(12) United States Patent
`Brand et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,606,989 B1
`Aug. 19, 2003
`
`US006606989B1
`
`4,057,945
`4,114,608
`4,268,460
`4,431,691
`4,986,269
`5,033,593
`5,063,922
`5,080,093
`5,280,784
`5,377,473
`5,507,281
`5,543,204
`5,713,349
`FOREIGN PATENT DOCUMENTS
`
`11/1977 Kessler
`* 9/1978 Russo ...................... .. 600/538
`* 5/1981 Boiarski et al. ..... .. 128/200.16
`2/1984 Greenlee
`* 1/1991 Hakkinen ............ .. 128/200.21
`7/1991 Kazuhito
`11/1991 Hakkinen ............ .. 128/200.16
`* 1/1992 Raabe et al.
`128/200.21
`* 1/1994 Kohler ................ ..128/200.21
`1/1995 Narayan et al.
`4/1996 Kuhnel et al. ....... .. 128/20315
`8/1996 Ray
`* 2/1998 Keaney ............... .. 128/204.21
`
`DE
`DE
`DE
`DE
`DE
`DE
`EP
`FR
`GB
`WO
`
`28 09 255 A1
`3610002
`3827636
`3901963
`69203372
`43 00 880 A1
`0642802
`2 604 093
`2164569
`96/13293
`
`9/1978
`3/1986
`8/1988
`1/1989
`4/1992
`7/1994
`8/1994
`3/1988
`* 3/1986
`5/1996
`
`* cited by examiner
`
`Primary Examiner—Aaron J. LeWis
`(74) Attorney, Agent, or Firm—Fish & Richardson PC.
`(57)
`ABSTRACT
`
`A device for administration of a medicated aerosol via the
`lungs consists of an inhalation mouthpiece 11, With an
`associated adjustable vaporizer 12, and of a compressed-air
`control valve 14 through Which a pre-settable (13) volumet
`ric How of compressed air can be discharged to the vaporizer
`12 containing the liquid medicament throughout a settable
`period of time. For operation of the device an electronic
`controller is provided on Which the vaporizing period of the
`vaporizer and a pause interval can be set, With provisions
`being made for triggering the beginning of the vaporizing
`operation by means of a pressure sensor responsive to a
`suction pressure in the mouthpiece.
`
`20 Claims, 1 Drawing Sheet
`
`(54) PRECISE ADMINISTRATION OF A
`MEDICATED AEROSOL VIA THE LUNGS
`
`(75) Inventors: Peter Brand, Gauting (DE); Titus
`Selzer, Munich (DE); Holger Schulz,
`Landsberg (DE); Christa Roth,
`Eschborn (DE); Joachim Heyder,
`Munich (DE)
`
`(73) Assignee: GSF-Forschungszentrum fur Umwelt
`und Gesundheit GmbH (DE)
`
`( * ) Notice:
`
`(21) Appl. No.:
`(22) PCT Filed:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`09/423,909
`May 8, 1998
`
`PCT/EP98/02703
`
`(86) PCT No.:
`§ 371 (6X1),
`(2), (4) Date: Apr. 3, 2000
`(87) PCT Pub. No.: WO98/52633
`
`PCT Pub. Date: Nov. 26, 1998
`Foreign Application Priority Data
`
`(30)
`
`May 16, 1997
`
`(DE) ....................................... .. 197 20 701
`
`(51) Int. Cl.7 ............................................. .. A61M 11/00
`(52)
`128/200.16; 128/200.21
`(58) Field of Search ..................... .. 128/200.16, 200.21,
`128/203.13; 600/538
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`9/1940 Eichelberger et al.
`2,215,241 A
`2,616,283 A 11/1952 Branstrator et al.
`3,446,692 A
`5/1969 Turnbull
`3,812,854 A * 5/1974 Michaels et al. .... .. 128/200.16
`3,872,641 A
`3/1975 Falkenberg
`3,921,637 A 11/1975 Bennie et al. ....... .. 128/203.15
`4,057,944 A 11/1977 Wyatt, Jr. et a1.
