United States Patent [19]
`Lloyd et al.
`
`llllllllllllllllllllllllllllllllIllIlllllllllllllllllllIlllllllllllllllll
`5,544,646
`Aug. 13, 1996
`
`[11] Patent Number:
`[45] Date of Patent:
`
`US005544646A
`
`[54] SYSTEMS FOR THE INTRAPULMONARY
`DELIVERY OF AEROSOLIZED AQUEOUS
`FORMULATIONS
`
`[75] Inventors: Lester J. Lloyd, Orinda; Peter M.
`Lloyd, Oakland; Reid M. Rubsamen;
`Jeffrey A. Schuster, both of Berkeley,
`all of Calif.
`
`[73] Assignee: Aradigm Corporation, Hayward, Calif.
`
`[21] Appl. No.: 247,012
`[22] Filed:
`May 20, 1994
`
`Related US. Application Data
`
`[63] Continuation-in-part of Ser. No. 166,972, Dec. 14, 1993,
`Pat. No. 5,497,763, which is a continuation-in-part of Ser.
`No. 65,660, May 21, 1993.
`
`......................... .. A61M 11/00
`[51] Int. Cl.6
`[52] US. Cl. .............................. .. 128/200.14; 128/200.22;
`128120312
`[58] Field of Search ....................... .. l28/200.14, 200.22,
`128120312; 222/5413, 541.4; 206/531,
`532
`
`[56]
`
`.
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,187,748
`3,565,070
`
`6/1965 Mitchell et a1. ...................... .. 128/173
`211971 Hanson et a1. ........................ .. 128/173
`
`(List continued on next page.)
`
`FOREIGN PATENT DOCUMENTS
`
`0186280 10/1985
`8121383 5/1983
`2837040 211980
`' 4133274 211993
`0530625 3/1993
`1518998 7/1978
`2055046 211981
`2104393A 3/1983
`2255918 1111992
`2256805B 12/ 1992
`0546607 6/1993
`
`European Pat. Off. .
`
`France .
`
`Germany .
`Germany .................... .. A6lM 15/00
`Germany ....................... .. BOSB 7114
`United Kingdom .
`United Kingdom ............ .. l28/200.l9
`United Kingdom .
`United Kingdom .
`United Kingdom .
`United Kingdom .......... .. BOSB 11/02
`
`WlPO .
`
`WIPO .
`
`WIPO ......................... .. A61M 15/00
`
`WO90/l3327 1111990
`WO9l/l4468 1011991
`WO92/07599 5/1992
`WO92/09322 6/ 1992
`WO92/1l050 7/1992
`WO93/03785 311993
`WO93/09832 5/1993 WIPO ..
`WO93/l7728 9/1993 WIPO.
`
`WIPO .
`
`WIPO ......................... .. A6lM 15/00
`
`WlPO ..
`
`.. A61M 15100
`
`................ .. A6lM 15/00
`
`OTHER PUBLICATIONS
`
`Byron, P. R., ed., Respiratory Drug Delivery CRC Press,
`Inc., Boca Raton, FL (1990).
`
`(List continued on next page.)
`
`Primary Examiner-Aaron J. Lewis
`Attorney, Agent, or F irm-Karl Bozicevic; Fish & Richard
`son RC.
`
`[57]
`
`ABSTRACT
`
`A disposable package, tape, and cassette are provided which
`makes it possible to hold and disperse therefrom liquid,
`?owable formulations including aqueous formulations
`(solutions or dispersions with particles less than 0.25
`microns in diameter) of a pharmaceutically active drug. in
`one embodiment formulation is packaged in individual
`dosage unit containers which containers are preferably inter
`connected. The package is designed to be integrated into a
`cassette which can be loaded into a dispersing device
`capable of individually opening dosage unit containers and
`aerosolizing the contents through a porous membrane, into
`a mouth piece on the cassette, for delivery to a patient. In
`addition to and alongside of each porous membrane, the
`package may include one or more openings through which
`air is forced in order to aid in avoiding the accumulation of
`aerosolized particles. The package may be con?gured so that
`the formulation is held in a container not positioned directly
`vertical to and below the porous membrane, thus making it
`necessary to channel formulation horizontally to the porous
`membrane and making it possible to include a vibrating
`mechanism directly below a chamber covered by the porous
`membrane. Release of aerosolized drug is breath actuated
`based on simultaneous measurements of inspiratory flow
`and volume so as to provide for repeatable dosing of drug to
`the patient.
`
`17 Claims, 17 Drawing Sheets
`
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`

