United States Patent (19)
`Ingebrethsen
`
`56
`
`54 AEROSOL DELIVERY ARTICLE
`76 Inventor: Bradley J. Ingebrethsen, 3522 Kittery
`Ct., Winston-Salem, N.C. 27104
`(21) Appl. No.: 99,015
`22 Filed:
`Jul. 29, 1993
`51) Int. Cl'............................................. A61M 15/00
`52 U.S. C. .......................... 125/203.17; 125/200.16;
`125/203.26
`58) Field of Search ...................... 128/200.14, 200.15,
`128/200.16, 200.17, 200.18, 200.19, 200.20,
`200.21, 200.22, 200.23, 203.16, 203.17, 203.26
`References Cited
`U.S. PATENT DOCUMENTS
`1,771,366 7/1930 Wyss et al. .
`1,968,509 7/1934 Tiffany .................................. 219/38
`2,030,075 2/1936 Robinson .............................. 128/92
`2,057,353 10/1936 Whittemore, Jr. ................... 219/38
`2,248,591 5/1942 Rose ...................................... 299/38
`2,332,799 10/1943
`... 28/175
`2,764,154 9/1956
`... 128/201
`3,297,029 1/1967
`... 128/188
`3,820,540 6/1974
`... 128/212
`3,859,398 1/1975
`... 261/14
`3,864,544 2/1975 van Amerongen.
`... 219/301
`3,990,441 11/1976 Hoyt et al...................
`... 128/193
`4,036,224 7/1977 Choporis et al. ...
`... 128/212
`4,190,046 2/1980 Virag...............
`... 128/200
`4,214,146 7/1980 Schimanski.
`... 219/274
`4,303,083 12/1981 Burruss, Jr. .
`... 131/271
`4,523,589 6/1985 Krauser ............................... 128/203
`4,655,229 4/1987 Sensabaugh, Jr. et al. ........ 131/273
`4,655,959 4/1987
`252/305
`4,715,387 12/1987
`... 131/270
`o
`4,735,217 4/1988
`131/273
`4,765,347 8/1988 Sensabaugh, Jr. et al. ........ 131/270
`4,832,012 5/1989 Raabe et al. ................... 128/200.21
`4,922,901 5/1990 Brooks et al. ....................... 128/203
`4,941,482 7/1990 Ridings et al. ...................... 131/194
`4,951,659 8/1990 Weiler et al.....
`... 128/200.18
`4,963,367 10/1990 Ecanow .......
`... 424/485
`5,145,604 9/1992 Neumiller ........................... 252/312
`OTHER PUBLICATIONS
`Paul C. Hiemenz; Principles of Colloid and Surface
`Chemistry; 1986; pp. 467-474.
`Anthony J. Hickey; Summary of Common Approaches
`
`
`
`USOO.5388574.A.
`Patent Number:
`Date of Patent:
`
`(11)
`45
`
`5,388,574
`Feb. 14, 1995
`
`to Pharmaceutical Aerosol Administration; (1992);
`255-288.
`Giuseppe Tarroni, et al; An Indication on the Biological
`Variability of Aerosol Total Deposition in Humans;
`Am. Ind. Hyg. Assoc. J.; 41; Nov. 1980; pp. 826-831.
`Richard N. Berglung, et al; Generation of Monodis
`perse Aerosol Standards; Environ SciTechnol vol. 7,
`No. 2, Feb., 1973; pp. 147-153.
`M. J. Fulwyler; Electronic Separation of Biological
`Cells by Volume; Science, vol. 150; 1965; pp. 910-911.
`Lars Strom; The Generation of Monodisperse Aerosols
`by Means of a Disintergrated Jet of Liquid; The Review
`of Scientific Instruments; vol. 40, No. 6; Jun., 1969; pp.
`778-782.
`Vittorio Prodi, A Condensation Aerosol Generator for
`Solid Monodisperse Particles; Assessment of Airborne
`Particles Fundamentals Applications and Implications
`to Inhalation Toxicity; 1972; pp. 169-181.
