MXPA00012388A - Pharmaceutical formulations for aerosols with two or more active substances - Google Patents

Abstract

The present invention relates to new pharmaceutical formulations for aerosols with at least two or more active substances for administration by inhalation or by nasal route. Specifically, the invention relates to pharmaceutical preparations for propellant-driven metered dose aerosols using a fluorohydrocarbon (HFC) as propellant, which contain a combination of active substance of two or more active substances, wherein at least one active substance is present in dissolved form together with at least one other active substance in the form of suspended particles.

Description

Pharmaceutical formulation for aerosols with two or more active substances Description of the invention The present invention relates to new pharmaceutical formulations for aerosols with at least two or more active substances for oral or nasal administration. STATE OF THE ART In the metered dose inhalers powered by propellants, the active substances can be formulated as a solution or suspension. In most cases, aerosol formulations for metered dose inhalers are prepared in suspension form, especially if the preparation contains more than one active substance. Only in a small proportion of cases are formulations in solution used. In these cases, normally, the formulations only contain an active substance. In a suspension, generally, the chemical stability of the active substances is clearly higher than in solution. In addition, the active substance can be concentrated more in a suspension than in a solution, so that the suspension formulation allows higher dosages.

In suspension formulations it is a great disadvantage that, over time (for example in storage), the suspended particles coalesce into large more or less stable agglomerates or form loose flakes, sediment or float or, in the worst case, show growth of the particles, which clearly worsens the pharmaceutical quality of the product. The size of the particles originated with this or the rate of growth of the particles are influenced by the solvent properties of the liquid phase. Thus, the penetration of moisture during storage or an intentional increase in polarity, for example by the addition of co-solvents, act catastrophically on the quality of the final drug product, Ref: 125569 especially if the suspended particles show polar structural elements. By the addition of surfactants, a physical stabilization of the suspension can be achieved by reducing the disturbing influence of moisture and / or particle growth and being able to keep the suspended particles suspended for longer. Solution formulations, by nature, are not affected by the problems of increasing particle size or segregation processes of the mixture, such as sedimentation or flocculation. In this case, however, there is a great danger of chemical degradation processes. Another disadvantage is that the limited solubility of the constituent substances can prevent administration of high doses. In times past, the fluorochlorocarbon TG11 (trichlorofluoromethane), TG12 (dichlorodifluoro-methane), TG114 (dichlorotetrafluoroethane) have proven to be particularly suitable solvents. The solubility of the constituent substances can be increased by the addition of co-solvents. In addition, in solution formulations, most of the time additional measures must be taken to chemically stabilize the dissolved components. As propellant gases, CFCs have often been used to date, such as, for example, the mentioned TG11. Since, on the other hand, CFCs are associated with the destruction of the ozone layer, their production and use are progressively suspended. As substitute substances, the use of special fluorinated hydrocarbons (HFA) is considered, which are considered to be less harmful to the ozone layer, but which also have completely different solubility properties. The toxicological profile and physical properties, such as vapor pressure, for example, determine which HFAs are suitable for metered aerosols. The most promising representatives until the date are TG 134a (1, 1, 2, 2 -tetrafluoroethane) and TG 227 (1,1,1,2,3,3,3--heptafluoropropane). For the inhalation treatment, aerosol formulations with two or more active ingredient components may be desired. In this case, the active substances are formulated in the necessary concentration in the form of an individual solution or in the form of an individual suspension, which is often linked with problems relating to the chemical stability or the level of concentration of the individual active substances. Great difficulties arise if in a suspension formulation of this type one of the active substances can not be suspended or is unstable, or if in a solution formulation one of the active substances is chemically unstable or does not dissolve, especially with the use of HFA as a propellant agent. Therefore, one task of the invention is to develop a formulation for dosed aerosols with two or more active substances that overcomes the disadvantages mentioned above. Description of the invention Surprisingly, it was now found that various active substances can be formulated in a formulation, coexisting as a solution and in the form of a suspension.

