Pharmaceutical aerosol formulations.

The invention relates to a pharmaceutical composition with chlorine-free propellant gases for use as an aerosol formulation, process for the preparation of this pharmaceutical composition and its use in a therapeutic process, in particular in inhalation therapy.

The administration of active ingredients with aerosols is becoming increasingly important, especially with inhalation aerosols, for the treatment of diseases of the respiratory tract, for example asthma or allergic rhinitis (hay fever). With such an aerosol, the active substance can reach the actual application site, for example the bronchioles, in an effective dose, without burdening the entire organism to the extent that is the case, for example, with oral administration.

An aerosol is a mixture of substances that consists of a gaseous dispersant and liquid or solid disperse constituents (ABC Chemie, Volume 1, page 23, 2nd edition 1974, Verlag Harri Deutsch, D-6000 Frankfurt / Main).

The gaseous dispersant is called a propellant, which can also consist of a mixture of several propellants. For pharmaceutical use, the disperse constituents consist of liquid or solid active substances, a distinction being made between powder or suspension aerosols (solid / gaseous) and emulsion or liquid aerosols (liquid / gaseous). Aerosols can also contain other auxiliary substances such as surfactants.

In particular, aerosols are mixtures of substances in pressure-tight containers (spray cans) which contain the gaseous dispersant at room temperature in a liquid state under excess pressure. The pressure-tight containers are closed with a metering valve. During administration, the actual aerosol with the dispersed active ingredient, for example, escapes from the pressurized container after actuation of the metering valve solid particles or droplets dispersed in the propellant.

Discussions and studies on the cause of damage to the atmospheric ozone layer by chlorofluorocarbons (CFCs) have resulted in their technical use as propellant gases in spray cans being regulated in many countries by law. It is known from various research projects that only the chlorine atoms in the CFCs and the reactive radicals that result from them are responsible for the damage to the ozone layer.

So-called alternative propellant gases or propellants, for example saturated hydrocarbons such as propane or n-butane, or chlorine-free fluorocarbons (HFC or PFC), for example tetrafluoroethane, or mixtures of these propellant gases are therefore increasingly being used for technical, non-pharmaceutical applications. The ecological aspect alone makes it necessary to replace CFCs that are potentially damaging to the ozone layer for pharmaceutical applications with more environmentally friendly, alternative propellants.

Suitable propellants for pharmaceutical applications or as propellants or propellants for pharmaceutical aerosols are those which can be liquefied under pressure at room temperature and which are toxicologically safe in the case of inhalations or topical use and have no side effects.

Particularly for inhalation therapy, there is a need for aerosols in which the solid particles or droplets dispersed in the propellant gas have a preferred diameter of approximately 0.5-6 μm. Suspensions should contain the active ingredient as homogeneously as possible, so that it remains in the finely dispersed state for as long as possible after shaking. So that the size distribution of the particles does not change, the active ingredient in suspension aerosols should not be dissolved in the propellant / auxiliary mixture.

European patent application 372 777 describes aerosol formulations with the "alternative" propellant tetrafluoroethane (134a). To increase the stability of suspensions in this liquefied propellant, it is proposed to use a suspending aid in the form of a nonionic surfactant, for example SPAN sorbitan fatty acid esters, for example SPAN 85 (sorbitan trioleate). Due to the insufficient solubility of such surfactants in the liquefied propellant 134a, a solvent, for example ethanol, is added which has a higher polarity than the propellant itself.

The object of the present invention is to find a special suspending agent for active substances in aerosol formulations which dissolves better in liquefied "alternative" propellants than the known suspending agents previously used for it. In solving this problem, it was surprisingly found that non-ionic surfactants from the group of monoacetylated or diacetylated monoglycerides are readily soluble in the "alternative" propellants mentioned, in particular in heptafluoropropane (227), and favor the production of homogeneous suspensions, whereby they also have excellent lubrication properties for the metering valve.

The present invention relates to a pharmaceutical composition for use as an aerosol containing:<ul id="ul0001" list-style="none"><li>a) a liquefied propellant gas or propellant gas mixture with a vapor pressure of more than 1 bar and less than 6 bar (20 ° C.) from the group of unsubstituted or partially to fully fluorinated hydrocarbons;</li><li>b) a nonionic surfactant from the group of the monoacetylated or diacetylated monoglycerides;</li><li>c) a pharmaceutical active ingredient or combination of active ingredients and optionally</li><li>d) further customary pharmaceutical auxiliaries which are suitable for aerosol formulations.</li></ul>

In a particularly preferred embodiment, the aerosol contains the alternative propellant gas heptafluoropropane (227). This propellant has the advantage of the lower vapor pressure of approx. 4 bar compared to the higher vapor pressure of approx. 5.7 bar at the same temperature as the alternative propellant tetrafluoroethane (134a).