`C. N. Davies; Generation and use of Monodisperse
`Aerosols; Aerosol Science; 1966; pp. 1-30.
`Primary Examiner-Edgar S. Burr
`Assistant Examiner-Eric Raciti
`57
`ABSTRACT
`An aerosol delivery article provides delivery of aerosol
`particles of relatively small size without the necessity of
`exposing the material which is aerosolized to a signifi
`cant degree of heat or high temperatures. An aerosol
`forming material is a multi-component material com
`prising an active ingredient and another ingredient hav
`ing a relatively low vaporization temperature, and pref
`erably that aerosol forming material is in the form of an
`emulsion. The aerosol forming material is nebulized so
`as to provide first stage multi-component aerosol parti
`cles of fairly large size. The first stage aerosol particles
`then are subjected to heat so as to vaporize the other
`ingredient of that aerosol and cause further dispersion
`of that first stage aerosol. As such, a second stage aero
`sol composed of fine particles of active ingredient is
`provided. The heat used to cause the further dispersion
`of the first stage aerosol is less than that sufficient to
`cause vaporization, thermal decomposition or undesir
`able chemical alteration of the active ingredient.
`
`13 Claims, 1 Drawing Sheet
`
`SSA2ESES
`
`an
`
`Philip Morris Products, S.A.
`Exhibit 1029
`Page 001
`
`

`

`U.S. Patent
`
`Feb. 14, 1995
`
`5,388,574
`
`99
`
`
`
`6/. 241
`
`/4.4. / OI
`
`
`
`Philip Morris Products, S.A.
`Exhibit 1029
`Page 002
`
`

`

`5
`
`10
`
`35
`
`1.
`AEROSOL DELIVERY ARTICLE
`BACKGROUND OF THE INVENTION
`The present invention relates to aerosol delivery
`articles, and in particular, to such articles which are
`capable of providing aerosol particles of relatively small
`size while subjecting the material to be aerosolized to
`relatively low temperatures.
`It has been desirable to deliver certain medications to
`a patient in vapor or aerosol form. As such, the patient
`inhales the medication, and that medication directly
`enters that patient's respiratory system. See, Science,
`Vol. 260, p. 912 (1993). As a result, there have been
`15
`efforts towards developing various aerosol delivery
`devices, principally for the delivery of certain pharma
`ceutical compositions or drugs. As used herein, the term
`"drug' includes articles and substances intended for use
`in the diagnosis, cure, mitigation, treatment or preven
`20
`tion of disease; and other substances and articles re
`ferred to in 21 U.S.C. S321(g)(1). Certain aerosol deliv
`ery articles and articles for delivering medicaments in
`vapor form are described in U.S. Pat. No. 1,771,366 to
`Wyss et al.; U.S. Pat. No. 1,968,509 to Tiffany; U.S. Pat.
`25
`No. 2,030,075 to Robinson; U.S. Pat. No. 2,057,353 to
`Whittemore, Jr.; U.S. Pat. No. 3,820,540 to Hirtz et al.;
`U.S. Pat. No. 4,036,224 to Choporis et al.; U.S. Pat. No.
`4,214,146 to Schimanski; U.S. Pat. No. 4,303,083 to
`Burruss, Jr.; U.S. Pat. No. 4,735,217 to Gerth et al.; U.S.
`30
`Pat. No. 4,922,901 to Brooks et al.; and U.S. Pat. No.
`4,941,483 to Ridings et al.; as well as by Hickey in Drugs
`Pharm. Sci, Vol. 54, p.255 (1992). Certain other deliv
`ery articles are described in U.S. Pat. No. 3,297,029 to
`Brinkman et al.; U.S. Pat. No. 3,859,398 to Havstad;
`U.S. Pat. No. 3,864,544 to Van Amerongen; U.S. Pat.
`No. 3,990,441 to Hoyt et al.; U.S. Pat. No. 4,190,046 to
`Virag and U.S. Pat. No. 4,523,589 to Krauser.
