the terms “ active drug ,” “ active ingredient ,” “ active ,” “ active compound ”, “ active substance ,” “ medicament ,” and “ therapeutic agent ” are used synonymously . ‘ the terms “ nozzle block ” or “ nozzle assembly ” are synonyms to define an almost cylindrical element , which accommodates the valve stem of the aerosol canister and directs the emitted dose towards the mouthpiece . it rigidly extends in the actuator housing adapted to receive the canister from a central internal position of its base . the term “ aligned ” when referring to two axes means “ coinciding or parallel to each other ”. by “ substantially aligned with ” it is meant that the axes deviate by less 30 °, preferably less than 15 °, more preferably less than 5 °, even more preferably less than 3 °, even more preferably less than 2 °, even more preferably less than 1 °. by “ substantially coinciding with ” it is meant that the axes deviate by less 30 °, preferably less than 15 °, more preferably less than 5 °, even more preferably less than 3 °, even more preferably less than 2 °, even more preferably less than 1 °, and that the axes are offset by no more than 10 mm , preferably no more than 5 mm , more preferably no more than 2 mm , even more preferably no more than 1 mm , even more preferably no more than 0 . 5 mm , even more preferably no more than 0 . 1 mm . the term “ longitudinal axis ” refers to a center longitudinal axis of the respective concavity of component . “ respirable fraction ” also defined as “ fine particle fraction ” refers to an index of the percentage of active particles which would reach the deep lungs in a patient . the respirable fraction is calculated by the ratio between the “ respirable dose ” and the “ delivered dose .” they are evaluated in vitro using a next generation impactor ( ngi ) fitted with an induction port ( apparatus e , european pharmacopoeia 8 th ed . suppl 8 . 5 , 2014 , which is incorporated herein by reference in its entirety ). the “ delivered dose ” is determined from the cumulative deposition in the apparatus , while the “ respirable dose ,” also defined as “ fine particle dose ” ( fpd ) is calculated as the amount of particles with aerodynamic diameter less or equal to 5 μm . the “ extra - fine particle dose ” ( efpd ) is etermined as the amount of particles with aerodynamic diameter less or equal to 1 μm . the “ non - respirable ” dose is the amount of larger aerosol particles that , upon inhalation , impact within the mouth and throat of the patient and may be swallowed , potentially causing side effects . it is mainly determined by the amount of the emitted aerosol particles blocked at the level of the induction port . exemplary embodiments of the invention will now be described with reference to the drawings . the features of the embodiments may be combined with each other unless specifically stated otherwise . fig2 a is a schematic lateral cross - sectional view taken along the center symmetry plane , of an actuator 1 ′ for a pmdi inhaler according to the present invention comprising , in its vertical hollow portion , a housing adapted to receive a canister 2 . the canister 2 contains an aerosol formulation wherein one or more medicament is in solution or in suspension in a pressure liquified low boiling point propellant system optionally comprising at least one suitable pharmaceutically acceptable additive . the canister 2 may be configured as a conventional canister for a pmdi , provided with a metering valve and a hollow valve stem 3 . the metering valve , allows a metered dose of the medicament formulation to be dispensed through the hollow valve stem 3 on each actuation . the actuator 1 ′ includes a nozzle assembly or nozzle block 5 , which may be integrally formed with the housing of the actuator . the nozzle block 5 defines the walls of the valve stem receptacle 13 , an expansion chamber or sump 6 , and a nozzle channel 7 , which ends in an aperture 8 , having an enlarging frusto - conical section . the nozzle channel 7 has been provided such that its longitudinal axis is aligned with a longitudinal axis 9 of the actuator mouthpiece portion 14 , so that the aerosol cloud 4 exits the channel in a mean direction towards its opening 15 . the mouthpiece portion 14 central longitudinal axis 9 , aligned with the longitudinal axis of the nozzle channel 7 , is located at an angle greater or equal to 90 ° to the direction of the longitudinal axis of the hollow valve stem 3 of the aerosol canister 2 and terminates in a mouthpiece opening 15 , through which the user inhales . the angle between the longitudinal axis 9 of the mouthpiece portion 14 and the longitudinal axis of the hollow valve stem 3 is preferably in the range from approximately 90 ° to approximately 120 °, and more preferably from approximately 90 ° to approximately 110 °. the mouthpiece portion 14 , terminating in a mouthpiece through which the user inhales , comprises a central rounded opening 15 of a defined width and distance d from the nozzle channel external aperture 8 and whose central axis is aligned with the central longitudinal axis 9 of the actuator mouthpiece portion 14 , substantially coinciding with the central longitudinal axis of the nozzle