Patent Publication Number: US-5290539-A

Title: Device for delivering an aerosol

Description:
This application is a continuation in part of U.S. Ser. No. 07/632,133 filed on Dec. 21, 1990 now abandoned. 
    
    
     TECHNICAL FIELD 
     This invention relates to devices delivering aerosols. In another aspect this invention relates to sealing members. In yet another aspect this invention relates to sealing members for use in devices for delivering aerosols. This invention also relates to thermoplastic polymer blends. 
     DESCRIPTION OF THE RELATED ART 
     The continuing use of aerosol formulations comprising conventional chlorofluorocarbon propellants is being debated due to the suspected role of such propellants in atmospheric depletion of ozone. Accordingly, alternative propellants such as HFC-134a (1,1,1,2-tetrafluoroethane) and HFC-227 (1,1,1,2,3,3,3-heptafluoropropane) are being developed to replace those conventional propellants thought to contribute to atmospheric ozone depletion. 
     Containers for aerosol formulations commonly include a rubber valve seal intended to allow reciprocal movement of the valve stem while preventing leakage of propellant from the container. These rubber valve seals are commonly made of thermoset rubbers such as butyl rubber, butadiene-acrylonitrile rubbers, (&#34;Buna&#34;) and neoprene (polychloroisoprene), which are compounded with vulcanizing agents prior to being fashioned into valve seals. 
     SUMMARY OF THE INVENTION 
     It has been found that some conventional devices for delivering aerosols suffer impaired performance when used in connection with HFC-134a and/or HFC-227.  Accordingly, this invention provides a device for delivering an aerosol, comprising: a valve stem, a diaphragm having walls defining a diaphragm aperture, and a casing member having walls defining a casing aperture, wherein the valve stem passes through the diaphragm aperture and the casing aperture and is in slidable sealing engagement with the diaphragm aperture, and wherein the diaphragm is in sealing engagement with the casing member, the diaphragm material comprising: a thermoplastic elastomer comprising a copolymer of about 80 to about 95 mole percent ethylene and a total of about 5 to about 20 mole percent of one or more comonomers selected from the group consisting of 1-butene, 1-hexene, or 1-octene (i.e., the total amount of comonomer in the copolymer is about 5 mole percent to about 20 mole percent). 
     This invention also provides a metered-dose device for delivering an aerosol that comprises, in addition to the above-discussed valve stem, diaphragm, and casing member, a tank seal having walls defining a tank seal aperture, and a metering tank of a predetermined volume and having an inlet end, an inlet aperture, and an outlet end, wherein the outlet end is in sealing engagement with the diaphragm, the valve stem passes through the inlet aperture and the tank seal aperture and is in slidable engagement with the tank seal aperture, and the tank seal is in sealing engagement with the inlet end of the metering tank, and wherein the valve stem is movable between an extended closed position, in which the inlet end of the metering tank is open and the outlet end is closed, and a compressed open position in which the inlet end of the metering tank is substantially sealed and the outlet end is open to the ambient atmosphere. 
     In a preferred embodiment the casing member defines a formulation chamber, and in a further preferred embodiment the formulation chamber contains an aerosol formulation comprising a propellant, said propellant comprising 1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoropropane, or a mixture thereof. 
     In another aspect, this invention provides an elastomeric sealing member, e.g., for maintaining a desired atmosphere in a sealed chamber or for minimizing and/or preventing escape of propellants, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, from a sealed chamber. Such sealing members can be used as appropriate in connection with static seals or dynamic seals, with pressurized or unpressurized systems, and with liquid or dry systems. The sealing member comprises a thermoplastic elastomer comprising a copolymer of about 80 to about 95 mole percent ethylene and a total of about 5 to about 20 mole percent of one or more comonomers selected from the group consisting of 1-butene, 1-hexene, and 1-octene. In a preferred embodiment the sealing member is used in a dynamic seal in a pressurized system in order to prevent escape of formulation components, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, from a device for delivering an aerosol. 
     This invention also provides thermoplastic polymer blends comprising at least two thermoplastic copolymers, each comprising a copolymer of about 80 to about 95 mole percent ethylene and a total of about 5 to about 20 mole percent of one or more comonomers selected from the group consisting of 1-butene, 1-hexene, and 1-octene. 
     Devices, sealing members, and thermoplastic polymer blends of this invention find use in connection with aerosol formulations involving HFC-134a or HFC-227 as a propellant as well as with formulations containing other propellants such as chlorofluorocarbon propellants. Conventional devices involving thermoset diaphragms of neoprene (polychloroprene), butyl rubber, or butadiene-acrylonitrile &#34;buna&#34; copolymers allow excessive leakage of HFC-134a and HFC-227 from some formulations over time. Particularly in low volume formulations such as pharmaceutical formulations for use in inhalation therapy, this leakage can cause a substantial increase in concentration of the active ingredient in the formulation, resulting in delivery of an improper dose. Furthermore, with some formulations the valve stem tends to stick, pause, or drag during the actuation cycle when neoprene or butadiene-acrylonitrile &#34;buna&#34; diaphragms are used. Leakage and smoothness of operation are improved in the devices of the invention compared to like devices involving the conventional diaphragm materials. Hence this invention is particularly desirable for use with aerosol formulations wherein the propellant comprises HFC-134a, HFC-227, or a mixture thereof. Moreover, the thermoplastic elastomers used in the sealing members of the invention, including the thermoplastic polymer blends of the invention, are not compounded with vulcanizing agents and therefore they are free of complications that might arise from contamination by leaching of such vulcanizing agents. 
    
    
     BRIEF DESCRIPTION OF THE DRAWINGS 
     The drawing is represented by FIGS. 1 and 2. FIG. 1 is a partial cross-sectional view of one embodiment of a device of the invention, wherein the valve stem is in the extended closed position. 
     FIG. 2 is a partial cross-sectional view of the embodiment illustrated in FIG. 1, wherein the valve stem is in the compressed open position. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     Unless otherwise indicated the copolymers described herein are random copolymers, i.e., the respective monomer units are substantially randomly distributed in the copolymer. 
     In order to minimize and/or prevent leakage of refrigerants, propellants, or other formulation components, especially propellants such as 1,1,1,2-tetrafluoroethane and 1,1,1,2,3,3,3-heptafluoropropane, from a sealed chamber, this invention provides thermoplastic elastomeric sealing members comprising a copolymer of about 80 to about 95 mole percent ethylene and a total of about 5 to about 20 mole percent of one or more comonomers selected from the group consisting of 1-butene, 1-hexene, and 1-octene. The thermoplastic elastomer can also contain minor amounts of conventional polymer additives such as processing aids, colorants, lubricants, and talc. 
     Suitable thermoplastic elastomers can be prepared using methods known to those skilled in the art. A preferred thermoplastic elastomer is FLEXOMER™ DFDA 1137 NT7 polyolefin (commercially available from Union Carbide), a thermoplastic elastomer comprising a copolymer of about 91 mole percent ethylene and about 9 mole percent 1-butene. This copolymer is said to have a density of 0.905 g/cm 3  (ASTM D-1505) and a melt index of 1.0 g/10 min (ASTM D-1238). FLEXOMER™ DFDA 1138 NT polyolefin (commercially available from Union Carbide), a thermoplastic elastomer comprising a copolymer of about 91mole percent ethylene and about 9 mole percent 1-butene and having a density of 0.900 g/cm 3  (ASTM D-1505) and a melt index of 0.4 g/10 min (ASTM D-1238) is also suitable. A further suitable thermoplastic elastomer comprises a copolymer of about 88 mole percent ethylene and about 12 mole percent 1-butene. An example of such a thermoplastic elastomer is FLEXOMER™DEFD 8923 NT polyolefin (obtained on an experimental basis from Union Carbide). This elastomer is said to have a density of 0.890 g/cm 3  (ASTM D-1505), and a melt index of 1.0 g/10 min (ASTM D-1238). 
     Other exemplary suitable thermoplastic elastomers include: 
     FLEXOMER™ GERS 1085 NT polyolefin (Union Carbide), comprising a copolymer of about 80 mole percent ethylene and about 20 mole percent 1-butene, having a density of 0.884 g/cm 3  (ASTM D-1505) and a melt index of about 0.8 g/10 min (ASTM D 1238); 
     FLEXOMER™ DFDA 1163 NT7 polyolefin (Union Carbide), comprising a copolymer of about 95 mole percent ethylene, about 1 mole percent 1-butene, and about 4 mole percent 1-hexene, having a density of 0.910 g/cm 3  (ASTM D 1238) and a melt index of about 0.5 g/10 min (ASTM D 1238); 
     FLEXOMER™ DFDA 1164 NT7 polyolefin (Union Carbide), comprising a copolymer of about 94 mole percent ethylene, about 1 mole percent 1-butene, and about 5 mole percent 1-hexene, having a density of about 0.910 g/cm 3  (ASTM D 1505) and a melt index of about 1.0 g/10 min (ASTM D 1238). 
     FLEXOMER™ 1491 NT7 polyolefin (Union Carbide), comprising a copolymer of about 90 mole percent ethylene and about 10 mole percent 1-butene, having a density of 0.900 g/cm 3  (ASTM D 1505) and a melt index of about 1.0 g/10 min (ASTM D 1238); 
     FLEXOMER™ 9020 NT7 polyolefin (Union Carbide), comprising a copolymer of about 92 mole percent ethylene and about 8 mole percent 1-butene, having a density of 0.905 g/cm 3  (ASTM D 1505) and a melt index of about 0.85 g/10 min (ASTM D 1238); 
     FLEXOMER™ 9042 NT polyolefin (Union Carbide), comprising a copolymer of about 80 mole percent ethylene and about 20 mole percent 1-butene, having a density of 0.900 g/cm (ASTM D 1505) and a melt index of about 5.0 g/10 min (ASTM D 1238). 
     ATTANE™ 4602 polyolefin (Dow), comprising a copolymer of about 90 mole percent ethylene and about 10 mole percent 1-octene, having a density of 0.912 g/cm 3  (ASTM D 792) and a melt index of about 3.3 g/10 min (ASTM D 1238); 
     ATTANE™ 4701 polyolefin (Dow), comprising a copolymer of about 92 mole percent ethylene and about 8 mole percent 1-octene, having a density of 0.912 g/cm 3  (ASTM D 792) and a melt index of about 1.0 g/10 min (ASTM D 1238). 
     Blends of two or more of the above-described thermoplastic elastomers in any proportion are also suitable. Preferred thermoplastic polymer blends of the invention include blends of two or more thermoplastic copolymers, each comprising about 80 to 95 mole percent ethylene and about 5 to about 20 mole percent 1-butene. More preferred are blends comprising (i) a copolymer of about 91 mole percent ethylene and about 9 mole percent 1-butene (e.g., FLEXOMER™ DFDA 1137 polyolefin), and (ii) a copolymer of about 80 mole percent ethylene and about 20 mole percent 1-butene (e.g., FLEXOMER™ GERS 1085 NT polyolefin). Blends comprising one part by weight of component (i) and about 0.25 to about 4 parts by weight of component (ii) are particularly preferred, especially for use in a dynamic seal and in a pressurized system, e.g., in a metered-dose inhaler. 
     The polymer blends of the invention can also comprise minor amounts of conventional polymer additives such as processing aids, colorants, lubricants, and talc. 
     As illustrated in the TABLES below, some of the seal materials and sealing members of the invention are superior to others for use in the dynamic seal of a pressurized aerosol container. Those seal materials that are less than optimal for use in the exemplified systems can nonetheless find use, e.g., in connection with a different general type of drug or a different valve stem than exemplified, as a static seal in a pressurized system, or in a non-pressurized system having a dynamic seal. The TABLES below occasionally contain data that appear somewhat inconsistent with other data (e.g., a single very high standard deviation as in TABLE 17). These aberant results are generally attributable to failure of one or two vials in the test group. 
     The device of the invention will be described with reference to the Drawing. FIG. 1 shows device 10 comprising valve stem 12, casing member 14, and diaphragm 16. The casing member has walls defining casing aperture 18, and the diaphragm has walls defining diaphragm aperture 17. The valve stem passes through and is in slidable sealing engagement with the diaphragm aperture. The diaphragm is also in sealing engagement with casing member 14. Diaphragm 16 represents a thermoplastic elastomeric sealing member of the invention. 
     The illustrated embodiment is a device for use with pharmaceutical formulations. The diaphragm in the illustrated embodiment is of a thickness sufficient to form an effective seal with the casing member, preferably about 0.005 inch to about 0.050 inch. It has an outside diameter of about 0.340 inch, and an inside diameter sufficient to form an effective seal with the valve stem. As valve stems having an outside diameter of about 0.110 inch are commonly used, suitable diaphragm inside diameter can be in the range of about 0.080 inch to about 0.105 inch. Diaphragm dimensions suitable for use with other general types of devices can be easily selected by those skilled in the art. 
     Valve stem 12 is in slidable engagement with diaphragm aperture 17. Helical spring 20 holds the valve stem in an extended closed position as illustrated in FIG. 1. Valve stem 12 has walls defining orifice 22 which communicates with exit chamber 24 in the valve stem. The valve stem also has walls defining channel 26. 
     In the illustrated embodiment Casing member 14 comprises mounting cup 28 and canister body 30 and defines formulation chamber 32. The illustrated embodiment further comprises tank seal 34 having walls defining tank seal aperture 35, and metering tank 36 having inlet end 38, inlet aperture 40, and outlet end 42. The metering tank also has walls defining metering chamber 44 of predetermined volume (e.g., 50 μL). Outlet end 42 of metering tank 36 is in sealing engagement with diaphragm 16, and valve stem 12 passes through inlet aperture 40 and is in slidable engagement With tank seal 34. 
     When device 10 is intended for use with a suspension aerosol formulation it further comprises retaining cup 46 fixed to mounting cup 28 and having walls defining retention chamber 48 and aperture 50. When intended for use with a solution aerosol formulation retaining cup 46 is optional. Also illustrated in device 10 is sealing member 52 in the form of an O-ring that substantially seals formulation chamber 32 defined by mounting cup 28 and canister body 30. Sealing member 52 preferably comprises the elastomeric copolymer described above. 
     Operation of device 10 is illustrated in FIGS. 1 and 2. In FIG. 1, the device is in the extended closed position. Aperture 50 allows open communication between retention chamber 48 and formulation chamber 32, thus allowing the aerosol formulation to enter the retention chamber. Channel 26 allows open communication between the retention chamber and metering chamber 44 thus allowing a predetermined amount of aerosol formulation to enter the metering chamber through inlet aperture 40. Diaphragm 16 seals outlet end 42 of the metering tank. 
     FIG. 2 shows device 10 in the compressed open position. As valve stem 12 is depressed channel 26 is moved relative to tank seal 34 such that inlet aperture 40 and tank seal aperture 35 are substantially sealed, thus isolating a metered dose of formulation within metering chamber 44. Further depression of the valve stem causes orifice 22 to pass through aperture 18 and into the metering chamber, whereupon the metered dose is exposed to ambient pressure. Rapid vaporization of the propellant causes the metered dose to be forced through the orifice, and into and through exit chamber 24. Device 10 is commonly used in combination with an actuator that facilitates inhalation of the resulting aerosol by a patient. 
     A particularly preferred device of the invention is a metered dose configuration substantially as described above and illustrated in the Drawing. Other particular configurations, metered dose or otherwise, are well known to those skilled in the art are suitable for use with the sealing members of this invention. For example the devices described in U.S. Pat. Nos. 4,819,834 (Thiel), U.S. Pat. No. 4,407,481 (Bolton), U.S. Pat. No. 3,052,382 (Gawthrop), U.S. Pat. No. 3,049,269 (Gawthrop), U.S. Pat. No. 2,980,301 (DeGorter), U.S. Pat. No. 2,968,427 (Meshberg), U.S. Pat. No. 2,892,576 (Ward), U.S. Pat. No. 2,886,217 (Thiel), and U.S. Pat. No. 2,721,010 (Meshberg) (all incorporated herein by reference) involve a valve stem, a diaphragm, and a casing member in the general relationship described herein. Generally any and all sealing members (such as diaphragms, seals, and gaskets) that serve to minimize and/or prevent escape of components, especially propellant, from such assemblies can comprise the above described thermoplastic elastomer. 
     The devices, sealing members, and polymer blends of the invention can be used in connection with aerosol formulations involving propellants such as fluorotrichloromethane, dichlorodifluoromethane, and 1,2-dichlorotetrafluoroethane. However, this invention finds particular use with aerosol formulations involving a propellant comprising HFC-134a or HFC-227. Any such formulation can be used. Pharmaceutical formulations are preferred. 
     Preferred pharmaceutical formulations generally comprise HFC-134a, HFC-227, or a mixture thereof in an amount effective to function as an aerosol propellant, a drug having local or systemic action and suitable for use by inhalation, and any optional formulation excipients. Exemplary drugs having local effect in the lung include bronchodilators such as albuterol, formoterol, pirbuterol, and salmeterol, and pharmaceutically acceptable salts and derivatives thereof, and steroids such as beclomethasone, fluticasone, and flunisolide, and pharmaceutically acceptable salts, derivatives, solvates, and clathrates thereof. Exemplary drugs having systemic effect include peptides such as insulin, calcitonin, interferons, colony stimulating factors, and growth factors. 
     The drug is present in the formulation in an amount sufficient to provide a predetermined number of therapeutically effective doses by inhalation, which can be easily determined by those skilled in the art considering the particular drug in the formulation. Optional excipients include cosolvents (e.g., ethanol, water) and surfactants (e.g., oleic acid, sorbitan esters, polyoxyethylenes, glycols) and others known to those skilled in the art. 
     A particularly preferred formulation comprises, by weight, 0.40% albuterol sulfate, 0.48% oleic acid, 14.26% absolute ethanol, and 84.86% HFC-134a. Another preferred formulation comprises, by weight, 0.337% beclomethasone dipropionate, 8.0% absolute ethanol, and 91.663% HFC-134a. Yet another preferred formulation comprises, by weight, 0.084% of beclomethasone dipropionate, 8.0% absolute ethanol, and 91.916% HFC-134a. 
     BLEND PREPARATION 
     Polymer blends of the invention, from which sealing members of the invention can be made, can be prepared by conventional polymer blending techniques well known to those skilled in the art. Those blends exemplified herein were prepared as follows: 
     Small Scale Compounding 
     Selected quantities of the blend components are added to a heated 100 mL bowl in a BRABENDER™ laboratory mixer equipped with high shear mixing shafts. The components are mixed under temperature, speed, and time conditions selected according to the characteristics of the components of the blend. After mixing the mixing head is operated in reverse in order to expel the hot, mixed blend, which is compression molded as described below. 
     Large Scale Compounding 
     Selected quantities of the blend components are fed at room temperature into a APV Model 2030 TC twin screw extruder via feeders that are calibrated to match the extrusion rate. 
     Screw speed and extruder temperature are selected according to the characteristics of the components of the blend. The melt is extruded through a 0.63 cm (0.25 inch) strand dye having two strand openings. The strands are fed through a water bath, dried, and pelletized with a BERLYN™ Model Pe 112 chopper. The pellets are dried in trays for 1-3 days at about 50° C. and extruded into a sheet as described below. 
     DIAPHRAGM PREPARATION 
     Diaphragms of the invention can be prepared by conventional techniques known to those skilled in the art, such as compression molding, extrusion, and injection molding. Those diaphragms exemplified herein were prepared according to the general methods set forth below: 
     Compression Molding 
     An amount of a selected elastomer sufficient to provide a compression molded sheet of the desired thickness is compression molded between appropriately spaced aluminum press plates in a CARVER™ Laboratory Press Model 2696 (Fred S. Carver, Inc., Menomonie Falls, Wis.) at elevated temperature (e.g., about 150° C.) and pressure (e.g., 170 kPa) and for a time sufficient to form a molded sheet. The press is then cooled until the mold plates can be handled. The compression molded sheet is removed from the mold and hand punched with a die of the desired size to afford a diaphragm of the invention. 
     Extrusion 
     A sample of a selected elastomer is fed into the feed throat of a Haake RHEOCORT™ single-screw extruder fitted with a Haake RHEOMIX™ three-zone extruder head and equipped with a 1.9 cm (0.75 inch) diameter screw having a 3:1 pitch and a length to diameter ratio of 25:1. Appropriate screw speed and operating temperatures are selected according to the characteristics of the selected elastomer. The melt is extruded through a flat film die, fitted with a shim to provide the desire opening, and over a cooled chrome roller. The thickness of the resulting sheet is controlled by appropriate adjustment of screw speed and speed of the cooled roller. Diaphragms of the invention were hand cut from the sheet with a die of appropriate size. 
     Injection Molding 
     The selected elastomer is fed into the feed throat of a Van Dorn 75 ton injection molding machine equipped with a 5 ounce barrel. Operating conditions are selected according to the characteristics of the selected elastomer. The melt is injected into a mold having cavity dimensions appropriate to provide the desired sealing member. Cooling and opening of the mold affords the sealing member. 
     TEST METHODS 
     Sealing members were tested as follows: 
     Leak Rate 
     Aerosol canister bodies (10 mL) are filled with an aerosol formulation and fitted with a metered dose valve substantially as described and illustrated above and comprising a diaphragm of a selected size and material. The valve is actuated several times in order to assure its function. The mass of the filled device is measured. The filled device is allowed to stand in an upright position under the indicated conditions (30° C. unless otherwise indicated) for a period of time, after which time mass is again measured. The loss of mass over time is extrapolated to one year and reported in mg/year. 
     Valve Delivery 
     The mass of a filled device is measured. The device is then inverted and actuated one time. Mass is again determined and the valve delivery is recorded as the difference. 
     The formulations used in the TABLES below in order to demonstrate the invention are as follows, wherein all parts and percentages are by weight: 
     