`Certain of the aerosol delivery articles provide medi
`cation in aerosol form by mechanical action. In particu
`lar, the medication is provided in the form of an aerosol
`using nebulizers and metered dose inhalers. Such aero
`sol delivery articles are desirable in that the pharmaco
`logical composition to be aerosolized is not subjected to
`exposure to heat and high temperatures. However, me
`chanically generated aerosols typically comprise signifi
`45
`cant numbers of particles of relatively large size (i.e.,
`greater than about 5 um in diameter). Such large size
`particles do not always provide the pharmaceutical
`composition in a form which provides for maximum
`effectiveness in treating the patient. Aerosol delivery
`50
`articles which employ heat to evaporate aerosol form
`ing materials which later condense into aerosol particles
`of relatively small size provide aerosols which are
`readily inhaled. However, the pharmacological proper
`ties of certain pharmaceutical compositions which are
`55
`aerosolized by vaporization often are undesirably al
`tered, because certain pharmaceutical compositions are
`quite sensitive to the effects of heat and temperature.
`It would be desirable to provide an aerosol delivery
`article which is capable of producing aerosol particles
`of relatively small size (e.g., submicron size) without the
`necessity of subjecting the material to be aerosolized to
`exposure to a significant degree of heat or high tempera
`tures.
`
`5,388,574
`2
`which is capable of generating an aerosol from a multi
`component aerosol forming material. Typically, the
`aerosol generating means includes a means for mechani
`cally producing aerosol particles from the multi-compo
`nent material (e.g., a first stage aerosol in the form of a
`first stage dispersion of aerosol particles). Typically, the
`multi-component material includes at least one active
`ingredient to be aerosolized, and at least one other in
`gredient which provides a capability for causing those
`first stage aerosol particles to undergo a second stage
`dispersion or transformation such that aerosol particles
`of significantly smaller size result. The aerosol delivery
`article also includes a means for causing the first stage
`aerosol particles to undergo a second stage dispersion.
`Typically, the first stage aerosol particles are subjected
`to heat or other conditions sufficient to destroy the
`integrity of a significant number of those particles, and
`hence cause the formation of second stage aerosol parti
`cles of relatively small size. Most preferably, the second
`stage aerosol particles are formed from the active ingre
`dient. The article also includes a delivery means which
`provides for delivery of the resulting second stage aero
`sol to the user. Preferably, the aerosol is inhaled by the
`user into the mouth and/or nose of that user.
`In another aspect, the present invention relates to a
`method for producing an aerosol. A multi-component
`material capable of forming an aerosol is provided. As
`such, there is provided an aerosol forming material
`capable of undergoing a first stage dispersion to form a
`first aerosol, which first aerosol is capable of undergo
`ing a second stage dispersion to form a second aerosol.
`The aerosol forming material includes at least one ac
`tive ingredient and at least one other ingredient capable
`causing aerosol particles formed from the aerosol form
`ing material to be further dispersed. The aerosol form
`ing material is subjected to conditions sufficient to pro
`vide an aerosol from that material. Such conditions
`typically involve mechanically producing an aerosol
`from the aerosol forming material, and most preferably
`involve producing that aerosol under conditions which
`do not cause the components of that aerosol to experi
`ence significant vaporization. The aerosol in the form of
`a first stage dispersion then is subjected to conditions
`sufficient to cause a further dispersion of those aerosol
`particles. Typically, the first stage dispersion is sub
`jected to heat or other conditions sufficient to destroy
`the integrity of a significant number of those aerosol
`particles of the first stage dispersion, and hence cause an
`aerosol in the form of a second stage dispersion of aero
`sol particles of relatively small size (i.e., of reduced size
`relative to the first stage aeroso). In such a regard,
`much of the aerosol of the second stage dispersion can
`include vapors, gases, and the like. The aerosol so pro
`vided then is allowed to pass through a passageway so
`as to be delivered to the user. As such, an aerosol is
`delivered into the respiratory system of the user.
