Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
1999-06-08
2002-07-23
Dees, Jose′ G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C424S046000
Reexamination Certificate
active
06423298
ABSTRACT:
The present invention relates to new pharmaceutical formulations for aerosols with at least two or more active substances for use by inhalation or by the nasal route.
STATE OF THE ART
In propellant-driven metered dose inhalers (MDI) the active substances can be formulated as solutions or suspensions. The vast majority of aerosol formulations for MDI's are prepared as suspensions, especially if the preparation contains more than one active substance. Formulations in the form of solutions are used only to a limited extent. In these cases, the formulations normally contain only one active substance.
As a rule, in a suspension, the chemical stability of the active substances is noticeably higher than in a solution. Additionally, in a suspension the active substance can be more highly concentrated than in a solution, with the result that suspension type formulation enable higher doses to be administered.
A major disadvantage of suspension-formulations is the fact that over time (e.g. during storage) the suspended particles clump together to form bigger, more or less stable agglomerates or form loose flakes, sediments or floating layers, or in the worst case, particle growth, which significantly impairs the pharmaceutical quality of the product. The size of the particles formed or the speed of particle growth are influenced by the solubility features of the liquid phase. Thus, ingress of humidity during storage or a desired increase in polarity, e.g. achieved by adding co-solvents, can have a devastating effect on the quality of the medical end product, particularly if the suspended particles have polar structure elements. The suspension can be physically stabilised by the addition of surfactants, by reducing the harmful effects of moisture and/or particle growth so that suspended particles can be held in suspension for longer.
Natural solution-type formulations are not affected by the problems of increasing particle size or de-mixing processes such as sedimentation or flocculation. However, in this case there is a serious risk of chemical degradation. A further disadvantage is the fact that the limited solubility of the ingredients can prevent administration in high doses. In the past, the chlorofluorohydrocarbons TG 11 (trichlorofluoromethane), TG 12 (dichlorodifluoromethane) and TG 114 (dichlorotetrafluoroethane) have proved particularly suitable as solvents. The solubility of the ingredients can be increased by the addition of co-solvents. In addition, it is usually necessary to take additional measures to chemically stabilise the dissolved components.
Up till now, CFCs such as the above-mentioned TG 11, for example, have often been used as propellants. However, since CFCs have been linked with the destruction of the ozone layer, their manufacture and use are being phased out. The intention is to replace them with special fluorohydrocarbons (HFC) which are less destructive to the ozone layer but have completely different solubility features. The toxicological profile and physico-chemical properties such as the steam pressure, for example, determine which HFCs are suitable for MDIs. The most promising representatives at present are TG 134a (1,1,2,2-tetrafluoroethane)and TG 227 (1,1,1,2,3,3,3-heptafluoropropane).
For inhalative treatment it may be desirable to have aerosol formulations with two or more active substances. In such cases the active substances are formulated in the necessary concentrations as solutions or suspensions, frequently giving rise to problems regarding the chemical stability of the individual substances or the degree of concentration which can be attained. Major problems are encountered if one of the active substances cannot be suspended or is unstable in a suspension-type formulation of this kind or if one of the active substances is chemically unstable or will not dissolve in a solution-type formulation of this kind, particularly when HFC is used as the propellant.
It is therefore one object of the present invention to develop a formulation for metering aerosols having two or more active substances which overcomes the above-mentioned disadvantages.
DESCRIPTION OF THE INVENTION
Surprisingly, it has been found that a plurality of active substances can be formulated as a solution and a suspension combined in one formulation.
The invention relates to stable aerosol formulations with fluorohydrocarbons as propellants, particularly TG 134a and/or TG 227, consisting of two or more active substances, wherein at least one active substance is formulated as a solution and at least one active substance is formulated as a suspension. The pharmaceutical preparation according to the invention is used for inhalative treatment, particularly for treating diseases of the pharynx and respiratory tract, e.g. asthmatic diseases and COPD.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment a medicinally useful combination of two or more active substances is used, containing beclometasone, budesonide, cromoglycinic acid, fenoterol, flunisolide, fluticasone, ipratropium bromide, nedocromil, orciprenaline, oxitropium bromide, reproterol, salbutamol (albuterol), salmeterol, terbutalin, N-[[2,2-dimethyl-4(2-oxo-2H-pyridin-1-yl)-6-trifluoromethyl-2H-1-benzopyran-3-yl]methyl]-N-hydroxy-acetamide, the esters, salts and/or solvates thereof. Which of the above-mentioned active substances is formulated as a solution and which as a suspension in the preparation according to the invention depends on the particular combinations of active substance and can be determined relatively quickly by solution and suspension trials.
In a preferred embodiment, one or more of the following active substances are suspended: budesonide, cromoglycinic acid, nedocromil, reproterol and/or salbutamol (albuterol) or the esters, salts and/or solvates derived from these compounds and one or more of the following substances are dissolved: 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 the esters, salts and/or solvates derived from these compounds. Embodiments having two different active substances are preferred.
A particularly preferred embodiment contains dissolved ipratropium bromide, particularly combined with salbutamol sulphate (albuterol sulphate) as the suspended active substance.
In all the embodiments, the active substances are used in a therapeutically effective quantity, i.e. in a quantity that can induce a successful treatment. The concentration of the active substances and the volume per stroke of spray are adjusted in such a way that the quantity of active substance which is medically necessary or recommended is released by a single spray or by a few sprays.
One embodiment relates to formulations in which the suspended particles are stabilised by the addition of surfactant substances (surfactants) or other suspension-stabilising agents to stabilise the suspended particles against physical changes. The benefit of this is that the particle size will remain pharmaceutically acceptable even over lengthy periods, e.g. during storage. Preferred particle sizes are up to 20 &mgr;m, whilst particularly preferred particle sizes are between 5 and 15 &mgr;m, best of all not exceeding 10 &mgr;m. The advantage of these particle sizes is that the particles are small enough to penetrate deeply into the lungs but not so small as to be breathed out again with the exchanged air.
Suitable surfactants and suspension-stabilising agents include all pharmacologically acceptable substances which have a lipophilic hydrocarbon group and one or more functional hydrophilic groups, especially C
5-20
fatty alcohols, C
5-20
fatty acids, C
5-20
fatty acid esters, lecithin, glycerides, propyleneglycol esters, polyoxyethylenes, polysorbates, sorbitan esters and/or carbohydrates. C
5-20
fatty acids, propyleneglycol diesters and/or triglycerides and/or sorbitans of the C
5-20
fatty acids are preferred, whilst oleic acid and sorbitan
DeStefano George A.
McNamara Daniel P.
Boehringer Ingelheim Pharmaceuticals Inc.
Datlow Philip I.
Dees Jose′ G.
Haghighatian M.
Raymond Robert P.
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