channel 7 . the said central rounded opening 15 has a reduced width with respect to a typical mouthpiece 10 of a conventional pmdi actuator 1 as shown in fig1 , which is normally totally opened ( as being defined by the parallel lateral walls of the mouthpiece portion of the actuator ). the central rounded opening 15 is configured on a planar surface 16 normal to the lateral walls of the mouthpiece portion 14 and has a shape that could be selected from circular , elliptical and ovoidal shape but the circular shape , as shown in fig2 b is preferred . in an alternative embodiment as shown in the actuator of fig3 , the central opening is located on a convex , rounded frustoconical restriction of the walls of the mouthpiece portion . the width of the central rounded opening 15 of the actuator with circular shape is defined by its internal diameter d of the opening . the said diameter is selected in the range which is from 5 to 14 mm , preferably from 8 to 12 mm , even more preferably from 9 to 12 mm and the particularly preferred diameter is selected from about 9 , 10 , 11 , and 12 mm . in this case , manufacturing tolerances of from ± 0 . 3 to ± 0 . 1 mm are acceptable and are also included in the present invention . the width of central rounded opening 15 of the actuator with ellipsoidal or ovoidal shape is defined by its respective area , corresponding to the area of the circular shape opening with the diameter selected in the range as described above . in particular , the corresponding area is from 20 to 153 mm 2 , preferably from 50 to 113 mm 2 , even more preferably from 64 to 113 mm 2 , and the particularly preferred area is selected from about 64 , 79 , 95 and 113 mm 2 . the central rounded opening 15 has a distance d from the nozzle channel external aperture 8 which is from 16 to 58 mm , preferably from 28 . 5 to 58 mm , even more preferably from 38 . 5 to 54 . 1 mm , and the particularly preferred length is selected from about 38 . 5 , 41 . 0 , 50 . 3 , and 54 . 1 mm . in this case , manufacturing tolerances of from ± 0 . 5 to ± 0 . 0 . 2 mm are acceptable and are also included in the invention . fig4 a to 4 f are schematic different views of an embodiment of the present invention wherein a circular shaped mouthpiece opening is provided on a tubular element to be securely snapped into place with the external mouthpiece portion of a conventional actuator 1 of fig1 as shown in fig2 a and 2 b . fig4 a and fig4 b represent respectively an upper and a lateral view of the tubular element having the circular shaped mouthpiece opening according to the invention . fig4 c and fig4 d represent , respectively , section views of fig4 a on the plane a - a , and fig4 b on the plane b - b . fig4 e is a front view from the side of the circular mouthpiece opening and fig4 f is a schematic perspective view of the tubular element . as shown in the figures , one side of said tubular member is provided with a circular shaped mouthpiece opening 15 of diameter d according to the invention ( fig4 e ). the other side of said tubular member , opposite to the mouthpiece opening , is provided with an opening with suitable shape and dimensions as to be fitted and to be securely snapped into place over the external mouthpiece portion 14 of an actuator 1 as shown in fig2 a and 2 b so that the distance d between the circular mouthpiece opening 15 and the nozzle channel external aperture 8 is maintained the same as above described . in an alternative embodiment the other side of said tubular member , opposite to the circular mouthpiece opening , is provided with an opening with suitable shape and dimensions as to be fitted and to be securely snapped into place internally to the mouthpiece portion 14 of the actuator 1 of fig1 . the thickness t of the wall 16 defining the central opening 15 of the actuator mouthpiece according to the invention as shown in fig2 a is defined by the conventional thickness of the walls of the mouthpiece portion for a pmdi device , well known to the skilled in the art . however , as shown for instance in fig4 d , a suitable thickness t of the wall defining the central opening may be from 0 . 1 to 3 mm or more , preferably from 0 . 2 to 2 mm , more preferably from 0 . 8 to 1 . 8 mm and most preferably of 1 or 1 . 5 mm . in this case , manufacturing tolerances of from ± 0 . 05 to ± 0 . 2 mm are acceptable and are also included in the present invention . in an alternative embodiment , as schematically shown in fig6 , the profile of the central circular opening has the edge facing towards the inside of the mouthpiece portion with an internal extension of the edge forming an angle a of 90 ° with respect to the plane of the wall defining the central opening . in alternative embodiments , the angle a may be selected in the range from 30 ° to 150 °, preferably from 45 ° to 135 °, even more preferably from 80 ° to 120 ° and the most preferred is 90 °± 2 ° and in particular it is selected from 88 °, 89 °, 90 °, 91 °, and 92 °. the said internal extension of the edge may have the shape of a cylindrical recess when the angle a = 90 °, as shown also in a schematic perspective view in fig5 g , or the shape of a truncated cone whose larger base and smaller base may