`BRIEF DESCRIPTION OF THE DRAWINGS
`FIG. 1 is a partial sectional view of an aerosol deliv
`ery article of the present invention.
`DETALED DESCRIPTION OF THE
`PREFERRED EMBOOMENTS
`Referring to FIG. 1, aerosol delivery article 10 in
`cludes an aerosol generator 13 having a reservoir 18 for
`an aerosol forming material 23; an enclosuremember 30
`for providing a passageway 35 which allows passage of
`
`SUMMARY OF THE INVENTION
`The present invention relates to an aerosol delivery
`article. The article includes an aerosol generating means
`
`65
`
`Philip Morris Products, S.A.
`Exhibit 1029
`Page 003
`
`

`

`O
`
`5,388,574
`3
`4.
`a first aerosol 40 produced by the aerosol generator
`way can vary, such area typically ranges from about 7
`through the aerosol delivery article towards mouthend
`cm2 to about 10 mm2.
`The enclosuremember 30 then includes aheating unit
`42 of that article; a heating unit 45, or other suitable
`means for providing a heating region 46 thus causing
`45, or other suitable means for causing the first aerosol
`particles to undergo a further dispersion to yield a sec
`the aerosol particles to undergo further dispersion or a
`ond aerosol 50. The heating unit typically includes a
`transformation to yield a second aerosol 50; and a deliv
`region within the enclosure number 30, and such a re
`ery portion 55, or other suitable means for providing
`gion can be characterized as a heating region 46. That
`delivery of the second aerosol orally and/or nasally to
`heating region can have the form of tubes, baffles, or the
`the user.
`like. The heating unit provides for a heating region 46
`The aerosol generator 13 produces a first aerosol 40
`where the first aerosol is heated sufficiently to form the
`from the aerosol forming material 23 contained in the
`second aerosol, and as such, heat is exchanged between
`reservoir 18 of that aerosol generator. Typically, the
`the heating unit and the first aerosol. Exemplary heat
`first aerosol 40 is mechanically produced using a nebu
`exchange units and technology are described in Perry's
`lizer, or other suitable means for producing an aerosol.
`Chemical Engineer's Handbook, Section 11, Sixth Edit.
`15
`A representative nebulizer is available as Microstat
`(1984). A case 71 or other means for housing other
`Ultrasonic from Mountain Medical Equipment, Inc.,
`components of the heating unit 45, typically is provided
`Littleton, Colo. Such a nebulizer 13 includes an electri
`outside of the enclosure member 30. The case 71 pro
`cally powered ultrasonic nebulizer head 60 powered by
`vides a convenient and aesthetic holder or chamber for
`an electrical power source 62; a valve 64 for inlet of
`drawn atmospheric air; an inner valve 66 for allowing 20 components of the heating unit which are suited to be
`positioned outside of the enclosure member 30. Typi
`drawn air to pass near the reservoir. 18 containing the
`cally, the heating unit generates heat as a result of an
`aerosol forming material 23. A connection collar 65
`electrical resistance heating element 72 and an electrical
`allows the nebulizer to be assembled and disassembled
`power source 74. The power source can be a battery
`in order to load that nebulizer with aerosol forming
`power supply having one or more batteries (as shown in
`25
`material. The inner valve 66 can be adapted to provide
`FIG. 1) or provided by normal household current
`for passage of drawn air containing nebulized aerosol
`stepped down by an appropriate transformer. The resis
`forming material (i.e., the first aerosol 40) out of the
`tance heating element 72 and vary in terms of size,
`aerosol generator through exit passage 70. As such, the
`composition and configuration. For example, the resis
`inner valve can include a cyclone region (not shown) so
`tance heating element can be provided by graphite
`30
`as to provide for a fairly lengthy aerosol passage, and a
`yarns, graphite fabrics, Nichrome film or wire, metal
`collection cone (not shown) so as to provide for deposi
`Screens, metal or ceramic resistance heating materials,
`tion of overly large size aerosol particles back into the
`or the like. The resistance heating element also can be in
`reservoir.