`
`Inhalation period: 45
`
`pause interval: 103%
`7 I
`
`20
`
`18
`
`19
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1010, p. 1 of 5
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`

`

`U.S. Patent
`
`Aug. 19, 2003
`
`US 6,606,989 B1
`
`Inhalation period: 45
`pause interval: 105
`
`FIG. 1
`
`9/20
`22
`14 —="
`r23
`
`E'/24
`
`vaporisation period
`
`.mmnfv
`wmm
`
`U6U 3/0 01.00 ultrasonic vaporiser
`8 // mw
`mm
`
`
`
`control/er
`
`FIG. 2
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1010, p. 2 of 5
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`

`

`US 6,606,989 B1
`
`1
`PRECISE ADMINISTRATION OF A
`MEDICATED AEROSOL VIA THE LUNGS
`
`The present invention relates to a device for administra
`tion of a medicated aerosol via the lungs in accordance With
`the introductory clause of Patent claim 1.
`The use of the respiratory tract for the administration of
`medicaments is gaining an ever-increasing importance. In
`this approach not only the application of neW medicaments
`producing local effects for the treatment of pulmonary
`diseases is being developed, but also neW therapeutic strat
`egies are being designed Which employ the lungs as the
`organ through Which substances enter the body Which pro
`duce systemic effects.
`For the employment of the inhalation canal for the
`administration of medicaments continuously groWing
`demands are made on the quality of the process of
`inhalation, Which cannot be satis?ed by the devices pres
`ently available in the market. For instance, it is necessary
`that the dosage of the medicament, Which the physician has
`prescribed, Will be administered as precisely as possible and
`in a reproducible manner, With the administered dose and its
`reproducibility depending substantially on the so-called res
`piration manoeuvre. The term “respiration manoeuvre” is to
`be understood to encompass the aerosol volume inhaled and
`the respiratory ?oW by Which the patient performs the
`inhalation. With an appropriate selection of the respiration
`manoeuvre and the vaporiser or by matching the applied
`respiratory manoeuvre With the used vaporiser (particle siZe)
`the location of deposition of the medicament in the lungs
`could be selectively in?uenced so as to provoke a predomi
`nantly central or predominantly peripheral administration of
`the pharmaceutical.
`A device of the general type outlined by Way of intro
`duction is disclosed already in the French Patent FR-A
`2604093. What must be considered to be a disadvantage in
`this device is the fact that, on the one hand, the handling is
`complex and that, on the other hand, an administration
`dependent on the individual respiratory manoeuvre cannot
`be performed or realised only insuf?ciently.
`As in every-day clinical routine the respiratory manoeu
`vre performed by the patient can usually be in?uenced only
`to a small extent or as the respiratory manoeuvre actually
`performed is almost entirely beyond control by the physi
`cians a precise pre-determination of the respiratory volume
`and the respiratory ?oW in the inhalation of therapeutic
`aerosol Were desirable because this Would entail a substan
`tial improvement of the inhalation therapy and its reproduc
`ibility. As a consequence, the administered dose could be
`estimated With a higher precision, With a precise observation
`of a particular respiratory manoeuvre, Whilst at the same
`time savings in terms of costs could be achieved as Well
`When particularly expensive pharmaceuticals are adminis
`tered.
`The present invention is therefore based on the problem
`of responding to the needs outlined in the foregoing With a
`device having a functionally simple design.
`In accordance With this invention this problem is solved
`by the features de?ned in the claims. Preferred features
`providing an expedient improvement of the invention are
`also de?ned in the claims.
`The inventive device expediently consists of an inhala
`tion mouthpiece, an associated adjustable vaporiser and a
`compressed-air control valve through Which a pre-settable
`volumetric ?oW of compressed air Which can be supplied to
`the vaporiser containing the liquid medicament during an
`adjustable period of time, With a pressure sensor being
`
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`provided for triggering the beginning of the vaporising
`operation of the vaporiser.