         __________________________________________________________________________
       Albuterol                                                          
             Beclomethasone          HFC 134a                             
Formulation                                                               
       Sulfate (%)                                                        
             Dipropionate (%)                                             
                      Oleic Acid (%)                                      
                              Ethanol (%)                                 
                                     (%)                                  
__________________________________________________________________________
A1     0.5   --       0.1     15     84.4                                 
A2      0.47 --        0.097  14.24  85.2                                 
A3     0.4   --       0.5     15     84.1                                 
A4     0.8   --       0.5     15     83.7                                 
A5     1.2   --       0.5     15     83.3                                 
A6     0.8   --       0.5     14.9   83.8                                 
B1     --    0.164    --      5.87   93.96                                
B2     --    0.166    --      6.04   93.78                                
B3     --    0.44     --      15     84.56                                
D      --    --       0.5     15.0   84.5                                 
       Pirbuterol                    HFC-227                              
       Acetate                                                            
P       0.89 --       --      10.0   89.11                                
       Albuterol                     HFC-227                              
       Sulfate                                                            
A7     0.4   --       --             99.6                                 
__________________________________________________________________________
 
    
     Diaphragms of FLEXOMER™DEFD 8923 NT polyolefin were incorporated in a device substantially as described and illustrated above, and tested alongside devices comprising a neoprene diaphragm or a butadieneacrylonitrile &#34;buna&#34; resin diaphragm. Results are shown in TABLE 1 below wherein &#34;RH&#34; designates relative humidity. 
     
                                           TABLE 1                                 
__________________________________________________________________________
LEAK RATE AND VALVE DELIVERY                                              
Diaphragm     Storage                                                     
                    Time     Leak Rate                                    
                                   Valve Delivery                         
Material.sup.1                                                            
       Formulation                                                        
              Condition                                                   
                    (Weeks)                                               
                         N.sup.2                                          
                             (mg/yr)                                      
                                   (mg/actuation)                         
__________________________________________________________________________
Buna   A5     30° C.                                               
                    0    25/15                                            
                             --    46.46 ± 8.52                        
                    4    &#34;   451 ± 71                                  
                                   48.90 ± 1.11                        
                    12   &#34;   526 ± 76                                  
                                   49.64 ± 0.71                        
Neoprene                                                                  
       A5     30° C.                                               
                    0    25/15                                            
                             --    55.61 ± 0.69                        
                    4    &#34;   331 ± 54                                  
                                   55.31 ± 0.69                        
                    12   &#34;   395 ± 55                                  
                                   54.91 ± 0.92                        
DEFD   A6     30° C.                                               
                    0    24/24                                            
                             --    55.05 ± 1.64                        
8923 NT             1    &#34;    99 ± 17                                  
                                   55.09 ± 0.85                        
                    2    &#34;   135 ± 14                                  
                                   55.02 ± 1.50                        
                    4    &#34;   185 ± 11                                  
                                   54.28 ± 1.29                        
DEFD   A6     40° C.                                               
                    0    24/24                                            
                             --    54.07 ± 3.48                        
8923 NT       85% RH                                                      
                    1    &#34;   192 ± 17                                  
                                   54.20 ± 2.92                        
                    2    &#34;   288 ± 13                                  
                                   55.32 ± 1.03                        
                    4    &#34;   384 ± 12                                  
                                   54.54 ± 2.47                        
DEFD   B3     30° C.                                               
                    0    24/24                                            
                             --    57.39 ± 1.15                        
8923 NT             1    &#34;   108 ± 15                                  
                                   57.31 ± 0.79                        
                    2    &#34;   160 ± 13                                  
                                   57.08 ± 1.08                        
                    4    &#34;   223 ± 12                                  
                                   57.20 ± 0.89                        
DEFD   B3     40° C.                                               
                    0    24/24                                            
                             --    57.43 ± 1.03                        
8923 NT       85% RH                                                      
                    1    &#34;   286 ± 39                                  
                                   58.09 ± 2.52                        
                    2    &#34;   392 ± 34                                  
                                   58.78 ± 2.66                        
                    4    &#34;   491 ± 31                                  
                                   59.64 ± 3.40                        
__________________________________________________________________________
 .sup.1 Buna and neoprene diaphragms from American Gasket and Rubber,     
 Chicago, Illinois. &#34;DEFD 8923 NT&#34; designates FLEXOMER ™ DEFD 8923NT   
 polyolefin. All DEFD 8923 NT diaphragms were 0.035 inch thick with 0.095 
 inch inside diameter and 0.34 inch outside diameter. The buna and neopren
 diaphragms were 0.038 inch thick with a 0.093 inch inside diameter and a 
 0.340 inch outside diameter. The valve stem had a 0.110 inch outside     
 diameter.                                                                
 .sup.2 N is the number of vials per group. The first number of the pair i
 the number of valves whose individual measurements were averaged to give 
 the reported leak rate. The second number of the pair is the number of   
 individual measurements which were averaged to give the reported valve   
 delivery.                                                                
 
    
     The results in TABLE 1 show that, with the designated formulations using HFC-134a as the propellant, leak rates are substantially lower in the devices comprising the diaphragm of the invention than in the devices comprising diaphragms of materials that are commonly used in commercially available metered dose aerosol devices. Only under conditions of thermal stress (40° C., 85% RH) did the devices of the invention have leak rates comparable to those of the comparative devices tested at 30° C. Furthermore, valve delivery is more precise and more constant over time with devices of the invention than in the comparative devices of the prior art. Moreover, while the valves in the comparative devices often stuck, paused, or dragged during actuation, the valves in the devices of the invention generally exhibited smooth operation over the duration of the study. 
     Diaphragms of the invention of the specified composition and having a thickness of 0.035 inch, an outside diameter of 0.34 inch, and various inside diameters were tested with HFC-134a alone and with a model formulation (containing HFC-134a, ethanol, and a surfactant) in devices having either stainless steel (&#34;ss&#34;) or DELRIN™ acetal resin (DuPont, &#34;plastic&#34;) valve stems having a diameter of 0.110 inch. Results are shown in 
     TABLE 2 (FLEXOMER™ DEFD 8923 NT polyolefin), TABLE 3 (FLEXOMER™ DFDA 1137 polyolefin), and TABLE 4 (FLEXOMER™ DFDA 1138 polyolefin) below, wherein each entry represents the mean of seven independent determinations. 
     
