United States Patent
`
`1191
`
`[11]
`
`Patent Number:
`
`5,743,251
`
`Howell et al.
`[45] Date of Patent:
`Apr. 23, 1998
`
`US005743 25 1 A
`
`[54] AEROSOL AND A METHOD AND
`APPARATUS FOR GENERATING AN
`AEROSOL
`.
`
`-
`
`,
`
`~
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`[73] Ass1gnee: Phlllp Morns Incorporated. New
`York NY-
`
`-
`
`‘
`
`4.848.374
`4-877.939
`,
`,
`5,021,802
`
`5,050,571
`5,063,921
`5,228,444
`5,259,370
`5,327,915
`
`7/1939 Chard et 31-
`10/1939 D{eW5 81 31-
`CIIIOIJ B
`gm?‘ ta!
`6/1991 Allred.
`
`-
`9
`
`.
`
`10/1991 Counts et al.
`11/1991 H
`.
`7,1993 Bfizfi
`11/1993 Howe .
`7/1994 Porenslci et a].
`
`..........................
`
`250f283
`
`.......................... 131/329
`
`.
`
`[21] APP1, No; 543,253
`
`5,342,130
`
`3/1994 Daoud ..................................... 417/412
`
`[22] Filed:
`May 15,1996
`[51]
`. A61M 5/oo
`Int. Cl.‘ ....................
`
`[s2] U.S. Cl. ................................ 128/200.14; 128/203.25;
`
`OTHER PUBLICATIONS
`‘‘_Generation of Aerosol Particles D1 B_oi1ing of Suspen-
`S1°11S”~YaS“° K°"S=‘-k3~ 6‘ “L 46”” 50'8"“ and Techno’-
`
`[56]
`
`[ss] Field of Search ..................... 131/329; 417/412.
`,
`7 .477; 2
`417/474,
`, 2 2.
`
`.
`6
`50,281
`8
`288, 128/200.14. 200.18. 200.21. 203.12.
`203.21. 203.25. 203.26; 239/10
`Refemnces Cimd
`Us. PATENT
`3/1969 Km) dz
`43] 393
`~
`“
`3:
`v
`1/1975 Havstad .
`3,859,398
`9/1975 Pedna etal..
`3,903,883
`11/1977 Lintlgergetal.
`4,060,082
`9/1931 Wmjams ,
`4,291,333
`4,303,083 12/1981 Burruss, In .
`.................... .. 219/121 PY
`4,575,609
`3/1986 Fassel et al.
`4,627,432 12/I986 Nev/ell e!al..
`4,730,111
`3/1938 V6131 et 31.
`............................ 250/238
`4744332
`5/1938 B'°w“°'
`4,752,995
`3/1933 Browneretal.
`....... 250/232
`‘£776,515
`I0/1938 M_ichakhik_
`4,311,731
`3/1989 Newell et al.
`.
`4,819,625
`4/1939 Howe.
`
`....................... 417/437
`
`o’:°§1°;“‘3‘§';,‘“g:::r:f “(‘:‘;$§mA‘L‘:5:‘zr::§l:‘ :"6a°‘f:°;1j
`,
`_
`,
`Umfonty of Dosage Umts <905>". Peter R. Bryon. Ph.D..
`.
`.
`Pharmacopeuzl Forum. vol. 20. No. 3. May—Jun.
`Primary Examiner—Vincent Millin
`Assistant
`J. Deane. I1’.
