Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
1999-07-13
2001-03-06
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C424S043000
Reexamination Certificate
active
06197280
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a pharmaceutical composition comprising glyceryl trinitrate for delivery in aerosol form and to a device for delivering such a composition as an aerosol.
Glyceryl trinitrate is well established in the treatment and prophylaxis of angina pectoris and, when used to relieve acute attacks, is most commonly administered lingually, sub-lingually or buccally in the form of a spray, buccal tablet or chewable lozenge. Absorption of glyceryl trinitrate via the oral mucosa, particularly the sub-lingual oral mucosa, is rapid and haemodynamic effects and relief from pain are almost immediate.
Current aerosol spray formulations of glyceryl trinitrate use one or more chlorofluorocarbon as a propellant; dichlorodifluoromethane being commonly used. However, chlorofluorocarbons have been implicated in the depletion of the ozone layer and their production, therefore, is being phased out. It as been found that certain hydrofluorocarbons, which are both of low toxicity and of suitable vapour pressure for use as aerosol propellants, are significantly less harmful to the ozone layer. Among such hydrofluorocarbons, 1,1,1,2-tetrafluoroethane (HFC-134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFC-227) have been proposed as suitable propellants for pharmaceutical aerosols.
It has now been found that HFC-134a and HFC-227 can be used in combination with glyceryl trinitrate, without causing any degradation of the latter or reduction in its physiological effect.
Devices for administering metered aerosol doses of pharmaceutical preparations are well known in the art. Such devices include those disclosed in WO 92/11190, U.S. Pat. No. 4,819,834, U.S. Pat. No. 4,407,481. Many of these devices include metering valves having components formed from plastic materials, such as the valves available from Bespak PLC of Bergen Way, Kings Lynn, Norfolk PE30 2JJ, United Kingdom, in which the valve core, metering chamber and some other structural components are formed from plastic materials. The plastic materials currently used for forming these structural parts in valves employed with chlorofluorocarbon containing formulations of glyceryl trinitrate include certain acetal co-polymers.
Although the plastics employed to manufacture metering valves, including the aforementioned acetal co-polymers, have also been found to be stable in the presence of HFC-134a alone, the applicants, to their surprise, have determined that many of these plastics materials can be caused to swell in the presence of formulations which include glyceryl trinitrate and HFC-134a. When such swelling takes place in a valve, the fit of mutually slidable components, such as metering chambers and valve cores, is adversely effected and they can bind together or become loose, causing the valve to leak or cease functioning altogether.
SUMMARY OF THE INVENTION
This problem was solved in accordance with a first aspect of the invention which provides a device for providing pharmaceutical doses, comprising a container, filled with a pharmaceutical composition including glyceryl trinitrate and 1,1,1,2-tetrafluoroethane (HFC-134a) or 1,1,1,2,3,3,3-heptafluoropropane (HFC-227) as a propellant, and valve means arranged for delivering aerosol doses of said pharmaceutical composition to the exterior of the container, wherein at least a portion of the device is formed from a polyester. Preferably, the valve means includes at least one component formed from a polyester which component, more preferably, is a metering chamber and/or a valve core. Preferably, devices in accordance with the invention are arranged to provide metered doses of glyceryl trinitrate.
In further embodiments, the container comprises a polyester and, preferably, consists of metal lined with a polyester. The canister cap can also be so formed.
Apart from allowing the aforementioned swelling problem to be avoided, an advantage of the present invention is that use of expensive metal valve components can be avoided.
During the course of the work leading to the present invention, tests carried out on glyceryl trinitrate/ethanol/HFC-134a filled metered dose aerosol devices, with acetyl copolymer or nylon valve components, showed that they failed to provide uniform doses after storage under controlled conditions. Such effects are normally associated with problems involving the gaskets or seals employed within the valve mechanisms. Thus, it came as a surprise to the applicants when they discovered that these failures were being caused by the valve components swelling to an unacceptable extent, particularly since at least one of the materials used to form them (acetyl co-polymer) was known to be stable in the presence of HFC-134a, either alone or in admixture with ethanol, or conventional glyceryl trinitrate/ethanol/chlorofluoro carbon formulations.
The preferred polyesters are polyalkylene benzene dicarboxylates, more preferably polyalkylene terephthalates and, most preferably, a polybutylene terephthalate.
Such materials, preferably, have a density of about 1.3g/cm
3
and a water absorption of about 0.6% (23° C. saturation). The polyesters, also, are preferably partially crystalline in nature and have a crystalline melting range of 220-225° C.
Examples of suitable polybutylene terephthalates include those available under the Trademark Celanex® from Hoechst UK Limited, Walton Manner, Milton Keynes, Bucks MK7 7AJ, United Kingdom. Particularly preferred are Celanex® 2500 and Celanex® X 500/2.
The preferred propellant for use in the inventive device is HFC-134a and, in embodiments, the preparation further comprises, as a co-solvent, a lower alkyl alcohol, preferably ethanol, or a pharmaceutically acceptable polyol, preferably propylene glycol, glycerol or polyethylene glycol. The preferred co-solvent is ethanol. The lower alkyl alcohols can be C
2
-C
4
alkyl alcohols.
In embodiments, the composition included in the inventive device further comprises a flavouring oil, preferably peppermint oil Ph Eur. In all embodiments, it is preferred that the composition within the device comprises a solution of the propellant, glyceryl trinitrate and any co-solvent and flavouring agent employed.
In a second aspect, the invention provides a pharmaceutical composition for use in a device in accordance with the first aspect of the invention, comprising glyceryl trinitrate and HFC-134a or HFC-227 as a propellant. The preferred propellant is HFC-134a and it is further preferred that ethanol is included in the preparation.
In preferred embodiments of the invention, pharmaceutical compositions for use in devices in accordance with the first, aspect of the invention can comprise 75-95% w/w HFC-134a, or HFC-227 as a propellant, an optional amount of 0.5-2% w/w of a flavouring oil, and 5-25% w/w of a combination of 2-8% w/w glyceryl trinitrate and 92-98% w/w of a lower alkyl alcohol or a pharmaceutically acceptable polyol as a co-solvent. An advantage of such embodiments is that, because they include a greater proportion of volatile propellant than usual, the risk of a potentially clogging deposit of non-volatile material building up around the outlet nozzel of the device is minimised. This is particularly so in embodiments where no non-volatile agents, other than the active agent and a minimal amount (as specified above) of flavouring oil, are included in the composition.
Preferably, the flavouring oil is peppermint oil. The preferred lower alcohol is ethanol and the preferred pharmaceutically acceptable polyols are propylene glycol, glycerol and polyethylene glycol. It is preferred that compositions in accordance with the second aspect of the invention are in the form of liquid solutions, when maintained under pressure in devices in accordance with the first aspect of the invention, and are especially suited to use therein, since they do not cause significant degradation of the valve components employed in such devices.
Further excipients can be included in the formulations employed in the present invention. For example, neutral oils and surfactants (the latter for aiding
Goodman Michael
Howlett David John
Bioglan Laboratories Limited
McQueeney P. E.
Page Thurman K.
Wolf Greenfield & Sacks P.C.
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