represent the mouthpiece opening when the angle is , respectively , 90 °& lt ; a & lt ; 150 ° and 30 °& lt ; a & lt ; 90 °. in this case , manufacturing tolerances of ± 2 ° are acceptable and are also included in the present invention . fig5 a to 5 g are schematic different views of an alternative embodiment of the tubular element to be securely snapped into place with the external mouthpiece portion of the actuator and wherein the profile of the central opening has the edge facing towards the inside of the mouthpiece . the extension of the edge forms an angle a of 90 ° with respect to the plane of the central opening , similarly to that of fig6 . fig5 a and fig5 b represent respectively an upper and a lateral view of the tubular element . fig5 c and fig5 d represent , respectively , section views of fig5 a on the plane a - a , and fig5 b on the plane b - b . fig5 e is a front view from the side of the circular mouthpiece opening , fig5 f is a schematic perspective view of the tubular element and fig5 g is another schematic perspective view wherein is visible the cylindrical recess formed by the central opening edges , facing towards the inside of the mouthpiece . the other side of said tubular member , opposite to the mouthpiece opening , and the thickness of its walls have the same features as those above described for the tubular element of fig4 a to 4 e . in this case , however , as shown in fig5 d , the cylindrical recess formed by the central opening edges , facing towards the inside of the mouthpiece , has a length t from 2 to 15 mm , preferably 4 to 10 mm and even more preferably the length t is selected among 4 , 5 , and 6 mm . in another embodiment , the tubular element provided with the central rounded opening of the invention to be snapped into place with the external mouthpiece portion of the actuator may be formed of the same material as the actuator or of a different material and may be molded as separate parts . in a further alternative embodiment , the tubular element provided with the central rounded opening of the invention and the rest of the actuator may be molded in one piece , as a single unit , through single injection molding tools . examples of suitable materials for the actuator and or of the tubular element of the invention include metal materials such as aluminium , aluminium alloy or stainless steel ; but also plastic polymeric materials , such as thermoplastic resins , optionally uv curable , including different grades of polypropylene ( pp ), the material of first choice in general for the pmdi actuators , but also polyethylene ( pe ), such as high density pe ( hdpe ); fluorinated polymers such as polytetrafluoroethylene ( ptfe ), fluorinated ethylene - propylene ( fep ), perfluoroalkoxy alkane ( pfa ); acrylonitrile - butadiene - styrene ( abs ); polyacrylate such as polymethyl methacrylate ( pmma ); polycarbonate ( pc ); polyamide ( pa , i . e . nylon ); polyamideimide ( pai ); polyimide ( pi ); polyesters such as polyethylene terephthalate ( pet ), polybutylene terephthalate ( pbt ); polysulfone ( ps ); polyarylsulfone ( pas ); polyethersulfone ( pes ); and polydimethylsiloxane ( pdms ). moreover the said plastic polymeric materials may be coated with antistatic agents by means of a molding or a coating process . the pmdi devices are known . said devices comprise a canister fitted with a metering valve . part or the entire canister may be made of a metal , for example aluminium , aluminium alloy , stainless steel or anodized aluminium . alternatively the canister may be a plastic can or a plastic - coated glass bottle . the metal canisters may have part or all of their internal surfaces lined with an inert organic coating . examples of preferred coatings are epoxy - phenol resins , perfluorinated polymers such as perfluoroalkoxyalkane , perfluoroalkoxyalkylene , perfluoroalkylenes such as poly - tetrafluoroethylene ( teflon ), fluorinated - ethylene - propylene ( fep ), polyether sulfone ( pes ) or fluorinated - ethylene - propylene polyether sulfone ( fep - pes ) mixtures or combination thereof . other suitable coatings could be polyamide , polyimide , polyamideimide , polyphenylene sulfide or their combinations . canisters having their internal surface lined with fep - pes or teflon may be used . canisters made of stainless steel may also be used . the canister is closed with a metering valve for delivering a therapeutically effective dose of the active ingredient . generally the metering valve assembly comprises a ferrule having an aperture formed therein , a body molding attached to the ferrule which houses the metering chamber , a stem consisting of a core and a core extension , an inner - and an outer - seal around the metering chamber , a spring around the core , and a gasket to prevent leakage of propellant through the valve . the gasket seal and the seals around the metering valve may comprise elastomeric material such as epdm , chlorobutyl rubber , bromobutyl rubber , butyl rubber , or neoprene . epdm rubbers are particularly preferred . the metering chamber , core and core extension are manufactured using suitable materials such as stainless steel , polyesters ( e . g . polybutyleneterephthalate ( pbt )), or acetals . the spring is manufactured from stainless steel eventually including titanium or other inert metal alloys . the ferrule may be made of a metal , for example aluminium , aluminium alloy , stainless steel or anodized aluminium . suitable valves are available from manufacturers such as valois , bespak plc and 3m - neotechnic ltd . the pmdi is actuated by a metering valve capable of delivering a volume of 25 to 100 μl preferably 40 to 70 μl and optionally 50 μl , or 63 μl per actuation . in a typical arrangement , the valve stem is seated in a nozzle block communicating to an expansion chamber or sump . the expansion chamber has a nozzle channel terminating in an aperture which extends into the mouthpiece . nozzle channels having a diameter in the range 0 . 