`

`5,544,646
`Page 2
`
`U.s. PATENT DOCUMENTS
`
`4/1972 Steil ...................................... .. 128/173
`3,658,059
`9/1973 Aiken ................................. .. 222/5413
`3,757,782
`5/1974 Michaels 91 a1-
`---- -- 128/194
`3,812,854
`6/1974 Warren ---------- --
`ZZZ/40213
`3,814,297
`7/1974 Warren
`ZZZ/40213
`3,826,413
`1/1975 1191989191
`128/200-16
`3,861,386
`3,991,304 11/1976 Hillsman
`235/151-34
`4,090,642
`5/1978 Baker ................................. .. 222/5413
`4,119,096 10/1978 Drews .............................. .. 128/20016
`4,275,840
`6/1981 Staar ..... ..
`222/5413
`4,294,407 10/1981 Reichl et a1.
`- 128/200 16
`
`
`
`
`
`6/1982 Reichl 61 a1. .................... .. 128/200.16 4,334,531 4,361,401 11/1982 Smith, Jr. 61 a1. ...................... .. 356/36
`
`239/102
`8/1984 Maeharaetal.
`4,465,234
`128/203.28
`4,484,577 11/1984 Sackner et a1.
`.... .. 239/102
`4,533,082
`8/1985 Maehara e131.
`128/20023
`4,592,348
`6/1986 Waters, Net 81.
`........ .. 53/75
`4,604,847
`8/1986 Moulding, Jr. et a1.
`.. 128/200.19
`4,627,432 12/1986 Nowell et a1. ....... ,.
`" 128120023
`4’648’393
`3/1987 Land“ et a1‘ "
`..128/200.14
`4,677,975
`7/1987 Edgaretal.
`.. 128/200.23
`4,790,305 1y1988 ZOlLan m1. .... ..
`4,790,479 12/1988 Matsumoto et a1. ............... .. 239/1022
`4,803,978
`2/1989 Johnson, W et a1. ........... .. 128/200.23
`
`8/1989 P611 ....................................... ..128/716
`4,852,582
`4,877,989 10/1989 Drews et al.
`128/200.16
`4,896,332 H1990 Hewlett
`239/322
`4,926,352
`5/1990 201mm etal
`123/200 23
`5,033,463
`7/1991 COCOZZZI ......... ..
`128/203.21
`5,114,240
`5/1992 Kindt-Larsen 61 a1. ........... .. 222/5413
`5,134,993
`8/1992 van der Linden et a1. ...... .. 128/20016
`5,152,456 10/1992 ROSS 6131. ............. ..
`..
`.
`5,348,191
`9/1994 Dekeyser ........................... .. 222/5414
`
`OTHER PUBLICATIQNS
`
`Newman et al., “Deposition of pressurised aerosols in the
`
`
`
`human respiratory tract” Thorax Newman et 31“ “How should a pressurized B_admnergic
`
`1981
`D.
`b . nh 31 do” E J R .
`h dil
`b
`“m o “or e 1
`e -
`"'-
`' “P” 13- <
`)
`6213*21
`Newman et 211., “Deposition of pressurized suspension aero
`so1s inhaled through extension devices1_3” Am. Rev. Respir.
`Dis_ (1981) 124;317_320_
`Costar® Life Science Filtration Catalog, “Nuc1eopore®
`P1 b
`M b
`,, 1992
`7
`Oycar ‘mate em mes (
`)P- -
`Ham'son’s Principles on Internal Medicine, “Diabetes M91
`litus” (10111 ed. 1983) 666—674.
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 131, p. 2 of 39
`
`

