Pharmaceutical compositions

Details Pharmaceutical compositions Pharmaceutical compositions

2000-06-15

2002-06-04

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S489000, C424S464000, C424S465000, C424S468000, C424S472000, C424S451000, C424S456000, C424S452000, C424S457000, C424S497000

Reexamination Certificate

active

06399104

ABSTRACT:

The present invention relates to pharmaceutical compositions and in particular to pharmaceutical compositions containing the leukotriene antagonist zafirlukast. The invention also relates to processes for preparing such compositions and to their use in treating disease conditions mediated by leukotriene antagonists.
Zafirlukast is an orally administered leukotriene antagonist marketed under the trade mark ‘ACCOLATE’. Zafirlukast is marketed for the treatment, including prophylactic treatment, of asthma and is presented as a tablet formulation containing 20 mg or 40 mg active ingredient. Asthma and related conditions are of particular concern in children and in the elderly. However, these patient groups have particular difficulties in swallowing medicaments in tablet form. The present invention provides a formulation of zafirlukast that permits easier administration and in particular should be of especial benefit for paediatric and geriatic patients.
Zafirlukast, which has the chemical name N-[4-[5-(cyclopentyloxycarbonyl)amino -1-methylindol-3-ylmethyl]-3-methoxybenzoyl]-2-methylbenzene, is known in a number of physical forms. U.S. Pat. No. 4,859,692 discloses this compound as Example 105. U.S. Pat. No. 5,319,097 discloses that this compound can exist in more than one physical form and that these physical forms have differing stabilities and bioavailabilities. Form A is disclosed as amorphous and as having good bioavailability. It is further disclosed that Form A tends to convert into Form B in the presence of water and that this is disadvantageous. It is unattractive to develop a formulation containing a mixture of physical forms with different bioavailabilities, especially where one form is physically unstable, because the effective dose of the compound can not be controlled properly. Form B is disclosed as a crystalline monohydrate with a defined X-ray powder diffraction pattern and a defined infra-red spectrum. Form X is disclosed as crystalline with a defined X-ray powder diffraction pattern.
U.S. Pat. No. 5,294,636 discloses particular formulations of Form X. Example 4 describes a tablet formulation prepared by a wet granulation process followed by drying, milling, blending and compression. Examples 2 and 3 describe pharmaceutical compositions of Form X that are suitable for administration by metered dose inhaler. Example 5 describes the micronisation of Form X to produce a powder which was extruded to form soft pellets; these pellets were free flowing and relatively dust free and, on shearing, broke back down to the original particle size distribution indicating that the pellets were suitable for inhalational use.
U.S. Pat. No. 5,319,097 discloses particular formulations of Form A. Example 3 describes a tablet formulation prepared by a wet granulation process followed by drying, milling, blending and compression. A particular feature of this Example is the presence of polyvinylpyrrolidone (also known as povidone). Example 5 describes a capsule formulation, a beadlet (spheroid) formulation and a powder formulation. The beadlet formulation is prepared by spraying an aqueous dispersion of polyvinylpyrrolidone and zafirlukast (in equal amounts) on to sugar spheres. This is an example of a suspension layering process, as zafirlukast, at the exemplified concentration would be partially soluble in the dispersion.
Pellets (also known as beadlets, spheroids, coated non-pareils, coated beads, coated seeds or granules) wherein a central core is surrounded by a layer containing drug may be prepared in a number of different ways. One method is to spray a solution of the drug optionally containing pharmaceutically acceptable ingredients on to the core material. Another method is to spray a suspension of the drug optionally containing pharmaceutically acceptable ingredients on to the core or seed material as was described in U.S. Pat. No. 5,319,097. A third method is to apply the drug and other pharmaceutically acceptable ingredients in the dry state. This third method is known as ‘dry powder layering’. Usually dry powder layering requires the presence of water alone, or water with an aqueous binder or other solvent to facilitate the binding of the drug layer to the core material.
As stated hereinabove, zafirlukast exists in a number of physical forms and it is known that unwanted interconversion between certain forms can occur, especially in the presence of water. The three layering methods outlined above normally require water (as solvent, as the suspension medium, or to facilitate binding). Therefore, Applicants faced a problem in preparing pellets containing zafirlukast in particular in the amorphous form as none of the three methods was especially promising for preparing layered pellets suitable for pharmaceutical use. Unexpectedly, however, Applicants found that the pellets prepared by the dry powder layering method were stable and the physical forms of zafirlukast did not interconvert during the preparation and processing (including conditions of elevated temperatures and humidity) of the formulation. The preferred pellets of this invention are stable, non-friable and resist attrition. In particular, there is a tendency for any amorphous material (for example Form A) to convert to a crystalline form during processing conditions—as crystalline forms are generally the more stable forms. As stated hereinabove, it is unattractive to develop a formulation containing a mixture of physical forms with different bioavailabilities, especially where one form is physically unstable, because the effective dose of the compound can not be controlled properly.
Accordingly, the present invention provides a process for preparing a pharmaceutical composition which comprises applying amorphous zafirlukast and a binding agent and optionally other pharmaceutically acceptable ingredients to a plurality of cores to form layered pellets in which zafirlukast is present essentially in amorphous form. Amorphous zafirlukast is in dry form, appropriate for dry powder layering, immediately before the composition process.
Preferably the binding agent is an aqueous binding agent and in particular is water alone or water with other solvents.
Optionally a further binding agent may be present in the drug layer to assist the binding to the core material and to improve the strength of the pellets. Such additional binding agents may be any known to the person skilled in the art for this purpose. Preferred binding agents are polyvinylpyrrolidone and hydroxypropylmethylcellulose; of these polyvinylpyrrolidone is most preferred.
The cores are typically rotated or tumbled in a container to which amorphous zafirlukast and binding agent, optionally with other pharmaceutically acceptable ingredients, are added. The zafirlukast and binding agent are typically kept separate until they are added to the container; they are added to the container in a common feed or preferably in separate feeds. The separate feeds are generally simultaneous although the binding agent feed may commence slightly before the zafirlukast feed and may end slightly after the zafirlukast feed. As stated hereinabove, the function of the binding agent is to facilitate the binding of zafirlukast (and any pharmaceutically acceptable ingredients) to the core. The pharmaceutical ingredients may be introduced to the container with the zafirlukast feed or with the binder feed or may be divided, selectively, into both feeds as the skilled person would understand. In general powders are fed into the container together and aqueous ingredients for example water are fed in separately. It is preferred that any aqueous feed is water or, if the aqueous feed contains other ingredients, it is in the form of a solution and not in the form of a suspension.
The nature of the central core of each pellet is not critical provided that it dissolves in aqueous media. Typically the central core material is a sugar sphere or non-pareil wherein the main ingredients are sugar, such as sucrose, and starch. Such sugar spheres or non-pareils are commercially avail

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