`Attorney Agent, or F/rm—Burns. Doane. Swecket &
`Mathis. LLP
`
`[57]
`
`ABSTRACT
`
`An aerosol is formed by supplying a material in liquid form
`to a tube and heating the tube such that the material volatizes
`and expands out of an open end of the tube. The volatized
`matefial combines with ambient air such that volatiz/ed
`material condenscs to fonn the aerosol An apparatus for
`generatin
`such an aerosol and a method for
`eneratin
`h
`1
`al dd (1
`g
`3
`3
`suc an aeroso. are
`so
`s ose
`
`51 Claims, 4 Drawing Sheets
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`
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`

`
`U.S. Patent
`
`Apr. 23, 1993
`
`Sheet 1 of 4
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`5,743,251
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`
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`

`
`U.S. Patent
`
`Apr. 28, 1993
`
`Sheet 2 of 4
`
`5,743,251
`
`
`
`27A"
`
`FlG.2A
`
`L\_\\\\\I\_\\
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`
`
`11111313232 1
`
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`

`
`U.S. Patent
`
`Apr. 28, 1993
`
`Sheet 3 of 4
`
`5,743,251
`
`
`
`mi.:1
`
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`

`
`U.S. Patent
`
`Apr. 23, 1998
`
`Sheet 4 of 4
`
`5,743,251
`
`bvm
`
`zmmm
`
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`

`
`5,743,251
`
`1
`AEROSOL AND A METHOD AND
`APPARATUS FOR GENERATING AN
`AEROSOL
`
`BACKGROUND AND SUMMARY OF THE
`INVENTION
`
`The present invention relates generally to aerosols and.
`more particularly. to aerosols generated without compressed
`gas propellants and methods and apparatus for generating
`such aerosols.
`Aerosols are useful in a wide variety of applications. For
`example. it is often desirable to treat respiratory ailments
`with. or deliver drugs by means of. aerosol sprays of finely
`divided particles of liquid and/or solid. e.g.. powder.
`medicaments. etc.. which are inhaled into a patient’s lungs.
`Aerosols are also used for purposes such as providing
`desired scents to rooms. applying scents on the skin. and
`delivering paint and lubricant.
`Various techniques are known for generating aerosols. For
`example. U.S. Pat. Nos. 4.811.731 and 4.627.432 both
`disclose devices for administering medicaments to patients
`in which a capsule is pierced by a pin to release a medica-
`ment in powder form. A user then inhales the released
`medicament through an opening in the device. While such
`devices may be acceptable for use in delivering medica-
`ments in powder form. they are not suited to delivering
`medicarnents in liquid form. The devices are also. of course.
`not well-suited to delivay of medicaments to persons who
`might have difficulty in generating a sufiicient flow of air
`through the device to properly inhale the medicaments. such
`as asthma sulferers. The devices are also not suited for
`delivery of materials in applications other than medicament
`delivery.
`Another well-known technique for generating an aerosol
`involves the use of a manually operated pump which draws
`liquid from a reservoir and forces it through a small nozzle
`opening to form a fine spray. A disadvantage of such aerosol
`generators, at least in medicament delivery applications. is
`the difliculty of properly synchronizing inhalation with
`pumping.
`One of the more popular techniques for generating an
`aerosol including liquid or powder particles involves the use
`of a compressed propellant. often containing a chloro-
`fluoro-carbon (CFC) or methylchloroforrn.
`to entrain a
`material. usually by the Venturi principle. For example.
`inhalers containing compressed propellants such as com-
`pressed oxygen for entraining a medicament are often oper-
`ated by depressing a button to release a short charge of the
`compressed propellant. The propellant entrains the medica-
`ment as the propellant flows over a reservoir of the medi-
`cament so that the propellant and the medicament can be
`inhaled by the user. Since the medicament is propelled by
`the propellant. such propellant-based arrangements are well-
`suited for those who might have difliculty inhaling.
`In propellant-based arrangements. however. a medica-
`ment may not be properly delivered to the patient's lungs
`when it is necessary for the user to time the depression of an
`actuator such as a button with inhalation. Moreover. such
`arrangements tend to be poorly suited for delivery of mate-
`rials in large quantities. Although propellant-based aerosol
`generators have wide application for uses such as antiper-
`spirant and deodorant sprays and spray paint. their use is
`often limited because of the well-known adverse environ-
`mental effects of CFC‘s and rnethylchloroforrn. which are
`among the most popular propellants used in aerosol genera-
`tors of this type.