                                           TABLE 2                                 
__________________________________________________________________________
LEAK RATE AND VALVE DELIVERY WITH STAINLESS STEEL                         
AND PLASTIC VALVE STEMS USING FLEXOMER ™ 8923 NT                       
POLYOLEFIN DIAPHRAGMS HAVING VARIOUS INSIDE DIAMETERS                     
               Time Leak Rate                                             
                            Valve Delivery                                
Formulation                                                               
       ID (in)                                                            
           Stem                                                           
               (Weeks)                                                    
                    (mg/yr) ± SD                                       
                            (mg/actuation) ± SD                        
__________________________________________________________________________
134a   0.080                                                              
           ss  0    --       86.90 ± 94.55                             
               5     34 ± 25                                           
                            64.30 ± 1.30                               
           plastic                                                        
               0    --      61.86 ± 2.80                               
               5     26 ± 12                                           
                            63.50 ± 0.62                               
134a   0.085                                                              
           ss  0    --      64.87 ± 7.61                               
               5     30 ± 17                                           
                            61.34 ± 6.19                               
           plastic                                                        
               0    --      63.29 ± 0.60                               
               5     26 ± 13                                           
                            63.27 ± 0.40                               
134a   0.090                                                              
           ss  0    --      64.44 ± 1.55                               
               5    26 ± 3                                             
                            65.76 ± 2.30                               
           plastic                                                        
               0    --      63.63 ± 0.83                               
               5     40 ± 27                                           
                            63.17 ±  0.72                              
134a   0.095                                                              
           ss  0    --      66.66 ± 1.11                               
               5    25 ± 2                                             
                            68.03 ± 1.33                               
           plastic                                                        
               0    --      64.61 ± 0.98                               
               5    24 ± 3                                             
                            64.63 ± 1.11                               
134a   0.100                                                              
           ss  0    --       58.79 ± 19.27                             
               5    27 ± 4                                             
                            67.27 ± 0.99                               
           plastic                                                        
               0    --      65.07 ± 0.49                               
               5     33 ± 22                                           
                            65.13 ± 0.73                               
134a   0.105                                                              
           ss  0    --      65.34 ± 1.80                               
               5    26 ± 2                                             
                            66.84 ± 0.81                               
           plastic                                                        
               0    --      65.13 ± 0.79                               
               5    27 ± 4                                             
                            65.14 ± 1.85                               
D      0.080                                                              
           ss  0    --      61.26 ± 1.33                               
               5    147 ± 13                                           
                            61.61 ± 1.26                               
           plastic                                                        
               0    --      60.46 ± 0.80                               
               5    143 ± 14                                           
                            59.73 ± 0.73                               
D      0.085                                                              
           ss  0    --      62.43 ± 1.00                               
               5    140 ± 19                                           
                            62.71 ± 1.11                               
           plastic                                                        
               0    --      61.21 ± 0.75                               
               5    138 ± 6                                            
                            60.46 ± 0.74                               
D      0.090                                                              
           ss  0    --      61.81 ± 0.83                               
               5    149 ± 20                                           
                            62.07 ± 0.87                               
           plastic                                                        
               0    --      61.23 ± 0.56                               
               5    140 ± 12                                           
                            60.61 ± 0.41                               
D      0.095                                                              
           ss  0    --      63.24 ± 0.73                               
               5    154 ±  8                                           
                            63,79 ± 0.81                               
           plastic                                                        
               0    --      62.26 ± 0.59                               
               5    165 ± 12                                           
                            62.07 ± 0.49                               
D      0.100                                                              
           ss  0    --      62.99 ± 0.94                               
               5    150 ± 10                                           
                            63.61 ± 0.97                               
           plastic                                                        
               0    --      62.21 ± 1.03                               
               5    167 ± 14                                           
                            62.39 ± 0.67                               
D      0.105                                                              
           ss  0    --      63.79 ± 0.66                               
               5    163 ±  7                                           
                            64.69 ± 0.64                               
           plastic                                                        
               0    --      61.66 ± 1.82                               
               5    171 ±  9                                           
                            61.77 ±  1.03                              
__________________________________________________________________________
 
    
     
                                           TABLE 3                                 
__________________________________________________________________________
LEAK RATE AND VALVE DELIVERY WITH STAINLESS STEEL                         
AND PLASTIC VALVE STEMS USING FLEXOMER ™ 1137                          
POLYOLEFIN DIAPHRAGMS HAVING VARIOUS INSIDE DIAMETERS                     
               Time Leak Rate                                             
                            Valve Delivery                                
Formulation                                                               
       ID (in)                                                            
           Stem                                                           
               (Weeks)                                                    
                    (mg/yr) ± SD                                       
                            (mg/actuation) ± SD                        
__________________________________________________________________________
134a   0.080                                                              
           ss  0    --      63.77 ± 9.37                               
               5    28.4 ± 3.4                                         
                            67.14 ± 0.83                               
           plastic                                                        
               0    --      62.73 ± 3.40                               
               5    28.6 ± 6.7                                         
                            61.91 ± 3.21                               
134a   0.085                                                              
           ss  0    --       67.57 ± 17.25                             
               5    30.7 ± 6.8                                         
                            67.77 ± 3.59                               
           plastic                                                        
               0    --      61.41 ± 4.20                               
               5    29.6 ± 11.0                                        
                            60.90 ± 7.20                               
134a   0.090                                                              
           ss  0    --       58.90 ± 19.00                             
               5    34.6 ± 6.7                                         
                            66.80 ± 0.88                               
           plastic                                                        
               0    --      62.07 ± 3.78                               
               5    27.7 ±  4.2                                        
                            61.23 ± 6.49                               
134a   0.095                                                              
           ss  0    --       59.83 ± 15.34                             
               5    25.9 ± 5.9                                         
                            66.67 ± 0.67                               
           plastic                                                        
               0    --      65.01 ± 0.95                               
               5    32.8 ± 18.5                                        
                            65.16 ± 0.72                               
134a   0.100                                                              
           ss  0    --      66.69 ± 0.57                               
               5    30.6 ± 3.6                                         
                            67.14 ± 0.76                               
           plastic                                                        
               0    --      64.36 ± 2.31                               
               5    30.7 ± 6.9                                         
                            65.74 ± 1.01                               
143a   0.105                                                              
           ss  0    --       56.66 ± 14.38                             
               5    39.0 ± 11.4                                        
                            67.81 ± 3.58                               
           plastic                                                        
               0    --      62.77 ± 3.25                               
               5    39.8 ± 16.6                                        
                            65.41 ± 1.83                               
D      0.080                                                              
           ss  0    --      59.34 ± 4.75                               
               5    163 ± 30.8                                         
                            62.84 ± 0.53                               
           plastic                                                        
               0    --      56.31 ± 5.38                               
               5    197 ± 34.1                                         
                            61.04 ± 0.26                               
D      0.085                                                              
           ss  0    --      61.83 ± 1.64                               
               5    179 ± 61.8                                         
                            63.13 ± 0.87                               
           plastic                                                        
               0    --      59.59 ± 2.41                               
               5    156 ± 16.4                                         
                            60.74 ± 0.37                               
D      0.090                                                              
           ss  0    --      60.83 ± 2.39                               
               5    169 ± 40.8                                         
                            61.90 ± 2.31                               
           plastic                                                        
               0    --      59.04 ± 1.31                               
               5    225 ± 31.0                                         
                            60.10 ± 2.66                               
D      0.095                                                              
           ss  0    --      59.59 ± 4.07                               
               5    210 ± 53.0                                         
                            60.00 ± 3.66                               
           plastic                                                        
               0    --      54.99 ± 5.41                               
               5    243 ± 35.9                                         
                            56.20 ± 1.58                               
D      0.100                                                              
           ss  0    --      61.49 ± 1.37                               
               5    187 ± 12.9                                         
                            61.41 ± 1.25                               
           plastic                                                        
               0    --      54.89 ± 3.36                               
               5    282 ± 118                                          
                            56.14 ± 1.95                               
D      0.105                                                              
           ss  0    --      50.81 ± 5.07                               
               5    200 ± 11.9                                         
                            53.00 ± 3.28                               
           plastic                                                        
               0    --      48.43 ± 2.57                               
               5    232 ± 30.8                                         
                            48.51 ± 1.02                               
__________________________________________________________________________
 
    
     
                                           TABLE 4                                 
__________________________________________________________________________
LEAK RATE AND VALVE DELIVERY WITH STAINLESS STEEL                         
AND PLASTIC VALVE STEMS USING FLEXOMER ™ 1138                          
POLYOLEFIN DIAPHRAGMS HAVING VARIOUS INSIDE DIAMETERS                     
               Time Leak Rate                                             
                            Valve Delivery                                
Formulation                                                               
       ID (in)                                                            
           Stem                                                           
               (Weeks)                                                    
                    (mg/yr) ± SD                                       
                            (mg/actuation) ± SD                        
__________________________________________________________________________
134a   0.080                                                              
           ss  0    --       66.17 ± 56.10                             
               5    16.4 ± 2.51                                        
                             63.03 ± 20.22                             
           plastic                                                        
               0    --      62.27 ± 6.85                               
               5    14.9 ± 1.8                                         
                            64.89 ± 1.30                               
134a   0.085                                                              
           ss  0    --       59.77 ± 18.00                             
               5    36.8 ± 44.4                                        
                             64.77 ± 17.07                             
           plastic                                                        
               0    --       69.40 ± 15.00                             
               5    15.0 ± 3.9                                         
                            65.26 ± 1.07                               
134a   0.090                                                              
           ss  0    --       52.64 ± 18.28                             
               5    45.7 ± 43.5                                        
                            68.67 ± 2.12                               
           plastic                                                        
               0    --       57.86 ± 15.78                             
               5    14.8 ± 3.6                                         
                            70.34 ± 8.47                               
134a   0.095                                                              
           ss  0    --       57.57 ± 17.59                             
               5    22.5 ± 7.3                                         
                            68.43 ± 1.07                               
           plastic                                                        
               0    --      64.84 ± 1.69                               
               5    14.5 ± 3.4                                         
                            65.97 ± 2.67                               
134a   0.100                                                              
           ss  0    --       59.70 ± 20.32                             
               5    20.3 ± 7.3                                         
                            67.59 ± 1.95                               
           plastic                                                        
               0    --      64.79 ± 0.61                               
               5    21.1 ± 18.8                                        
                            65.53 ± 0.72                               
134a   0.105                                                              
           ss  0    --      65.64 ± 0.90                               
               5    23.7 ± 3.0                                         
                            67.34 ± 0.80                               
           plastic                                                        
               0    --      65.11 ± 1.67                               
               5    17.4 ± 3.4                                         
                            68.56 ± 3.86                               
D      0.080                                                              
           ss  0    --      60.23 ± 0.57                               
               5    187 ± 14.3                                         
                            60.90 ± 0.63                               
           plastic                                                        
               0    --      58.41 ± 0.52                               
               5    204 ± 6.2                                          
                             50.16 ±  22.12                            
D      0.085                                                              
           ss  0    --      60.74 ± 1.12                               
               5    178 ± 5.4                                          
                            61.30 ± 0.92                               
           plastic                                                        
               0    --      58.43 ± 0.45                               
               5    220 ± 30.4                                         
                            59.04 ± 2.10                               
D      0.090                                                              
           ss  0    --      60.11 ± 1.36                               
               5    237 ± 42.8                                         
                            61.04 ± 1.39                               
           plastic                                                        
               0    --      56.87 ± 0.79                               
               5    258 ± 24.5                                         
                            56.36 ± 1.01                               
D      0.095                                                              
           ss  0    --      58.37 ± 5.54                               
               5    252 ± 40.8                                         
                            60.69 ± 1.98                               
           plastic                                                        
               0    --      52.76 ± 6.49                               
               5    270 ± 21.6                                         
                            55.26 ± 1.52                               
D      0.100                                                              
           ss  0    --      58.66 ± 0.45                               
               5    217 ± 13.3                                         
                            58.60 ± 0.60                               
           plastic                                                        
               0    --      56.97 ± 1.37                               
               5    288 ± 74.6                                         
                            56.66 ± 1.87                               
D      0.105                                                              
           ss  0    --      58.31 ± 0.85                               
               5    243 ± 16.3                                         
                            58.51 ±  0.85                              
           plastic                                                        
               0    --      57.40 ± 0.98                               
               5    251 ± 11.0                                         
                            56.61 ± 0.52                               
__________________________________________________________________________
 
    
     The results in TABLES 2, 3, and 4 show that diaphragms of the invention having various inside diameters afford low leak rates and reproducible valve delivery with stainless steel (&#34;ss&#34;) and DELRIN™ acetal resin (&#34;plastic&#34;) valve stems when used with the designated formulations. Leak rate results with the ethanol-containing formulation, while not as low as with only HFC-134a, compare favorably to the data in TABLE 1 involving buna and neoprene diaphragms. Furthermore, the valves in the devices of the invention generally exhibited smooth operation over the duration of the study. 
     Diaphragms of the invention prepared from FLEXOMER™DEFD 8923 NT polyolefin and having an inside diameter of 0.090 inch and various specified thicknesses were tested with HFC-134a alone or with a model formulation (containing HFC-134a, ethanol, and a surfactant) in devices comprising either stainless steel (&#34;ss&#34;) or DELRIN™ acetal resin (&#34;plastic&#34;) valve stems. Results are shown in TABLE 5 below, wherein each entry represents the mean of 7 independent determinations. 
     
                       TABLE 5                                                     
______________________________________                                    
LEAK RATE USING FLEXOMER ™ 8923 NT                                     
POLYOLEFIN DIAPHRAGMS                                                     
OF VARIOUS THICKNESSES                                                    
         Thickness          Time   Leak Rate                              
Formulation                                                               
         (in)      Stem     (Weeks)                                       
                                   (mg/yr) ± SD                        
______________________________________                                    
134a     0.038     ss       0      --                                     
                            5      25.8 ± 4.0                          
                   plastic  0      --                                     
                            5      24.6 ± 3.9                          
134a     0.035     ss       0      --                                     
                            5      27.3 ± 4.3                          
                   plastic  0      --                                     
                            5       48.5 ± 66.0                        
134a     0.029     ss       0      --                                     
                            5      24.5 ± 2.0                          
                   plastic  0      --                                     
                            5      22.2 ± 3.5                          
134a     0.025     ss       0      --                                     
                            5      24.5 ± 6.5                          
                   plastic  0      --                                     
                            5      24.5 ± 11                           
134a     0.020     ss       0      --                                     
                            5      21.9 ± 2.5                          
                   plastic  0      --                                     
                            5      20.0 ± 1.6                          
134a     0.015     ss       0      --                                     
                            5      22.2 ±  2.6                         
                   plastic  0      --                                     
                            5      50.0 ± 2.6                          
134a     0.010     ss       0      --                                     
                            5       46.7 ± 38.7                        
                   plastic  0      --                                     
                            5      16.5 ± 2.3                          
D        0.038     ss       0      --                                     
                            5      200 ± 17                            
                   plastic  0      --                                     
                            5      217 ± 14                            
D        0.035     ss       0      --                                     
                            5       185 ± 8.7                          
                   plastic  0      --                                     
                            5      209 ± 12                            
D        0.029     ss       0      --                                     
                            5       182 ± 2.5                          
                   plastic  0      --                                     
                            5      201 ± 12                            
D        0.025     ss       0      --                                     
                            5       176 ± 6.4                          
                   plastic  0      --                                     
                            5       210 ± 4.8                          
D        0.020     ss       0      --                                     
                            5       190 ± 6.5                          
                   plastic  0      --                                     
                            5       207 ± 7.4                          
D        0.015     ss       0      --                                     
                            5       182 ± 7.8                          
                   plastic  0      --                                     
                            5       196 ± 6.4                          
D        0.010     ss       0      --                                     
                            5       180 ± 5.4                          
                   plastic  0      --                                     
                            5      201 ± 20                            
______________________________________                                    
 
    
     The results in TABLE 5 show that with the designated formulations leak rate is lower in devices comprising a diaphragm of the invention than in devices such as those tested in connection with TABLE 1 above comprising a buna or neoprene diaphragm. TABLE 5 also shows that relatively thin diaphragms can be used with little or no loss of performance. 
     In the TABLES that follow, the inside diameter of the diaphragms (ID) is given in thousandths of an inch, &#34;pl&#34; represents a valve stem made of DELRIN™ acetal resin (DuPont) having a diameter of 0.110 inch, and &#34;N&#34; refers to the number of independent determinations used in calculating the leak rate and valve delivery values. 
     Diaphragms of the invention were prepared by compression molding, injection molding, and extrusion from FLEXOMER™ GERS 1085 NT polyolefin and tested with the formulations indicated in TABLES 6-8 below. 
     
