United States Patent: 5,976,576
Inventors: Makovec; Francesco (Monza, IT); Senin; Paolo (Monza, IT); Rovati; Lucio Claudio (Monza, IT)Assignee: Rotta Research Laboratories S.p.A. (Monza, IT)
Appl. No.: 129794Filed: August 6, 1998
A pharmaceutical composition comprising, as active ingredient,
N-4-(1H-tetrazol-5-yl)phenyl-4-(1H-tetrazol-5-yl)benzamide disodium salt
(CR 2039, Andolast) or another pharmaceutically-acceptable salt thereof
and a flavoring, and optionally including a pharmaceutically-acceptable
inert carrier and/or a pharmaceutically-acceptable sweetener, the
composition being suitable for administration by oral inhalation
CR 2039 is a compound having potent anti-allergic and anti-asthmatic activity, the pharmacological activities of which have already been described, for example, in Revel L. et al. (1992), Eur. J. Pharmacol. 229, 45-53 and in U.S. document No. 5 232 937.
Many drugs used in the treatment of disorders of the respiratory tract are administered by oral inhalation. However, the dispensing of CR 2039 as a micronized powder for administration by this route has involved considerable problems which limit its use, in spite of its potent pharmacological activity.
One of these problems is that CR 2039 is extremely bitter. Another considerable problem is that CR 2039 disodium salt, like other salts thereof, is a hygroscopic substance of which the particles tend to form aggregates easily. In fact, small particles are quite unstable thermodynamically in view of the high ratio between their surface area and the space they occupy. When the product is used in the form of a micronized powder, the aggregation phenomena therefore make it difficult in use to maintain a particle diameter of the substance of less than 5 microns, beyond which limit it is difficult for a substance to penetrate the air passages deeply in order to be absorbed and thus perform its pharmacological activity. Administration by this route has therefore been somewhat unpleasant for patients who have not demonstrated the expected benefit from the treatment.
The object of the present invention is to provide, for the treatment of asthma and other pathological conditions of the respiratory tract, a novel pharmaceutical composition comprising, as active ingredient, CR 2039 disodium salt or another pharmaceutically-acceptable salt thereof for administration by oral inhalation. This novel pharmaceutical composition comprises, in addition to the active ingredient, a flavouring such as, for example, menthol or peppermint oil or mixtures thereof, and may also contain one or more pharmaceutically-acceptable inert carriers as well as one or more suitable sweeteners. The use of flavourings such as, for example, menthol or peppermint oil is important for various reasons. In the first place their use masks the unpleasant taste of CR 2039, increasing "compliance" in relation to this preparation. In the second place, their appropriate use succeeds, in particular, in increasing both the respirable fraction of the drug, that is, the so-called "fine-particle fraction" and the uniformity of the dose of the drug administered.
The sweeteners may be selected from carbohydrates such as, for example, sucrose, fructose, glucose, mannitol, etc., or aspartame, sodium cyclamate, saccharin, sodium saccharin, etc.
The novel pharmaceutical composition comprises, as active ingredient, CR 2039, preferably in the form of the disodium salt, as a fine micronized powder having a particle diameter preferably of between 0.1 and 10 microns and an average diameter preferably of between 1 and 3 microns, and a flavouring, preferably menthol, which is present in the composition in a ratio by weight (weight/weight) of between 0.5% and 10%, preferably 3%, with reference to the weight of the active ingredient.
The pharmaceutical composition may comprise sweeteners, preferably sodium saccharin, which may be present in the composition in a ratio by weight (weight/weight) of between 1% and 30%, preferably between 10% and 20%, with reference to the weight of active ingredient.
The composition may also comprise one or more inert, water-soluble carrier, preferably lactose or dextrose, in a ratio by weight (weight/weight) of between 0.5 and 5 times the weight of the active ingredient.
The pharmaceutical composition of the invention is preferably prepared by dissolving the flavouring, for example, the menthol or peppermint oil, in a volatile, non-aqueous solvent such as, for example, ethyl ether or, preferably, methylene chloride and mixing this solution with the active ingredient in the ratios indicated above. The advantage of this method is that, after evaporation of the solvent, a homogeneous, free flowing, non-sticky mixture is thus obtained, in contrast to what occurs if the components are simply mixed dry. Moreover, with this method the tendency of the particles of the active ingredient to form aggregates is greatly reduced.
As stated above, the composition may include an inert carrier such as, for example, lactose or dextrose, and a sweetener or, preferably, both. In this case, these components are mixed by conventional techniques with the active ingredient, flavoured as described above.
If inert carriers and sweeteners are used, these may also be mixed dry with the active ingredient beforehand, the resulting mixture then being treated with the organic solution containing the flavouring. Upon completion, the solvent is evaporated by conventional techniques.
The pharmaceutical composition according to the invention may be used as it is, by means of a conventional portable inhaler for dry powders. Alternatively, in order to increase the fluidity of the pharmaceutical composition within the reservoir of the inhaler device, the mixture can be transformed in pellets by tumbling it with conventional techniques and sieved through stainless steel sieves to provide pellets having a size between 100-1000 micrometers. Alternatively, hard gelatine capsules filled with the pharmaceutical composition of the invention may be used. The capsules are loaded into a conventional single- or multi-dose inhaler which, after the capsule has been suitably perforated, enables the contents of the capsule to be dispensed in a suitable manner for inhalation by the patient.
Claim 1 of 31 Claims
1. A pharmaceutical composition comprising, as an active
ingredient, N-4-(1H-tetrazol-5-yl)phenyl-4-(1H-tetrazol-5-yl)benzamide
disodium salt (CR 2039, Andolast) or another pharmaceutically-acceptable
salt thereof, and a flavouring, wherein said composition optionally also
comprises a pharmaceutically-acceptable inert, water-soluble carrier, or a
pharmaceutically-acceptable sweetener, or both a
pharmaceutically-acceptable inert, water-soluble carrier and a
pharmaceutically-acceptable sweetener, and wherein said composition is in
a form suitable for administration by oral inhalation.
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