Abstract:
A device for providing pharmaceutical doses comprising a container, filled with a pharmaceutical composition including a pharmaceutically active agent in a solution of liquified 1,1,1,2-tetrafluoroethane (HFC-134 a ), or 1,1,1,2,3,3,3 heptafluoropropane (HFC-227) and a carrier. The carrier can be a pharmaceutically acceptable alcohol, polyol, (poly)alkoxy derivative, fatty acid alkyl ester, polyalkylene glycol, or dimethyl sulphoxide. The device includes a valve arranged for delivering aerosol doses of said pharmaceutical composition to the exterior of the container, and at least a portion of the device is formed from a polyester.

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     This application is a continuation-in-part of U.S. application Ser. No. 08/913,226, filed Sep. 9, 1997, and now abandoned and a continuation-in-part of International Application No. PCT/GB97/03360, filed Dec. 4, 1997. 
    
    
     BACKGROUND OF THE INVENTION 
     The present invention relates to pharmaceutical compositions comprising a pharmaceutically active agent in liquified 1.1.1.2-tetrafluoroethane (HFC-134a) or 1,1,1,2,3,3,3-heptafluoropropane (HFC-227) as a propellant, for delivery in aerosol form, and to a device for delivering such a composition as an aerosol. 
     Most current aerosol spray formulations use one or more chlorofluorocarbon as a propellant; dichloro-difluoromethane being commonly used. However, chlorofluorocarbons have been implicated in the depletion of the ozone layer and their production, therefore, is being phased out. It has 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. 
     SUMMARY OF THE INVENTION 
     It has now been found that HFC-134a and HFC-227 can be used in combination with many pharmaceutically active agents, without causing any degradation to them or reducing their physiological activity. 
     Devices for administering metered aerosol doses of pharmaceutical preparations are well known in the art. Such devices include those disclose in WO 92/11190, U.S. Pat. No. 4,819,834 and 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 many chlorofluorocarbon containing formulations 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 certain carriers or active agent solubilizing co-solvents with 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 affected and they can bind together or become loose, causing the valve to leak or cease functioning altogether. 
     This problem has now been solved in accordance with a first aspect of the invention by a device for providing pharmaceutical doses comprising a container, filled with a pharmaceutical composition including a pharmaceutically active agent in a solution of liquified HFC-134a, or HFC-227, and a carrier selected from pharmaceutically acceptable alcohols, polyols, (poly)alkoxy derivatives, fatty acid alkyl esters, polyalkylene glycols, and dimethylsulphoxide, and a valve 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 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 the pharmaceutically active agent included therein. 
     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 solved, an advantage of this aspect of the present invention is that use of expensive metal valve components can be avoided. 
     During the course of the work leading to this aspect of the present invention, tests carried out on active agent/carrier or co-solvent/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 alone, or conventional active agent/carrier or co-solvent/chlorofluorocarbon 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 1.3 g/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. 
     Preferably, the carrier is a lower alkyl (C 1 -C 4 ) alcohol, a polyol, or a (poly)alkoxy derivative. In embodiments, the carrier is a C 1 -C 4  alkyl alcohol or a lanolin alcohol and, preferably, is ethanol or isopropyl alcohol. The most preferred alcohol is ethanol. 
     The preferred polyols include propylene glycol and glycerol and the preferred (poly) alkoxy derivatives include polyalkoxy alcohols, in particular 2-(2-ethoxyethoxy) ethanol (available under the Trademark Transcutol®). 
     Further preferred (poly)alkoxy derivatives include polyoxyalkyl ethers and esters, such as polyoxyethylene ethers or esters. The preferred polyoxyethylene ethers and esters are polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters and polyoxyethylene stearates. 
     The preferred fatty acid alkyl esters are ethyl oleate, isopropyl myristate and isopropyl palmitate. The preferred polyalkylene glycol is polyethylene glycol. 
     In preferred embodiments, the inventive composition can comprise up to 50% or, preferably, 25% w/w carrier. More preferred embodiments include between 3% and 15% w/w, or between 4 and 10% w/w carrier. The pharmaceutical compositions can comprise between 50% and 99% w/w, preferably between 75% and 99% w/w, and, more preferably, between 88% and 95% w/w HFC-134a or HFC-227. 
     In further embodiments, compositions used in the present invention can comprise a plurality of different carriers. 
     Further excipients can be included in the formulations employed in the present invention. For example, neutral oils as well as surfactants (the latter for aiding the smooth operation of the valve), as are well known to those skilled in the art, may be included. 