`

`US. Patent
`
`Aug. 13, 1996
`
`Sheet 1 of 17
`
`5,544,646
`
`14
`
`<>\\\
`o\\<>
`
`0
`
`<>
`
`Q
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`o
`
`$0
`
`0)
`
`2
`
`3
`
`FIG. 1
`
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`

`

`US. Patent
`
`Aug. 13, 1996
`
`Sheet 2 0f 17
`
`5,544,646
`
`FIGURE 2
`
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`

`

`US. Patent
`
`Aug. 13, 1996
`
`Sheet 3 of 17
`
`5,544,646
`
`
`
`FIGURE 3
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 131, p. 5 of 39
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`

`

`US. Patent
`
`Aug. 13, 1996
`
`Sheet 4 of 17
`
`5,544,646
`
`FIGURE 4
`
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`

`

`U.S. Patent
`
`Aug. 13, 1996
`
`Sheet 5 of 17
`
`5,544,646
`
`\
`:: T"'- ' ""1
`
`/
`'
`
`F
`
`/
`61
`
`1o
`
`16
`
`13
`
`11
`
`2
`
`15
`
`FIGURE 5
`
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`

`

`US. Patent
`
`Aug. 13, 1996
`
`Sheet 6 of 17
`
`5,544,646
`
`50
`
`14
`
`4
`
`50'
`
`FIGURE 6
`
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`

`

`US. Patent
`
`Aug. 13, 1996
`
`Sheet 7 0f 17
`
`5,544,646
`
`/% rgfl/ll
`m
`
`IFIGURE7
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 131, p. 9 of 39
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`

`

`US. Patent
`
`Aug. 13, 1996
`
`Sheet 8 of 17
`
`5,544,646
`
`HEJUEIHEIH
`52
`\
`
`[:1
`
`a
`
`l]
`
`\
`
`[HUGH
`51/
`
`c1
`
`1:
`
`/
`
`1:1
`
`c1
`
`1:1
`\
`
`:1
`
`14
`
`FIGURE 8
`
`19
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 131, p. 10 of 39
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`

`

`US. Patent
`
`Aug. 13, 1996
`
`Sheet 9 of 17
`
`5,544,646
`
`39
`
`FIGURE 9
`
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`

`

`US. Patent
`
`Aug. 13, 1996
`
`Sheet 10 of 17
`
`5,544,646
`
`14
`
`4
`
`\ /
`::—T';-\ ---
`/
`12
`
`55
`62
`
`13
`
`<5
`
`6‘
`
`5s
`
`I
`
`/
`59
`
`63
`
`5s
`
`1
`
`/
`60
`
`57
`
`FIGURE 10
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 131, p. 12 of 39
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`

`

`U.S. Patent
`
`Aug. 13, 1996
`
`Sheet 11 of 17
`
`5,544,646
`
`“22.5.- 3 82.52
`
`Size (in microns)
`
`FIGURE 11
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 131, p. 13 of 39
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`

`

`U.S. Patent
`
`Aug. 13, 1996
`
`Sheet 12 0f 17
`
`5,544,646
`
`120
`
`121
`
`i
`
`ie 0/0
`
`4/4/00 \//0
`
`o
`
`123
`
`FIG. 12
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 131, p. 14 of 39
`
`

`

`US. Patent
`
`Aug. 13, 1996
`
`Sheet 13 0f 17
`
`5,544,646
`
`9
`
`128
`
`_\/4 127\
`X
`
`<G>
`
`<S>
`
`>124 >125
`
`126 -\
`
`129/
`
`120/
`
`FIG. 13
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 131, p. 15 of 39
`
`

`

`US. Patent
`
`Aug. 13, 1996
`
`Sheet 14 0f 17
`
`5,544,646
`
`FIG. 14
`
`150
`
`14
`
`61
`
`FIG. 15
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 131, p. 16 of 39
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`

`

`US. Patent
`
`Aug. 13, 1996
`
`Sheet 15 0f 17
`
`5,544,646
`
`W///// '
`‘If’ If V”,
`
`////A I
`
`\161
`
`,\162
`
`\.
`
`7 1
`
`\ 160
`
`164
`
`FIG. 16
`
`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 131, p. 17 of 39
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`