The invention relates to stable aerosol formulations with fluorinated hydrocarbons as a propellant gas, especially TG 134a and / or TG 227, which are composed of two or more active substances, at least one active substance being formulated as a solution and at least one active substance in the form of suspension. In this case, the pharmaceutical preparation according to the invention serves for the inhalation treatment, especially for diseases of the oral cavity and the pharyngeal tract and of the respiratory tract, for example asthmatic diseases and COPD. Detailed description of the invention In one embodiment, a combination of active substances suitable in medicine, based on two or more active substances, containing beclomethasone, budesonide, cromoglicidic acid, fenoterol, flunisolide, fluticasone, ipratropium bromide, nedocromil, orciprenaline, oxitropium bromide is used. , reproterol, salbutamol (albuterol), salmeterol, terbutaline, N- [[2, 2-dimethyl-4- (2-oxo-2H-pyridin-1-yl) -6-trifluoromethyl-2H-1-benzopyran-3 -yl] methyl] -N-hydroxy-acetamide, its esters, salts and / or solvates. Which of the active substances indicated above are formulated in the preparation according to the invention in the form of a solution and which in suspension form depends on the respective combinations of active substances and can be determined relatively quickly by solution and suspension tests. In a preferred embodiment, one or more of the following active substances are suspended: budesonide, cromoglicidic acid, nedocromil, reproterol and / or salbutamol (albuterol), or esters, salts and / or solvates derived from these compounds, and dissolve one or more of the following substances: beclomethasone, fenoterol, ipratropium bromide, orciprenaline and / or oxitropium bromide, N - [[2,2-dimethyl-4- (2-oxo-2H-pyridin-1-yl) -6-trifluoromethyl-2H-1-benzopyran-3-yl] methyl] -N-hydroxy-acetamide or esters, salts and / or solvates derived from these compounds. Preferred embodiments are two different active substances. An especially preferred embodiment contains dissolved ipratropium bromide, especially in combination with salbutamol sulphate (albuterol sulfate) as a suspended active substance. In all embodiments, the active substances are used in a therapeutically active amount, ie in an amount that can produce the good result of the treatment. In this case, the concentration of the active substances and the volume inhaled by pulsation of spray are adjusted in such a way that by means of a pulsation or a few inhalation pulsations the amount of the respective medicinal active substance necessary or recommended is released. One embodiment refers to formulations in which the suspended particles are stabilized in their physical consistency by the addition of surfactants or other suspension stabilizing agents. This has the advantage that the particle sizes remain pharmaceutically acceptable even for a prolonged period of time, for example during storage. Particle sizes up to 20 μm are preferred, particle sizes ranging from 5 to 15 μm being very particularly preferred, in the most favorable case a maximum of 10 μm. The advantage of these particle sizes is that the particles are small enough to penetrate deep into the lungs, but not so small as to be expired again with the exchange air. Suitable surfactants or suspension stabilizing agents are all pharmacologically compatible substances which have a lipophilic hydrocarbon radical and one or more functional hydrophilic group (s), with fatty acids (C5-C20) being particularly suitable. fatty acids (C5-C20), esters of fatty acids (C5-C20), lecithin, glycerides, esters of propylene glycol, polyoxyethylenes, polysorbates, sorbitan esters and / or carbohydrates. Preferred are (C3-C20) fatty acids, propylene glycol diesters and / or triglycerides and / or sorbitans of fatty acids (C5-C20), with oleic acid and sorbitan mono-, di- or tri-oleates being especially preferred. Alternatively, polymers and block polymers that are toxicologically and pharmaceutically harmless can also be used as stabilizing agents. The surfactants employees are not fluorinated, or are partially or completely fluorinated, the exchange of hydrogen radicals linked to carbon by fluorine radicals being understood as fluorinated. The amount of surfactant, based on the weight fraction of the suspended active substance, can be up to 1: 1, with amounts from 0.0001: 1 to 0.5: 1 being preferred, and particularly preferably amounts of 0.0001. : 1 to 0.25: 1. Another advantage of the aforementioned surfactants is that they can also be used as ventilation lubricants. Therefore, one embodiment relates to formulations in which said surfactant is added as a lubricating agent for ventilation. In another embodiment, the solubility of the active substance (s) to be dissolved is increased by the addition of co-solvents. This has the advantage that the active substance (s) to be dissolved can be formulated in higher concentrations. The addition of co-solvent must therefore not lead to exceeding the threshold of critical polarity of the liquid phase from which, for the particles of active substance, one of the disadvantages described above occurs. Suitable co-solvents are pharmacologically tolerable alcohols, such as ethanol, esters or water or mixtures thereof, with ethanol being preferred. The concentration of the co-solvent with respect to the complete formulation is from 0.0001 to 50% by weight, preferably from 0.0001 to 25% by weight. In another embodiment, a concentration of 0.0001 to 10% by weight is preferred, and embodiments in which the just amount of alcohol necessary to dissolve the active substance to be dissolved are particularly preferred. In another embodiment, other propellant gases are added to the propellant gas HFA. Such added propellant gases, together with other fluorinated hydrocarbons, can also be saturated hydrocarbons such as propane, butane, isobutane or pentane, as long as there is pharmacological harmlessness of the mixture. In one embodiment, stabilizing agents are added to the formulation, which favorably influences the pharmaceutical stability of the active substances, even over a long period of time, for example during storage. Stabilizing agents in the context of the invention are understood as those substances which prolong the inalterability and the suitability for the use of the pharmaceutical preparation, preventing or retarding chemical alterations of the individual substances contained, especially of the pharmaceutically active substances, for example by secondary reactions or degradation, or prevent biological impurities. In this regard, preferred stabilizing agents are those which influence the pH value of the liquid phase such as, for example, acids and / or their salts. Hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, ascorbic acid, citric acid and their salts are especially suitable. As bactericidal agents, fungicides, and the like, preferred are, together with these, benzalkonium chloride or ethylenediamine tetraacetate. Citric acid is the most preferred. The concentration of the stabilizers can be up to 1000 ppm, preferably up to 100 ppm and, particularly preferably, from 20 to 40 ppm. An especially preferred embodiment contains suspended salbutamol sulphate (albuterol sulfate), dissolved ipratropium bromide, ethanol as a co-solvent and citric acid as a stabilizing agent. E ploses Example 1: In a solution of 89.96 g (1 mole, 89.71% by weight) of liquefied TG 134a and 10.03 g (218 mmol, 10.00% by weight) of ethanol, they are dissolved mg (0.09 mmol, 0.037% by weight) of ipratropium bromide and 4 mg (20 μmol, 0.004% by weight) of citric acid and 210.5 mg (0.88 mmol, 0.21% in weight of salbutamol sulfate (albuterol sulfate) together with 0, 05% by weight of surfactant (for example 50 mg (177 mmol) of oleic acid). Example 2: Analogously to Example 1, with TG 227 as propellant gas instead of TG 134a. Example 3: In p134a fluidized and a small amount of ethanol disodium cromoglycate is suspended and fenoterol hydrobromide is dissolved. Example 4: Analogously to Example 3, with TG 227 as propellant gas instead of TG134a. It is noted that in relation to this date, the best method provided by the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Claims (16)