                       TABLE 6                                                     
______________________________________                                    
COMPRESSION MOLDED FLEXOMER ™                                          
GERS 1085 NT POLYOLEFIN                                                   
                                Leak                                      
Formu-               Time       Rate   Valve Delivery                     
lation ID     Stem   (Weeks)                                              
                            N   (mg/yr)                                   
                                       (mg/actuation)                     
______________________________________                                    
A1     80     ss     0      14  --     56.81 ± 0.74                    
                     6          243 ± 10                               
                                       57.18 ± 0.82                    
       85     ss     0      14  --     55.94 ± 3.64                    
                     6          247 ± 10                               
                                       58.74 ± 1.26                    
       90     ss     0      14  --     58.09 ± 6.45                    
                     6          240 ± 9                                
                                       59.74 ± 2.92                    
       95     ss     0      14  --     58.40 ± 0.95                    
                     6          231 ± 12                               
                                       59.33 ± 1.44                    
       100    ss     0      14  --     58.41 ± 1.46                    
                     6          227 ± 8                                
                                       60.40 ± 2.78                    
       105    ss     0      14  --     55.94 ± 7.25                    
                     6          224 ± 8                                
                                       62.52 ± 3.77                    
       80     pl     0      14  --     55.91 ± 1.48                    
                     6          270 ± 6                                
                                       55.62 ± 0.68                    
       85     pl     0      14  --     54.22 ± 4.63                    
                     6          270 ± 11                               
                                       56.71 ± 2.22                    
       90     pl     0      14  --     57.42 ± 4.56                    
                     6          265 ± 16                               
                                       58.67 ± 2.13                    
       95     pl     0      14  --     56.10 ± 4.14                    
                     6          260 ± 8                                
                                       58.67 ± 1.72                    
       100    pl     0      14  --     58.73 ± 3.30                    
                     6          256 ± 14                               
                                       60.96 ± 3.72                    
       105    pl     0      14  --     57.96 ± 3.17                    
                     6          243 ± 11                               
                                       61.50 ± 1.35                    
______________________________________                                    
 
    
     
                       TABLE 7                                                     
______________________________________                                    
INJECTION MOLDED FLEXOMER ™                                            
GERS 1085 NT POLYOLEFIN                                                   
Formu-              Time       Leak Rate                                  
                                       Valve Delivery                     
lation ID    Stem   (Weeks)                                               
                           N   (mg/yr) (mg/actuation)                     
______________________________________                                    
A1     84    ss     0      10  --      57.70 ± 1.06                    
                    6          263 ± 8                                 
                                       59.17 ± 1.12                    
       88    ss     0      10  --      56.51 ± 2.98                    
                    6          275 ± 10                                
                                       60.21 ± 2.34                    
       94    ss     0      10  --      58.87 ± 1.85                    
                    6          286 ± 12                                
                                       58.70 ± 0.64                    
       99    ss     0      10  --      58.12 ± 0.54                    
                    6          269 ± 11                                
                                       59.48 ± 2.75                    
       84    pl     0      10  --      55.49 ± 2.52                    
                    6          267 ± 9                                 
                                       55.92 ± 1.81                    
       88    pl     0      10  --      56.33 ± 0.34                    
                    6          284 ± 11                                
                                       56.56 ± 0.24                    
       94    pl     0      10  --      56.21 ±  1.23                   
                    6          286 ± 10                                
                                       56.72 ± 0.42                    
       99    pl     0      10  --      55.35 ± 2.74                    
                    6          282 ± 11                                
                                       56.54 ± 0.99                    
B1     84    ss     0      10  --      62.18 ± 0.92                    
                    6          231 ± 16                                
                                       63.24 ± 1.26                    
       88    ss     0      10  --      61.93 ± 0.50                    
                    6          232 ± 11                                
                                       64.20 ± 3.20                    
       94    ss     0      10  --      62.45 ± 0.79                    
                    6          243 ± 11                                
                                       63.78 ± 1.47                    
       99    ss     0      10  --      63.40 ± 2.61                    
                    6          240 ± 10                                
                                       63.56 ± 1.92                    
B1     84    pl     0      10  --      60.47 ± 0.42                    
                    6          256 ± 13                                
                                       60.37 ± 0.53                    
       88    pl     0      10  --      60.29 ± 0.78                    
                    6          246 ± 10                                
                                       60.57 ± 0.45                    
       94    pl     0      10  --      60.75 ± 0.96                    
                    6          251 ± 10                                
                                       60.73 ± 0.64                    
       99    pl     0      10  --      59.43 ± 3.11                    
                    6          264 ± 22                                
                                       60.46 ± 0.45                    
______________________________________                                    
 
    
     
                       TABLE 8                                                     
______________________________________                                    
EXTRUDED FLEXOMER ™                                                    
GERS 1085 NT POLYOLEFIN                                                   
                                Leak                                      
Formu-               Time       Rate   Valve Delivery                     
lation ID     Stem   (Weeks)                                              
                            N   (mg/yr)                                   
                                       (mg/actuation)                     
______________________________________                                    
A2     80     ss     0      10  --     58.26 ± 2.17                    
                     6          279 ± 9                                
                                       57.76 ± 0.96                    
       85     ss     0      10  --     57.49 ± 2.23                    
                     6          274 ± 15                               
                                       57.99 ± 2.24                    
       90     ss     0      10  --     58.66 ± 1.91                    
                     6          274 ± 15                               
                                       58.01 ± 0.66                    
       95     ss     0      10  --     57.29 ± 2.97                    
                     6          282 ± 18                               
                                       58.30 ± 1.11                    
       100    ss     0      10  --     58.49 ± 1.64                    
                     6          284 ± 18                               
                                       58.16 ± 0.77                    
       105    ss     0      10  --     57.97 ± 1.40                    
                     6          307 ± 11                               
                                       57.99 ± 1.10                    
       80     pl     0      10  --     55.91 ± 0.69                    
                     6          270 ± 14                               
                                       55.50 ± 0.66                    
       85     pl     0      10  --     55.18 ± 1.41                    
                     6          275 ± 8                                
                                       55.25 ± 0.48                    
       90     pl     0      10  --     56.38 ± 0.66                    
                     6          277 ± 12                               
                                       55.54 ± 0.53                    
       95     pl     0      10  --     56.68 ± 0.71                    
                     6          284 ± 14                               
                                       55.67 ± 0.58                    
       100    pl     0      10  --     56.37 ± 0.70                    
                     6          282 ± 13                               
                                       55.41 ± 0.51                    
       105    pl     0      10  --     56.38 ± 0.65                    
                     6          318 ± 25                               
                                       55.56 ± 0.64                    
A3     80     ss     0      10  --     58.35 ± 0.74                    
                     6          232 ± 18                               
                                       not measured                       
       85     ss     0      10  --     58.35 ± 1.00                    
                     6          233 ± 20                               
                                       57.96 ± 0.92                    
       90     ss     0      10  --     57.60 ±  2.61                   
                     6          247 ± 62                               
                                       57.85 ± 0.87                    
       95     ss     0      10  --     58.82 ± 0.73                    
                     6          226 ± 22                               
                                       58.41 ± 0.74                    
       100    ss     0      10  --     58.97 ± 0.83                    
                     6          231 ± 23                               
                                       58.59 ± 0.65                    
       105    ss     0      10  --     58.87 ± 1.02                    
                     6          253 ± 22                               
                                       not measured                       
       80     pl     0      10  --     55.98 ± 0.55                    
                     6          236 ± 13                               
                                       54.97 ± 0.35                    
       85     pl     0      10  --     56.17 ± 0.50                    
                     6          239 ± 15                               
                                       54.65 ± 0.72                    
       90     pl     0      10  --     56.27 ± 0.55                    
                     6          230 ± 9                                
                                       55.01 ± 0.58                    
       95     pl     0      10  --     56.78 ± 1.80                    
                     6          239 ± 20                               
                                       55.93 ± 0.52                    
       100    pl     0      10  --     57.38 ± 0.69                    
                     6          231 ± 11                               
                                       55.95 ± 0.74                    
       105    pl     0      10  --     57.34 ± 0.70                    
                     6          245 ± 16                               
                                       55.56 ± 0.49                    
B2     80     ss     0      10  --     60.32 ± 3.80                    
                     6          157 ± 16                               
                                       62.60 ± 0.94                    
B2     85     ss     0      10  --     62.49 ± 1.02                    
                     6          190 ± 60                               
                                       63.34 ± 0.78                    
       90     ss     0      10  --     62.68 ± 0.89                    
                     6          153 ± 11                               
                                       63.16 ± 0.71                    
       95     ss     0      10  --     62.60 ± 0.66                    
                     6          156 ± 10                               
                                       64.36 ± 3.29                    
       100    ss     0      10  --     63.39 ± 2.36                    
                     6          155 ± 10                               
                                       65.12 ± 2.70                    
       105    ss     0      10  --     64.08 ± 1.67                    
                     6          155 ± 7                                
                                       64.39 ± 0.85                    
       80     pl     0      10  --     61.20 ± 3.22                    
                     6          158 ± 9                                
                                       59.90 ± 0.33                    
       85     pl     0      10  --     60.15 ± 1.02                    
                     6          156 ± 11                               
                                       60.05 ± 0.71                    
       90     pl     0      10  --     60.95 ± 2.00                    
                     6          158 ± 28                               
                                       60.14 ± 0.68                    
       95     pl     0      10  --      54.61 ± 19.10                  
                     6          158 ± 7                                
                                       60.94 ± 0.59                    
       100    pl     0      10  --     61.05 ± 1.37                    
                     6          153 ± 10                               
                                       61.71 ± 2.26                    
       105    pl     0      10  --     60.85 ± 0.62                    
                     6          154 ± 9                                
                                       60.71 ± 0.66                    
______________________________________                                    
 
    
     The results in TABLES 6-8 show that these diaphragms of the invention exhibit acceptable leak rate and valve delivery variability when used with the indicated formulations, regardless of the method of preparation or the valve stem material. 
     Diaphragms of the invention were prepared by injection molding and by compression molding from FLEXOMER™ DFDA 1137 NT 7 polyolefin and tested with the formulations indicated in TABLES 9A and 9B below. 
     
                       TABLE 9A                                                    
______________________________________                                    
INJECTION MOLDED FLEXOMER ™                                            
DFDA 1137 NT 7 POLYOLEFIN                                                 
Formu-              Time       Leak Rate                                  
                                       Valve Delivery                     
lation ID    Stem   (Weeks)                                               
                           N   (mg/yr) (mg/actuation)                     
______________________________________                                    
A2     84    ss     0      10  --      61.51 ± 2.04                    
                    6          297 ± 41                                
                                       61.79 ± 1.78                    
       88    ss     0      10  --      59.56 ± 0.80                    
                    6          298 ± 35                                
                                       61.28 ± 3.39                    
       94    ss     0      10  --      61.57 ± 3.81                    
                    6          312 ± 18                                
                                       66.49 ± 7.58                    
       98    ss     0      10  --      61.88 ± 5.25                    
                    6          289 ± 17                                
                                       63.31 ± 7.20                    
       84    pl     0      10  --      60.88 ± 2.38                    
                    6          298 ± 32                                
                                       59.47 ± 1.12                    
       88    pl     0      10  --      59.68 ± 1.80                    
                    6          288 ± 35                                
                                       59.33 ± 1.25                    
       94    pl     0      10  --      59.14 ±  1.05                   
                    6          303 ± 23                                
                                       61.38 ± 4.29                    
       98    pl     0      10  --      58.81 ± 2.06                    
                    6          292 ± 16                                
                                       60.56 ± 1.75                    
______________________________________                                    
 
    
     
                       TABLE 9B                                                    
______________________________________                                    
COMPRESSION MOLDED FLEXOMER ™                                          
DFDA 1137 NT 7 POLYOLEFIN                                                 
Formu-              Time       Leak Rate                                  
                                       Valve Delivery                     
lation ID    Stem   (Weeks)                                               
                           N   (mg/yr) (mg/actuation)                     
______________________________________                                    
A4     95    pl     0      24  --      53.14 ± 7.34                    
                    2          198 ± 51                                
                                       56.13 ± 0.99                    
                    4          249 ± 50                                
                                       54.71 ± 3.07                    
                    8          296 ± 50                                
                                       55.60 ± 1.55                    
                    12         330 ± 52                                
                                       53.96 ± 7.10                    
                    24         361 ± 52                                
                                       54.62 ± 5.58                    
B3     95    pl     0      24  --      56.09 ± 2.41                    
                    2          221 ± 26                                
                                       57.07 ± 1.27                    
                    4          265 ± 27                                
                                       56.67 ± 1.67                    
                    8          311 ± 29                                
                                       57.25 ± 1.61                    
                    12         345 ± 31                                
                                       57.32 ± 2.23                    
                    24         373 ± 32                                
                                       59.10 ±  3.22                   
______________________________________                                    
 
    
     The results in TABLES 9A and 9B show that these diaphragms of the invention exhibit acceptable leak rate (which increases over time) and valve delivery variability when used with the indicated formulations. Little difference is seen between valve stem types or between injection molded diaphragms and compression molded diaphragms. A similar increase in leak rate was observed over time when compression molded FLEXOMER™ DFDA 1138 NT polyolefin was used as the diaphragm material with formulations A4 and B3. 
     Diaphragms of the invention were prepared from FLEXOMER™ DFDA 1163 NT7 polyolefin and tested with the formulations indicated in TABLE 10 below. 
     
                       TABLE 10                                                    
______________________________________                                    
COMPRESSION MOLDED FLEXOMER ™                                          
DFDA 1163 NT 7 POLYOLEFIN                                                 
For-                                                                      
mula-               Time       Leak Rate                                  
                                       Valve Delivery                     
tion  ID     Stem   (Weeks)                                               
                           N   (mg/yr) (mg/actuation)                     
______________________________________                                    
A1    80     ss     0      14    --    60.09 ± 0.81                    
                    6          259 ± 9                                 
                                       60.31 ± 0.68                    
      85     ss     0      14    --    60.28 ± 0.78                    
                    6          279 ± 14                                
                                       60.46 ± 0.86                    
      90     ss     0      14    --    60.31 ± 1.20                    
                    6          278 ± 17                                
                                       60.56 ± 0.90                    
      95     ss     0      14    --    59.44 ± 1.33                    
                    6          299 ± 20                                
                                       60.18 ± 0.94                    
      100    ss     0      14    --    59.64 ± 1.35                    
                    6          394 ± 341                               
                                       60.09 ± 1.15                    
      105    ss     0      14    --    60.01 ± 0.85                    
                    6          293 ± 22                                
                                       59.79 ± 0.76                    
      80     pl     0      14    --    58.96 ± 0.61                    
                    6          286 ± 72                                
                                       not measured                       
      85     pl     0      14    --    59.44 ± 0.56                    
                    6          275 ± 13                                
                                       58.07 ± 1.80                    
      90     pl     0      14    --    59.22 ± 0.65                    
                    6          295 ± 45                                
                                       58.51 ± 0.57                    
      95     pl     0      14    --    58.96 ± 0.65                    
                    6          300 ± 23                                
                                       58.34 ± 0.76                    
      100    pl     0      14    --    58.73 ± 0.70                    
                    6          315 ± 34                                
                                       58.73 ± 2.18                    
      105    pl     0      14    --    58.19 ± 0.67                    
                    6          899 ± 2183                              
                                       58.08 ± 1.43                    
______________________________________                                    
 
    
     The results in TABLE 10 show that these diaphragms of the invention exhibit higher but generally acceptable leak rates and valve delivery variability when used with the indicated formulations, regardless of valve stem type. However, increasing inside diameter appears to increase leak rate with the plastic valve stem. 
     Diaphragms of the invention were prepared from FLEXOMER™ DFDA 1164 NT7 polyolefin and tested with the formulations indicated in TABLES 11-13 below. 
     