`
`2
`In drug delivery applications. it is typically desirable to
`provide an aerosol having average mass median particle
`diameters of less than 2 microns to facilitate deep lung
`penetration. Most known aerosol generators are incapable of
`5 generating aerosols having average mass median particle
`diameters less than 2 to 4 microns. It is also desirable. in
`certain drug delivery applications. to deliver medicaments at
`high flow rates. e.g.. above 1 milligram per second. Most
`known aerosol generators suited for drug delivery are inca-
`pable of delivering such high flow rates in the 0.2 to 2.0
`micron size range.
`In accordance with one aspect of the present invention. an
`aerosol generator includes a tube having a first open end.
`The aerosol generator further includes means for heating the
`tube to a temperature sufiicient to volatilize material in a
`liquid form in the tube such that the volatilized material
`expands out of the open end of the tube and mixes with
`ambient air to form an aerosol.
`In accordance with another aspect of the present
`invention. a method for generating an aaosol is disclosed.
`According to the method. a material in liquid form is
`suppliedto a tube having an open end The material supplied
`to the tube is heated to a temperature sufficient to volatilize
`the supplied material such that
`the volatilized material
`expands out of the open end of the tube. the volatilized
`material condensing upon mixing with ambient atmospheric
`air to form an aerosol.
`In accordance with yet another aspect of the present
`invention. an aerosol is provided The aerosol is formed by
`supplying a material in liquid form to a tube and heating the
`tube such that the material volatilizes and expands out of an
`open end of the tube. The volatilized material combines with
`ambient air such that volatilized material condenses to form
`the aerosol.
`In accordance with still another aspect of the present
`invention. an aerosol is provided. A first material is supplied
`in liquid form to a first tube and the first tube is heated such
`that the first material volatilizes and expands out of an open
`, end of the first tube. A second material is supplied in liquid
`form to a second tube and the second tube is heated such that
`the second material volatilizes and expands out of an open
`end of the second tube. The volatilized first and second
`material are combined together with ambient air such that
`the volatilized first and second materials form first and
`second aerosols. respectively. the first and second aerosols
`being mixed to form the aerosol.
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`30
`
`35
`
`45
`
`55
`
`The features and advantages of the present invention are
`well understood by reading the following detailed descrip-
`tion in conjunction with the drawings in which like numerals
`indicate similar elements and in which:
`FIG. 1 is a schematic view of an aerosol generator
`according to a first embodiment of the present invention;
`FIGS. 2A and 2B are schematic views of a portion of an
`aerosol generator including heaters according to embodi-
`ments of the present invention;
`FIG. 3 is a schematic View of an aerosol generator
`according to a second embodiment of the present invention;
`and
`FIG. 4 is a schematic View of an aerosol generator
`according to a third embodiment of the present invention;
`and
`
`65
`
`FIG. 5 is a graph of the effects of power applied in the
`aerosol generator on the mass median particle diameter of an
`aerosol generated thereby. according to the present
`invention.
`
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`

`
`5.743.251
`
`3
`DETAILED DESCRJPTION
`
`An aerosol generator 21 according to a first embodiment
`of the present invention is schematically shown with refer-
`ence to FIG. 1. The aerosol generator 21 includes a tube 23
`having an open end 25. A heater 27 is positioned adjacent to
`at least a portion of the tube 23. but preferably in a way that
`provides a heated zone around the tube that maximizes heat
`transfer evenly throughout the heated zone. The heater 27 is
`connected to a power supply 29. preferably a D.C. power
`supply such as a battery.