`thermal contact with a conducting agent 77 (e.g., an
`The first aerosol 40 exits the aerosol generator 13 and
`aluminum metal sheet) which is configured so as to
`35
`enters a passageway 35. As a practical matter, the pas
`distribute heat over a desired region of the aerosol de
`sageway also can be provided by a region of the aerosol
`livery article. As shown in FIG. 1, the resistance heat
`generator. The passageway can vary in terms of its
`ing element 72 is provided by winding a resistance heat
`length, cross-sectional dimensions, construction and
`ing wire 72 around a coiled length of metal tubing 77
`format. The length of the passageway typically is quite
`which acts as a conducting agent for electrically gener
`short in order to keep the dimensions of the article small
`ated heat. It is desirable that the surface temperature of
`for ease of use and for ease of draw, and in order to
`that portion of the heating unit be sufficiently high, the
`avoid loss of aerosol by deposition so that the concen
`residence time of the aerosol be sufficiently long, and
`tration of the drawn aerosol is not adversely affected.
`the surface configuration be such to provide a suffi
`However, the length of the passageway typically is
`ciently high surface area, in order that the aerosol can
`45
`sufficiently long in order that the first aerosol is given
`be adequately heated. The heating region can have the
`sufficient ability to form without being adversely af.
`form of a tubular passageway, a coiled passageway, an
`fected by other components of the aerosol delivery
`annular tube, abaffled passageway, passageways having
`article. For example, for the type of aerosol delivery
`resistance heating screens positioned thereacross, or the
`article shown in FIG. 1, the first aerosol can pass
`like. Typically, the effective length of the passageway
`50
`through a passageway of about 5 cm to about 10 cm
`of the heating region (i.e., the average distance travelled
`from the reservoir 18 to the heating unit 45. As such, it
`by the aerosol during heating) is less than about 30 cm,
`is possible to construct the enclosure member 30 from a
`often less than about 25 cm and occasionally less than
`material (e.g., a heat resistant plastic material such as a
`about 20 cm; but most often is at least about 10 cm.
`polycarbonate or a polyimide) which is adapted so as to
`Insulating material 79 (e.g., glass fiber or ceramic fiber)
`55
`have a smooth inner surface in order to provide for
`can be positioned within enclosure member 30 so as to
`ready transfer of aerosol through the passageway. In
`surround the tubular conducting agent 77, and hence
`addition, it can be desirable to construct the enclosure
`ensure that heat generated by resistance heating is effi
`member 30 from a material which has a low coefficient
`ciently used to heat the aerosol.
`for thermal conductivity, in order that heat generated
`The manner in which the heat is provided by the
`by the heating unit 45 does not adversely affect the
`heating unit can vary. Typically, the heating unit in
`aerosol generator 13 and the formation of the first aero
`cludes a current regulating means 82 to control the
`temperature of the heating element, and representative
`sol 40. The enclosure member 30 can have a variety of
`shapes, such as a generally tubular shape which is
`current regulating means are described in U.S. Pat. No.
`shown in FIG. 1. However, the cross-sectional shape of
`4,922,901 to Brooks et al., which is incorporated herein
`65
`by reference. The current regulating means can be time
`the enclosure member does not need to be consistent
`based in that a particular current can be passed through
`along its length, and can be fruscoconical or helical in
`shape. Although the cross-sectional area of the passage
`a particular resistance heating element for a controlled
`
`60
`
`Philip Morris Products, S.A.