     Thus, in further preferred embodiments, compositions employed in the invention can comprise an organic surfactant. The preferred organic surfactant is oleyl alcohol, although others can be employed, including sorbitan trioleate, sorbitan mono-oleate, sorbitan monolaurate, polyoxyethylene (20) sorbitan monolaurate, polyoxyethylene (20) sorbitan mono-oleate, natural lecithin, oleyl polyoxytheylene (2) ether, stearyl polyoxyethylene (2) ether, lauryl polyoxyethylene (4) ether, block copolymers of oxyethylene and oxypropylene, oleic acid, synthetic lecithin, diethylene glycol dioleate, tetrahydrofurfuryl oleate, ethyl oleate, isopropyl myristate, glyceryl mono-oleate, glyceryl monostearate, glyceryl monoricinoleate, cetyl alcohol, stearyl alcohol, cetyl pyridinium chloride, olive oil, glyceryl monolaurate, corn oil, cotton seed oil or sunflower seed oil. 
     The pharmaceutically active agent, preferably, is insoluble, or only sparingly soluble in pure liquified HFC-134a or HFC-227. Preferably, the solubility of the active agent in liquified HFC-134a or HFC-227 is from 3 to 0.001% w/v, preferably from 1 to 0.01% w/v. However, in certain preferred embodiments, the solubility of the active agent in liquified HFC-134a or HFC-227 is from 3 to 1% w/v. 
     The preferred active agents include: 
     (1) steroid drugs such as, for example, beclomethasone, betamethasone, dexamethasone, fluticasone, hydrocortisone, budesonide, flunisolide, triamcinolone flumethasone, and prednisolone; 
     (2) antibiotic and antibacterial agents such as, for example, neomycin, mupirocin and chlorhexidine; 
     (3) systemically active drugs such as, for example, isosorbide dinitrate, isosorbide mononitrate, apomorphine and nicotine; 
     (4) antihistamines such as, for example, azelastine, chlorpheniramine, astemizole and terfenadine; 
     (5) anti-inflammatory agents such as, for example, piroxicam, nedocromil, cromoglycate, fasafungine and iodoxamide; 
     (6) anticholinergic agents such as, for example, ipratropium bromide and oxitroprium bromide; 
     (7) anti-emetics such as, for example, domperidone, hyoscine, cinnarizine metoclopramide, cyclizine, dimenhydrinate and promethazine; 
     (8) hormonal drugs such as, for example, vasopressin or desmopressin; 
     (9) bronchodilators, such as salbutamol, fenoterol and salmeterol; 
     (10) sympathomimetic drugs, such as tramazoline and xylometazoline; 
     (11) anti-fungal drugs such as miconazole; 
     (12) local anaesthetics such as benzocaine and lignocaine; 
     (13) opiates, preferably for pain management, such as buprenorphine, dextromoramide diamorphine, fentanyl, methadone, morphine, oxycodone, phenazocine, pethidine and combinations thereof with an anti-emetic; 
     (14) analgesics and drugs for treating migraine such as clonidine, codine, coproxamol, dextropropoxypene, ergotamine, sumatriptan, tramadol and non-steroidal anti-flammatory drugs; 
     (15) narcotic agonists and opiate antidotes such as naloxone, and pentazocine; 
     (16) phosphodiesterase type 5 inhibitors, such as sildenafil (viagra); and 
     (17) pharmaceutically acceptable salts of any of the foregoing. 
     Of these, the most preferred pharmaceutically active agent is beclomethasone dipropionate. Beclomethasone dipropionate may be employed in an anhydrous, hydrated or solvated state but, preferably, is employed in an anhydrous state. The preferred propellant is HFC-134a. 
     Preferably, the pharmaceutical composition includes a solution of the pharmaceutically active agent in HFC-134a or HFC-227, with the carrier as a co-solvent. It is further preferred that the co-solvent solubilises the active agent, in the sense that its presence increases the solubility of the active agent in the composition and, thus, causes or allows all or a proportion of the active agent present in the composition to dissolve and/or remain in solution. 
     The pharmaceutical compositions can be partial solutions in which only a proportion of the pharmaceutically active agent present therein is dissolved in the propellant and co-solvent, with the remainder being in suspension or suspendible. The exact proportions of dissolved and suspended active agent will depend upon the active agent concerned, its concentration and the identity and quantity of the co-solvent(s) used. In preferred embodiments the compositions are in the form of liquid solutions when maintained under pressure in devices in accordance with the invention. 
     A particularly preferred embodiment of the invention comprises a device in accordance with the first aspect of the invention filled with a solution of beclomethasone, preferably beclomethasone dipropionate, in ethanol as a co-solvent and HFC-134a as a propellant. 
     Devices and formulations in accordance with the invention can be used to provide sprays suitable for nasal, or sublingual administration, or for inhalation. Preferably, the compositions of this invention are formulated for administration to the nasal passages or the sublingual, mucosa and devices in accordance with the invention are arranged for providing a spray of the inventive composition to either of the latter locations. 
     In embodiments wherein the composition is intended for sublingual administration, it can further comprise a flavoring oil such as, for example peppermint oil Ph Eur. 
     In a second aspect, the invention provides the use of a polyester in contact with a composition of the type present in devices in accordance with the first aspect of the invention. 
     Preferably the polyester is one of those described above, and the use takes place in a metered dose dispensing aerosol device. 
     An embodiment of the first aspect of the present invention will now be described, by way of example only, and with reference to the following drawing. 
    
