Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
1998-06-18
2003-05-06
Bawa, Raj (Department: 1615)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C424S046000, C424S489000
Reexamination Certificate
active
06558651
ABSTRACT:
This application is filed pursuant to 35 U.S.C. §371 as a United States National Phase Application of International Application No. PCT/GB96/03154 filed Dec. 19, 1996 which claims priority from GB 9526392.7 filed Dec. 22, 1995.
This invention relates to aerosol formulations of use for the administration of medicaments by inhalation. More particularly, the invention relates to aerosol formulations comprising a fluorocarbon or hydrogen-containing chlorofluorocarbon propellant.
Drugs for treating respiratory and nasal disorders are frequently administered in aerosol formulations through the mouth or nose. One widely used method for dispensing such aerosol drug formulations involves making a suspension formulation of the drug as a finely divided powder in a liquefied gas known as a propellant. The suspension is stored in a sealed container capable of withstanding the pressure required to maintain the propellant as a liquid. The suspension is dispensed by activation of a dose metering valve affixed to the container. Devices used for dispensing drugs in this way are known as “metered dose inhalers” (MDI's). See Peter Byron,
Respiratory Drug Delivery,
CRC Press, Boca Raton, Fla. (1990) for a general background on this form of therapy.
Patients often rely on medication delivered by MDI's for rapid treatment of respiratory disorders which are debilitating and in some cases, even life threatening. Therefore, it is essential that the prescribed dose of aerosol medication delivered to the patient consistently meet the specifications claimed by the manufacturer and comply with the requirements of regulatory authorities. That is, every dose in the can must be the same within close tolerances.
Some aerosol drugs tend to adhere to the inner surfaces, i.e. walls, valves, and caps, of the MDI. This can lead to the patient getting significantly less than the prescribed amount of drug upon each activation of the MDI. The problem has been observed particularly in relation to formulations comprising salbutamol sulphate and hydrofluoroalkane (also known as simply “fluorocarbon”) propellant systems, for example 1,1,1,2-tetrafluoroethane, under development in recent years to replace conventional chloroflurocarbon propellants.
We have found that using a recrystallised form of salbutamol sulphate, can reduce or eliminate the problem of drug adhesion or deposition and thus ensures consistent delivery of medicament from the metered dose inhaler.
Accordingly, there is provided in one aspect of the invention a pharmaceutical aerosol formulation which comprises particulate salbutamol sulphate having a crystalline form in which the outer layer of the crystals is substantially non-amorphous; and 1,1,1,2-tetrafluorethane.
In a further aspect of the invention, there is provided a pharmaceutical aerosol formulation which comprises particulate salbutamol sulphate having a water content of less than about 0.4% by weight; and 1,1,1,2-tetrafluoroethane.
In another aspect of the present invention, there is provided a pharmaceutical aerosol formulation which comprises particulate salbutamol sulphate having substantially no thermal activity as measured by microcalorimetry at about 25° C. and between about 30% to about 90% relative humidity; and 1,1,1,2-tetrafluoroethane.
In yet another aspect of the present invention, there is provided a pharmaceutical aerosol formulation which comprises particulate salbutamol sulphate having reduced thermal activity substantially as shown in
FIG. 1
; and 1,1,1,2-tetrafluorethane.
The salbutamol sulphate used in the formulations of the present invention hereinafter referred to as ‘annealed’ salbutamol sulphate can suitably be prepared by subjecting particulate salbutamol sulphate to a temperature of between 0° C. to about 100° C. with a relative humidity of between about 20% to about 90%. Alternatively, the salbutamol sulphate can be prepared by subjecting particulate sulphate to elevated temperatures, such as about 40° C. to about 100° C. under vacuum.
Whilst not being bound by theory, treating the salbutamol sulphate in either of the above ways is believed to recrystallise a layer of high energy or amorphous material on the drug surface to provide a stable, relatively low energy ie lacks significant thermal activity, crystalline form which has a reduced water content typically of less than about 0.4% by weight, referred to as ‘annealed’ salbutamol sulphate. Preferably the salbutamol sulphate employed in the formulations of the present invention will have a water content of less than about 0.35% by weight and more preferably less than about 0.3% by weight. Particulate salbutamol sulphate, as described in U.S. Pat. No. 3,664,353, which has not been so treated has significantly greater thermal activity and a higher water content normally of about 0.5% by weight or more.
Thus, there is provided in a further aspect of the present invention a pharmaceutical aerosol formulation which comprises
(a) particulate salbutamol sulphate obtainable by subjecting said particulate salbutamol sulphate to a temperature of between about 0° C. to about 100° C. with a relative humidity of between about 20% to about 90%; and
(b) 1,1,1,2-tetrafluoroethane.
In yet a further aspect of the present invention, there is provided a pharmaceutical aerosol formulation which comprises
(a) particulate salbutamol sulphate obtainable by subjecting said particulate salbutamol to elevated temperatures under vacuum: and
(b) 1,1,1,2-tetrafluoroethane.
Whilst the desired particulate form of sulbutamol sulphate (that is substantially non-amorphous, reduced water content or substantially no thermal activity) has been prepared by the methods described herein, it will be appreciated that other methods which give salbutamol sulphate having said desired characteristics may also be used.
Preferably the annealed salbutamol sulphate employed in the aerosol formulations of the present invention is obtainable by subjecting the particulate salbutamol sulphate to a temperature of about 10° C. to 50° C. with a relative humidity of about 55% to about 65%. A temperature of about 20° C. to 30° C., for example 25° C., with a relative humidity of about 60% is particularly preferred.
Alternatively, the annealed salbutamol sulphate can be obtained by elevated temperatures such as between about 40° C. to about 100° C., preferably greater than about 60° C., especially greater than about 80° C.
The time required for treating the salbutamol sulphate will naturally depend upon the amount of drug to be treated, the way in which it is presented, and the temperature and/or relative humidity selected. Thus, the time required may be from hour(s) to day(s). At lower humidities and/or where lower temperatures are used, the time required may be longer, for example, one or more weeks. For to manufacturing purposes, shorter treatment times, for example of 1 to 5 hours, are preferred.
To ensure that the micronised salbutamol sulphate is substantially uniformly annealed, particularly when large quantities of drug are to be treated, the drug may advantageously be presented such that the surface area of drug in contact with the humid and/or warm air is maximised. For example, a quantity of drug may be presented in an open tray the base of which comprises a plurality of small apertures to permit access of the humid and/or warm air to the salbutamol sulphate.
The particle size of the particulate (e.g. micronised) salbutamol sulphate should be such as to permit inhalation of substantially all of the medicament into the lungs upon administration of the aerosol formulation and thus will be less than 100 microns, desirably less than 20 microns, and preferably in the range of 1 to 10 microns, for example 1 to 5 microns.
The final aerosol formulation desirably contains 0.005 to 10% w/w, preferably 0.005 to 5% w/w, especially 0.01 to 1% w/w of salbutamol sulphate relative to the total weight of the formulation. Particularly preferred are formulations containing 0.05-0.2% w/w of salbutamol sulphate relative to the total weight of the formulation.
The final aeros
Dwivedi Sarvajna Kumar
Li-Bovet Li
Riebe Michael Thomas
Bawa Raj
Rogers Christopher P.
Smith Robert J.
SmithKline Beecham Corporation
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