid and / or propionic acid, and preferably hydrochloric acid or fumaric acid. Active substance concentrate according to any one of the preceding claims 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 especially between 4.5 and 5.5. Active substance concentrate according to any one of the preceding claims 1 to 10, characterized in that the active substance concentrate contains a preservative, an antioxidant and / or a complexing agent. Active substance concentrate according to one of the preceding claims 1 to 11, characterized in that the formulation contains one or more inhalable active substance (s), preferably from the group of betamimetics, anticholinergics, antiallergics, antagonists leukotrienes and / or steroids. 13. Stable formoterol concentrate as active substance characterized by 65350 B1, that formoterol is in the form of an aqueous suspension in a concentration of between 250 mg / ml and 350 mg / ml and that the concentrate of the active substance has a pH value of 4.5 to 5.5 and optionally contains one pharmacologically acceptable 5 mA salt in such a quantity that the formoterol is dissolved to less than 0.5 wt. %, preferably less than 0.1 wt. %. Use of a concentrate of the active substance formoterol according to one of the preceding claims 1 to 13 for inhalation administration, characterized in that before administration the formulation is diluted with a pharmacologically acceptable diluent containing no propellant such that the concentration of formoterol is between 0.9 and 1.5 mg / ml. Use of the formoterol active substance concentrate according to claim 14, characterized in that the diluent is water, aqueous saline, ethanol or a mixture thereof. Use of the formoterol active substance concentrate according to claim 14, characterized in that the formoterol formulation is a formulation according to claim 13 and the diluent is a mixture of water and ethanol, contains a preservative and Na-EDTA, and is of pH value. set between 4.5 and 5.5. 17. A solution for inhalation therapy comprising as a solvent a mixture of ethanol / water with a pH of about 4.5 to 5.5, formoterol at a concentration of about 0.9 to 1.5 mg / ml, one preservative in a pharmacologically tolerable amount and Na -EDTA in a pharmacologically acceptable amount. Use of a concentrate of the active substance formoterol according to one of claims 1 to 13 for the preparation of an aerosol formulation for inhalation administration containing formoterol. The use of the active substance concentrate formoterol according to one of the preceding claims 1 to 13 and 17 in inhalation therapy inhalers.