`In operation. a material (not shown) in liquid form is
`introduced to the tube 23. The heater 27 heats the portion of
`the tube 23 to a suflicient temperature to volatilize the liquid
`material. In the case of an organic liquid material. the heater
`preferably heats the liquid material just to the boiling point
`of the liquid material. and preferably maintains the surface
`temperature of the tube 23 below 400° C.. as most organic
`materials are not stable when they are exposed to tempera-
`tures above that temperature for periods of time. The vola-
`tilized material expands out of the open end 25 of the tube
`23. The volatilized material mixes with ambient air outside
`of the tube and condenses to form particles. thereby forming
`an aerosol.
`
`In a presently preferred embodiment, the tube 23 is a
`capillary tube or a portion thereof having an inside diameter
`of between 0.05 and 0.53 millimeter. Aparticularly preferred
`inside diameter of the tube is approximately 0.1 millimeter.
`The tube 23 is preferably a portion of a fused silica capillary
`column or an aluminum silicate ceramic tube. however.
`other substantially non-reactive mataials capable of with-
`standing repeated heating cycles and generated pressures
`and having suitable heat conduction properties may also be
`used. If desired or necessary. an inside wall of the tube 23
`may be provided with a coating for reducing the tendency of
`material to stick to the wall of the tube. which may result in
`clogging.
`The tube 23 may be closed at a second end 31 and material
`in liquid form may be introduced into the tube 23 through
`the open end 25 when it is desired to form an aerosol. Thus,
`when the liquid material is heated by the heater 27. the
`volatilized material is only able to expand by exiting the tube
`23 through the open end 25. However. it is preferred that the
`second end 31 of the tube be connected to a source 33
`(shown by dotted lines in FIG. 1) of liquid material. The
`liquid material in the portion of the tube 23 volatilized by the
`heater 27 is prevented from expanding in the direction of the
`second end 31 of the tube. and is forced out of the open end
`25 of the tube. as a result of back pressure of liquid from the
`source 33 of liquid material. The back pressure of the liquid
`is preferably between about 20 to 30 psi.
`The heater 27 is preferably an electrical resistance heater.
`According to a preferred embodiment. the heater 27 is a
`heater wire having an outside diameter of 0.008 inches. a
`resistance of 13.1 ohms per foot. and a specific heat of 0.110
`BTU/lb °F. The composition of the heater wire is 71.7%
`iron. 23% chromium. and 5.3% aluminum. Such a heater
`wire is available from Kanthal Furnace Products. Bethel.
`Conn.
`According to another preferred embodiment. the heater
`27A and 27B shown in FIGS. 2A and 2B. respectively.
`includes a thin platinum layer 27A‘ and 27B‘. respectively.
`which is deposited on the outside of a lapped ceramic
`capillary tube 23 serving as a substrate. In addition to the
`aluminum silicate ceramic tube noted above. the tube may
`include a ceramic such as titania. zirconia. or yttria—
`stabilized zirconia which does not experience oxidation at
`
`4
`normal operating temperatures afterrepeated cyclings. Pref-
`erably the ceramic is alumina having an approximately 99%
`purity. and more preferably a 99.6% purity. available from
`the Accumet Engineering Corporation of Hudson. Mass.
`The tube and the heater layer preferably have a roughly
`matching coeflicient of thamal expansion to minimize ther-
`mally induced delarnination. The ceramic has a determined
`roughness to affect the electrical resistance and to achieve
`adhesion of the deposited platinum layer. The platinum layer
`does not experience oxidation degradation or other corrosion
`during projected life cycles.
`The thin film heater layer is deposited on the ceramic tube
`23. The heater layer is preferably a thin platinum film having
`a thickness of. eg. less than approximately 2 pm. The heater
`layer is deposited onto the tube by any suitable method such
`as DC magnetron sputter deposition. e.g.. using an HRC
`magnetron sputter deposition unit. in argon at 8.0x 104 Torr.
`Alternatively. other conventional techniques such as vacuum
`evaporation. chemical deposition. electroplating. and chemi-
`cal vapor deposition are employed to apply the heater layer
`to the tube.