`

`US. Patent
`
`Aug. 13, 1996
`
`Sheet 16 0f 17
`
`5,544,646
`
`FIG. 17
`
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`

`

`US. Patent
`
`Aug. 13, 1996
`
`Sheet 17 of 17
`
`5,544,646
`
`FIG. 18
`
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`

`

`5,544,646
`
`1
`SYSTEMS FOR THE INTRAPULMONARY
`DELIVERY OF AEROSOLIZED AQUEOUS
`FORMULATIONS
`
`CROSS-REFERENCES
`
`This application is a continuation-in-part of our earlier
`?led U.S. application Ser. No. 08/166,972 ?led Dec. 14,
`1993 now U.S. Pat. No. 5,497,763, which is a continuation~
`in-part of our earlier ?led U.S. application Ser. No. 08/065,
`660 ?led May 21, 1993, pending, both of which applications
`are incorporated herein by reference and to which applica
`tions we claim priority under 35 U.S.C. § 120.
`
`10
`
`FIELD OF THE. INVENTION
`
`This invention relates generally to methods of drug deliv
`ery, containers and systems used in the intrapulmonary
`delivery of drugs. More speci?cally, the invention relates to
`a disposable package which includes one or more containers
`which containers may be loaded into a cassette which can be
`included in a device used for the controlled delivery of
`aerosolized ?owable, liquid formulations.
`
`BACKGROUND OF THE INVENTION
`The intrapulmonary delivery of pharmaceutically active
`drugs is accomplished by two distinct methodologies. In
`accordance with one method, a pharrnaceutically active drug
`is dispersed in a low boiling point propellant (a CFC or
`HFA) and loaded in a pressurized canister from which the
`drug/propellant formulation may be released by the use of a
`device generally known as a metered dose inhaler (MDI).
`Once released, the propellant evaporates and particles of the
`drug are inhaled by the patient. The other method involves
`the use of a nebulizer which creates a mist of ?ne particles
`from a solution or suspension of a drug which mist is inhaled
`by the patient. Both methods are hindered by signi?cant
`problems relating to patient compliance and dosing as
`described further below.
`Metered dose inhalers that are generally manually oper
`ated and some breath actuated devices have been proposed
`and produced. Breath actuated inhalers typically contain a
`pressurized propellant and provide a metered dose automati
`cally when the patient’s inspiratory effort either moves a
`mechanical lever or the detected ?ow rises above a preset
`threshold, as detected by a hot wire anemometer. See, for
`example, U.S. Pat. Nos. 3,187,748; 3,565,070; 3,814,297;
`3,826,413; 4,592,348; 4,648,393; 4,803,978; 4,896,832; and
`a product available from 3M Healthcare known as Aerosol
`Sheathed Actuator and Cap.
`A major problem with manual metered dose inhalers is
`that the patient frequently actuates the device at the incorrect
`point during the breathing cycle to obtain the bene?ts of the
`intended drug therapy or breathes at the wrong ?ow rate.
`Thus, patients may inspire too little medication, or take a
`second dose and receive too much medication. The problem
`is, therefore, the inability to administer precise dosages.
`Another problem with metered dose inhalers is that the
`devices include low boiling point propellants such as halo
`hydrocarbons and halocarbons which have adverse environ
`mental e?ects. Further, other low boiling point propellants
`are not desirable in that they may have adverse medical
`effects on patients.
`A problem with breath activated drug delivery is that the
`dose is triggered on crossing a ?xed threshold inspiratory
`effort. Thus, an inspiration effort may be su?icient to release
`
`25
`
`30
`
`35
`
`40
`
`50
`
`55
`
`65
`
`2
`a metered dose, but the inspiratory flow following the
`release may not be su?icient to cause the aerosol medication
`to pass into the desired portion of the patient’s airways.