The term pharmaceutical composition defines a mixture of substances which is suitable for various applications as an aerosol, preferably for inhalations, but also topically, on humans and animals, preferably on humans, and can be used for the treatment of various diseases, for example asthma or allergic rhinitis.

The term aerosol is defined earlier. In the pressure vessel for producing the aerosol itself, the active ingredient or combination of active ingredients can be contained either in solid form as a suspension or in liquid form as an emulsion or solution in the propellant gas or propellant gas mixture compressed into a liquid. In the specialist literature, the pressure vessel with its contents and metering valve is sometimes referred to as metered dose aerosol. In the context of the description of this invention, the term metered dose aerosol should only refer to the content of the pressure vessels.

The propellant gas or propellant gas mixture of component a) is selected so that it is in a liquid state at a temperature of approx. 20 ° C. and has a minimum overpressure higher than approx. 1 bar up to a maximum overpressure of approx. 6 bar. Propellants or propellant gas mixtures are therefore suitable which have a constant internal pressure in the metering vessel until it has been completely emptied and which, owing to the environmental problem mentioned earlier, have no chlorine atoms which can be eliminated.

Such propellant gases or propellant gas mixtures are known per se for the production of pharmaceutical aerosols, for example unsubstituted saturated hydrocarbons, for example n-propane, n-butane or isobutane or mixtures thereof, or partially fluorinated or fully fluorinated (perfluorinated) hydrocarbons.

Partially fluorinated hydrocarbons are derived from aliphatic hydrocarbons with preferably 1-4 C atoms, for example methane, ethane, propane, n-butane or isobutane, or cycloaliphatic hydrocarbons with preferably 3 and 4 C atoms, for example Cyclopropane or cyclobutane, in which the hydrogen atoms are substituted by at least one fluorine atom and preferably at least two fluorine atoms in such a way that at least one hydrogen atom and thus a hydrocarbon bond remains in the molecule.

Fully fluorinated (perfluorinated) hydrocarbons are derived from the aliphatic hydrocarbons with 1-4 C atoms and the cycloaliphatic hydrocarbons with 3 and 4 C atoms mentioned by substituting the hydrogen atoms with corresponding fluorine atoms.

Suitable partially or fully fluorinated hydrocarbons are, for example, methane derivatives with 1-4, ethane derivatives with 1-6, propane derivatives with 1-8, n-butane derivatives with 1-10, cyclopropane derivatives with 1-6 and cyclobutane derivatives with 1-8 fluorine atoms. In these partially or fully fluorinated hydrocarbons, the hydrogen atom (s) can be located at various points on the hydrocarbon skeleton. The following isomeric cases are possible for partially fluorinated hydrocarbons:

If only one hydrogen atom is present, this can be terminal in the propane and butane derivatives or on an intermediate link of the C chain.

If there is more than one hydrogen atom, further isomeric cases are possible for the ethane, propane, n-butane, cyclopropane and cyclobutane derivatives and for hydrocarbons with an even higher number of carbon atoms. The hydrogen atoms can be partially or completely terminal and can be partially or completely on one or on different intermediate links of the C chains. "Mixed" isomeric cases are also possible in that the hydrogen atoms are located in different distributions in the case of aliphatic derivatives on the terminal C atom and on the same or on different carbon intermediate members or in the case of cycloaliphatic derivatives on the same or on different carbon ring members.

To abbreviate the usual nomenclature and to differentiate between the partially fluorinated hydrocarbons mentioned and also the fully fluorinated hydrocarbons mentioned below, code names are common that are used in pharmaceutical technology, H.Sucker, P.Fuchs, P.Speiser (editor), Thieme Verlag, D -7000 Stuttgart 1978, explained on page 735 and are also applicable to CFCs. For the numerous isomeric cases mentioned, additional designations with the letters a, b ... are common.

Preferred partially fluorinated hydrocarbons are tetrafluoroethane (134 and 134a), trifluoroethane (143a), difluoroethane (152 and 152a) and heptafluoropropane (227).