    
     BRIEF DESCRIPTION OF THE DRAWING 
     FIG. 1 is a cross sectional view of an embodiment of a device in accordance with the invention. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     The device  1  comprises a substantially cylindrical canister  2  sealed with a cap  3 . Both the canister  2  and the cap  3  are formed from an aluminum alloy and can be lined with a polyester (such as Celanex® 2500) or a lacquer (not shown). 
     A valve body moulding  4  comprises a cylindrical portion  5 , which defines a metering chamber  6  and a stepped flange portion  7 , and is formed by injection moulding from Celanex® 2500. The stepped flange portion  7  defines a first and outwardly facing annular seat  8  and a second, inwardly facing annular seat  9 . The first annular seat  8  accommodates an annular sealing ring  10  and the second annular seat  9  accommodates a first sealing washer  11 . The first sealing washer  11  is located so as to cooperate with the cylindrical portion  5  of the valve body moulding  4 , in defining the metering chamber  6 . 
     A base  12  of the cylindrical portion  5  of the valve body moulding  4  completes the boundary to the metering chamber  6  and provides a seat for a second sealing washer  13 . 
     The sealing ring  10  and the first and second sealing washers  11  and  13  can be formed from a butyl rubber, neoprene or one of the elastomers disclosed for such purposes in WO 92/11190. 
     An elongate, substantially cylindrical and partially hollow valve core  14  is slidably located within the first and second sealing washers  11  and  13  and extends through an orifice  15 , defined in the base  12 . The valve core  14  is formed by injection moulding from Celanex® 2500. 
     A stepped inlet passage  16  communicates between a first end  17  of the valve core  14  and an inlet orifice  18 , formed through the side of the valve core  14 . In a likewise manner, an outlet passage  19  communicates between the second end  20  of the valve core  14  and an outlet orifice  21  formed through the side of the valve core  14 . An annular flange  22  extends radially outwardly from the valve core  14  between the inlet and outlet orifices  18  and  21  and adjacent to the outlet orifice  21 . 
     A stainless steel compression coil spring  23  acts between the annular flange  22  and the second sealing washer  13 , urging the annular flange  22  into contact with the first sealing washer  11 , such that the outlet orifice  21  lies inside the first sealing washer  11  and is thereby isolated from the metering chamber  6 . In this position, as shown in FIG. 1, the inlet orifice  18  is located within the metering chamber  6 . A flexible tube  24  is engaged within the stepped inlet passage  16  and extends from the valve core  14  to the base of the canister  2  (as shown in FIG.  1 ). Thus, the inlet orifice  18  is in communication with a region within the canister  2  adjacent to its base  12 . 
     The cap  3  is firmly attached to the canister  2  by crimping and, thus, holds the assembly of the valve body moulding  4 , valve core  14 , coil spring  23 , sealing washers  11  and  13  and sealing ring  10  in place as shown in FIG. 1, with the sealing ring  10  and first sealing washer  11  sufficiently compressed to seal the interior of the device  1  and prevent the egress of its contents. Downward movement of the valve core, in the direction of arrow A, against the action of the spring  22  will bring the outlet orifice  21  into the metering chamber immediately after the first orifice  18  has been sealed from the metering chamber  6  by the second sealing washer  13 . 
     When filled with a composition in accordance with the present invention, as shown at  25 , the device  1  will provide metered doses of the composition when used as follows. The device  1  should be held in the position shown in FIG. 1, so that the composition  25 , by virtue of its pressure, enters the metering chamber  6  via the tube  24 , the inlet passage  16  and the inlet orifice  18 . Subsequent depression of the valve core  14 , in the direction of arrow A, seals the inlet orifice  18  and hence the remainder of the canister  2 , from the metering chamber  6  and opens the outlet passage to the metering chamber  6 , via the outlet orifice  21 . Since the composition  25  in the metering chamber  6  is pressurized with the propellant, it will be expelled from the metering chamber  6  through the outlet orifice  21  and the outlet passage  19 . If the valve core  14  is then allowed to return to the position shown in FIG. 1, under the influence of the spring  22 , the outlet orifice  21  is again sealed from the metering chamber  6  and the metering chamber  6  will be filled with pressurized composition  25  from the canister  2 , via the tube  24 , stepped inlet passage  16  and inlet orifice  18 . 
     EXAMPLE 1 
     A composition comprising beclomethasone dipropionate (BDP) with HFC- 134a suitable for use in a device as described above was formulated from the following ingredients: 
     