`Another problem exists with patients whose inspiratory
`effort is not su?icient to rise above the threshold to trigger
`the release valve at all. Yet another problem is that the
`particle size can vary greatly and larger particles carmot
`enter the smaller lung passages and therefore are not deliv
`ered to the same degree arid/or rate as are smaller particles.
`Any of these problems can make it di?icult or impossible to
`monitor the delivery of a precise dosage of medication to a
`patient.
`Attempts have been made to solve the patient inspiration
`synchronization problem. U.S. Pat. No. 4,484,577 refers to
`using a bidirectional reed Whistle to indicate to the patient
`the maximum rate of inhalation for desired delivery of the
`drug and ?ow restrictor to prevent the patient from inhaling
`too rapidly. U.S. Pat. No. 3,991,304 refers to using biofeed
`back techniques to train the patient to adopt a desired
`breathing pattern. U.S. Pat. No. 4,677,975 refers to using
`audible signals and preselected time delays gated on the
`detection of inspiratory ?ow to indicate to the patient when
`to inhale and exhale, and delivering inhalable material a
`selected time after the detected onset of flow. However,
`these devices also suffer from improper operation by
`patients who are not properly trained or do not conform their
`breathing to the instructed breathing pattern and whose
`inspiratory ?ow does not provide adequate delivery of the
`medication. Such problems make reproducible delivery of
`predetermined dosages virtually impossible.
`Studies in Byron (ed), Respiratory Drug Delivery, CRC
`Press, Inc. (1990); Newman et al., Thorax, 1981, 36:52— 55;
`Newman et al., Thorax, 1980, 35:234; Newman et al., Eur.
`J. Respir: Dis., 1981, 62:3—2l; and Newman et al., Am. Rev.
`Respir. Dis., 1981, 124:3 l7—320 indicate that during a single
`breath of an aerosol compound, only about ten percent of the
`total aerosol material presented is deposited into the lungs
`and that the location of deposition in the lung depends upon
`(1) breath parameters such as volume of inspiration, inspira
`tory ?ow rate, inspiratory pause prior to expiration, the lung
`volume at the time the bolus of medication is administered,
`and expiratory ?ow rate, (2) the size, shape and density of
`the aerosol particles (i.e., the medicinal compound, any
`carrier, and propellant), and (3) the physiological character
`istics of the patient. Present devices and methods cannot
`eliminate these variables and as such cannot control dosage
`administration.
`A problem with existing metered dose inhalers, whether
`or not breath actuated, is that they are factory preset to
`deliver a ?xed dose at a given particle size distribution. Such
`devices are not capable of reducing the dose to re?ect
`improvement in the patient’s condition, or selecting a maxi
`mum desired respirable fraction of the aerosol mist that is
`suitable for a desired location of delivery of the medication
`in the particular patient.
`Devices for controlling particle size of an aerosol are
`known. U.S. Pat. No. 4,790,305 refers to controlling the
`particle size of a metered dose of aerosol for delivery to the
`walls of small bronchi and bronchioles by ?lling a ?rst
`chamber with medication and a second chamber with air
`such that all of the air is inhaled prior to the inhaling
`medication, and using ?ow control ori?ces to control the
`?ow rate. U.S. Pat. No. 4,926,852 refers to metering a dose
`of medication into a ?ow-through chamber that has ori?ces
`to limit the How rate to control particle size. U.S. Pat. No.
`4,677,975 refers to a nebulizer device that uses baf?es to
`remove from any aerosol particles above a selected size.
`
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`