A non-ionic surfactant from the group of monoacetylated or diacetylated monoglycerides is a monoglyceride (glycerol esterified with a saturated or unsaturated fatty acid) which preferably has one or two acetyl radicals in addition to the acyl radical of a fatty acid. The acyl radical is preferably derived from an unsaturated fatty acid with more than ten and an even number of carbon atoms. Preference is given to a monoglyceride which can be obtained from a mixture of monoacetylated or diacetylated monoglycerides using the customary separation methods, for example fractional distillation.

The acetylated monoglyceride contains as acyl radical of a saturated fatty acid, for example a C₁₀₋₂₀alkanoyl radical with an even number of carbon atoms, for example n-dodecanoyl, n-tetradecanoyl, n-hexadecanoyl, n-octadecanoyl or n-icosanoyl.

As the acyl residue of an unsaturated fatty acid, the acetylated monoglyceride preferably contains a C₁₀₋₂₀alkenoyl residue with an even number of carbon atoms, for example 9-cis-dodecenoyl, tetradecenoyl or -hexadecenoyl, 6-cis or 6-trans-octadecenoyl, 9-cis- or 9-trans-octadecenoyl or 11-cis-octadecenoyl.

Particularly preferred are acetylated monoglycerides, which are commercially available under the trademark MYVACET (Eastman) and have been approved as additives for processed foods by health authorities, for example the FDA in the USA. Acetylated monoglycerides from the MYVACET series are used as lubricants, plasticizers, non-ionic emulsifiers and solubilizers. The products commercially available under the name MYVACET 5-07, 7-00, 7-07, 9-08, 9-40 and 9-45 are particularly preferred.

The liquid acetylated monoglycerides, for example MYVACET 9-40 and MYVACET 9-45 K, are particularly suitable and can be characterized as follows:<dl id="dl0001"><dt>Freezing point:</dt><dd>7-8 ° C</dd><dt>Density at 20 ° C:</dt><dd>0.98-0.99 [g / cm³]</dd><dt>Hydroxyl number:</dt><dd>15</dd><dt>Acid number:</dt><dd>3</dd><dt>Iodine number:</dt><dd>40-51</dd><dt>Saponification number:</dt><dd>370-380</dd></dl>

Surprisingly, it has now been found that using liquid MYVACET types, in particular with active substances from the group of beta sympathomimetics, for example salbutamol or formoterol fumarate, results in particularly homogeneous and stable liquefied propellant gases or propellant gas mixtures of component a) which do not damage the ozone layer Have suspensions made. Surprisingly, it was also found that by adding a polar solvent such as ethanol, undesired adhesions on the wall of the pressure vessel can be avoided. In addition, it was found that the combination MYVACET and ethanol can also be used to convert other active substances from chemically different substance classes with propellant gases such as 227 or 134a and n-butane into homogeneous and easily redispersible suspensions, which can be used as aerosol formulations.

The nonionic surfactant b) is contained in the pharmaceutical composition in a concentration of approximately 0.0001 to 5.0, preferably approximately 0.001 to 0.5% by weight.

In principle, all active ingredients or active ingredient combinations c) which are inert to the propellant gas component a) and component b), nonionic surfactant, and any additional auxiliaries present are suitable for the aerosol formulation. The choice of active ingredients is defined by the indication and limited by the task of applying the selected active ingredient or combination of active ingredients as an aerosol formulation, preferably by inhalation, but also topically.

Examples of suitable active ingredients are: Alkaloids: bromocriptine, ergotamine, atropine; Antiallergics: azelastine, cetirizine, epinastine, nedocromil, sodium cromoglicate, ketotifen, pemirolast, traxanost, amlexanox, protopin, tepoxaline, midaglizole, picumast, quazolast, repirinast, suplatast; Antibiotics: fusefungin, gentamycin, neomycin, minocycline, erythromycin, streptomycin, ofloxacin, ciprofloxacin, cephalexin, cefatrizine, cefaclor, ceftriaxone; Antifungals: clotrimazole, ketoconazole, amorolfine, bifonazole; Beta sympathomimetics: Bambuterol, Salbutamol, Formoterol, Salmeterol, Pirbuterol, Carbuterol, Clenbuterol, Reproterol, Rimiterol, Hexprenalin, Fenoterol, Bitolterol, Terbutaline, Mabuterol, Tulobuterol; Anticholinergics: ipratropium bromide, oxitropium bromide, telenzepin, troventol; Potassium channel opener: Cromakalim ,, Lemakalim; Corticoids: budesonide, flunisolide, beclometasone, fluticasone, triamcinolone, fluocortin butyl, butixocort, cloprednol, fluticasone, mometasone, tipredan; Mucolytics: acetylcysteine, ambroxol, carbocysteine, furosemide, amiloride; Phosphodiesterase inhibitors: theophylline, isbuphylline, zandaverine, enprophylline; Thromboxane inhibitors: Vapiprost, Ozagrel; Leukotriene inhibitors: Bunaprolast, Ibudilast; Platelet aggregation factor (PAF) antagonists, e.g. Ginkgolide or mequitamium; Anti-infectives: pentamidine, hydroxychloroquine; Cytostatics: methotrexate.