`
`The surface morphology of the ceramic tube substrate is
`important to accomplish a successful deposition of the
`heater layer. Preferably. the tube 23 is lapped by a conven-
`tional serrated lmife. Typical lapped alumina has an unpol-
`ished surface roughness between approximately 8 and 35
`microinches. ‘The ceramic tube substrate is then polished to
`a surface roughness having an arithmetic average greater
`than approximately one microinch and. more specifically,
`between one and approximately 100 rnicroinches. and most
`preferably between 12 and 22 rnicroinches. If the substrate
`is polished to further reduce surface roughness as in con»
`ventional ceramic substrate preparation. ie. to a surface
`roughness of one rnicroinch or less. an adequate deposition
`interface will not be formed.
`
`As seen in FIG. 2A. the heater layer 27A’ is coupled to the
`power supply by means of appropriate contacts 27A" for
`resistive heating of the heater layer. As seen in FIG. 2B. the
`heater layer 27B‘ is coupled to the power supply by con-
`ductive posts 2713" for resistive heating of the heater layer.
`The contacts or posts preferably have a lower resistance than
`the associated heater layer to prevent or reduce heating of
`these connections prior to heating of the heater layer. As
`seen in FIG. 2A. the contacts 27A" may comprise a gold
`coated tungsten wire. such as a W-wire wool. commercially
`available from the Teknit Corporation of New Jasey. which
`is gold coated. Alternatively. the contacts may comprise
`copper leads. The contacts 27A" contact the platinum heater
`layer 27A’ on orin the heater layer top surface or at any other
`location so long as an adequate electrical contact
`is
`achieved. The contacts 27A‘ may be electrically connected
`to mounds 28A‘ of the platinum heata layer 27A‘. the heater
`layer further having an active area 28A" for heating the tube
`23 therebetween. The resistance of the heater layer 27A‘ is
`aflected by the morphology of the tube 23.
`As seen in FIG. 2B. electrically conductive contact posts
`2713'‘ may be used instead of the above-described contact
`arrangements and may be formed to improve the mechanical
`strength of the assembly. The contact posts are connected to
`the outside of the tube 23 prior to deposition of the heater
`layer 27B’ and are connected to the power supply by means
`of wires. The contact posts may be comprised of any desired
`material having good electrical conductance such as copper
`or other copper alloys such as phosphur bronze or Si bronze.
`and are preferably copper or any alloy having at least
`approximately 30% copper. The posts 2715“. or a bonding
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`65
`
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`
`5,743,251
`
`5
`layer. as discussed below. provide a low electrical resistance
`connection for use with a desired current. If copper or a
`copper alloy is not employed for the posts. then preferably
`an intermediate copper bonding layer (not shown) is con-
`nected by any conventional technique to tire end of the post
`to permit bonding between the post and the tube 23 without
`affecting the electrical path.
`The connection of the ends of the posts 27B " to the tube
`23 is preferably achieved by eutectic bonding wherein a
`surface of copper is oxidized. the resulting copper oxide
`surface is contacted with the ceramic substrate or tube. the
`copper-copper oxide is heated to melt the copper oxide but
`not the copper such that the melted copper oxide flows into
`grain boundaries of the ceramic. and then the copper oxide
`is reduced back to copper to form a strong bond. This
`connection can be achieved by a eutectic bonding process
`used by Brush Wellman Corporation of Newbury Port.
`Mass.
`
`Next. the platinum heater layer 27B‘ is applied to the
`ceramic tube 23. The heater layer comprises an initial layer
`27C‘ extending around the tube 23 and the posts 27B" and
`a contact layer 27D’ which electrically connects the posts to
`the initial layer. The active heating area 28B" is defined on
`the portion of the heater layer 273' which is not covered by
`the contact layer 27D‘ as a result of masking the heating area
`prior to applying the contact layer. Mounds or thick regions
`23B’ are formed by the contact layer 27D‘ around the posts
`27B" and rise from the tube surface to function as contacts.