                       TABLE 11                                                    
______________________________________                                    
COMPRESSION MOLDED FLEXOMER ™                                          
DFDA 1164 NT 7 POLYOLEFIN                                                 
                                Leak                                      
Formu-               Time       Rate   Valve Delivery                     
lation ID     Stem   (Weeks)                                              
                            N   (mg/yr)                                   
                                       (mg/actuation)                     
______________________________________                                    
A1     80     ss     0      14  --     60.57 ± 0.62                    
                     6          421 ± 195                              
                                       60.74 ± 0.56                    
       85     ss     0      14  --     61.04 ± 0.99                    
                     6          338 ± 108                              
                                       61.30 ± 0.88                    
       90     ss     0      14  --     61.16 ± 0.77                    
                     6          357 ± 264                              
                                       58.94 ± 7.77                    
       95     ss     0      14  --     61.26 ± 0.73                    
                     6          628 ± 634                              
                                       61.74 ± 0.80                    
       100    ss     0      14  --     60.19 ± 0.65                    
                     6          458 ± 229                              
                                       60.93 ± 0.90                    
       105    ss     0      14  --     60.60 ± 0.52                    
                     6          478 ± 263                              
                                       60.90 ± 0.67                    
       80     pl     0      14  --     59.82 ± 0.92                    
                     6          276 ± 50                               
                                       59.23 ± 0.71                    
       85     pl     0      14  --     59.90 ± 0.78                    
                     6          264 ± 19                               
                                       59.44 ± 0.75                    
       90     pl     0      14  --     60.02 ± 1.05                    
                     6          262 ± 16                               
                                       59.64 ± 1.63                    
       95     pl     0      14  --     60.20 ± 1.05                    
                     6          268 ± 17                               
                                       59.76 ± 1.38                    
       100    pl     0      14  --     58.68 ± 1.74                    
                     6          380 ± 385                              
                                       58.69 ± 2.87                    
       105    pl     0      14  --     58.41 ± 1.94                    
                     6          308 ± 48                               
                                       59.73 ± 1.84                    
______________________________________                                    
 
    
     
                       TABLE 12                                                    
______________________________________                                    
INJECTION MOLDED FLEXOMER ™                                            
DFDA 1164 NT 7 POLYOLEFIN                                                 
                                Leak                                      
Formu-               Time       Rate   Valve Delivery                     
lation ID     Stem   (Weeks)                                              
                            N   (mg/yr)                                   
                                       (mg/actuation)                     
______________________________________                                    
A1     84     ss     0      10  --     62.34 ± 2.83                    
                     6          305 ± 35                               
                                       69.99 ± 7.80                    
       88     ss     0      10  --     63.45 ± 4.87                    
                     6          301 ± 23                               
                                       69.30 ± 9.12                    
       94     ss     0      10  --     65.22 ± 6.21                    
                     6          304 ± 14                               
                                       69.09 ± 7.02                    
       99     ss     0      10  --     65.51 ± 5.42                    
                     6          308 ± 19                               
                                        81.53 ± 25.99                  
       84     pl     0      10  --     62.62 ± 2.15                    
                     6           428 ± 334                             
                                       60.99 ± 4.02                    
       88     pl     0      10  --     60.67 ± 2.76                    
                     6           350 ± 110                             
                                       59.67 ± 3.38                    
       94     pl     0      10  --     64.18 ± 5.65                    
                     6           582 ± 397                             
                                       60.67 ± 2.30                    
       99     pl     0      10  --     62.19 ± 3.86                    
                     6          327 ± 23                               
                                       not measured                       
B1     84     ss     0      10  --     69.83 ± 6.84                    
                     6          284 ± 22                               
                                       76.36 ± 8.94                    
       88     ss     0      10  --     70.33 ± 5.42                    
                     6          260 ± 33                               
                                       74.86 ± 6.29                    
       94     ss     0      10  --     67.83 ± 4.70                    
                     6          273 ± 33                               
                                       71.89 ± 4.32                    
       99     ss     0      10  --     69.73 ± 4.97                    
                     6          255 ± 19                               
                                       81.76 ± 8.71                    
B1     84     pl     0      10  --     69.04 ± 5.87                    
                     6          286 ± 29                               
                                       69.72 ± 6.85                    
       88     pl     0      10  --     68.16 ± 6.78                    
                     6           629 ± 1064                            
                                       69.30 ± 6.70                    
       94     pl     0      10  --     66.15 ±  2.89                   
                     6          292 ± 38                               
                                       67.20 ± 8.22                    
       99     pl     0      10  --     69.45 ± 7.39                    
                     6           491 ± 654                             
                                       70.29 ± 7.77                    
______________________________________                                    
 
    
     
                       TABLE 13                                                    
______________________________________                                    
EXTRUDED FLEXOMER ™                                                    
DFDA 1164 NT 7 POLYOLEFIN                                                 
                                Leak                                      
Formu-               Time       Rate   Valve Delivery                     
lation ID     Stem   (Weeks)                                              
                            N   (mg/yr)                                   
                                       (mg/actuation)                     
______________________________________                                    
B2     80     ss     0      10  --     66.90 ± 0.37                    
                     6          306 ± 154                              
                                       67.05 ± 0.42                    
       85     ss     0      10  --     65.26 ± 1.26                    
                     6          321 ± 271                              
                                       63.81 ± 1.61                    
       90     ss     0      10  --     65.10 ± 0.96                    
                     6          232 ± 122                              
                                       66.55 ± 0.76                    
       95     ss     0      10  --     65.67 ± 1.30                    
                     6          425 ± 292                              
                                       66.53 ± 0.90                    
       100    ss     0      10  --     66.58 ± 2.91                    
                     6          757 ± 380                              
                                       66.39 ± 1.54                    
       105    ss     0      10  --     65.03 ± 2.90                    
                     6          698 ± 499                              
                                       67.02 ± 1.61                    
       80     pl     0      10  --     64.77 ± 2.20                    
                     6          184 ± 29                               
                                       64.29 ± 1.45                    
       85     pl     0      10  --     63.55 ± 1.17                    
                     6          211 ± 23                               
                                       63.53 ± 1.07                    
       90     pl     0      10  --     63.40 ± 0.57                    
                     6          198 ± 21                               
                                       64.45 ± 1.60                    
       95     pl     0      10  --     63.43 ± 0.63                    
                     6          226 ± 24                               
                                       64.70 ± 1.85                    
       100    pl     0      10  --     63.59 ± 0.71                    
                     6          341 ± 388                              
                                       66.27 ± 4.49                    
       105    pl     0      10  --     63.17 ± 0.85                    
                     6          226 ± 29                               
                                       69.72 ± 8.48                    
______________________________________                                    
 
    
     The results in TABLES 11-13 show that these diaphragms of the invention exhibit higher but generally suitable leak rate and valve delivery variability when used with the indicated formulations. Valve delivery is least variable for the compression molded diaphragms. With the extruded diaphragms leak rate with the beclomethasone dipropionate formulation is improved when a plastic valve stem is used. 
     Diaphragms of the invention were prepared from FLEXOMER™ DEFD 1491 NT7 polyolefin and tested with the formulations indicated in TABLE 14 below. 
     
                       TABLE 14                                                    
______________________________________                                    
COMPRESSION MOLDED                                                        
FLEXOMER ™ DEFD 1491 NT 7 POLYOLEFIN                                   
                                Leak                                      
Formu-               Time       Rate   Valve Delivery                     
lation ID     Stem   (Weeks)                                              
                            N   (mg/yr)                                   
                                       (mg/actuation)                     
______________________________________                                    
A1     80     ss     0      14  --     58.69 ± 1.15                    
                     6          275 ± 26                               
                                       58.86 ± 1.46                    
       85     ss     0      14  --     59.00 ± 0.83                    
                     6          277 ± 23                               
                                       59.42 ± 0.75                    
       90     ss     0      14  --     59.13 ± 0.97                    
                     6          268 ± 20                               
                                       59.59 ± 0.96                    
       95     ss     0      14  --     58.95 ± 0.91                    
                     6          284 ± 26                               
                                       59.50 ± 0.79                    
       100    ss     0      14  --     59.07 ± 0.79                    
                     6          279 ± 19                               
                                       59.04 ± 1.08                    
       105    ss     0      14  --     59.06 ± 0.53                    
                     6          272 ± 18                               
                                       59.51 ± 1.18                    
       80     pl     0      14  --     57.39 ± 2.06                    
                     6          267 ± 10                               
                                       57.33 ± 1.33                    
       85     pl     0      14  --     58.22 ± 0.54                    
                     6          283 ± 28                               
                                       57.66 ± 0.64                    
       90     pl     0      14  --     58.35 ± 0.69                    
                     6          296 ± 8                                
                                       56.83 ± 3.43                    
       95     pl     0      14  --     58.02 ± 0.84                    
                     6          276 ± 13                               
                                       57.68 ± 0.58                    
       100    pl     0      14  --     57.72 ± 0.74                    
                     6          281 ± 17                               
                                       57.26 ± 0.88                    
       105    pl     0      14  --     58.29 ± 0.65                    
                     6          276 ± 19                               
                                       56.21 ± 3.22                    
______________________________________                                    
 
    
     The results in TABLE 14 show that these diaphragms of the invention exhibit acceptable leak rates and valve delivery variability when used with the indicated formulations. 
     Diaphragms of the invention were prepared from FLEXOMER™ DFDA 9020 NT7 polyolefin and tested with the formulations indicated in TABLES 15-16. 
     
                       TABLE 15                                                    
______________________________________                                    
EXTRUDED FLEXOMER ™ DFDA 9020 NT 7                                     
POLYOLEFIN                                                                
                                        Valve De-                         
Formu-               Time       Leak Rate                                 
                                        livery (mg/                       
lation ID     Stem   (Weeks)                                              
                            N   (mg/yr) actuation)                        
______________________________________                                    
A2     80     ss     0      14  --      58.82 ± 3.64                   
                     6          262 ± 14                               
                                        59.68 ± 0.77                   
       85     ss     0      14  --      59.57 ± 1.24                   
                     6          278 ± 22                               
                                        59.71 ± 0.84                   
       90     ss     0      14  --      59.54 ± 0.73                   
                     6          271 ± 20                               
                                        59.46 ± 0.41                   
       95     ss     0      14  --      59.91 ± 1.15                   
                     6          296 ± 22                               
                                        59.51 ± 0.64                   
       100    ss     0      14  --      60.09 ± 0.84                   
                     6          289 ± 17                               
                                        60.83 ± 4.08                   
       105    ss     0      14  --      59.99 ± 1.31                   
                     6          283 ± 15                               
                                        60.04 ± 0.92                   
       80     pl     0      14  --      57.99 ± 1.83                   
                     6          281 ± 41                               
                                        57.30 ± 2.62                   
       85     pl     0      14  --      58.18 ± 0.89                   
                     6          302 ± 20                               
                                        57.77 ± 0.63                   
       90     pl     0      14  --      59.11 ± 0.69                   
                     6          291 ± 21                               
                                        58.42 ± 0.68                   
       95     pl     0      14  --      58.54 ± 0.80                   
                     6           354 ± 103                             
                                        57.79 ± 0.63                   
       100    pl     0      14  --      58.59 ± 1.09                   
                     6          319 ± 16                               
                                        58.58 ± 2.84                   
       105    pl     0      14  --      58.20 ± 0.74                   
                     6          319 ± 30                               
                                        57.99 ± 1.23                   
______________________________________                                    
 
    
     
                       TABLE 16                                                    
______________________________________                                    
COMPRESSION MOLDED                                                        
FLEXOMER ™ DFDA 9020 NT POLYOLEFIN                                     
                                        Valve De-                         
Formu-               Time       Leak Rate                                 
                                        livery (mg/                       
lation ID     Stem   (Weeks)                                              
                            N   (mg/yr) actuation)                        
______________________________________                                    
A3     80     pl     0      14  --      59.43 ± 0.70                   
                     6          not     58.82 ± 0.74                   
                                measured                                  
       85     pl     0      14  --      59.27 ± 0.78                   
                     6          240 ± 15                               
                                        58.76 ± 0.41                   
       90     pl     0      14  --      59.44 ± 2.03                   
                     6          230 ± 18                               
                                        58.67 ± 0.83                   
       95     pl     0      14  --      59.09 ± 0.73                   
                     6          236 ± 17                               
                                        58.95 ± 0.79                   
       100    pl     0      14  --      58.51 ± 2.49                   
                     6          243 ± 76                               
                                        58.06 ± 2.04                   
       105    pl     0      14  --      59.00 ± 1.27                   
                     6           304 ± 253                             
                                        58.63 ± 1.98                   
B2     80     ss     0      14  --      65.57 ± 1.14                   
                     6          221 ± 90                               
                                        66.66 ± 0.86                   
       85     ss     0      14  --      65.75 ± 0.80                   
                     6           338 ± 228                             
                                        66.67 ± 1.42                   
       90     ss     0      14  --      65.56 ± 1.30                   
                     6           471 ± 482                             
                                        66.74 ± 0.80                   
       95     ss     0      14  --      66.35 ± 2.19                   
                     6           424 ± 381                             
                                        67.03 ± 0.93                   
       100    ss     0      14  --      65.72 ± 0.67                   
                     6           564 ± 490                             
                                        66.40 ± 0.60                   
       105    ss     0      14  --      66.40 ± 1.32                   
                     6           671 ± 622                             
                                        66.43 ± 1.14                   
B2     80     pl     0      14  --      63.26 ± 0.48                   
                     6          174 ± 18                               
                                        63.41 ± 0.50                   
       85     pl     0      14  --      62.93 ± 0.86                   
                     6          186 ± 21                               
                                        63.80 ±  0.78                  
       90     pl     0      14  --      63.50 ± 0.97                   
                     6          179 ± 13                               
                                        64.24 ± 0.89                   
       95     pl     0      14  --      62.82 ± 1.71                   
                     6          175 ± 10                               
                                        64.58 ± 1.13                   
       100    pl     0      14  --      62.60 ± 2.83                   
                     6          174 ± 33                               
                                        63.43 ± 1.69                   
       105    pl     0      14  --      63.51 ± 1.47                   
                     6          168 ± 18                               
                                        66.57 ± 8.55                   
______________________________________                                    
 
    
     The results in TABLES 15 and 16 show that the extruded and compression molded diaphragms have valve delivery and leak rate especially suitable for use with a polar ionized drug (albuterol sulfate), while the compression molded diaphragms used with the plastic valve stem are particularly suitable for use with a steroid formulation (beclomethasone dipropionate). 
     Diaphragms of the invention were prepared from FLEXOMER™ DEFD 9042 NT polyolefin and tested with the formulations indicated in TABLES 17-19 below. 
     