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 Component 
                 percent w/w 
                 g/can 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 BDP (anhydrous) 
                 0.164 
                 0.010 
               
               
                   
                 Ethanol 96% BP 
                 4.992 
                 0.305 
               
               
                   
                 HFC-134a 
                 94.844 
                 5.795 
               
               
                   
                 Total 
                 100 
                 6.11 
               
               
                   
                   
               
             
          
         
       
     
     The BDP was dissolved in the ethanol in the proportions set out above and 0.315 g of the resulting solution was then placed in a canister  2  and a valve assembly, comprising a valve body moulding  4 , first sealing washer  11 , second sealing washer  13 , spring  22 , tube  23 , and annular seal  10 , was then sealed onto the canister  2  by crimping as shown in FIG. 1 by the cap  3 . The propellant (HFC-134a) was then added to the canister, by being forced through the valve core  14  at great pressure, and the complete device was then checked for leaks. After the propellant entered the canister it dissolved the remaining portions of the composition. 
     In a preferred embodiment, each expelled dose of the above formulation is of approximately 25 μl and provides 50 μg of BDP. 
     EXAMPLE 2 
     A second composition comprising BDP and suitable for use in a device as described above was formulated from the following ingredients: 
     
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 Component 
                 percent w/w 
                 g/can 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 BDP (anhydrous) 
                 0.164 
                 0.010 
               
               
                   
                 Ethanol 96% BP 
                 7.5 
                 0.458 
               
               
                   
                 HFC-134a 
                 92.336 
                 5.641 
               
               
                   
                 Total 
                 100 
                 6.11 
               
               
                   
                   
               
             
          
         
       
     
     The BDP was dissolved in the ethanol in the proportions set out above and 0.315 g of the resulting solution was then placed in a canister  2 . A valve assembly (as described in Example 1) was than sealed onto the canister  2  by crimping and the HFC-134a propellant was then added to the canister, by being forced through the valve core  14  at great pressure, and the complete device was then checked for leaks. After the propellant entered the canister it dissolved the remaining portions of the composition. 
     In a preferred embodiment, each expelled dose of the above formulation is approximately 25 μl and provides 50 μl of BDP. 
     EXAMPLE 3 
     Further compositions comprising BDP with HFC-134a, suitable for use in a device as described herein, were formulated in accordance with the details set out in the following table, in which all figures are given on a percent by weight basis. 
     
       
         
               
               
               
               
               
               
             
               
               
               
               
               
               
             
           
               
                   
               
               
                 Formulation 
                 A 
                 B 
                 C 
                 D 
                 E 
               
               
                   
               
             
             
               
                   
               
             
          
           
               
                 BDP 
                 0.164 
                 0.164 
                 0.164 
                 0.164 
                 0.164 
               
               
                 Transcatol 
                 9.984 
                 4.992 
                   
                   
                   
               
               
                 Oleyl alcohol 
                   
                   
                 2.496 
                   
                   
               
               
                 Propylene glycol 
                   
                   
                   
                 4.992 
                   
               
               
                 Ethanol 
                   
                 4.992 
                 7.488 
                 4.992 
                 20.51 
               
               
                 p134a 
                 89.852 
                 89.852 
                 89.852 
                 89.852 
                 79.326 
               
               
                 Total 
                 100 
                 100 
                 100 
                 100 
                 100 
               
               
                   
               
             
          
         
       
     
     Formulations A-E are prepared using a similar technique to that set out in Example 1 above. Briefly, the BDP is dissolved with the other excipient or excipients (excepting the HFC-134a) and the resulting solution is then placed in a canister  2 . A valve assembly is then sealed onto the canister  2  by crimping and the HFC-134a propellant is then added to the canister  2 , by being forced through the valve core  14  at great pressure. After the propellant enters the canister  2 , it dissolves the remaining portions of each composition. 
     Although only BDP is referred to in this example, other ones of the active agents previously discussed in this application may be substituted therefor in quantities which would dissolve at least partially in the propellant/co-solvent mixture. 
     EXAMPLES 4-13 
     Eight further compositions suitable for use in a device as described herein, were formulated in accordance with the details set out in the following table. 
     