15 to 0 . 45 mm and a length from 0 . 30 to 1 . 7 mm are generally suitable . preferably , a nozzle channel having a diameter from 0 . 2 to 0 . 44 mm is used , and in particular nozzle channel diameter of 0 . 22 , 0 . 25 , 0 . 30 , 0 . 33 , or 0 . 42 mm is particularly preferred . it may be useful to utilize actuators with nozzle channels having a diameter ranging from 0 . 10 to 0 . 22 mm , in particular from 0 . 12 to 0 . 18 mm , such as those described in wo 03 / 053501 , which is incorporated herein by reference in its entirety . the use of said fine orifices may also increase the duration of the cloud generation and , hence , may facilitate the coordination of the cloud generation with the slow inspiration of the patient . the canister contains an aerosol formulation which may be an aerosol solution formulation or an aerosol suspension formulation . the aerosol formulation may contain at least one active ingredient in a propellant or in a propellant / solvent system and , optionally , further pharmaceutical acceptable additive or excipient . the at least one active ingredient of the formulation may be any known pharmaceutical active ingredient , administrable by inhalation alone or in combination for separate , sequential or simultaneous use . preferably the active ingredient is known for prophylaxis or treatment of respiratory diseases and their symptoms , and in particular in diseases characterized by obstruction of the peripheral airways as a result of inflammation and presence of mucus , such as asthma of all types , chronic obstructive pulmonary disease ( copd ), asthma - copd overlap syndrome ( acos ), bronchiolitis , chronic bronchitis , emphysema , acute lung injury ( ali ), cystic fibrosis , and adult or acute respiratory distress syndrome ( ards ). the at least one active ingredient is selected from beta - 2 agonists , inhaled corticosteroids , anti - muscarinic agents , phosphodiesterase iv inhibitors , dual muscarinic antagonist and beta - 2 - agonist , and combinations thereof . more preferably the beta - 2 agonist is selected from salbutamol , ( r )- salbutamol ( levalbuterol ) fenoterol , formoterol ( including the dihydrate ), arformoterol , carmoterol ( ta - 2005 ), indacaterol , milveterol , vilanterol , olodaterol , abediterol , terbultaline , salmeterol , bitolterol , procaterol and metaproterenol in form of single stereoisomers , diastereoisomeric mixtures , and a pharmaceutically acceptable salt thereof or hydrate thereof . more preferably the inhaled corticosteroid is selected from beclometasone dipropionate , fluticasone propionate , fluticasone furoate , butixocort , mometasone furoate , triamcinolone acetonide , budesonide and its 22r - epimer , ciclesonide , flunisolide , loteprednol , and rofleponide . more preferably the anti - muscarinic agent is selected from methscopolamine , ipratropium , oxitropium , tiotropium , glycopyrronium , aclidinium , umeclidinium , trospium and a salt thereof with a pharmaceutical acceptable counter ion . more preferably the phosphodiesterase iv inhibitor is selected from cilomilast , piclomilast , roflumilast , tetomilast , chf 6001 , rpl 554 and a pharmaceutically acceptable salt thereof . even more preferred active ingredients may be selected from beclometasone dipropionate , fluticasone propionate , fluticasone furoate , mometasone furoate and budesonide alone or in combination with one or more active ingredient selected from salbutamol , formoterol , salmeterol , indacaterol , vilanterol , glycopyrronium , tiotropium , aclidinium , umeclidinium and a salt thereof . the most preferred active ingredients are selected from beclometasone dipropionate , budesonide , formoterol fumarate ( including the dihydrate ), beclometasone dipropionate - salbutamol sulphate combination , beclometasone dipropionate - formoterol fumarate ( including the dihydrate ) combination and beclometasone dipropionate - formoterol fumarate ( including the dihydrate )- glycopyrronium bromide combination . the propellant may be any pressure - liquefied propellant and is preferably a hydrofluoroalkane ( hfa ), a hydrofluoroolefin ( hfo ) or a mixture of different hfas or hfos or , more preferably , it is selected from the group consisting of hfa 134a ( 1 , 1 , 1 , 2 - tetrafluoroethane ), hfa 227 ( 1 , 1 , 1 , 2 , 3 , 3 , 3 - heptafluoropropane ), and mixtures thereof . the solvent which may be incorporated into the formulation has generally a higher