`3
`
`4
`
`5,544,646
`
`US. Pat. No. 3,658,059 refers to a bafile that changes the
`size of an aperture in the passage of the suspension being
`inhaled to select the quantity and size of suspended particles
`delivered. A problem with these devices is that they process
`the aerosol after it is generated and thus are ineflicient and
`wasteful.
`
`It is well known that pulmonary functions, such as forced
`expiratory volume in one second, forced vital capacity, and
`peak expiratory flow rate, can be measured based on mea-
`sured flow rates and used to (1) diagnose the existence of
`medical conditions, (2) prescribe medication, and (3) ascer-
`tain the efficiency of a drug therapy program. See, for
`example, US. Pat. Nos. 3,991,304 and 4,852,582 and the
`publications of Newman et al. discussed above. Heretofore,
`these tests have been performed using available spirometers.
`US. Pat. No. 4,852,582 also refers to using a peak flow rate
`meter to measure changes in peak flow rate before and after
`administration of a bronchodilator. The results of such tests
`before and after administration of several different medica-
`tions are used to evaluate the efficiency of the medications.
`A problem with the foregoing pulmonary function test
`devices is that they are too complicated for most patients to
`use effectively and obtain repeated delivery of a given
`amount of drug i.e. user error in administration causes
`significant variability in the amount of drug the patient
`receives. Another problem is that the data obtained does not
`directly eiTect the operation of the device, i.e. it must be
`examined and interpreted by a trained medical practitioner
`to be meaningful. Another problem is that they do not
`provide adequately for altering the dosage of the medication
`administered in a single patient during the course of therapy,
`or from patient to patient, using the same delivery device for
`generating an aerosol of the same or different medications.
`Attempts have been made to solve many of the above-
`referred-to problems. However, inconsistent user compli-
`ance combined with undesirably large particle size continues
`to cause problems with obtaining precise dosing.
`Nebulizers utilize various means in order to create a fog
`or mist from an aqueous solution or suspension containing
`a pharrnaceutically active drug. The mist created by the
`nebulizer device is directed towards the face of the patient
`and inhaled through the mouth and nose. Nebulizer devices
`and methodology can be quite useful when the precise
`dosing of the drug being delivered to the patient is not of
`particular importance. For example, in some situations the
`nebulizer creates a mist from an aqueous solution containing
`a bronchodilator which can be inhaled by the patient until
`the patient feels some improvement in lung function. When
`precise dosing is more important the nebulizer device and
`delivery methodology suffers from many of the disadvan-
`tages of metered dose inhaler devices and methodology as
`described above. In addition, nebulizers are large in size and
`not hand-held, easily transportable devices like MDIs.
`Accordingly, a nebulizer can only be used within a fixed
`location such as the patient’s home,
`the doctor’s office
`and/or hospital. However, a portable nebulizer is taught in
`published PCT application WO92/11050 incorporated
`herein by reference. Another nebulizer which uses a high
`frequency generator to create an aerosol is described in US.
`Pat. No. 3,812,854 issued May 28, 1974. Dmg formulations
`placed in nebulizers are generally diluted prior to delivery.
`The entire diluted formulation must generally be adminis-
`tered at a single dosing event in order to maintain the desired
`level of sterility and the nebulizer cleaned after use. Yet.
`another disadvantage of nebulizers is that they produce an
`aerosol which has a distribution of particle sizes not all of
`which are of appropriate size to reach the targeted areas of
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`the lung. The present invention endeavors to address and
`solve these and other problems.
`
`SUMMARY OF THE INVENTION
`
`The present invention includes several aspects as follows:
`(1) A disposable, collapsible package comprised of porous
`membrane surface area having pores with a diameter in
`the range of 0.25 micron to 6 rrricrons and a pore
`density in the range of 1><104 to 1><108 pores per square
`centimeter (alternatively about 10 to about 10,000
`pores in an area of about 1 mm2 to about 1 cm2) and at
`least one surface which is collapsible in a manner so as
`to force the contents of the container out of the porous
`membrane;
`(2) A dual package in the form of a compartment container
`wherein the first compartment is as described in (l) and
`includes a dry powder form of a drug and a second
`compartment which is connected to the first compart-
`ment by a rupturable membrane the second compart-
`ment being comprised of such that when pressure is
`applied liquid within the second compartment is forced
`through the rupturable membrane into the first com-
`partment
`to dissolve or suspend the dry powder
`whereby the contents can be aerosolized;
`(3) A package in the form of a cellular array of containers
`of the type described in (l) or (2) which cellular array
`may be in any configuration and include any number of
`containers;
`(4) A member preferably in the form of a tape which
`includes areas covered by the porous membrane which
`member may be loaded into a dispensing-device which