                       TABLE 17                                                    
______________________________________                                    
COMPRESSION MOLDED                                                        
FLEXOMER ™ 9042 NT POLYOLEFIN                                          
For-                                                                      
mula-               Time       Leak Rate                                  
                                       Valve Delivery                     
tion  ID     Stem   (Weeks)                                               
                           N   (mg/yr) (mg/actuation)                     
______________________________________                                    
A1    80     ss     0      14  --      61.59 ± 1.50                    
                    3          270 ± 20                                
                                       63.14 ± 0.88                    
      85     ss     0      14  --      60.77 ± 2.30                    
                    6          249 ± 22                                
                                       63.18 ± 1.04                    
      90     ss     0      14  --      58.94 ± 4.45                    
                    6          252 ± 19                                
                                       60.86 ± 2.81                    
      95     ss     0      14  --      59.81 ± 2.42                    
                    6          251 ± 21                                
                                       60.46 ± 2.22                    
      100    ss     0      14  --       44.61 ± 13.56                  
                    6          270 ± 33                                
                                       50.75 ± 5.58                    
      105    ss     0      14  --      58.16 ± 1.23                    
                    6          187 ± 25                                
                                       59.01 ± 0.82                    
      80     pl     0      14  --      61.14 ± 0.59                    
                    6          268 ± 22                                
                                       61.29 ± 0.66                    
      85     pl     0      14  --      59.96 ± 1.28                    
                    6          265 ± 14                                
                                       60.41 ± 0.88                    
      90     pl     0      14  --      57.35 ± 1.68                    
                    6           339 ± 141                              
                                       55.71 ± 5.71                    
      95     pl     0      14  --      54.95 ± 2.84                    
                    6          286 ± 30                                
                                       55.44 ± 3.48                    
      100    pl     0      14  --      55.37 ± 4.10                    
                    6          304 ± 24                                
                                       56.25 ± 3.33                    
      105    pl     0      14  --      57.83 ± 0.67                    
                    6          208 ± 31                                
                                       60.14 ± 2.62                    
______________________________________                                    
 
    
     
                       TABLE 18                                                    
______________________________________                                    
EXTRUDED FLEXOMER ™ DEFD 9042 NT                                       
POLYOLEFIN                                                                
For-                                                                      
mula-               Time       Leak Rate                                  
                                       Valve Delivery                     
tion  ID     Stem   (Weeks)                                               
                           N   (mg/yr) (mg/actuation)                     
______________________________________                                    
A2    80     ss     0      14  --      61.21 ± 1.86                    
                    6          289 ± 85                                
                                       61.10 ± 1.26                    
      85     ss     0      14  --      60.89 ± 1.62                    
                    6          281 ± 63                                
                                       60.50 ± 3.44                    
      90     ss     0      14  --      61.18 ± 2.86                    
                    6          294 ± 64                                
                                       60.65 ± 1.09                    
      95     ss     0      14  --      58.47 ± 1.01                    
                    6          252 ± 18                                
                                       60.59 ± 1.20                    
      100    ss     0      14  --      59.40 ± 1.27                    
                    6          255 ± 12                                
                                       60.35 ± 1.16                    
      105    ss     0      14  --      59.94 ± 1.22                    
                    6           437 ± 375                              
                                       60.97 ± 0.69                    
      80     pl     0      14  --      57.99 ± 0.72                    
                    6          246 ± 9                                 
                                       57.71 ± 0.52                    
      85     pl     0      14  --      58.12 ± 0.98                    
                    6          262 ± 10                                
                                        53.93 ± 15.53                  
      90     pl     0      14  --      57.88 ± 0.85                    
                    6          262 ± 16                                
                                       57.40 ± 1.79                    
      95     pl     0      14  --      58.15 ± 1.10                    
                    6          256 ± 14                                
                                       57.88 ± 1.44                    
      100    pl     0      14  --      57.06 ± 1.40                    
                    6          268 ± 26                                
                                       57.31 ± 0.79                    
      105    pl     0      14  --      56.21 ± 1.68                    
                    6          316 ± 94                                
                                       59.84 ± 6.31                    
______________________________________                                    
 
    
     
                       TABLE 19                                                    
______________________________________                                    
INJECTION MOLDED                                                          
FLEXOMER ™ DEFD 9042 NT POLYOLEFIN                                     
                                Leak                                      
Formu-               Time       Rate   Valve Delivery                     
lation ID     Stem   (Weeks)                                              
                            N   (mg/yr)                                   
                                       (mg/actuation)                     
______________________________________                                    
A2     84     ss     0      10  --     60.40 ± 1.70                    
                     6          282 ± 13                               
                                       67.20 ± 8.78                    
       88     ss     0      10  --     60.40 ± 1.28                    
                     6          282 ± 13                               
                                        75.56 ± 25.41                  
       94     ss     0      10  --     61.60 ± 2.07                    
                     6          282 ± 14                               
                                        66.63 ± 13.64                  
       99     ss     0      10  --     60.83 ± 2.18                    
                     6          297 ± 16                               
                                       62.80 ± 3.61                    
       84     pl     0      10  --     59.00 ± 1.82                    
                     6          272 ± 14                               
                                       61.30 ± 8.54                    
       88     pl     0      10  --      65.99 ± 12.41                  
                     6          286 ± 22                               
                                       60.32 ± 4.43                    
       94     pl     0      10  --     61.20 ± 3.64                    
                     6          284 ± 18                               
                                       60.28 ± 3.42                    
       99     pl     0      10  --     61.22 ± 4.87                    
                     6          291 ± 8                                
                                       59.40 ± 3.19                    
B2     84     ss     0      10  --      70.48 ± 10.53                  
                     6          198 ± 11                               
                                       69.54 ± 3.92                    
       88     ss     0      10  --     64.71 ± 1.23                    
                     6          202 ± 18                               
                                       71.80 ± 7.10                    
       94     ss     0      10  --     65.01 ± 2.66                    
                     6          199 ± 18                               
                                        86.26 ± 31.64                  
       99     ss     0      10  --     66.80 ± 5.98                    
                     6          208 ± 30                               
                                        80.90 ± 34.78                  
B2     84     pl     0      10  --     64.81 ± 3.57                    
                     6          207 ± 15                               
                                       63.90 ± 1.47                    
       88     pl     0      10  --     63.96 ± 4.78                    
                     6          200 ± 10                               
                                       64.46 ± 2.31                    
       94     pl     0      10  --     65.17 ± 4.19                    
                     6          207 ± 14                               
                                       69.00 ± 7.64                    
       99     pl     0      10  --     65.27 ± 3.27                    
                     6          219 ± 22                               
                                        78.26 ± 40.98                  
______________________________________                                    
 
    
     The results in TABLES 17-19 show that in this instance compression molded and extruded diaphragms generally perform better than the injection molded diaphragms with these formulations. 
     Diaphragms of the invention were prepared from polymer blends of the invention as set forth in TABLES 20-25 (parts and percentages are by weight) and tested with the formulations indicated in said TABLES. 
     
                       TABLE 20                                                    
______________________________________                                    
COMPRESSION MOLDED POLYMER BLEND.                                         
DFDA 1137 NT 7/GERS 1085 NT (25/75)                                       
                                Leak                                      
Formu-               Time       Rate   Valve Delivery                     
lation ID     Stem   (Weeks)                                              
                            N   (mg/yr)                                   
                                       (mg/actuation)                     
______________________________________                                    
A1     80     ss     0      10  --     55.70 ± 1.91                    
                     6          271 ± 18                               
                                       56.55 ± 0.62                    
       85     ss     0      10  --     54.38 ± 6.57                    
                     6          261 ± 12                               
                                       57.31 ± 0.88                    
       90     ss     0      10  --     56.08 ± 1.96                    
                     6          264 ± 10                               
                                       57.22 ± 0.96                    
       95     ss     0      10  --     56.00 ± 1.08                    
                     6          264 ± 15                               
                                       56.97 ± 1.09                    
       100    ss     0      10  --     55.54 ± 1.03                    
                     6          266 ± 12                               
                                       56.91 ± 0.84                    
       105    ss     0      10  --     56.45 ± 0.89                    
                     6          278 ± 19                               
                                       57.49 ± 0.62                    
       80     pl     0      10  --     54.29 ± 1.45                    
                     6          259 ± 12                               
                                       54.81 ± 0.41                    
       85     pl     0      10  --     54.93 ± 0.89                    
                     6          271 ± 18                               
                                       55.79 ± 0.71                    
       90     pl     0      10  --     55.63 ± 0.89                    
                     6          264 ± 7                                
                                       55.39 ± 0.60                    
       95     pl     0      10  --     55.43 ± 1.02                    
                     6          271 ± 13                               
                                       55.34 ± 1.32                    
       100    pl     0      10  --     55.56 ± 0.47                    
                     6          283 ± 24                               
                                       55.70 ± 0.88                    
       105    pl     0      10  --     55.75 ± 0.75                    
                     6          280 ± 17                               
                                       56.17 ± 1.06                    
B1     80     ss     0      10  --     60.45 ± 0.85                    
                     6          234 ± 12                               
                                       61.10 ± 0.80                    
       85     ss     0      10  --     59.99 ± 1.88                    
                     6          224 ± 16                               
                                       62.23 ± 0.92                    
       90     ss     0      10  --     60.23 ± 0.74                    
                     6          232 ± 17                               
                                       61.52 ± 0.54                    
       95     ss     0      10  --     60.27 ± 0.95                    
                     6          242 ± 28                               
                                       61.37 ± 0.58                    
       100    ss     0      10  --     60.77 ± 0.59                    
                     6          230 ± 17                               
                                       61.65 ± 0.62                    
       105    ss     0      10  --     60.56 ± 0.87                    
                     6          240 ± 17                               
                                       63.19 ± 3.70                    
       80     pl     0      10  --     59.08 ± 0.64                    
                     6          222 ± 22                               
                                       59.35 ± 0.46                    
       85     pl     0      10  --     58.83 ± 2.94                    
                     6          236 ± 22                               
                                       60.18 ± 0.87                    
       90     pl     0      10  --     59.55 ± 0.79                    
                     6          234 ± 20                               
                                       60.05 ± 1.17                    
       95     pl     0      10  --     59.14 ± 1.68                    
                     6          255 ± 24                               
                                       59.80 ± 2.01                    
       100    pl     0      10  --     59.91 ± 0.48                    
                     6          249 ± 20                               
                                       60.39 ± 1.38                    
       105    pl     0      10  --     59.32 ± 0.61                    
                     6          249 ± 16                               
                                       60.00 ± 0.37                    
______________________________________                                    
 
    
     
                       TABLE 21                                                    
______________________________________                                    
COMPRESSION MOLDED POLYMER BLEND.                                         
DFDA 1137 NT 7/GERS 1085 NT (50/50)                                       
                                Leak                                      
Formu-               Time       Rate   Valve Delivery                     
lation ID     Stem   (Weeks)                                              
                            N   (mg/yr)                                   
                                       (mg/actuation)                     
______________________________________                                    
A1     80     ss     0      10  --     57.35 ± 1.07                    
                     6          267 ± 15                               
                                       58.50 ± 0.54                    
       85     ss     0      10  --     56.97 ± 0.64                    
                     6          273 ± 14                               
                                       57.92 ± 0.64                    
       90     ss     0      10  --     56.87 ± 0.87                    
                     6          279 ± 24                               
                                       57.99 ± 0.74                    
       95     ss     0      10  --     57.65 ± 1.16                    
                     6          267 ± 10                               
                                       58.46 ± 0.89                    
       100    ss     0      10  --     57.17 ± 1.06                    
                     6          265 ± 16                               
                                       57.98 ± 0.85                    
       105    ss     0      10  --     57.83 ± 1.10                    
                     6          266 ± 11                               
                                       58.77 ± 0.88                    
       80     pl     0      10  --     56.73 ± 0.66                    
                     6          284 ± 17                               
                                       55.55 ± 3.81                    
       85     pl     0      10  --     56.13 ± 1.85                    
                     6          282 ± 23                               
                                       56.23 ± 0.77                    
       90     pl     0      10  --     56.87 ± 0.59                    
                     6          267 ± 9                                
                                       56.41 ± 0.99                    
       95     pl     0      10  --     56.69 ± 0.73                    
                     6          285 ± 29                               
                                       57.21 ± 0.38                    
       100    pl     0      10  --     55.28 ± 3.52                    
                     6          269 ± 8                                
                                       56.98 ± 0.55                    
       105    pl     0      10  --     57.15 ± 0.41                    
                     6          271 ± 12                               
                                       57.06 ± 0.62                    
B1     80     ss     0      10  --     61.83 ± 0.93                    
                     6          206 ± 9                                
                                       63.37 ± 0.87                    
       85     ss     0      10  --     60.98 ± 0.78                    
                     6          206 ± 17                               
                                       62.90 ± 0.99                    
       90     ss     0      10  --     61.80 ± 0.85                    
                     6          196 ± 11                               
                                       63.12 ± 0.94                    
       95     ss     0      10  --     61.94 ± 1.11                    
                     6          205 ± 11                               
                                       63.26 ± 0.86                    
       100    ss     0      10  --     61.94 ± 0.95                    
                     6          201 ± 13                               
                                       62.99 ± 0.97                    
       105    ss     0      10  --     62.61 ± 0.96                    
                     6          192 ± 12                               
                                       63.70 ± 0.78                    
       80     pl     0      10  --     60.39 ± 0.60                    
                     6          210 ± 19                               
                                       61.08 ± 0.71                    
       85     pl     0      10  --     59.80 ± 0.38                    
                     6          211 ± 11                               
                                       61.44 ± 1.31                    
       90     pl     0      10  --     61.52 ± 0.58                    
                     6          202 ± 10                               
                                       61.89 ± 0.63                    
       95     pl     0      10  --      55.62 ± 17.44                  
                     6          193 ± 8                                
                                       61.96 ± 0.94                    
       100    pl     0      10  --     61.30 ± 0.52                    
                     6          202 ± 13                               
                                       62.18 ± 0.56                    
       105    pl     0      10  --     61.53 ± 0.86                    
                     6          203 ± 15                               
                                       61.68 ± 0.75                    
______________________________________                                    
 
    
     
