Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
2002-02-04
2004-06-15
Badio, Barbara P. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C540S114000
Reexamination Certificate
active
06750210
ABSTRACT:
The present invention relates to a pharmaceutical formulation containing novel anti-inflammatory and anti-allergic compound of the androstane series and to processes for its preparation. The present invention also relates to therapeutic uses thereof, particularly for the treatment of inflammatory and allergic conditions.
Glucocorticoids which have anti-inflammatory properties are known and are widely used for the treatment of inflammatory disorders or diseases such as asthma and rhinitis. For example, U.S. Pat. No. 4,335,121 discloses 6&agr;, 9&agr;-Difluoro-17&agr;-(1-oxopropoxy)-11&bgr;-hydroxy-16&agr;-methyl-3-oxo-androsta-1,4-diene-17&bgr;-carbothioic acid S-fluoromethyl ester (known by the generic name of fluticasone propionate) and derivatives thereof. The use of glucocorticoids generally, and especially in children, has been limited in some quarters by concerns over potential side effects. The side effects that are feared with glucocorticoids include suppression of the Hypothalamic-Pituitary-Adrenal (HPA) axis, effects on bone growth in children and on bone density in the elderly, ocular complications (cataract formation and glaucoma) and skin atrophy. Certain glucocorticoid compounds also have complex paths of metabolism wherein the production of active metabolites may make the pharmacodynamics and pharmacokinetics of such compounds difficult to understand. Whilst the modern steroids are very much safer than those originally introduced, it remains an object of research to produce new molecules which have excellent anti-inflammatory properties, with predictable pharmacokinetic and pharmacodynamic properties, with an attractive side effect profile, and with a convenient treatment regime.
We have now identified a novel glucocorticoid compound and formulation thereof which substantially meets these objectives.
Thus, according to one aspect of the invention, there is provided a pharmaceutical aerosol formulation comprising (i) a compound of formula (I).
Thus, according to one aspect of the invention, there is provided a pharmaceutical aerosol formulation comprising (i) a compound of formula (I)
or a solvate thereof as medicament, (ii) a liquified hydrofluoroalkane (HFA) gas as propellant; and characterised in that the compound of formula (I) or a solvate thereof is completely dissolved in the formulation.
The chemical name of the compound of formula (I) is 6&agr;, 9&agr;-Difluoro-17&agr;-[(2-furanylcarbonyl)oxy]-11&bgr;-hydroxy-16&agr;-methyl-3-oxo-androsta-1,4-diene-17&bgr;-carbothioic acid S-fluoromethyl ester.
References hereinafter to the compound according to the invention include both the compound of formula (I) and solvates thereof, particularly pharmaceutically acceptable solvates.
The compound of formula (I) and formulations thereof have potentially beneficial anti-inflammatory or anti-allergic effects, particularly upon topical administration to the lung or nose, demonstrated by, for example, its ability to bind to the glucocorticoid receptor and to illicit a response via that receptor, with long acting effect. Hence, the compound of formula (I) is useful in the treatment of inflammatory and/or allergic disorders, especially in once-per-day therapy.
The efficiency of an aerosol device, such as an MDI, is a function of the dose deposited at the appropriate site in the lungs. Deposition is affected by several factors, of which one of the most important is the aerodynamic particle size. Solid particles and/or droplets in an aerosol formulation can be characterised by their mass median aerodynamic diameter (MMAD, the diameter around which the mass aerodynamic diameters are distributed equally).
Particle deposition in the lung depends largely upon three physical mechanisms:
1. impaction, a function of particle inertia;
2. sedimentation due to gravity; and
3. diffusion resulting from Brownian motion of fine, submicrometer (<1 &mgr;m) particles.
The mass of the particles determines which of the three main mechanisms predominates.
The effective aerodynamic diameter is a function of the size, shape and density of the particles and will affect the magnitude of forces acting on them. For example, while inertial and gravitational effects increase with increasing particle size and particle density, the displacements produced by diffusion decrease. In practice, diffusion plays little part in deposition from pharmaceutical aerosols. Impaction and sedimentation can be assessed from a measurement of the MMAD which determines the displacement across streamlines under the influence of inertia and gravity, respectively.
Aerosol particles of equivalent MMAD and GSD (geometric standard deviation) have similar deposition in the lung irrespective of their composition. The GSD is a measure of the variability of the aerodynamic particle diameters.
For inhalation therapy there is a preference for aerosols in which the particles for inhalation have a diameter of about 0.5 to 51 &mgr;m. Particles which are larger than 5 &mgr;m in diameter are primarily deposited by inertial impaction in the orthopharynx, particles 0.5 to 5 &mgr;m in diameter, influenced mainly by gravity, are ideal for deposition in the conducting airways, and particles 0.5 to 3 &mgr;m in diameter are desirable for aerosol delivery to the lung periphery. Particles smaller than 0.5 &mgr;m may be exhaled.
In suspension formulations, particle size in principle is controlled during manufacture by the size to which the solid medicament is reduced, usually by micronisation. However, if the suspended drug has the slightest solubility in propellant, a process known as Ostwald Ripening can lead to particle size growth. Also, particles may have a tendency to aggregate, adhere to or diffuse into parts of the MDI eg. canister or valve. The effect of Ostwald ripening and particularly of drug deposition may be particularly severe for potent drugs which need to be formulated in low doses. Solution formulations do not suffer from these disadvantages since the particle size is defined by the function of rate of evaporation of the propellant from the formulation, and the time between release of formulation from canister, solute (e.g. drug and/or excipient) concentration and the moment of inhalation.
In the case of administration of formulations to the nose, ciliary clearance is very rapid and drug delivered by means of suspension formulations may be cleared by the cilia before it has had the opportunity to dissolve and enter the target cells of the target organ. Thus a solution formulation has advantages since it speeds up absorption thus affording the active ingredient a greater opportunity to exert a therapeutic effect before ciliary clearance takes place. This may also lead to faster onset of action.
The aerosol formulation may be delivered from a pressurised pack, such as a metered dose inhaler. The preferred hydrofluoroalkane propellants are 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane and mixtures thereof, most especially 1,1,1,2-tetrafluoroethane.
The formulation according to the invention will generally contain a solubilising agent to aid solubilisation of the compound of formula (I) or a solvate thereof in the formulation.
In a first embodiment of the invention the solubilising agent is a hydroxy containing co-solvent liquid such ethanol or a glycol eg propylene glycol (eg PEG200, PEG400), propylene glycol, especially ethanol.
Such a solubilising agent will generally be employed in an amount of 5-20% depending on the particular solubilising agent and the amount of compound of formula (I) needing to be solubilised. In the case of ethanol, and amount of 5-15 especially 5-10% is generally suitable.
In a particularly preferred aspect of this embodiment, the formulation also contains a low volatility component to increase the mass median aerodynamic diameter (MMAD) of the aerosol particles on actuation of the inhaler.
The presence of the low volatility component in the solution formulation increases the fine particle mass (FPM) as defined by content of stages 3-5 of an Andersen Cascade Impactor on actuation
Badio Barbara P.
Riek James P.
SmithKline Beecham Corporation
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