polarity than that of the propellant and may include one or more substances selected from a pharmaceutically acceptable alcohol or a polyol . advantageously the solvent is selected from the group of lower branched or linear alkyl ( c 1 - c 4 ) alcohols such as ethanol and isopropyl alcohol . preferably , the solvent is ethanol . it is preferred that the at least one pharmaceutically active ingredient of the formulation is substantially completely and homogeneously dissolved in the propellant / solvent , system , i . e . the composition is preferably a solution formulation . optionally the formulation may comprise other known pharmaceutical acceptable additives or excipients which are substantially inert materials which are non - toxic and do not interact in negative manner with other components of the formulation . in particular , the formulation may comprise one or more solvents , surfactants , carbohydrate , phospholipid , polymer , wetting agent , stabilizers , lubricants , or low volatility components . among the stabilizers , it is envisaged to use a suitable amount of an acid which may be organic or inorganic acid ( mineral acids ) which may be selected from pharmaceutically acceptable monoprotic or polyprotic acid , such as ( but not limited to ): hydrogen halides ( hydrochloric acid , hydrobromic acid , hydroiodic acid , etc . ), phosphoric acid , nitric acid , sulphuric acid , and halogen oxoacids . low volatility components are useful in order to increase the mass median aerodynamic diameter ( mmad ) of the aerosol particles upon actuation of the inhaler and / or to improve the solubility of the active ingredient in the propellant / solvent system . the low volatility component , when present , has a vapour pressure at 25 ° c . lower than 0 . 1 kpa , preferably lower than 0 . 05 kpa . examples of low - volatility components are esters such as isopropyl myristate , ascorbyl myristate , tocopherol esters ; glycols such as propylene glycol , polyethylene glycol ; or polyols such as glycerol ; and surface active agents such as saturated organic carboxylic acids ( e . g . lauric , myristic , stearic acid ) and unsaturated carboxylic acids ( e . g . oleic or ascorbic acid ). the amount of low volatility component may vary from 0 . 1 to 10 % w / w , preferably from 0 . 5 to 5 % ( w / w ), more preferably from 1 and 2 % ( w / w ), based on the entire weight of the formulation . in another embodiment , an amount of water comprised between 0 . 005 and 0 . 3 % ( w / w ), based on the total weight of the formulation , may optionally be added to the formulations in order to favourably affect the solubility of the active ingredient without increasing the mmad of the aerosol droplets upon actuation . other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof . a range of actuators according to the present invention , terminating in a mouthpiece opening through which the user inhales , comprising a central circular opening of a defined width and distance from the nozzle channel external aperture were designed and manufactured . in particular said opening was designed on a tubular element to be securely snapped into place with the external mouthpiece portion of a conventional actuator 1 of fig1 a or 1 b as shown in fig2 a and 2 b , wherein the basic premise of the design and the respective diameter d and distance d of the tested geometries are represented . the tubular elements were manufactured in polypropylene ( pp ), the same material of the actuator . all the tubular elements were fitted on actuators with 0 . 30 mm nozzle channel diameter . the actuators provided with the tubular element based on fig2 a and 2 b were tested with respect to a conventional actuator of fig1 a and 1 b with 0 . 30 mm nozzle channel diameter . the experiments used pressurised solution formulations of beclometasone dipropionate ( bdp ) 25 μg / actuation in hfa 134a ethanol , added with different amount of glycerol , as low volatility component , to simulate formulations emitting , after evaporation , fine , medium and coarse aerosol particles . each formulation , detailed in table 1 , was manufactured according to wo 98 / 56349a1 , which is incorporated herein by reference in its entirety , packaged in a standard aluminium 19 ml canister , fitted with a conventional 63 μl valve . drug delivery characterization of the actuators according to the invention , in comparison with a conventional actuator , in conjunction with the bdp formulation of table 1 , was determined with a fast screening andersen ( fsa ) cascade impactor ( from copley scientific ) an abbreviated version of the standard full - resolution andersen cascade impactor ( aci ) a suitably modified version of the andersen cascade impactor ( apparatus d , european pharmacopoeia 8 th ed . suppl 8 . 5 , 2014 , which is incorporated herein by reference in its entirety ). two replications for each configuration were performed . the procedure according to common pharmacopoeias , was conducted at a flow rate of 28 . 