`includes a multiple dose container from which doses of
`pharmaceutically active drug may be dispersed through
`membranes;
`
`(5) A disposable or reloadable cassette which may be
`loaded with any package of (1), (2), (3) or (4) which
`cassette is designed so as to position individual con-
`tainers of the package or membranes in a manner such
`that the contents of each container or a unit dose of drug
`from a multiple dose container can be dispersed to a
`patient;
`(6) A dispensing device into which the member, cassette
`or package of (1), (2), (3) or (4) may be loaded so that
`a formulation of any pharrnaceutically active drug can
`be dispersed to a patient;
`(7) Methodology for delivering an aerosolized rrrist of a
`formulation such as therapeutic drugs to a patient
`which methodology uses a device for dispersing for-
`mulation from porous membranes thereby providing
`for intrapulmonary drug delivery to a patient—wherein
`the device is preferably a hand-held, self-contained,
`portable device comprised of a means for removing a
`surface cover from individual porous membranes and
`automatically dispersing formulation through the mem—
`branes, preferably in response to a signal obtained as a
`result of measuring both the inspiratory flow and
`inspiratory lung volume of a patient to calculate an
`optimal point for release of drug to optimize repeat-
`ability of dosing;.
`An important object of the invention is to provide a
`disposable container which includes an opening covered by
`a porous membrane and which preferably contains a liquid
`flowable formulation such as an aqueous formulation of a
`drug used in the treatment of lung diseases.
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 131, p. 21 of 39
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 131, p. 21 of 39
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`Another important object of the invention is to provide a
`disposable container comprised of unitary, surfaces inter~
`connected wherein one of the surfaces includes an area of
`
`having pores therein wherein the pores are configured as the
`porous membrane defined herein and wherein at least sur-
`face of the container is collapsible in a manner so as to force
`pharmaceutical formulation contained in the container out
`thru the pores.
`Another object is to provide a dual compartment container
`wherein one compartment includes a dry powder form of a
`drug and a second compartment separated from the first by
`a rupturable membrane includes a solvent such as water
`which when combined with the dry powder forms a solution
`or suspension which can be forced through a porous mem-
`brane and delivered to a patient as an aerosol.
`Another object is to provide a cellular array of a single
`compartment or dual compartment containers;
`Another object is to provide a disposable cassette which
`can incorporate a package (e.g., a cellular array of containers
`or interconnected membranes) and which cassette may be
`loaded into a device which can disperse a formulation thru
`a membrane which membrane may cover an opening in the
`container or be formed by drilling holes in an area of the
`container.
`
`Another object is to provide a dispensing device which is
`a hand—held easily portable device that functions so as to
`disperse formulation from the containers, preferably in
`response to measuring both inspiratory flow and inspiratory
`volume of a patient simultaneously to determine an optimal
`point for the release of drug needed to obtain repeatability in
`dosing.
`An advantage of the invention is that the membrane is
`used only once thereby eliminating any problems with
`respect to clogging and/or contamination.
`Another advantage when disposable containers are used is
`that the containers include a single dose thereby avoiding
`issues with respect to contamination and negating the need
`for the inclusion of bacteriostatic compounds within the
`formulation.
`Another advantage is that the formulation does not require
`the use of low boiling point propellants which may cause
`environmental damage.
`Another object of the invention is to provide a dispersing
`device which is capable of simultaneously measuring
`inspiratory flow and inspiratory volume as well as other
`parameters and making calculations based on the measure—
`ments to determine an optimal point for the release of drug
`which optimal point is calculated so as to maximize repeat-
`ability of the amount of drug delivered to the patient.
`Another object is to provide such a dispersing device
`wherein measurements such as inspiratory flow and inspira-
`tory volume are recorded prior to, during and after dispens-
`ing drug and wherein the measurements are recorded in
`order to determine the effectiveness of each drug release
`with respect to its ability to effectively provide drug to the
`patient via the intrapulmonary route.
`Another advantage of the invention is that the liquid dnig
`solutions contained within the individual containers need
`not and preferably do not include preservatives and/or any
`type of bacteriostatic compounds in that the containers are
`originally packaged in a sterile form and preferably consist
`essentially of liquid drug alone or in combination with a
`liquid and excipient carrier and the contents of the individual
`containers are used completely upon opening.
`Another advantage is that the system makes it possible to
`disperse aerosolized drug at a relatively low velocity as
`compared to the velocity of aerosols dispersed from con-
`ventional metered dose inhalers.