Active substances which are used in inhalation therapy for the prophylactic and / or acute treatment of bronchial obstructions such as asthma are particularly preferred, for example salbutamol, formoterol, salmeterol, disodium cromoglicate, nedocromil, oxitropium, ipratropium, budesonide, beclomolonolidonasone, fluninolonolidonone.

If they have a salt-forming group, the active compounds mentioned can be present in the aerosol as free compounds or in the form of their pharmaceutically acceptable salts.

The aerosol contains a proportion of approximately 0.0001-5.0% by weight of active ingredient or combination of active ingredients, preferably approximately 0.001-2.5% by weight.

The pharmaceutical composition can be admixed, for example, with customary pharmaceutical auxiliaries which are suitable for aerosol formulations. For example, a solvent can be added which has a higher polarity than the liquefied propellant component a). Since the propellant gases or propellant gas mixtures of component a) are not very polar, numerous other more polar solvents such as ethanol, isopropanol, propylene glycol, dimethyl ether and mixtures of these solvents, which are present in any concentrations, for example from about 0.1 to 30% by weight, are suitable as additives. -%, can be added.

Additional non-ionic surfactants can be added as additional auxiliaries to component b), which further increase the wetting and dispersibility of active pharmaceutical ingredients and / or improve the mechanical valve functions as a lubricant and the deposition of solids by absorption on the inside of the pressure vessel avoid.

Such additional nonionic surfactants are, for example, sorbitan fatty acid esters, for example sorbitan trioleate, sesquioleate, monooleate or monolaurate, which are commercially available, for example, under the name SPAN, for example SPAN 85, 80 and 20, polyoxyethylene sorbitan esters, for example polyoxyethylene (20) sorbitan monolaurate or monooleate, for example esters, which are commercially available under the name TWEEN, for example TWEEN 20, 40, 60 and 80, oleyl, stearyl or lauryl polyoxyethylene esters, which are commercially available under the name BRIJ or GENAPOL, for example BRIJ 92, 72, 30 or GENAPOL 0-020, and block copolymers, which are commercial under the name SYNPERONIC are available.

Further auxiliaries are, for example, pharmaceutically approved oils, for example oils of vegetable origin, for example from corn, olives, cotton seeds, rapeseed or sunflowers, phospholipids, for example synthetic lecithin or natural lecithin derivatives, which are commercially available under the name EPIKURON, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate, glyceryl trioleate, glyceryl monolaurate, oleate or ricinoleate, cetyl alcohol, polyethyleneglycol ester, or polyol glycol glycol 400, polychloride. Flavor corrections such as saccharin, aspartame and aromas, for example dentomint, can also be added.

The stated auxiliaries of component d) can be added in a quantitative ratio of approximately 0.0001 to 10% by weight, preferably approximately 0.001 to 1% by weight, based on the total weight of the pharmaceutical formulation.

The present invention preferably relates to a pharmaceutical composition comprising:<ul id="ul0002" list-style="none"><li>a) a propellant or propellant mixture from the group consisting of propane, n-butane, isobutane, di-, tri- or tetrafluoroethane (134a) and heptafluoropropane (227);</li><li>b) a nonionic surfactant from the group of monoacetylated monoglycerides;</li><li>c) a pharmaceutically active ingredient or an active ingredient combination from the group of antiallergics, eg Dinatriumcromoglicat or nedocromil, beta-sympathomimetics, for example, salbutamol, salmeterol or formoterol, anticholinergics, eg Oxitropium- or ipratropium bromide, and corticosteroids such as budesonide, flunisolide, beclomethasone, or triamcinolone, and optionally</li><li>d) further customary pharmaceutical auxiliaries which are suitable for aerosol formulations.</li></ul>

The present invention preferably relates to a pharmaceutical composition comprising:<ul id="ul0003" list-style="none"><li>a) a propellant or propellant mixture from the group consisting of propane, n-butane, isobutane, tetrafluoroethane (134a) and heptafluoropropane (227);</li><li>b) a nonionic surfactant from the group of monoacetylated monoglycerides;</li><li>c) a pharmaceutical active ingredient or combination of active ingredients from the group disodium cromoglicate, salbutamol, salmeterol, formoterol, oxitropium bromide, ipratropium bromide, budesonide, flunisolide, beclometasone and triamcinolone and optionally</li><li>d) further customary pharmaceutical auxiliaries which are suitable for aerosol formulations.</li></ul>