                       TABLE 22                                                    
______________________________________                                    
COMPRESSION MOLDED POLYMER BLEND.                                         
DFDA 1137 NT 7/GERS 1085 NT (75/25)                                       
                                Leak                                      
Formu-               Time       Rate   Valve Delivery                     
lation ID     Stem   (Weeks)                                              
                            N   (mg/yr)                                   
                                       (mg/actuation)                     
______________________________________                                    
A1     80     ss     0      10  --     57.92 ± 1.25                    
                     6          374 ± 24                               
                                       58.18 ± 0.84                    
       85     ss     0      10  --     58.31 ± 0.90                    
                     6          385 ± 27                               
                                       58.85 ± 0.80                    
       90     ss     0      10  --     58.01 ± 0.58                    
                     6          332 ± 16                               
                                       58.85 ± 0.80                    
       95     ss     0      10  --     57.93 ± 0.84                    
                     6          314 ± 28                               
                                       58.86 ± 0.77                    
       100    ss     0      10  --     57.23 ± 1.01                    
                     6          294 ± 16                               
                                       58.20 ± 0.94                    
       105    ss     0      10  --     58.07 ± 1.13                    
                     6          324 ± 19                               
                                       58.61 ± 1.07                    
       80     pl     0      10  --     57.07 ± 1.02                    
                     6          392 ± 20                               
                                       57.31 ± 0.62                    
       85     pl     0      10  --     57.39 ± 0.39                    
                     6          380 ± 41                               
                                       57.83 ± 0.53                    
       90     pl     0      10  --     57.14 ± 0.51                    
                     6          340 ± 27                               
                                       57.45 ± 0.81                    
       95     pl     0      10  --     57.54 ± 0.50                    
                     6          299 ± 16                               
                                       57.44 ± 0.57                    
       100    pl     0      10  --     56.95 ± 0.71                    
                     6          309 ± 13                               
                                       57.38 ± 2.62                    
       105    pl     0      10  --     56.13 ± 1.71                    
                     6          331 ± 29                               
                                       56.78 ± 0.80                    
B1     80     ss     0      10  --     61.92 ± 0.77                    
                     6          205 ± 13                               
                                       63.21 ± 0.61                    
       85     ss     0      10  --     61.81 ± 0.52                    
                     6          201 ± 6                                
                                       63.52 ± 0.57                    
       90     ss     0      10  --     61.80 ± 1.23                    
                     6          201 ± 11                               
                                       63.63 ± 1.68                    
       95     ss     0      10  --     61.86 ± 0.86                    
                     6          201 ± 15                               
                                       63.32 ± 0.98                    
       100    ss     0      10  --     62.16 ± 0.94                    
                     6          209 ± 23                               
                                       63.64 ± 0.97                    
       105    ss     0      10  --     62.46 ± 0.83                    
                     6          204 ± 11                               
                                       63.39 ± 1.11                    
       80     pl     0      10  --     60.75 ± 0.62                    
                     6          199 ± 11                               
                                       61.62 ± 0.64                    
       85     pl     0      10  --     60.93 ± 0.50                    
                     6          212 ± 16                               
                                       62.08 ± 0.72                    
       90     pl     0      10  --     60.44 ± 1.84                    
                     6          205 ± 14                               
                                       62.48 ± 1.21                    
       95     pl     0      10  --     61.06 ± 0.47                    
                     6          205 ± 7                                
                                       62.12 ± 0.95                    
       100    pl     0      10  --     60.49 ±  0.68                   
                     6          210 ± 27                               
                                       61.41 ± 0.67                    
       105    pl     0      10  --     60.54 ± 2.61                    
                     6          201 ± 13                               
                                       61.96 ± 0.74                    
______________________________________                                    
 
    
     
                       TABLE 23                                                    
______________________________________                                    
COMPRESSION MOLDED POLYMER BLEND.                                         
DFDA 1137 NT 7/GERS 1085 NT/TALC (23.2/69.8/7.0)                          
                                Leak                                      
Formu-               Time       Rate   Valve Delivery                     
lation ID     Stem   (Weeks)                                              
                            N   (mg/yr)                                   
                                       (mg/actuation)                     
______________________________________                                    
A2     80     ss     0      10  --     59.26 ± 1.00                    
                     6          296 ± 37                               
                                       59.82 ± 1.06                    
       85     ss     0      10  --     59.19 ± 0.85                    
                     6          265 ± 31                               
                                       60.39 ± 0.83                    
       90     ss     0      10  --     60.44 ± 1.07                    
                     6          278 ± 34                               
                                       62.03 ± 0.70                    
       95     ss     0      10  --     59.71 ± 1.90                    
                     6          313 ± 43                               
                                       61.78 ± 0.57                    
       100    ss     0      10  --     59.61 ± 0.84                    
                     6          303 ± 40                               
                                       61.31 ± 0.84                    
       105    ss     0      10  --     59.98 ± 1.21                    
                     6          311 ± 53                               
                                       61.49 ± 1.06                    
       80     pl     0      10  --     57.71 ± 0.70                    
                     6          300 ± 48                               
                                       57.54 ± 0.63                    
       85     pl     0      10  --     57.73 ± 0.54                    
                     6          264 ± 29                               
                                       57.56 ± 0.33                    
       90     pl     0      10  --     58.04 ± 0.78                    
                     6          287 ± 33                               
                                       58.46 ± 0.64                    
       95     pl     0      10  --     58.24 ± 0.70                    
                     6          282 ± 22                               
                                       58.79 ± 0.59                    
       100    pl     0      10  --     57.80 ± 0.44                    
                     6          310 ± 43                               
                                       59.33 ± 1.45                    
       105    pl     0      10  --     58.30 ± 0.61                    
                     6          366 ± 39                               
                                       59.16 ± 0.44                    
B2     80     ss     0      10  --     61.80 ± 1.00                    
                     6          194 ± 6                                
                                       not measured                       
       85     ss     0      10  --     61.94 ± 0.98                    
                     6          185 ± 16                               
                                       64.04 ± 0.69                    
       90     ss     0      10  --     61.40 ± 2.70                    
                     6          206 ± 28                               
                                       65.21 ± 0.88                    
       95     ss     0      10  --     62.82 ± 1.03                    
                     6          196 ± 15                               
                                       65.31 ± 0.81                    
       100    ss     0      10  --     60.04 ± 6.25                    
                     6          218 ± 35                               
                                       65.37 ± 0.67                    
       105    ss     0      10  --     63.57 ± 1.54                    
                     6          215 ± 36                               
                                       65.14 ± 0.77                    
       80     pl     0      10  --     60.74 ± 0.73                    
                     6          221 ± 41                               
                                       61.69 ± 0.65                    
       85     pl     0      10  --     60.69 ± 0.79                    
                     6          188 ± 7                                
                                       61.99 ± 0.72                    
       90     pl     0      10  --     61.33 ± 0.88                    
                     6          199 ± 13                               
                                       62.34 ± 0.53                    
       95     pl     0      10  --     61.13 ± 0.72                    
                     6          212 ± 18                               
                                       63.36 ± 1.23                    
       100    pl     0      10  --     60.71 ± 1.08                    
                     6          210 ± 24                               
                                       64.28 ± 2.53                    
       105    pl     0      10  --     61.28 ± 0.44                    
                     6          205 ± 33                               
                                       64.10 ± 1.27                    
______________________________________                                    
 
    
     
                       TABLE 24                                                    
______________________________________                                    
COMPRESSION MOLDED POLYMER BLEND.                                         
DFDA 1137 NT 7/GERS 1085 NT/TALC (46.5/46.5/7.0)                          
                                Leak                                      
Formu-               Time       Rate   Valve Delivery                     
lation ID     Stem   (Weeks)                                              
                            N   (mg/yr)                                   
                                       (mg/actuation)                     
______________________________________                                    
A2     80     ss     0      10  --     57.80 ± 3.05                    
                     6          241 ± 26                               
                                       61.25 ± 0.81                    
       85     ss     0      10  --     60.00 ± 0.91                    
                     6          229 ± 15                               
                                       61.72 ± 0.94                    
       90     ss     0      10  --     60.37 ± 0.90                    
                     6          266 ± 34                               
                                       62.18 ± 0.74                    
       95     ss     0      10  --     59.91 ± 0.95                    
                     6          266 ± 26                               
                                       61.84 ± 0.92                    
       100    ss     0      10  --     59.70 ± 1.15                    
                     6          231 ± 30                               
                                       61.31 ± 1.01                    
       105    ss     0      10  --     60.59 ± 1.22                    
                     6          293 ± 38                               
                                       61.76 ± 0.72                    
       80     pl     0      10  --     58.27 ± 0.56                    
                     6          248 ± 24                               
                                       57.59 ± 2.34                    
       85     pl     0      10  --     58.17 ± 1.13                    
                     6          238 ± 21                               
                                       59.03 ± 0.37                    
       90     pl     0      10  --     57.39 ± 2.30                    
                     6          244 ± 19                               
                                       57.94 ± 2.34                    
       95     pl     0      10  --     58.69 ± 0.61                    
                     6          280 ± 40                               
                                       59.20 ± 0.85                    
       100    pl     0      10  --     58.53 ± 0.52                    
                     6          297 ± 30                               
                                       59.55 ± 1.40                    
       105    pl     0      10  --     58.88 ± 0.30                    
                     6          280 ± 30                               
                                       60.89 ± 2.31                    
B2     80     ss     0      10  --     64.01 ± 1.29                    
                     6          186 ± 20                               
                                       65.56 ± 0.70                    
       85     ss     0      10  --     63.40 ± 0.71                    
                     6          191 ± 9                                
                                        65.8 ± 0.92                    
       90     ss     0      10  --     63.40 ± 1.26                    
                     6          200 ± 16                               
                                       65.74 ± 1.21                    
       95     ss     0      10  --     63.07 ± 0.74                    
                     6          197 ± 9                                
                                       65.83 ± 0.74                    
       100    ss     0      10  --     63.02 ± 1.44                    
                     6          194 ± 9                                
                                       65.51 ± 1.62                    
       105    ss     0      10  --     63.98 ± 0.64                    
                     6          185 ± 10                               
                                       65.71 ± 0.98                    
       80     pl     0      10  --     61.25 ± 0.50                    
                     6          200 ± 19                               
                                       62.19 ± 0.42                    
       85     pl     0      10  --     61.69 ± 0.62                    
                     6          197 ± 14                               
                                       62.58 ± 1.28                    
       90     pl     0      10  --     61.43 ± 1.51                    
                     6          200 ± 12                               
                                       62.77 ± 0.88                    
       95     pl     0      10  --     61.50 ± 0.57                    
                     6          208 ± 14                               
                                       63.75 ± 0.91                    
       100    pl     0      10  --     62.26 ± 0.54                    
                     6          203 ± 10                               
                                       64.25 ± 2.12                    
       105    pl     0      10  --     61.94 ± 0.58                    
                     6          188 ± 13                               
                                       63.39 ± 0.64                    
______________________________________                                    
 
    
     
                       TABLE 25                                                    
______________________________________                                    
COMPRESSION MOLDED POLYMER BLEND.                                         
DFDA 1137 NT 7/GERS 1085 NT/TALC (69.8/23.2/7.0)                          
                                        Valve Deliv-                      
Formu-               Time       Leak Rate                                 
                                        ery (mg/                          
lation ID     Stem   (Weeks)                                              
                            N   (mg/yr) actuation)                        
______________________________________                                    
A2     80     ss     0      10  --      60.31 ± 0.91                   
                     6          330 ± 53                               
                                        62.18 ± 0.90                   
       85     ss     0      10  --      60.53 ± 1.09                   
                     6           422 ± 197                             
                                        62.01 ± 0.70                   
       90     ss     0      10  --      59.66 ± 1.41                   
                     6          302 ± 59                               
                                        62.05 ± 0.74                   
       95     ss     0      10  --      60.06 ± 1.36                   
                     6          333 ± 74                               
                                        62.10 ± 0.77                   
       100    ss     0      10  --      61.05 ± 1.03                   
                     6          331 ± 42                               
                                        61.70 ± 0.83                   
       105    ss     0      10  --      60.86 ± 0.93                   
                     6          297 ± 41                               
                                        61.50 ±  1.01                  
       80     pl     0      10  --      58.44 ± 0.54                   
                     6          288 ± 41                               
                                        58.22 ± 1.62                   
       85     pl     0      10  --      58.73 ± 0.44                   
                     6          303 ± 30                               
                                        59.01 ± 0.56                   
       90     pl     0      10  --      58.79 ± 0.66                   
                     6          275 ± 29                               
                                        59.52 ± 0.61                   
       95     pl     0      10  --      58.87 ± 1.21                   
                     6          322 ± 59                               
                                        60.48 ± 1.39                   
       100    pl     0      10  --      59.35 ± 0.66                   
                     6          306 ± 33                               
                                        61.10 ± 1.59                   
       105    pl     0      10  --      59.24 ± 0.59                   
                     6          302 ± 38                               
                                        58.71 ± 3.32                   
B2     80     ss     0      10  --      64.24 ± 0.51                   
                     6          230 ± 69                               
                                        65.83 ± 0.56                   
       85     ss     0      10  --      63.78 ± 1.10                   
                     6           231 ± 145                             
                                        65.94 ± 1.09                   
       90     ss     0      10  --      64.50 ± 1.30                   
                     6          201 ± 17                               
                                        66.09 ± 0.66                   
       95     ss     0      10  --      62.51 ± 1.58                   
                     6          204 ± 19                               
                                        66.05 ± 1.10                   
       100    ss     0      10  --      64.14 ± 0.81                   
                     6          202 ± 27                               
                                        65.86 ± 0.92                   
       105    ss     0      10  --      64.41 ± 0.92                   
                     6          219 ± 70                               
                                        66.38 ± 0.96                   
       80     pl     0      10  --      62.09 ± 0.49                   
                     6          199 ± 10                               
                                        62.50 ± 0.59                   
       85     pl     0      10  --      61.77 ± 1.82                   
                     6          199 ± 16                               
                                        64.04 ± 1.66                   
       90     pl     0      10  --      62.47 ± 0.66                   
                     6          202 ± 17                               
                                        63.89 ± 1.54                   
       95     pl     0      10  --      62.50 ± 0.52                   
                     6          198 ± 13                               
                                        63.87 ± 1.27                   
       100    pl     0      10  --      62.67 ± 0.64                   
                     6          206 ± 18                               
                                        66.47 ± 4.74                   
       105    pl     0      10  --      62.35 ± 0.49                   
                     6          194 ± 12                               
                                        63.83 ± 0.92                   
______________________________________                                    
 
    
     The results in TABLES 20-25 show that the indicated blends are suitable seal materials for use with metered dose inhalers containing the indicated formulations. Moreover, the data indicate that blends in all proportions would be suitable. 
     Diaphragms of the invention were prepared from ATTANE™ 4602 polyolefin and ATTANE™ 4701 polyolefin and tested with the formulations indicated in TABLE 26 and TABLE 27 below, respectively: 
     
                       TABLE 26                                                    
______________________________________                                    
COMPRESSION MOLDED ATTANE ™                                            
4602 POLYOLEFIN                                                           
For-                                    Valve Deliv-                      
mula-               Time       Leak Rate                                  
                                        ery (mg/                          
tion  ID     Stem   (Weeks)                                               
                           N   (mg/yr)  actuation)                        
______________________________________                                    
A3    80     ss     0      10  --       62.21 ± 0.76                   
                    6          1442 ± 595                              
                                        61.43 ± 1.65                   
      85     ss     0      10  --       62.37 ± 1.64                   
                    6          1611 ± 499                              
                                        61.31 ± 1.07                   
      90     ss     0      10  --       62.17 ± 0.65                   
                    6          1917 ± 1245                             
                                        61.45 ± 1.90                   
      95     ss     0      10  --       61.71 ± 0.47                   
                    6          1410 ± 720                              
                                        60.41 ± 4.32                   
      100    ss     0      10  --       61.46 ± 1.04                   
                    6          1177 ± 644                              
                                        54.14 ± 16.75                  
      105    ss     0      10  --       61.78 ± 1.17                   
                    6          1824 ± 2007                             
                                        61.58 ±  0.96                  
      80     pl     0      10  --       59.41 ± 0.34                   
                    6          285 ± 23                                
                                        58.38 ± 0.58                   
      85     pl     0      10  --       58.74 ± 1.70                   
                    6          390 ± 216                               
                                        56.81 ± 5.49                   
      90     pl     0      10  --       59.42 ± 0.62                   
                    6          316 ± 46                                
                                        58.40 ± 1.08                   
      95     pl     0      10  --       59.59 ± 0.62                   
                    6          440 ± 430                               
                                        56.25 ± 4.51                   
      100    pl     0      10  --       59.89 ± 0.64                   
                    6          328 ± 91                                
                                        59.84 ± 1.74                   
      105    pl     0      10  --       59.38 ± 1.03                   
                    6          419 ± 218                               
                                        60.04 ± 2.83                   
B2    80     ss     0      10  --       66.53 ± 0.92                   
                    6           802 ± 1034                             
                                        67.86 ± 0.81                   
      85     ss     0      10  --       66.14 ± 0.55                   
                    6          812 ± 425                               
                                        66.70 ± 0.72                   
      90     ss     0      10  --       66.18 ± 1.18                   
                    6          812 ± 644                               
                                        66.61 ± 0.85                   
      95     ss     0      10  --       65.97 ± 1.11                   
                    6          925 ± 712                               
                                        66.76 ± 0.80                   
      100    ss     0      10  --       66.02 ± 0.98                   
                    6          1067 ± 1137                             
                                        66.36 ± 1.03                   
      105    ss     0      10  --       66.29 ± 0.88                   
                    6          1169 ± 1462                             
                                        66.39 ± 1.96                   
      80     pl     0      10  --       63.92 ± 0.40                   
                    6          163 ± 17                                
                                        63.64 ± 0.95                   
      85     pl     0      10  --       63.72 ± 0.95                   
                    6          187 ± 31                                
                                        63.93 ± 0.70                   
      90     pl     0      10  --       64.26 ± 3.81                   
                    6          189 ± 42                                
                                        64.36 ± 0.82                   
      95     pl     0      10  --       63.57 ± 1.13                   
                    6          166 ± 13                                
                                        64.99 ± 3.07                   
      100    pl     0      10  --       63.55 ± 1.47                   
                    6          198 ± 38                                
                                        65.23 ± 2.72                   
      105    pl     0      10  --       65.46 ± 2.42                   
                    6          2334 ± 3940                             
                                        74.03 ± 33.09                  
______________________________________                                    
 