       
         
               
               
               
               
             
               
               
               
               
             
           
               
                   
                   
               
               
                   
                 Example 
                 Component 
                 Percent w/w 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 EXAMPLE 4 
                 Mupirocin 
                 0.1 
               
               
                   
                   
                 Tween 20 
                 0.1 
               
               
                   
                   
                 Ethanol 
                 20.0 
               
               
                   
                   
                 HFC-134a 
                 79.8 
               
               
                   
                 EXAMPLE 5 
                 Isosorbide Dinitrate 
                 1.0 
               
               
                   
                   
                 Propylene Glycol 
                 3.0 
               
               
                   
                   
                 Peppermint Oil Ph Eur 
                 1.0 
               
               
                   
                   
                 Ethanol 
                 15.0 
               
               
                   
                   
                 HFC-134a 
                 80.0 
               
               
                   
                 EXAMPLE 6 
                 Cromoglycate 
                 0.2 
               
               
                   
                   
                 Span 5 
                 0.1 
               
               
                   
                   
                 Ethanol 
                 20.0 
               
               
                   
                   
                 HFC-134a 
                 79.7 
               
               
                   
                 EXAMPLE 7 
                 Domperidone 
                 0.2 
               
               
                   
                   
                 Oleyl alcohol 
                 0.1 
               
               
                   
                   
                 Transcutol 
                 4.0 
               
               
                   
                   
                 Ethanol 
                 10.0 
               
               
                   
                   
                 HFC-134a 
                 84.7 
               
               
                   
                 EXAMPLE 8 
                 Salbutamol 
                 0.2 
               
               
                   
                   
                 Oleic acid 
                 0.01 
               
               
                   
                   
                 Miglyol 840 
                 2.0 
               
               
                   
                   
                 Ethanol 
                 10.0 
               
               
                   
                   
                 HFC-134a 
                 87.89 
               
               
                   
                 EXAMPLE 9 
                 Xylometazoline 
                 0.1 
               
               
                   
                   
                 Oleic acid 
                 0.01 
               
               
                   
                   
                 Propylene glycol 
                 3.0 
               
               
                   
                   
                 Ethanol 
                 12.0 
               
               
                   
                   
                 HFC-134a 
                 84.89 
               
               
                   
                 EXAMPLE 10 
                 Miconazole 
                 1.0 
               
               
                   
                   
                 Oleic acid 
                 0.1 
               
               
                   
                   
                 Transcutol 
                 4.0 
               
               
                   
                   
                 Ethanol 
                 16.0 
               
               
                   
                   
                 HFC-134a 
                 78.9 
               
               
                   
                 EXAMPLE 11 
                 Benzocaine 
                 1.0 
               
               
                   
                   
                 PEG 400 
                 4.0 
               
               
                   
                   
                 Ethanol 
                 5.0 
               
               
                   
                   
                 HFC-134a 
                 90.0 
               
               
                   
                 EXAMPLE 12 
                 Fentanyl 
                 0.1 
               
               
                   
                   
                 Oleyl alcohol 
                 0.1 
               
               
                   
                   
                 Ethanol 
                 15.0 
               
               
                   
                   
                 HFC-227 
                 20.0 
               
               
                   
                   
                 HFC-134a 
                 64.3 
               
               
                   
                   
                 Peppermint oil 
                 0.5 
               
               
                   
                 EXAMPLE 13 
                 Naloxone 
                 0.1 
               
               
                   
                   
                 Oleic acid 
                 0.1 
               
               
                   
                   
                 Ethanol 
                 15.0 
               
               
                   
                   
                 HFC-227 
                 15.0 
               
               
                   
                   
                 HFC-134a 
                 69.3 
               
               
                   
                   
                 Peppermint oil 
                 0.5 
               
               
                   
                   
               
             
          
         
       
     
     These compositions are prepared using a similar technique to that set out in Examples 1-2. Briefly, the active agent is mixed with the other excipient or excipients (excepting the 1HFC-134a and the HFC-227 if used) and the resulting solution and/or suspension is then placed in a canister  2 . A valve assembly (as described in Example 1) is then sealed onto the canister  2  by crimping and the HFC-134a and HFC-227 (if used) propellant is then added to the canister, by being forced through the valve core  14  at great pressure. After the propellant enters the canister  2 , it at least partially and in some cases completely dissolves the remaining portions of each composition.