Having described the invention as above, the content of the following claims is claimed as property:

1. Pharmaceutical preparation for metered aerosols, activated by a propellant agent with a fluorinated hydrocarbon (HFA) as propellant, containing a combination of active substances, based on two or more active substances, and characterized in that at least one active substance is dissolved in the propellant agent by the addition of a co-solvent and, additionally, at least one other active substance is suspended in the mixture of propellant and co-solvent.

2. Pharmaceutical preparation according to claim 1, characterized in that the combination of active substances is composed of two active substances.

Pharmaceutical preparation according to one of the preceding claims, characterized in that the propellant is TG 134a and / or TG 227.

4. Pharmaceutical preparation according to claim 3, characterized in that the co-solvent contains one or more pharmacologically acceptable alcohols, an ester pharmacologically acceptable, water or mixtures thereof.

5. Pharmaceutical preparation according to claim 3, characterized in that the co-solvent is ethanol.

6. Pharmaceutical preparation according to claim 3, 4 or 5, characterized in that the co-solvent is present in a concentration of up to 25% by weight, based on the amount of liquefied propellant gas.

7. Pharmaceutical preparation according to claim 3, 4 or 5, characterized in that the co-solvent is present in a concentration of up to 10% by weight, based on the quantity of liquefied propellant gas. .

Pharmaceutical preparation according to one of claims 1, 2, 3, 4, 5, 6 or 7, characterized in that the preparation is stabilized by a stabilizing agent.

9. Pharmaceutical preparation according to claim 8, characterized in that the stabilizing agent contains an acid and / or its salt.

10. Pharmaceutical preparation according to claim 8 or 9, characterized in that the stabilizing agent contains hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, ascorbic acid, citric acid, benzalkonium chloride or ethylenediamine tetraacetate or a salt thereof. .

11. Pharmaceutical preparation according to claim 8 to 10, characterized in that the stabilizing agent is citric acid.

12. Pharmaceutical preparation according to one of the preceding claims 8, 9, 10 or 11, characterized in that the stabilizing agent has a fraction of up to 100 ppm.

13. Pharmaceutical preparation according to one of the preceding claims 8, 9, 10, 11 or 12, characterized in that the stabilizing agent has a fraction of up to 40 ppm.

14. Pharmaceutical preparation according to one of claims 1 to 13, characterized in that the preparation contains a surfactant or a suspension stabilizing agent.

15. Pharmaceutical preparation according to claim 14, characterized in that the surfactant or a suspension stabilizing agent contains fatty alcohols (C5-C20), fatty acids (C5-C20), esters of fatty acids (C3-C20), lecithin, glycerides, esters of propylene glycol, polyoxyethylenes, polysorbates, sorbitan esters and / or carbohydrates.

16. Pharmaceutical preparation according to claim 14, characterized in that the surfactant or a suspension stabilizing agent contains fatty acids (C3-C20) and / or esters thereof. 7. Pharmaceutical preparation according to claim 14, characterized in that the surfactant or a suspension stabilizing agent contains oleic acid and sorbitan mono-, di- or tri-oleates. Pharmaceutical preparation according to claim 14, characterized in that the surfactant or a suspension stabilizing agent contains oleic acid. Pharmaceutical preparation according to claim 14, characterized in that the surfactant or a suspension stabilizing agent is a toxicologically and pharmaceutically compatible polymer and / or block polymer. Pharmaceutical preparation according to one of the preceding claims, characterized in that the combination of active substances contains beclomethasone, budesonide, cromoglicidic acid, fenoterol, flunisolide, fluticasone, ipratropium, nedocromil, orciprenaline, oxitropium bromide, reproterol, salbutamol, salmeterol (albuterol), terbutaline, N- [[2, 2 -dimethyl-4- (2-oxo-2H-pyridin-1-yl) -6-trifluoromethyl-2H-1-benzopyran-3-yl] methyl] -N-hydroxy-acetamide, its esters, salts and / or solvates Pharmaceutical preparation according to one of claims 1 to 20, characterized in that the combination of active substances contains salbutamol sulphate (albuterol sulfate) and ipratropium bromide.