Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
2001-01-30
2004-05-18
Krass, Frederick (Department: 1614)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C424S489000, C128S200140, C128S200230, C514S002600, C514S826000, C514S951000
Reexamination Certificate
active
06737044
ABSTRACT:
The present invention relates to an aerosol composition. In particular the present invention relates to an aerosol composition in the form of a suspension comprising liquid propellant and particulate material.
Effective use of an aerosol composition in the form of a suspension usually requires the suspension to comprise a uniform dispersion of particulate matter in order to ensure the production of an aerosol of known components in known amounts. Inhomogeneous dispersions can occur due to poor dispersibility of the particulate matter in the propellant and/or a tendency of the particulate matter to aggregate and possibly even to aggregate irreversibly.
Aerosol compositions comprising particulate matter in the form of a suspension can be used for the delivery of a number of active agents. A particular application comprises pharmaceutical suspensions for administration of a drug in particulate form.
An example of a pharmaceutical application of a particulate-containing aerosol composition is inhaler suspensions. Inhaler suspensions are used for delivery of a particulate medicament to the lungs or upper airway passages. Suitably the suspension is contained in a container fitted with a metering valve. A known dose can thus be administered on each occasion of use. Such containers can be convenient to use and are readily portable.
Such a metered dose inhaler conventionally consists of a pressurised container which has a metering valve of fixed volume to measure individual doses of a suspension of medicament held in the container. In order to ensure the administration of an accurate dose of suspended particulate medicament it is essential that the suspension is consistently and homogeneously dispersed and the valve performance is reproducible and effective throughout the life of the container. The suspension conventionally comprises medicament particles dispersed in a liquefied gas which in use acts as a propellant. On depressing the valve stem of the metering valve the propellant fraction of the metered dose rapidly vaporises so as to aerosolise the suspended particulate medicament which is then inhaled by the user.
Traditionally, chlorofluorocarbons such as CFC-11, CFC-12 and CFC-114 have been employed as propellants in metered dose inhalers. A particulate medicament intended for pulmonary administration needs to have a particle size with a median aerodynamic diameter between about 0.05 &mgr;m and about 11 &mgr;m. This range of size of medicament particle is important in inhalers. Larger particles will not necessarily or readily penetrate into the lungs and smaller sized particles are readily breathed out. However, particles between about 0.05 &mgr;m and about 11 &mgr;m can possess a high surface energy and can therefore be difficult to disperse initially in the propellant, and once dispersed can exhibit a tendency to aggregate undesirably and rapidly, leading eventually to irreversible aggregation of the particles. In the case of CFC as a propellant this problem was overcome by the addition of a surfactant soluble in the CFC which coats the medicament particles and prevents aggregation by steric hindrance. The presence of surfactant is also believed to be an aid to valve performance. In practice medicament particles were homogenised in the liquid CFC-11 with the inclusion of a propellant soluble surfactant such as lecithin, oleic acid or sorbitan trioleate. The resulting bulk suspension was dispensed into individual metered dose inhalers and a high vapour pressure propellant such as liquefied gas CFC-12/CFC-114 added. Such arrangements proved satisfactory in use, although the added surfactant could adversely affect the perceived taste of the inhaler in use. For example oleic acid could impart a bitter taste.
In recent years the detrimental effect of chlorofluorocarbons on the ozone layer in the earth's stratosphere has become apparent. The continued use of CFC has therefore become unacceptable and in some instances has been banned by local regulations.
Alternative propellants which share some similar physical properties to those of previously used CFC propellants and which have been suggested for use in metered dose inhalers are hydrofluoroalkanes, notably HFA-134a and HFA-227. Problems however exist on attempting to formulate the hydrofluoroalkanes into an aerosol composition such as an inhaler suspension. Firstly, the acceptable surfactants employed in CFC based suspensions are not sufficiently soluble in hydrofluoroalkanes to prevent irreversible aggregation of the particulate medicament occurring. Secondly, neither HFA-134a nor HFA-227 is a liquid at an acceptable temperature so that bulk homogenisation with particulate material prior to filling into individual pressured containers is only possible if carried out under pressure.
A number of proposals have been made in an attempt to employ hydrofluoroalkanes as the propellant in pressurised metered dose inhalers for example a patent specification (WO 92/06675) in the name of Minnesota Mining and Manufacturing Company suggests the use of non-volatile co-solvents to modify the solvent characteristics of the hydrofluoroalkane propellant and thereby increase the solubility and hence permit the use of the surfactants traditionally employed in CFC based metered dose inhalers. The presence of the co-solvent however may result in less desirable aerosol properties. Moreover the alcohol nonvolatile co-solvents suggested can impart an unpleasant sharp taste.
Patent specifications (WO 91/11173 and WO 92/00061) in the name of Fisons suggest the use of alternative surfactants which are sufficiently soluble in HFA-134a and HFA-227. The surfactants proposed however may present toxicity problems in use. Extensive and expensive toxicity studies are therefore required before the pharmaceutical regulatory authorities will permit their inclusion in a product intended for human use.
Glaxo Group Limited in WO 96/19968 suggests a pharmaceutical aerosol formulation which comprises particulate medicament, at lease one sugar and a fluorocarbon or hydrogen containing chlorofluorocarbon propellant. The particle size of the sugars used in the formulations are said to be selected using conventional techniques such as milling or micronisation. The suspension stability of the aerosol formulations is said to be particularly impressive.
Other proposals to provide a metered dosed inhaler employing hydrofluoroalkane are found in patent specification no. WO 92/08477 in the name of Glaxo Group Limited and patent specification no. EP 372777 in the name of Riker Laboratories, Inc.
A need therefore exists to provide an aerosol composition suitable for use in for example, an inhaler, comprising a suspension of particulate matter in a propellant, which composition has good dispersion characteristics, a reduced tendency to aggregate and can in use be effectively aerosolised with good valve performance.
It is an object of the present invention to provide an aerosol composition including a particulate material suitable for use in for example an inhaler which composition exhibits both a reduced tendency for the particulate material to aggregate undesirably and ready and homogeneous dispersion of the particulate material, and permits acceptable delivery of the particulate material.
It is a further object of the present invention to provide an additive comprising a particulate material for use in the preparation of such an aerosol composition.
It is a further object of the present invention to provide a container, such as an inhaler, containing such a composition.
It is a further object of the present invention to provide a container, such as metered dose inhaler incorporating a valve dispensing mechanism, containing such a composition, the composition ensuring both good suspension properties and good valve performance over the life of the container.
Further objects of the present invention include a method of preparing a container containing such a composition and a method of administering the composition.
According to a first aspect of the present invention there is pro
Dickinson Paul Alfred
Warren Simon John
Krass Frederick
Ostrup Clinton Troy
University College Cardiff Consultants Limited
Woodcock & Washburn LLP
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