`With the inventive device the patient is therefore
`enabled, With simple means, to inhale a precisely predeter
`mined volume of a pharmaceutical substance at a precisely
`predetermined respiratory ?oW. With this device the separate
`air supply, Which is already envisaged for therapeutic vapor
`isers in the clinical every-day routine, is expediently con
`trolled in such a Way that only a predetermined volume of air
`is output to the vaporiser at a predetermined ?oW rate. In
`accordance With the present invention hence the air of the
`vaporiser is adjusted to a pre-settable intensity of the volu
`metric ?oW, Which the patient cannot take an in?uence on so
`that a constant ?oW Will be achieved. The ?oW of supplied
`air is preferably turned on by an electronic controller over an
`invariably set period of time so as to achieve the adminis
`tration of a precisely pre-determined air volume. On account
`of the length of a breathing pause, Which can be determined
`With a special design of the invention, the total deposition of
`the medicament is expediently increased Whilst the inter
`individual variability of the deposited quantity is reduced.
`For use of the device in practical application it is more
`over expedient to provide a pressure gauge responsive to a
`suction pressure in the inhalation mouthpiece for triggering
`the beginning of the vaporising operation of the vaporiser
`In accordance With a preferred con?guration a controller
`is disposed upstream of the adjustable vaporiser for main
`taining the volumetric ?oW constant, With a ?oW meter being
`preferably arranged doWnstream of the controller for control
`of a predetermined volumetric ?oW, Which ?oW meter
`comprises a ?oating body in a speci?c embodiment. These
`provisions contribute expediently to an ensured controlled
`inhalation of therapeutic aerosols by means of the inventive
`device.
`According to a preferred embodiment of the invention,
`the device comprises an electrical controller to control its
`operation, With a vaporising period and a pause interval
`being adjustable on the controller and With the electronic
`controller preferably including a visible and/or audible
`pause signal to indicate the pause betWeen inhalation and
`exhalation, preferably in the form of a light-emitting diode.
`Moreover, the number of the vaporising periods can expe
`diently be set in the form of a number of respiration cycles.
`As far as the con?guration of the vaporiser is concerned
`either a design in the form of a noZZle-type vaporiser With
`a separate compressed-air supply is envisaged, Which can be
`turned on and off by means of the compressed-air control
`valve, With the separate compressed-air supply for the
`noZZle-type vaporiZer being preferably branched off
`betWeen the compressed-air control valve and the ?oW
`meter.
`In an alternative design the vaporiser may be con?gured
`as ultrasonic transducer issuing high-frequency signals
`Which can be directly controlled by the electronic controller.
`The compressed-air control valve is preferably designed
`as solenoid valve, and a pressure reducer and a pressure
`gauge are arranged upstream of the control valve for adap
`tation to the individual compressed-air conditions.
`In accordance With the invention a Wide range of respi
`ratory manoeuvres can expediently be opened up for medi
`cal applications With the simultaneous selection of the
`respiratory ?oW and the inhaled volume, With the opportu
`nity to take an in?uence on the location of deposition in the
`lung in the desired manner. It is thus possible for the ?rst
`time to deposit medicaments Which are intended, for
`instance, to produce their effects in central areas of the lungs
`actually at the envisaged points.
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1010, p. 3 of 5
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`

`

`US 6,606,989 B1
`
`3
`Another advantage of the inventive device consists in the
`aspect that it permits an improvement of a routine perfor
`mance of inhalations on patients in the clinical environment
`because, by virtue of the envisaged respiration triggering of
`inhalation, a patient Will not encounter any problems With
`respect to the synchronisation of the start of operation of the
`vaporiser and hence the beginning of the inhalation opera
`tion. It is moreover eXpediently possible to reduce errors in
`inhalation substantially, Which are due to improper handling
`of the vaporiser.