    
     
                       TABLE 27                                                    
______________________________________                                    
COMPRESSION MOLDED ATTANE ™                                            
4701 POLYOLEFIN                                                           
For-                                    Valve Deliv-                      
mu-                 Time       Leak Rate                                  
                                        ery (mg/                          
lation                                                                    
      ID     Stem   (Weeks)                                               
                           N   (mg/yr)  actuation)                        
______________________________________                                    
A3    80     ss     0      10  --       61.73 ± 0.81                   
                    6          2377 ± 394                              
                                        60.04 ± 3.46                   
      85     ss     0      10  --       62.27 ± 0.88                   
                    6          2263 ± 1534                             
                                        61.84 ± 0.71                   
      90     ss     0      10  --       62.37 ± 0.69                   
                    6          1817 ± 793                              
                                        61.98 ± 0.46                   
      95     ss     0      10  --       61.81 ± 0.63                   
                    6          2447 ± 2861                             
                                        61.09 ± 1.57                   
      100    ss     0      10  --       61.79 ± 0.79                   
                    6          2441 ± 1081                             
                                        61.35 ± 0.94                   
      105    ss     0      10  --       61.21 ± 0.85                   
                    6          1480 ± 867                              
                                        60.67 ±  0.92                  
      80     pl     0      10  --       59.51 ± 0.85                   
                    6          356 ± 71                                
                                        58.45 ± 0.84                   
      85     pl     0      10  --       59.43 ± 1.31                   
                    6          294 ± 21                                
                                        57.03 ± 2.39                   
      90     pl     0      10  --       59.62 ± 0.65                   
                    6          322 ± 59                                
                                        58.96 ± 0.62                   
      95     pl     0      10  --       59.50 ± 0.69                   
                    6          297 ± 26                                
                                        58.77 ± 1.03                   
      100    pl     0      10  --       57.92 ± 2.91                   
                    6          326 ± 33                                
                                        58.49 ± 0.99                   
      105    pl     0      10  --       57.30 ± 5.32                   
                    6          1093 ± 1193                             
                                        58.23 ± 0.71                   
B2    80     ss     0      10  --       66.58 ± 1.01                   
                    6          617 ± 382                               
                                        67.42 ± 1.08                   
      85     ss     0      10  --       67.25 ± 1.56                   
                    6          745 ± 610                               
                                        67.40 ± 0.72                   
      90     ss     0      10  --       66.75 ± 1.01                   
                    6          716 ± 489                               
                                        67.44 ± 1.01                   
      95     ss     0      10  --       66.86 ± 0.74                   
                    6          797 ± 602                               
                                        67.05 ± 0.76                   
      100    ss     0      10  --       66.36 ± 0.66                   
                    6          1145 ± 1080                             
                                        67.06 ± 0.41                   
      105    ss     0      10  --       66.18 ± 0.98                   
                    6          1020 ± 731                              
                                        66.33 ± 0.90                   
      80     pl     0      10  --       64.11 ± 0.44                   
                    6          176 ± 20                                
                                        63.87 ± 0.74                   
      85     pl     0      10  --       63.45 ± 1.06                   
                    6          175 ± 17                                
                                        63.97 ± 0.79                   
      90     pl     0      10  --       64.14 ± 0.47                   
                    6          177 ± 16                                
                                        63.40 ± 3.13                   
      95     pl     0      10  --       63.17 ± 2.12                   
                    6          200 ± 68                                
                                        64.89 ± 1.22                   
      100    pl     0      10  --       63.96 ± 0.82                   
                    6          197 ± 11                                
                                        64.09 ± 0.78                   
      105    pl     0      10  --       63.46 ± 0.58                   
                    6          254 ± 174                               
                                        64.50 ± 1.25                   
______________________________________                                    
 
    
     The results in TABLES 26 and 27 show that diaphragms of these materials are suitable but perform notably better with the indicated albuterol sulfate and beclomethasone dipropionate formulations when used with a plastic valve stem. 
     For comparative purposes, diaphragms were prepared from &#34;Buna&#34; rubber and from butyl rubber, both materials being commonly used in commercially available metered dose inhalers. These diaphragms were tested with formulations as indicated in TABLES 28 and 29 below: 
     
                       TABLE 28                                                    
______________________________________                                    
BUNA RUBBER                                                               
For-                                    Valve Deliv-                      
mu-                Time         Leak Rate                                 
                                        ery (mg/                          
lation                                                                    
      ID    Stem   (Weeks)                                                
                          N     (mg/yr) actuation)                        
______________________________________                                    
A5    83    ss     0      20/12 --      50.56 ± 1.70                   
                   4            386 ± 20                               
                                        51.11 ± 1.33                   
                   12           377 ± 14                               
                                        53.82 ± 1.77                   
      88    ss     0      20/12 --      52.81 ± 1.64                   
                   4            347 ± 49                               
                                        52.97 ± 1.33                   
                   12           392 ± 13                               
                                        54.19 ± 2.70                   
      93    ss     0      20/12 --      53.05 ± 1.42                   
                   4            345 ± 12                               
                                        51.88 ± 3.76                   
                   12           386 ± 13                               
                                        54.14 ± 1.79                   
      98    ss     0      20/12 --      53.88 ± 1.80                   
                   4            345 ± 16                               
                                        53.78 ± 1.02                   
                   12           388 ± 19                               
                                        54.05 ± 1.14                   
      83    pl     0      20/12 --      50.62 ± 0.71                   
                   4            312 ± 18                               
                                        49.00 ± 1.18                   
                   12            395 ± 160                             
                                        51.02 ± 0.71                   
      88    pl     0      20/12 --      53.32 ± 1.80                   
                   4            335 ± 12                               
                                        52.53 ± 2.37                   
                   12           380 ± 13                               
                                        53.71 ± 0.79                   
      93    pl     0      20/12 --      51.22 ± 0.75                   
                   4            324 ± 19                               
                                        49.94 ± 1.36                   
                   12           378 ± 22                               
                                        51.00 ± 0.45                   
      98    pl     0      20/12 --      51.27 ± 0.60                   
                   4            322 ± 12                               
                                        50.57 ± 0.62                   
                   12           368 ± 13                               
                                        51.13 ± 0.63                   
______________________________________                                    
 
    
     
                       TABLE 29                                                    
______________________________________                                    
BUTYL RUBBER                                                              
For-                                    Valve Deliv-                      
mu-                Time         Leak Rate                                 
                                        ery (mg/                          
lation                                                                    
      ID    Stem   (Weeks)                                                
                          N     (mg/yr) actuation)                        
______________________________________                                    
A5    83    ss     0      20/12 --      58.86 ± 2.59                   
                   4            174 ± 24                               
                                        57.98 ± 2.04                   
                   12           216 ± 16                               
                                        58.13 ± 3.15                   
      88    ss     0      20/12 --      57.86 ± 2.49                   
                   4            152 ± 9                                
                                        58.02 ± 1.27                   
                   12           197 ± 10                               
                                        58.39 ± 3.32                   
      93    ss     0      20/12 --      59.12 ± 2.19                   
                   4            151 ± 8                                
                                        58.72 ± 3.35                   
                   12           195 ± 9                                
                                        58.92 ± 3.46                   
      98    ss     0      20/12 --      58.74 ± 2.54                   
                   4            168 ± 28                               
                                        58.02 ± 2.14                   
                   12           208 ± 30                               
                                        60.59 ±  4.11                  
      83    pl     0      20/12 --      55.92 ± 0.59                   
                   4            159 ± 12                               
                                        54.45 ± 1.73                   
                   12            247 ± 160                             
                                        54.62 ± 1.04                   
      88    pl     0      20/12 --      56.31 ± 0.28                   
                   4            169 ± 25                               
                                        54.50 ± 3.10                   
                   12           218 ± 22                               
                                        54.37 ± 2.59                   
      93    pl     0      20/12 --      56.20 ± 0.73                   
                   4            161 ± 14                               
                                        54.32 ± 1.58                   
                   12           211 ± 15                               
                                        55.04 ± 0.78                   
      98    pl     0      20/12 --      56.67 ± 1.11                   
                   4            156 ± 11                               
                                        55.16 ± 0.43                   
                   12           204 ± 11                               
                                        55.24 ± 0.78                   
______________________________________                                    
 
    
     The results in TABLES 28 and 29 show that, when used with the indicated formulations, &#34;Buna&#34; diaphragms generally exhibit leak rates higher than 300 mg/yr with generally acceptable valve delivery variability. The results also show that the butyl rubber diaphragms exhibit acceptable leak rates when used with the indicated formulations but valve delivery variability is not acceptable. 
     Diaphragms of the invention were prepared from the materials set forth in TABLES 30 and 31 and tested with the indicated formulations. In said TABLES, Valve &#34;A&#34; indicates that the valve used was a valve with a stainless steel valve stem, substantially as described herein and illustrated in the Drawing. Valve &#34;B&#34; indicates that the valve used was a 50 μL SPRAYMISER™ aerosol valve (Neotechnic Engineering Ltd.). 
     
                                           TABLE 30                                
__________________________________________________________________________
DIAPHRAGM PERFORMANCE WITH HFC-227 FORMULATIONS                           
                                 N = 10  N = 5                            
       Diaphragm            Time Leak Rate                                
                                         Valve Delivery                   
Formulation                                                               
       Material         Valve                                             
                            (Weeks)                                       
                                 (mg/hr) ± SD                          
                                         (mg/actuation)                   
__________________________________________________________________________
                                         ± SD                          
P      GERS 1085 NT     A   0    --      67.78 ± 0.51                  
                            3    13 ± 6                                
                                         65.22 ± 1.13                  
                        B   0    --      65.84 ± 1.14                  
                            3     8 ± 8                                
                                         66.08 ± 0.70                  
        ##STR1##        A   0 3  -- 12 ± 6                             
                                         66.40 ± 4.30 68.34 ± 0.86  
                        B   0    --      68.20 ± 1.02                  
                            3     3 ± 4                                
                                         68.68 ± 0.64                  
        ##STR2##        A   0 3  -- 15 ± 6                             
                                         69.08 ± 1.32 67.58 ± 1.70  
                        B   0    --      69.34 ± 0.89                  
                            3     6 ± 5                                
                                         68.94 ± 0.36                  
       Attane ™ 4602 A   0    --      70.72 ± 0.52                  
                            3    11 ± 3                                
                                         67.86 ± 1.99                  
                        B   0    --      70.70 ± 0.56                  
                            3    32 ± 59                               
                                         69.46 ± 3.16                  
       Attane ™ 4701 A   0    --      70.84 ± 1.23                  
                            3    12 ± 8                                
                                         69.78 ± 1.57                  
                        B   0    --      70.14 ± 2.10                  
                            3     5 ± 6                                
                                         69.76 ± 1.42                  
__________________________________________________________________________
 
    
     
                                           TABLE 31                                
__________________________________________________________________________
DIAPHRAGM PERFORMANCE WITH HFC-227 FORMULATIONS                           
                                 N = 10  N = 5                            
       Diaphragm            Time Leak Rate                                
                                         Valve Delivery                   
Formulation                                                               
       Material         Valve                                             
                            (Weeks)                                       
                                 (mg/hr) ± SD                          
                                         (mg/actuation)                   
__________________________________________________________________________
                                         ± SD                          
A7     GERS 1085 NT     A   0     --     68.27 ± 6.23                  
                            *     47 ± 9                               
                                         40.60 ± 28.88                 
                        B   0     --     75.42 ± 1.64                  
                            *     41 ± 9                               
                                         75.60 ± 0.91                  
        ##STR3##        A   0 *   --  66 ± 56                          
                                         75.88 ± 3.74 21.22 ± 7.61  
                        B   0     --     78.30 ± 1.13                  
                            *     37 ± 9                               
                                         77.92 ± 0.25                  
        ##STR4##        A   0 *   --  50 ± 14                          
                                         74.84 ± 1.62 76.70 ± 2.23  
                        B   0     --     79.70 ± 4.78                  
                            *     37 ± 9                               
                                         78.33 ± 0.71                  
       Attane ™ 4602 A   0     --     79.10 ± 4.46                  
                            *    7047 ± 4844                           
                                         80.00 ± 1.95                  
                        B   0     --     78.60 ± 0.83                  
                            *     60 ± 55                              
                                         58.82 ± 28.9                  
       Attane ™ 4701 A   0     --     77.44 ± 2.67                  
                            *     43 ± 8                               
                                         77.48 ± 12.02                 
                        B   0     --     76.30 ± 3.50                  
                            *     30 ± 15                              
                                         66.60 ± 13.02                 
__________________________________________________________________________
 *leak rate measured over one week during the fourth week of storage at   
 30°  C. The valve delivery measurements, however, were made after 
 weeks of storage at 30° C.                                        
 
    
     The results in TABLES 30 and 31 indicate that these diaphragms of the invention function as seal materials for use in the dynamic pressure seal of a metered dose inhaler containing a formulation that comprises HFC-227. Furthermore, these data demonstrate the dramatic difference in valve delivery variability depending on the presence of a small amount of ethanol as a formulation component and the nature of the drug substance. The difference between valve A and valve B is especially clear in TABLE 31 where Valve A affords unsatisfactory valve delivery variability while valve B exhibits very low variability. Within a valve type, for example valve B, the material from which the diaphragm is constructed also has an important effect, which is illustrated by the results for GERS 1085 NT and the several blends on one hand, and ATTANE™ 4602 and ATTANE™ on the other hand.