Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
2000-10-05
2003-09-02
Hartley, Michael G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C424S046000, C424S043000, C424S489000, C128S200140, C128S203120
Reexamination Certificate
active
06613307
ABSTRACT:
This application is a 371 of PCT/EP99/02748, filed Apr. 23, 1999.
The present invention relates to formulations comprising particulate products which may be prepared by methods and apparatus using supercritical fluids. More particularly, the invention relates to formulations comprising certain crystalline forms of 4-hydroxy-&agr;
1
-[[[6-(4-phenylbutoxy)hexyl]amino]methyl]-1,3-benzenedimethanol (salmeterol) 1-hydroxy-2-naphthalenecarboxylate (xinafoate).
Salmeterol is a selective and potent &bgr;
2
adrenoreceptor stimulant bronchodilator which has been very successfully used by inhalation for the immediate relief of spasm in asthma. Salmeterol is described in British Patent Specification No. 2140800. The xinafoate salt of salmeterol is a particularly preferred pharmaceutically acceptable salt for use in inhalation therapy.
The use of aerosols to administer medicaments by inhalation has been known for several decades. Such aerosols generally comprise the medicament, one or more chlorofluorocarbon propellants and either a surfactant or a solvent, such as ethanol. The most commonly used aerosol propellants for medicaments have been propellant 11 (CCl
3
F) and/or propellant 114 (CF
2
ClCF
2
Cl) with propellant 12 (CCl
2
F
2
). However these propellants are now believed to provoke the degradation of stratospheric ozone and there is thus a need to provide aerosol formulations for medicaments which employ so called “ozone-friendly” propellants.
A class of propellants which are believed to have minimal ozone-depleting effects in comparison to conventional chlorofluorocarbons comprise fluorocarbons hydrogen-containing fluorocarbons and hydrogen-containing chlorofluorocarbons, and a number of medicinal aerosol formulations using such propellant systems are disclosed in, for example, EP 0372777, WO91/04011, WO91/11173. WO91/11495, WO91/14422, WO92/00107, WO93/08447, WO93/08446. WO93/11743, WO93/11744 and WO93/11745. These applications are all concerned with the preparation of pressurised aerosols for the administration of medicaments and seek to overcome the problems associated with the use of the new class of propellants, in particular the problems of stability associated with the pharmaceutical formulations prepared.
Conventionally crystallised salmeterol xinafoate, even after micronisation (fluid milling), exists in a form with poor flow characteristics, for example it is cohesive and statically charged, which results in difficulties in handling the drug substance in pharmaceutical formulation processes and can, when the drug is mixed with fluorocarbon, hydrogen-containing fluorocarbon or hydrogen-containing chlorofluorocarbon propellants, lead to dispersion stability problems such as drug agglomeration or deposition onto components of the aerosol can, valve or actuator.
We have now surprisingly found that it is in fact possible to obtain satisfactory dispersions of salmeterol xinafoate in fluorocarbon, hydrogen-containing fluorocarbon or hydrogen-containing chlorofluorocarbon propellants such as 1,1,1,2-tetrafluoroethane (propellant 134a, or HFA 134a) by use of salmeterol xinafoate with a controlled particle size, shape and morphology.
International patent application PCT/GB94/01425 published under No. WO95/01324 (the disclosure of which is hereby incorporated herein by reference) describes a method and apparatus suitable for the formation of particulate salmeterol xinafoate in a controlled manner utilising a supercritical fluid particle formation system. The apparatus, further details of which are set out below, comprises a particle formation vessel with means for controlling the temperature of said vessel and means for controlling the pressure of said vessel, together with a means for the co-introduction into said vessel of a supercritical fluid and a vehicle containing at least one substance (such as salmeterol xinafoate) in solution or suspension, such that dispersion and extraction of the vehicle occur substantially simultaneously by the action of the supercritical fluid. The simultaneous co-introduction of the vehicle containing at least one substance in solution or suspension and the supercritical fluid, according to the method described in WO95/01324, allows a high degree of control of parameters such as temperature, pressure and flow rate, of both vehicle fluid and supercritical fluid, at the exact point when they come into contact with one another. This gives a high degree of control over the conditions under which particles of the drug substance suspended or dissolved in the vehicle form and thus of the physical properties of the particles formed.
Accordingly, the present invention provides an aerosol pharmaceutical formulation comprising salmeterol xinafoate with a controlled particle size, shape and morphology, and a fluorocarbon, hydrogen-containing fluorocarbon or hydrogen-containing chlorofluorocarbon propellant. Use of such particulate crystalline forms can give particular benefits in relation to reduction of agglomeration and of deposition of drug onto aerosol can walls, actuator and valve components and may permit the formation of stable dispersions without the use of additional components such as surfactants or co-solvents, or with relatively low levels of such components. Adsorption of drug into rubber components of the valve and/or actuator may also be reduced. Minimising and preferably avoiding the use of formulation excipients e.g. surfactants, cosolvents etc. in the aerosol formulations according to the invention may be advantageous since the formulations may be substantially taste and odour free, less irritant and less toxic than conventional formulations. Preferably the propellant is 1,1,1,2-tetrafluoroethane (propellant 134a), in which formulations the weight ratio of drug to propellant is preferably between 0.025:75 and 0.1:75, for example 0.05:75.
Further advantages for particles formed by the supercritical fluid particle formation method and apparatus include control over the quality of the crystalline and polymorphic phases, since the particles will experience the same stable conditions of temperature and pressure when formed, as well as the potential of enhanced purity. This latter feature can be attributed to the high selectivity of supercritical fluids under different working conditions, enabling the extraction of one or more of the impurities from the vehicle containing the substance of interest.
Moreover, the co-introduction of the vehicle and supercritical fluid, leading to simultaneous dispersion and particle formation, allows particle formation to be carried out, if desired, at temperatures at or above the boiling point of the vehicle, something not possible using previous supercritical fluid particle formation techniques. This enables operation in temperature and pressure domains which were previously inaccessible, which in turn can allow the formation of products, or particular forms of products, that previously could not have been achieved.
Control of parameters such as size and shape in the particulate product will be dependent upon the operating conditions used when carrying out the supercritical fluid method. Variables include the flow rates of the supercritical fluid and/or the vehicle containing substance(s), the concentration of the substance(s) in the vehicle, and the temperature and pressure inside the particle formation vessel. Thus the provision of formulations comprising salmeterol xinafoate as prepared by the supercritical fluid (SCF) particle formation method described herein and one or more fluorocarbon, hydrogen-containing fluorocarbon or hydrogen-containing chlorofluorocarbon propellants is a further aspect of the present invention.
In another aspect of the present invention, there is provided an aerosol pharmaceutical formulation comprising salmeterol xinafoate in a form with a dynamic bulk density of less than 0.1 g.cm
−3
, preferably in the range between 0.01 and 0.1 g.cm
−3
and, in particular, in the range between 0.01 and 0.075 g.cm
−3
and a fluorocarbon, hydrogen-conta
Bacon & Thomas
Haghighatian M.
Hartley Michael G.
SmithKline Beecham Corporation
LandOfFree
Aerosol formulations of salmeterol xinafoate does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Aerosol formulations of salmeterol xinafoate, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Aerosol formulations of salmeterol xinafoate will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3044281