`In the embodiments illustrated in FIGS. 2A and 2B. by
`providing the mounds or graded regions of platinum in the
`heater layer. such that it is thicker at the contacts or posts
`than at the active portion. a stepped resistance profile results
`which maximizes resistance in the active portion of the
`heater layer.
`The power supply 29 is sized to provide suflicient power
`for the heating element 27 that heats the portion of the tube
`E. The power supply 29 is preferably replaceable and
`rechargeable and may include devices such as a capacitor or.
`more preferably. a battery. For portable applications. the
`power supply is. in a presently preferred embodiment. a
`replaceable. rechargeable battery such as four nickel cad-
`mium battery cells connected in series with a total. non-
`loaded voltage of approximately 4.8 to 5.6 volts. The
`charactaislics required of the power supply 29 are. however.
`selected in view of the characteristics of other components
`of the aerosol generator 21. particularly the characteristics of
`the heater 27. One power supply that has been found to
`operate successfully in generating an aerosol from liquid
`propylene glycol is operated continuously at approximately
`25 Volts and 0.8 Amps. The power supplied by the power
`supply operating at this level is close to the minimal power
`requirements for volatizing propylene glycol at a rate of 1.5
`milligrams per second at atmospheric pressure. illustrating
`that the aerosol generator 23 may be operated quite efii—
`ciently.
`The aerosol generator 23 may generate an aerosol
`intermittently. e.g.. on demand. or, as discussed further
`below. continuously. When it is desired to generate an
`intermittent aerosol. the material in liquid form may be
`supplied to the portion of the tube 23 proximate the heater
`27 each time that it is desired to generate the aerosol.
`Preferably. the material in liquid form flows from the source
`33 of material to the portion of the tube 23 proximate the
`heater 27. such as by being pumped by a pump 35 (shown
`by dotted lines).
`If desired, valves (not shown) may be provided in line
`between the portion of the tube 23 proximate the heater 27
`
`6
`to interrupt flow. Preferably. the material in liquid form is
`pumped by the pump 35 in metered amounts suflicient to fill
`the portion of the tube 23 proximate the heater 27 so that
`substantially only the material in that portion of the tube will
`be volatilized to form the aerosol. the remaining material in
`the line between the source 33 of material and the portion of
`the tube 23 preventing expansion of the volatilized material
`in the direction of the second end 31 of the tube.
`
`When it is desired to generate an aerosol intermittently for
`drug inhalation. the aerosol generator 23 is preferably pro-
`vided with a puif-actuated sensor 37 (shown by dottedlines).
`which preferably forms part of a mouthpiece 39 (shown by
`dotted lines) disposed proximate the open end 25 of the tube
`23. for actuating the pump 35 and the heater 27 so that
`material in liquid form is supplied to the tube 23 and the
`material is volatilized by the heater. The puff-actuated sensor
`37 is preferably of the type that is sensitive to pressure drops
`occurring in the mouthpiece 39 when a user draws on the
`mouthpiece. The aerosol generator 23 is preferably provided
`with circuitry such that. when a user draws on the mouth-
`piece 39. the pump 35 supplies material in liquid form to the
`tube 25 and the heater 27 is heated by the power supply and
`the pump 35.
`A pufl”-actuated sensor 37 suitable for use in the aerosol
`generator may be in the form of a Model l63PC01D35
`silicon sensor. manufactured by the Microswitch division of
`Honeywell. Inc.. Freeport. Ill.. or an SLP004D 0-4" H20
`Basic Sensor Element. manufactured by SenSym. Inc..
`Milpitas. Calif. Other known flow-sensing devices. such as
`those using hot-wire anemometry principles. are also
`believed to be suited for use with the aerosol genmator.