`The invention Will noW be described in more details in
`the folloWing With reference to the attached draWing
`Wherein:
`FIG. 1 is a schematic vieW of one embodiment of an
`inventive Device; and
`FIG. 2 is a schematic diagram shoWing the components
`of the Embodiment of the invention according to FIG. 1.
`FIG. 1 illustrates a schematic vieW of the interaction of
`the individual components of an inventive device 10 With
`reference to a particular embodiment. The device 10 for the
`administration of a medicated aerosol through the lung
`consists of an inhalation mouthpiece 11 With an associated
`vaporiser 12 Which can be adjusted in terms of its operating
`phases as Well as intensity/frequency. A volumetric ?oW
`controller 13, a compressed-air control valve 14, Which is
`preferably con?gured as solenoid valve, a pressure reducer
`15 and a compressed-air inlet 16 are disposed to be in How
`communication With the inhalation mouthpiece 11. The
`reference numeral 17 denotes a pressure sensor Which is
`responsive to a suction pressure in the mouthpiece for
`triggering the beginning of the vaporising operation of the
`vaporiser 12.
`An electronic controller 18 is functionally connected to
`the compressed-air control valve 14, the pressure sensor 17
`and the vaporiser 12. The electronic controller 18 is sche
`matically represented as housing block Which is additionally
`provided With an optical display of a How meter 19 for
`checking the inhalatory ?oW, for instance over a range of
`values from 0 to 1000 cm3/s. The volumetric ?oW controller
`13 serves to maintain the inhalatory ?oW constant over a
`range from 0 to 1000 cm3/s, for eXample. The compressed
`air valve 14 is preferably designed as solenoid valve Which
`sWitches the air supply.
`Moreover, the inhalation period, the pause interval and
`the number of breathing cycles can be set on the electronic
`controller 18 in a manner not illustrated here, With a light
`emitting diode 20 being provided to issue a pause signal.
`A pressure gauge 21, Which is schematically shoWn in
`FIG. 2, is provided betWeen the pressure reducer 15 and the
`solenoid valve 14 for setting the operating pressure of the
`vaporiser, for instance over a range of values from 0 to 2 bar,
`as a supplement to the embodiment according to FIG. 1.
`Moreover, a compressed-air coupler 22 is provided in this
`embodiment, Which stops automatically and serves to supply
`the noZZle of a vaporiser Which is con?gured here as a
`noZZle-type vaporiser. For connection of the vaporiser 12 as
`such an adapter is illustrated by the reference numeral 23
`Whereas the numeral 24 denotes a signalling line for sWitch
`ing a vaporiser con?gured in the form of an ultrasonic
`vaporiser.
`The individual functions Which can be set, such as
`vaporising period or inhalation time, the pause interval and
`the ultrasonic vaporiser control, are mentioned in teXt form
`in the block of the electronic controller 18, With a breathing
`cycle counter being included for detection of the breathing
`cycles.
`For use of the inventive device 10 initially the nominal
`How of inhalation is controlled by means of the How meter
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`19, Which includes a ?oating body, and then set to the
`desired amount at the volumetric ?oW controller 13 or the
`controller, respectively, Which maintains the How constant.
`Then the desired inhalation period is set via keys on the
`electronic controller 18, Which are not illustrated here, e. g.
`Within a range from 0 to 20 seconds. The inhaled volume
`then derives from the inhalation period and the How of
`inhalation. The desired duration of the pause interval is
`equally set on the controller 18 via keys not illustrated here,
`for instance Within a range from 9 to 20 seconds.
`Additionally, the breathing cycle counter is set to Zero.
`FolloWing these preparations, inhalation can noW be
`performed in a Way that the patient sucks at the mouthpiece
`11, Which causes the pressure sensor 17 to respond and start
`inhalation automatically. The vaporiser 12 is supplied With
`compressed air throughout the pre-selected inhalation
`period, and the desired medicament is discharged in the form
`of a medicated aerosol from the mouthpiece 11 at a pre
`selected ?oW rate. Upon expiration of the inhalation period
`the compressed-air supply is interrupted so that the patient
`cannot continue inhalation. The light-emitting diode 20
`signals to the patient that he or she should hold his or her
`breath. As soon as the pause interval has elapsed the pause
`interval LED 20 is extinguished, the patient eXhales and the
`breathing cycle counter is incremented. NoW the device is
`ready for the neXt inhalation cycle.