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`Another advantage is that drugs which are unstable in a
`liquid (e.g. aqueous) state can be stored in a dry state and
`combined with a liquid immediately prior to aerosolization.
`Another feature of the present invention is that a wide
`range of different pharrnaceutically active dnigs (with an
`excipient carrier as needed to form a liquid formulation) can
`be packaged within the individual sterile containers.
`Another feature of the invention is that the individual
`containers of the package include one or more openings
`through which air can be forced, which openings are in close
`proximity to a thin membrane having cone shaped pores of
`substantially uniform diameter at their narrowest point in the
`range of about 0.25 micron to 6 microns.
`Another feature of the invention is that the individual
`
`containers of a package and/or the package may be unitary
`in configuration and have a surface with pores positioned
`therein wherein the pores have a diameter in the range of
`0.25 micron to 6 microns with about 10 to 10,000 pores
`being present in a surface area in the range of 1 mm2 to about
`1 cm2.
`Another feature of the invention is that the containers
`
`have channels leading therefrom to the porous membranes
`so that a vibrating mechanism in the cassette can be posi—
`tioned directly below the porous membrane.
`Yet another feature of the present invention is that the
`dispensing device or cassette includes a vibrator or high
`frequency signal generation device which vibrates the liquid
`being forced through the porous membrane of the package
`at different frequencies in a manner so as to promote regular
`sizing of the droplets from the stream forced from an
`opening and create an aerosol having uniform (or if desired
`a range of different) particle size in the range of 0.5 micron
`to 12 microns in diameter.
`Another feature of the invention is that it may be used for
`in the intrapulmonary delivery of all types of drugs includ—
`ing the systemic drugs, respiratory drugs and/or any drugs to
`a patient and obtained a fast acting effect on the patient.
`Another object of the present invention is to provide a
`disposable package comprised of a container for holding a
`liquid aerosolizable formulation, which container is con-
`nected via one or more channels to a chamber or resonance
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`cavity positioned directly below a porous membrane such
`that when formulation from a container is forced through the
`channel into the resonance cavity and out of the pores of the
`membrane, the formulation will be aerosolized into particles
`having a diameter in the range of 0.5 micron to 12 microns.
`Another advantage of the present invention is that the
`system including the device and disposable cassette is a
`hand-held, easily portable and usable device.
`Another feature of the invention is that the package may
`include indices thereon in the form of visually readable
`numbers or letters which can be readily perceived by the
`user whether a dose has been delivered for a particular day
`and/or time of day and/or indicate the number of doses in the
`cassette which have been used and the number which remain
`for use.
`Still another feature of the invention is to provide, in the
`cassette, a power source such as a battery in connection with
`indices on the package which are in the form of magnetic,
`optical and/or electronic records which can be read by the
`drug dispensing device which in turn presents a visual
`display to the user providing information on the amounts
`and times of doses released (in total or from a given cassette)
`and/or to be released.
`Another feature is to provide a battery integral with the
`disposable cassette, which battery provides sufficient energy
`to power the device, including providing power to control
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 131, p. 22 of 39
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`WATSON LABORATORIES, INC. , IPR2017-01621, Ex. 131, p. 22 of 39
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`5,544,646
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`7
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`the microprocessor, vibrating the device, and piston or
`bellows to force formulation through the membranes and
`thereby create an aerosol from all of the liquid and/or
`suspension material contained within all of the containers
`present in that cassette.
`It is another object of this invention to provide a pocket~
`sized, single, integrated device for recording the date, time
`and amount of aerosolized drug delivered at each drug
`delivery event which device is also capable of monitoring
`pulmonary function and maintaining a record of the date,
`time and value of each objective lung function and recording
`the information on a package.
`It is another object of this invention to provide a device
`capable of monitoring and recording objective pulmonary
`function information and displaying such information in a
`manner integrated with drug dosing event information so as
`to provide a means of evaluating quantitative, objective
`measures of pulmonary function in the context of actual
`administered therapy.
`It is another object of this invention to show that the
`evaluation of pulmonary function in light of actual patient
`compliance only has meaning if drug dosing events are
`actually associated with patient inspiration and firing of the
`aerosolized drug into; the patient’s mouth.
`It is another object of this invention to show that