`The mouthpiece 39 is disposed proximate the open end 25
`of the tube 23 and facilitates complete mixing of the
`volatilized material with coola ambient air such that the
`volalilized material condenses to form particles. For drug
`delivery applications,
`the mouthpiece 39 is preferably
`designed to permit passage of at least approximately 60
`liters of air per minute without substantial resistance. such a
`flow rate being the normal tidal flow for inhalation. Of
`course. the mouthpiece 39. if provided. may be designed to
`pass more or less air. depending upon the intended applica-
`tion of the aerosol generator and other factors. such as
`consumer prefuences. A preferred mouthpiece for a hand
`held asthma inhaler is approximately 1 inch in diameter and
`between 1.5 and 2 inches in length. with the open end 25 of
`the tube 23 centered at an end of the mouthpiece.
`An aerosol generator 121 according to a second embodi-
`ment of the present invention is seen with reference to FIG.
`3. The basic components of the aerosol generator 121 are
`substantially the same as the components of the aerosol
`generator 21 shown in FIG. 1. the aerosol generator 121
`shown in FIG. 3 including a presently preferred liquid
`material supply assembly 135. The aerosol generator 121
`includes a tube 123 having an open end 125. a heater 127
`attached to a port:ion of the tube 123 proximate the open end.
`and a power supply 129 for supplying power to the heater.
`A second end 131 of the tube 123 extends to a reservoir
`or source 133 of liquid material. such as a cylinda of a
`syringe. and the liquid material is delivered to the tube
`through the second end 131 thereof by means of a pump 135.
`such as a piston of the syringe. A mouthpiece 139 and
`pufl-actuated sensor 137 (both shown by dotted lines) may
`be provided as well. in substantially the same manner as
`discussed above with regard to the aerosol generator 23.
`The illustrated syringe pump 141. including the cylinder
`133 and piston 135. facilitates delivery of liquid material to
`
`20
`
`25
`
`30
`
`35
`
`45
`
`50
`
`Nu Mark LLC v. Fontem Holdings 1 B.V. |PR2016-01288
`Page 8 of 14
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`Fontem Ex. 2018
`
`Fontem Ex. 2018
`Nu Mark LLC v. Fontem Holdings 1 B.V. IPR2016-01288
`Page 8 of 14
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`

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`5,743,251
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`7
`the tube 123 at a desired flow rate. The syringe pump 141 is
`preferably provided with an assembly 143 for automatically
`moving the piston 135 relative to the cylinder 133. The
`assembly 143 preferably pamits incremental or continuous
`advancement or withdrawal of the piston 135 from the
`cylinder 133. as desired. If desired. of course. the piston 135
`may alternatively be manually compressible.
`The assembly 143 preferably includes a rod 145. at least
`a portion of which is extanally threaded. Preferably. the rod
`145 is attached at one end to a shaft 147 of a reversible motor
`149. preferably an electric motor. such that operation of the
`motor causes the rod to rotate clockwise or
`counterclockwise. as desired. The rod 145 is preferably
`attached to the shaft 147 by means of a coupling 151 that
`permits axial movement of the rod relative to the shaft. but
`not rotational movement of the rod relative to the shaft.
`An end of the rod 145 is attached to the piston 135. The
`rod 145 is preferably attached to the piston 135 by means of
`a bearing assembly 153 such that rotation of the rod does not
`cause rotation of the piston. however. if desired. the rod may
`be rigidly attached to the piston. The externally threaded
`portion of the rod 145 extends through an internally threaded
`opening 155 in a member 157. which ay simply be a nut.
`which is fixed in position relative to the motor 149 and the
`cylinder 133. both of which are preferably also fixed in
`position.