`Another possibility of adjusting the vaporising operation
`in a noZZle-type vaporiser consists in controlling the com
`pressed air supply Which is branched off betWeen the sole
`noid valve 14 and the How meter controller 13. When an
`ultrasonic vaporiser is used the required high-frequency
`signal can be separately controlled in an appropriate manner.
`What is claimed is:
`1. A device for deposition of a medicament in a liquid
`form in the lungs, comprising:
`an inhalation mouthpiece;
`a pressure sensor responsive to a suction pressure in said
`mouthpiece to produce a triggering signal;
`an adjustable vaporiser coupled to the inhalation mouth
`piece and to receive a noZZle How and a separate
`compressed-air ?oW, Which vaporiZer contains the
`medicament and delivers the vaporised medicament to
`the mouthpiece for a vaporising period in response to a
`vaporising signal;
`a compressed-air control valve, Which, in response to a
`valve signal, opens to alloW the noZZle How and the
`separate compressed-air How to enter the vaporiser
`throughout the vaporising period to provide a prede
`termined inhaled volume, and closes at the end of the
`vaporising period to stop the noZZle How and the
`separate compressed air ?oW;
`a volumetric ?oW controller coupled to the compressed
`air control valve to preset a determined quantity of a
`volumetric How of the noZZle ?oW;
`a How meter disposed doWnstream of said volumetric
`?oW controller for control of a predetermined volumet
`ric ?oW; and
`an electronic controller connected to receive the trigger
`ing signal from the pressure sensor to produce the valve
`signal and the vaporising signal, said electronic con
`troller being con?gured With the settable vaporising
`period and a settable pause interval and operable to set
`the varporing period of the adjustable vaporiser to an
`invariable value from opening of the compressed-air
`control valve and causes a predetermined volume for
`each respiratory manoeuvre at the inhalation mouth
`piece.
`
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`US 6,606,989 B1
`
`5
`2. The device of claim 1 further comprising a compressed
`air coupler connecting to a compressed-air line Which is
`branched off betWeen the compressed-air control valve and
`the volumetric ?oW controller for carrying the separate
`compressed air ?oW, Wherein the compressed-air coupler
`stops the separate compressed air ?oW from entering the
`vaporiser if the vaporiser is con?gured as an ultrasonic
`transducer.
`3. The device according to claim 1, Wherein said volu
`metric ?oW controller is disposed upstream of said vaporiser
`Which is adapted to be set in terms of time, for maintaining
`the volumetric ?oW constant.
`4. The device according to claim 1, Wherein said How
`meter includes a ?oating body.
`5. The device according to claim 1, Wherein said elec
`tronic controller comprises a visible and/or audible pause
`signal to indicate the pause period betWeen inhalation and
`exhalation.
`6. The device according to claim 5, Wherein said pause
`signal is generated by a light-emitting diode.
`7. The device according to claim 1, Wherein the number
`of vaporising periods is set in a form of a number of
`breathing cycles.
`8. The device according to claim 1, Wherein said vaporiser
`is con?gured in a form of an ultrasonic transducer issuing
`high frequency signals Which are controllable by means of
`said electronic controller.
`9. The device according to claim 1, Wherein said
`compressed-air control valve is con?gured in the form of a
`solenoid valve.
`10. The device according to claim 1 further comprising a
`pressure reducer and a pressure gauge disposed upstream of
`said compressed-air control valve.