3 (± 5 %) l / min and the drug deposition in each stage and in the induction port was quantified by hplc / uv ( high - performance liquid chromatography / uv detection ). the performance of each actuator with the three different kinds of formulations ( fine , medium , coarse ) in terms of induction port ( ip ) deposition , fine particle dose ( fpd ) and extra - fine particle dose ( e - fpd ) is reported in the following tables 3a , 3b , 3c and 3d . the results showed that through changes in the mouthpiece actuator shape the oropharyngeal deposition of the aerosol ( corresponding to the induction port ( ip ) deposition ) could be significantly decreased , with respect to a conventional actuator , without affecting the aerodynamic particle size distribution performance . in particular the configuration of actuator 3 with a circular mouthpiece opening having a diameter 10 mm placed at a distance of 38 . 5 mm from the nozzle channel aperture allows to halve the ip deposition keeping almost constant the fine and extra - fine particle dose of pressurized solution formulations independently from the fact they may originate fine , medium or coarse particles depending from their level in low volatility component . drug delivery tests on the actuator according to the present invention were performed by using three different pmdi products available in the market and compared with the data obtained with their respective actuator with which they are sold . the tested actuator was the conventional actuator of the marketed product provided with the tubular element according to the invention with a central circular opening of 10 mm diameter ( d ), at a distance ( d ) of 38 . 5 mm from the nozzle channel aperture of the nozzle block , corresponding to a ratio diameter / distance d / d = 0 . 26 . ( 1 ) atimos pmdi , containing a formulation of formoterol fumarate ( ff ), 12 μg / actuation , dissolved in a solution of fifa 134a , ethanol and hydrochloric acid ; ( 2 ) foster pmdi , containing a formulation of the combination of formoterol fumarate ( ff ), 6 μg / actuation , and beclometasone dipropionate ( bdp ) 100 mg / actuation both dissolved in a solution of hfa 134a , ethanol and hydrochloric acid ; and ( 3 ) clenil 100 pmdi , containing a formulation of beclometasone dipropioate ( bdp ), 100 μg / actuation , dissolved in a solution of hfa 134a , ethanol and glycerol as low volatility component . the drug delivery characterization of the actuators according to present the invention , in comparison with the conventional actuator was conducted in vitro using a next generation impactor ( ngi ) fitted with an induction port ( apparatus e , european pharmacopoeia 8 th ed . suppl 8 . 5 , 2014 , which is incorporated herein by reference in its entirety ) set at a flow rate of 30 l / min . three replicaations for each product were performed except for foster wherein four replications were used . validated hplc methods were used for the determination of the two drugs . the performance of each actuator with the three different products in terms of induction port ( ip ) deposition , fine particle dose ( fpd ) and extra - fine particle dose ( e - fpd ) plus the respective standard deviations (± sd ) and percent variation between actuator according to the invention versus conventional actuator is reported in the following tables 4a to 4 c . opening of d = 10 mm and d = 38 . 5 mm ( d / d = 0 . 26 ) opening of d = 10 mm and d = 38 . 5 mm ( d / d = 0 . 26 ) opening of d = 10 mm and d = 38 . 5 mm ( d / d = 0 . 26 ) in the results confirmed that the actuator according to the present invention significantly reduced by about − 63 %, − 46 %/− 47 %, and − 42 % the induction port ( ip ) deposition ( corresponding to the amount of “ non - respirable ”, larger aerosol particles that , upon inhalation , impact within the mouth and throat of the patient ) respectively of atimos , foster , and clenil active ingredients in comparison with a conventional actuator . on the contrary , no significant differences were shown in the fine particle dose ( fpd ) between the actuator of the invention and conventional actuators . in fact , according to the ema ( european medicines agency ) guideline cpmp / ewp / 4151 / 00 rev . 1 , which is incorporated herein by reference in its entirety , differences within ± 15 % are considered equivalent . the only exception was for formoterol in foster which resulted in − 19 % which is , however , very close to the limit . drug delivery investigations on the actuator according to the present invention , consisting of a conventional actuator provided with a tubular element with a central circular opening of 10 mm diameter ( d ), at a distance ( d ) of 38 . 5 mm ( d / d = 0 . 26 ) from the nozzle channel aperture of the nozzle block were also performed by using a pmdi containing a triple combination of three different active ingredients dissolved in the formulation . in the experiment a solution formulation of beclometasone dipropionate ( bdp ) 100 μg / actuation , formoterol fumarate ( ff ), 6 μg / actuation , and glycopyrronium bromide ( gly ), 12 . 5 μg / actuation , detailed in table 5 and manufactured according to wo 2011076843a1 , which is incorporated herein by reference in its entirety , was used . the formulation was packaged in 19 ml canister fitted with a conventional 63 μl valve and a conventional actuator with 0 . 