`Preferably. when the motor 149 is operated. the shaft 147
`turns the rod 145 and the rod turns in the opening 155
`relative to the fixed member 157. As the rod 145 turns in the
`opening 155. the end of the rod attached to the piston 135 is
`advanced or withdrawn from the cylinder 133. depending
`upon the thread of the rod and the opening and the direction
`in which the rod is turned. The coupling 151 permits the rod
`145 to move axially relative to the shaft 147. Sensors (not
`shown) are preferably provided to ensure that the rod 145 is
`not moved excessively into or out of the cylinder 133. It will
`be appreciated that a liquid supply arrangement such as the
`above-described syringe pump 14] is well suited to supply
`liquid at a rate of 1 milligram/second or greater. as needed.
`and that. provided a suficiently powerful heater 127 is
`provided. an aerosol may be continuously produced at a rate
`of 1 milligramlsecond or greater. which is understood to be
`a much greater rate of delivery of particles in sizes between
`0.2 and 2 microns mass median particle diameter than is
`available with conventional aerosol drug delivery systems.
`It will often be desirable to minimize contact of the liquid
`in the cylinder 13 with oxygen. such as to avoid contami-
`nation or decomposition. To this end, the aerosol generator
`121 is preferably provided with an arrangement for conve-
`niently refilling the cylinder 133 of the syringe pump 14].
`such as a line 159 having a valve 161 that may be opened as
`the piston 135 is withdrawn in the cylinder to draw liquid
`from another source of supply. Another valve 163 may be
`provided in the tube 123 to ensure that liquid flowing into
`the aerosol generator is charged into the cylinder and not
`inadvertently wasted by flowing out of the open end 125 of
`the tube. If desired, a three-way valve may be provided to
`alternatively pmnit flow from the cylinder 133 to the tube
`, 123 and from the line 159 to the cylinder.
`In addition. or in the alternative. the cylinder 133 and
`piston 135 may be configured to be easily replaced when
`emptied. such as by providing appropriate fittings where the
`end of the cylinder meets the second end 131 of the tube 123
`and where the rod 145 is attached to the piston. A new.
`preferably hermetically sealed piston 135 and cylinder 133
`can be provided to replace a used piston and cylinder. Such
`
`8
`an arrangement may be particularly desirable in applications
`such as hand held inhalers and the like.
`
`The aerosol generator 121 may continuously generate an
`aerosol. such as by continuously operafing the motor 149
`and the heater 127 such that liquid material is continuously
`supplied to the tube 123 and the supplied liquid material is
`continuously volatilized. In addition. or in the alternative.
`the aerosol generator may intermittently generate an aerosol.
`such as by intermittently operating the motor 149 and the
`heater 127 such that a desired amount of liquid material is
`supplied to the tube 123 over a period of time and the heater
`is operated for a suflicient length of time to volatilize the
`supplied liquid. the motor and the heater thereafter being
`turned off. Intermittent operation in drug delivery applica-
`tions is preferably achieved by actuation of the motor 149
`and the heater 127 by the puif-actuated sensor 137 in
`combination with appropriate interconnecting circuitry.
`Alternative actuating devices, e.g.. push buttons. may. of
`course. be used.
`An aerosol generator 221 according to a third embodi-
`ment of the present invention is seen with reference to FIG.
`4. The aerosol generator 221 includes two or more separate
`aerosol generators. which may be substantially the same as
`the aerosol generator described above. in combination. The
`parallel aerosol generator arrangement facilitates forming a
`combination aerosol formed by mixing together two or more
`separately generated aerosols. The parallel aerosol generator
`arrangement is particularly useful where it is desired to form
`an aerosol comprising two or more materials which do not
`mix well in liquid form.
`Each aerosol generator preferably includes a tube 223' and
`223". respectively, cad) tube having an open end 225‘ and
`225". respectively. Heaters 227' and 227" are preferably
`provided for each tube 223' and 223". respectively. although.
`in some applications. it may be convenient or possible to
`provide a single heater for heating both tubes. The heaters
`are powered by power supplies 229' and 229". respectively.
`If desired. a single power supply may be used to power both
`heaters.
`Each tube 223' and 223" is connected. at its second end
`231' and 231". respectively.
`to sources 233' and 233",
`respectivel