The present invention relates primarily to a pharmaceutical composition containing:<ul id="ul0004" list-style="none"><li>a) the propellant gas heptafluoropropane (227);</li><li>b) a nonionic surfactant from the group of monoacetylated monoglycerides;</li><li>c) a pharmaceutical active ingredient or combination of active ingredients from the group disodium cromoglicate, salbutamol, salmeterol, formoterol, oxitropium bromide, ipratropium bromide, budesonide, flunisolide, beclometasone and triamcinolone and optionally</li><li>d) further customary pharmaceutical auxiliaries which are suitable for aerosol formulations.</li></ul>

The present invention also relates to a production process for the pharmaceutical composition, which takes place in a manner known per se and is described, for example, in the pharmaceutical technology mentioned above on pages 736-737.

The pharmaceutical composition can be prepared by placing the pharmaceutical active ingredient or combination of active ingredients c) in a pressure-tight container and, in any order of the measures, the non-ionic surfactant b), optionally the usual pharmaceutical adjuvants d), and in addition the propellant or propellant mixture a) initiates, homogenizes and fills the homogeneous mixture into dosing containers suitable for aerosol formulations.

If the active ingredient is present or if the active ingredient is in a solid, for example crystalline, form, it should be comminuted, preferably micronized. The upper limit of the average particle size is considered to be an average particle diameter of less than 100 for topical formulations and less than 10 micrometers for inhalation formulations for the purpose of deposition in the respiratory tract. A particle size of approx. 0.1-5 micrometers is preferred for inhalation formulations which can be achieved by using conventional comminution methods, for example grinding in an air jet mill.

In an open batch pressure vessel, which is provided with a stirring and homogenizing device, component c) is weighed in and in accordance with the formulation specification in the appropriate sequence with components b) - surfactant - and optionally d) other auxiliaries, for example ethanol , filled. The pressure vessel is closed and the propellant gas or propellant mixture of component a) is introduced. The active ingredient is homogenized in the propellant gas / excipient mixture in the usual way, for example by stirring, shaking or treating with ultrasound. With the known filling techniques, the contents of the pressure container are filled through the valve into metering containers, for example pressure-tight containers made of tinplate or aluminum, which are vulgarly referred to as spray cans or spray cans and are provided with the usual metering valves. The pressure-resistant valves give approx. 25-100 microliters from.

The invention also relates to the use of the pharmaceutical composition in therapeutic processes for which there is a need based on the indication of the active substances or combinations of active substances contained therein. In particular, the pharmaceutical composition is used for the inhalation treatment of allergic diseases of the airways such as asthma or allergic rhinitis (hay fever), in particular if the aerosol contains active ingredients such as formoterol, disodium cromoglycate or salbutamol. Treatment is preferably by oral or nasal inhalation in humans.

The invention also relates to the use of a nonionic surfactant from the group of the monoacetylated or diacetylated monoglycerides for the production of a pharmaceutical preparation which can be used as an aerosol. The use of a liquid, non-ionic acetylated monoglyceride, which is known under the name MYVACET, is particularly preferred.

The following examples illustrate the invention:

The active substance, micronized to a particle size of less than 6 micrometers, is weighed into a predried pressure vessel and mixed with the propellant or propellant mixture, which contains the auxiliary ethanol, the non-ionic surfactant MYVACET, and optionally other auxiliary substances in the respective concentration Contains recipe example. After stirring and homogenization, the pressurized suspension is optionally diluted with propellant gas and filled with the usual pressure filling technique into aluminum or glass containers with a volume of approx. 20 ml closed with a metering valve. In the recipe examples, the weight is given in percentages by weight:<tables id="tabl0001" num="0001"><img file="EP0504112A2_D0001.tif" /></tables><tables id="tabl0002" num="0002"><img file="EP0504112A2_D0002.tif" /></tables><tables id="tabl0003" num="0003"><img file="EP0504112A2_D0003.tif" /></tables><tables id="tabl0004" num="0004"><img file="EP0504112A2_D0004.tif" /></tables>

With the above recipe examples, easily redispersible suspension dose aerosols can be produced. For better homogenization and to avoid adsorption, the addition of 0.5-20%, in particular 0.5-12%, of ethanol is preferred.