30 mm orifice diameter . the drug delivery characterization of the actuator according to the present invention , in comparison with the conventional actuator was conducted in vitro , as reported for example 2 . validated hplc methods were used for the determination of the three drugs . the performance of each actuator , in terms of induction port ( ip ) deposition , fine particle dose ( fpd ) and extra - fine particle dose ( e - fpd ) plus the respective standard deviations (± sd ) and percent variation between actuator according to the invention versus conventional actuator , is reported in the following table 6 . for all the three active ingredients , there is no significant difference in the fne fpd and e - fpd between the actuator of the invention and a conventional actuator . for all the three active ingredients , the actuator according to the invention reduced the ip deposition of about 50 %. further drug delivery tests were performed by using the marketed foster pmdi product of example 2 , containing a formulation of the combination of formoterol fumarate , 6 μg / actuation ( ff ), and beclometasone dipropionate ( bdp ), 100 μg / actuation , both dissolved in a solution of hfa 134a , ethanol and hydrochloric acid . the product was tested with the conventional actuator of the marketed product provided with two different tubular elements of fig4 a - 4 f according to the invention , with a central circular opening of 10 mm and 11 mm diameter ( d ), at a distance ( d ) respectively of 38 . 5 mm and 42 . 15 mm from the nozzle channel aperture of the nozzle block ( d / d = 0 . 26 in both cases ) and produced by 3d - printing with a conventional 3d - printing photopolymer material ( rgd875 veroblackplus ). the data were compared with those obtained with the conventional actuator with which the product is sold . the methods were the same as those described in example 2 , with three replicas performed . validated hplc methods were used for the determination of the two drugs . the data showed that 3d - printed tubular element according to the invention still reduced the induction port deposition of both the active ingredients of values higher than 50 % (− 55 /− 57 % and − 68 /− 61 %) with respect to a conventional actuator but without significatively affecting the particle size distribution performance and in particular the fine and extra - fine particle dose . drug delivery tests were performed by using the marketed foster pmdi product of example 2 , containing a formulation of the combination of formoterol fumarate , 6 μg / actuation , ( ff ) and beclometasone dipropionate ( bdp ), 100 μg / actuation , both dissolved in a solution of hfa 134a , ethanol and hydrochloric acid . the product was tested with the conventional actuator of the marketed product provided with the tubular element of fig5 a - 5 g according to the invention , with a central circular opening of 11 mm diameter ( d ), at a distance ( d ) of 45 mm from the nozzle channel aperture of the nozzle block ( d / d = 0 . 245 ) having a cylindrical recess , formed by the central opening edges , facing towards the inside of the mouthpiece portion , at an angle a of 90 °, with respect to the plane of the wall defining the central opening , for a length t of 5 mm , produced by 3d - printing with a conventional 3d - printing photopolymer material ( rgd875 veroblackplus ). the data were compared with those obtained with the conventional actuator with which the product is sold . the methods used for the study were the same as those described in example 2 with three replications . validated hplc methods were used for the determination of the two drugs . the data showed that an optimised 3d - printed tubular element according to the invention having a cylindrical recess , facing towards the inside of the mouthpiece portion , still reduced the induction port deposition of both the active ingredients to values higher than 70 % (− 72 % and − 74 %) with respect to a conventional actuator but without significatively affecting the particle size distribution performance and in particular the fine and extra - fine particle dose ( differences lower than 10 %). drug delivery tests were performed by using the formulation of example 3 ( table 5 , constituted by a pressurised solution formulation of beclometasone dipropionate ( bdp ), 100 μg / actuation , formoterol fumarate ( ff ), 6 μg / actuation , and glycopyrronium bromide ( gly ) 12 . 5 μg / actuation . the product , packaged in 19 ml canister fitted with a conventional 63 μl valve was tested with a conventional actuator with 0 . 30 mm orifice provided with the tubular element of fig5 a - 5 g according to the invention , having a central circular opening of 11 mm diameter ( d ), at a distance ( d ) of 45 mm from the nozzle channel aperture of the nozzle block ( d / d = 0 . 