`11. A device for deposition of a medicament in a liquid
`form in the lungs, comprising:
`an inhalation mouthpiece;
`a pressure sensor responsive to a suction pressure in said
`mouthpiece to produce a triggering signal;
`an adjustable vaporiser coupled to the inhalation mouth
`piece and to receive a noZZle ?oW, Which vaporiZer
`contains the medicament and issues high frequencies to
`deliver the vaporised medicament to the mouthpiece for
`a vaporising period in response to a vaporising signal;
`a compressed-air control valve, Which, in response to a
`valve signal, opens to alloW the noZZle How to enter the
`vaporiser throughout the vaporising period to provide a
`predetermined inhaled volume, and closes at the end of
`the vaporising period to stop the noZZle ?oW; a volu
`metric ?oW controller coupled to the compressed-air
`control valve to preset a determined quantity of a
`volumetric How of the noZZle ?oW;
`a How meter disposed doWnstream of said volumetric
`?oW controller for control of a predetermined volumet
`ric ?oW; and
`an electronic controller that receives the triggering signal
`from the pressure sensor to produce the valve signal
`and the vaporising signal, said electronic controller
`being con?gured With the settable vaporising period
`and a settable pause interval and controlling the high
`frequencies issued by the vaporiZer and operable to set
`the varporing period of the adjustable vaporiser to an
`invariable value from opening of the compressed-air
`control valve and causes a predetermined volume for
`each respiratory manoeuvre at the inhalation mouth
`piece.
`
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`12. The device according to claim 11, Wherein said
`volumetric ?oW controller is disposed upstream of said
`vaporiser Which is adapted to be set in terms of time, for
`maintaining the volumetric ?oW constant.
`13. The device according to claim 11, Wherein said
`electronic controller comprises a visible and/or audible
`pause signal to indicate the pause period betWeen inhalation
`and exhalation.
`14. The device according to claim 11, Wherein said
`compressed-air control valve is con?gured in the form of a
`solenoid valve.
`15. The device according to claim 11 further comprising
`a pressure reducer and a pressure gauge disposed upstream
`of said compressed-air control valve.
`16. A method for administration of a medicated aerosol
`via lungs, comprising:
`providing an adjustable vaporiser to vaporiZe a medica
`tion to be delivered through a mouthpiece for inhala
`tion; providing a controllable air ?oW via a
`compressed-air control valve to the adjustable vapor
`iser to produce the medicated aerosol and direct the
`medicated aerosol to the mouthpiece;
`using a volumetric ?oW controller coupled to the
`compressed-air control valve to preset a determined
`quantity of a volumetric ?oW;
`using a How meter doWnstream of the compressed-air
`control valve to control the air ?oW at a constant ?oW
`rate;
`using a pressure sensor at the mouthpiece to produce a
`triggering signal upon sensing a suction at the mouth
`piece;
`in response to the triggering signal, turning on the adjust
`able vaporiZer to operate and opening the compressed
`air control valve to alloW the controllable air ?oW into
`the adjustable vaporiser, for a predetermined invariable
`vaporiZing period; and
`turning off both the adjustable vaporiser and the
`compressed-air control valve at the end of the vapor
`iZing period to provide a predetermined constant vol
`ume of the medication for different respiratory manoeu
`vres.
`17. The method as in claim 16, further comprising:
`using an indicator light to signal to a patient to hold a
`breath after an inhalation; and
`after expiration of a predetermined pause interval, using
`the indicator light to signal to the patient to exhale and
`thus to begin a subsequent inhalation cycle.
`18. The method as in claim 16, further comprising adjust
`ing a How rate of the controllable air How to change the
`predetermined constant volume of the medication.
`19. The method as in claim 16, further comprising adjust
`ing the predetermined invariable vaporiZing period to
`change the predetermined constant volume of the medica
`tion.
`20. The method as in claim 16, further comprising:
`using the How meter to initially control the air ?oW prior
`to setting the volumetric ?oW controller;
`subsequently setting the volumetric ?oW controller to a
`desired setting; and
`using an electronic controller to set the predetermined
`invariable vaporiZing period to aWait the triggering
`signal to begin delivery of the medicated aerosol.
`
`*
`
`*
`
`*
`
`*
`
`*
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 1010, p. 5 of 5
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