245 ) having a cylindrical recess at an angle a of 90 °, with respect to the plane of the wall defining the central opening , for a length ( t ) of 5 mm , produced by 3d - printing with a conventional 3d - printing photopolymer material ( rgd875 veroblackplus ). the data were compared with those obtained with the conventional actuator only . the methods were the same as those described in example 3 with three replications . validated hplc methods were used for the determination of the three drugs . the data showed that an optimised 3d - printed tubular element according to the present invention having a cylindrical recess , facing towards the inside of the mouthpiece portion , still reduced the induction port deposition of a triple combination of active ingredients in solution to values higher than 70 % ( and in particular 74 % for all the three components ) with respect to a conventional actuator , but without significantly affecting the particle size distribution performance and in particular the fine and extra - fine particle dose ( with differences lower or around 10 %). the aim of the study was to estimate the risk that , during the patient use of the device , the coarse particles of the medicament doses sprayed , but retained in the actuator , after cumulative administrations , may escape from the actuator in form of high spots reaching the patient mouth or oropharynx . these high spots may contain high amounts of active ingredients and may be swallowed causing potential safety risk to patients . the test was conducted quantifying the amount of active ingredients particles which could detach from the actuator during a patient use simulation study . the study was carried out on actuators provided with the tubular element according to the invention described in example 5 ( fig5 a - 5 g , diameter d = 11 mm , at a distance d = 45 mm from the nozzle channel aperture , having a cylindrical recess at an angle a = 90 °) by firing two actuations twice daily , up to end of labelled canister life ( 180 actuations in a 45 - days treatment ) of the currently marketed foster pmdi described in example 2 ( containing as active ingredients ff 6 , μg / actuation , and bdp , 100 μg / actuation ). the tests were performed at 6 different time points corresponding to 6 different canister lives : after 32 , 60 , 88 , 120 , 148 , and 180 cumulative actuations . two parameters were determined at each time point : the amount of active ingredients migrated and the amount of active ingredients residues . the active ingredients particles migrated were evaluated recovering in a next generation impactor ( ngi ) cup the particles detached from the actuators provided with the tubular element according to the invention , after 300 automatic taps , in 70 seconds , using autotap tap density analyser ( quantachrome ). the recovered particles were then dissolved with suitable solvent and quantified by a validated hplc / uv method . the amount of active ingredients residues , still present both in the actuator and in the tubular element ( not detached ), were recovered rinsing the actuator and the tubular element with solvent and quantifying the active ingredients by validated hplc / uv method . three replications both for reference ( conventional , actuator only ) and actuator with the tubular element according to the invention were carried out . the mean results are reported in table 10 . the data showed that despite the higher amount of active ingredients collected , less than 3 μg were able to migrate ( detached ) from the internal wall of the actuator with the tubular element according to the invention up to the end of canister life . the migrated amount is comparable to the amount migrated from the conventional ( reference actuator ). the risk of exposure of a patient to high spots , evaluated as amount of drug particles migration during patient use was therefore negligible . where a numerical limit or range is stated herein , the endpoints are included . also , all values and subranges within a numerical limit or range are specifically included as if explicitly written out . as used herein the words “ a ” and “ an ” and the like carry the meaning of “ one or more .” obviously , numerous modifications and variations of the present invention are possible in light of the above teachings . it is therefore to be understood that , within the scope of the appended claims , the invention may be practiced otherwise than as specifically described herein . all patents and other references mentioned above are incorporated in full herein by this reference , the same as if set forth at length .
actuators for a pressurised metered dose inhalers containing a housing adapted to receive an aerosol canister containing a pressurised medicament formulation , a nozzle block defining the receptacle for the aerosol canister valve stem , the expansion chamber or sump , the nozzle channel its external aperture , and a mouthpiece portion comprising a central rounded opening of a defined width and distance from the nozzle aperture and a cylindrical recess , whose central axis is aligned with the central longitudinal axis of the mouthpiece portion and with the central longitudinal axis of the nozzle channel , provide a significant reduction in the non - respirable coarse fraction of the emitted aerosol medicament via inertial impaction and retention in the actuator rather than in the oro - pharynx , with consequent less associated side effects and oral candidiasis in the patient . in addition , the presence of the central rounded opening has minimal , negligible impact on the fine particle dose of the delivered aerosol particles .