`Exhibit 1029
`Page 004
`
`

`

`10
`
`15
`
`5
`
`5,388,574
`6
`5
`ing material is correspondingly placed into the aerosol
`period of time in order that a predetermined tempera
`generator, and prepared for aerosol generation and
`ture can be reached and maintained by a time-based
`delivery. For aerosol forming materials in the form of
`on/off switching mechanism which provides sufficient
`emulsions which can be characterized as stable, the
`current over controlled intervals of time to maintain a
`controlled, essentially constant temperature. Current
`emulsions can be used as such. However, emulsions
`which can be characterized as unstable may require
`regulating means which modulate current flow through
`agitation prior to use. Meanwhile, the heating unit 45 is
`the heating element can be employed in place of on/off
`turned on so as to generate heat in the heating region of
`time-based circuits. In addition, on/off and current
`the aerosol delivery article. When the heating unit is
`modulating means can be connected to temperature
`capable of generating a sufficient amount of heat, the
`sensors or other sensing means, rather than to a time
`aerosol delivery article is drawn upon at the extreme
`based circuit, in order to control the passage of current
`mouth end 42. However, the heating unit also can be
`through the resistance heating element. Such sensors
`draw controlled in order that current is provided to the
`can be temperature sensors such as infrared sensors,
`resistance heating element immediately upon draw and
`piezoelectric films or the like, or thermostats such as
`during the draw period. As such, drawn air entering the
`bimetallic strips. Such temperature sensors can sense
`aerosol generator through valve 64 is used to provide
`either the temperature of the resistance element directly
`the first aerosol 40 from the aerosol forming material 18.
`or the temperature of the aerosol passing the heating
`The first aerosol 40 passes from the aerosol generator 13
`element. Alternatively, the temperature sensors can
`through the passageway 35 and is heated in the heating
`sense the temperature of a second "model” resistance
`region 46 to provide the second aerosol 50. The second
`heating element having a heating and cooling character
`20
`aerosol then passes into the mouth of the user. As such,
`related to that of the resistance heating element. An
`the finely dispersed particles of the second aerosol 50
`other type of sensor which can be employed is a dy
`can be drawn into, and hence delivered to, the respira
`namic resistance sensor which senses the change in
`tory system (e.g., the nose and/or mouth, throat, and
`electrical resistance of the heating element during the
`lungs) of the user. As such, fine particles of the active
`heating period.
`25
`ingredient can be delivered to the respiratory system of
`The heating unit can include a switch (not shown) for
`turning that heating unit on prior to use, and for turning
`the user.
`The aerosol forming material is a multi-component
`that heating unit off after use. However, the heating unit
`material, and as such, includes at least one active ingre
`can be activated an deactivated by a pressure activated
`dient and at least one other ingredient. The active ingre
`switch (not shown); which is actuated to allow current
`30
`dient can include at least one flavoring agent. The fla
`flow and hence heat generation upon draw, and is deac
`voring agent can provide fruit, coffee, tobacco, spice
`tuated to prevent current flow and hence heat genera
`flavor or any other desired flavor, to the aerosol. The
`tion when draw ceases. A representative pressure actu
`flavor can be an artificial flavor or natural flavor (e.g.,
`ated switching mechanism and method for operation in
`as provided by fruit or tobacco extracts). Ingredients
`a draw controlled aerosol delivery article are set forth
`such as glycerine, triethylene glycol and propylene
`in U.S. Pat. No. 4,922,901 to Brooks et al.
`glycol can be ingredients within the multi-component
`The resistance heating element 72, the electrical
`material. The active ingredient most preferably includes
`power source 74, the current regulating means 82, the
`at least one pharmaceutical material.
`switching mechanism, and other electronic components
`Pharmaceutical materials useful herein most prefera
`of the heating unit 45 are connected together using
`bly are those which can be administered in an aerosol
`known techniques by electrically conductive wires (not
`form directly into the respiratory system of the user.
`shown). As such, one skilled in the art of electronics can
`Typical of such materials are drugs or other types of
`provide the circuitry capable of producing heat neces
`sary to cause further dispersion of the first stage aerosol
`medicaments which are used in the treatment of asthma,
`pneumonia, influenza, emphysema, bronchitis, epilepsy,
`particles 40.
`45
`depression, shock, respiratory stress in adults and pre
`The heat provided by the heating unit acts to alter the
`mature infants, hypertension, Alzheimer's disease, Par
`character of the first aerosol 40 passing through that
`kinson's disease, cardiac arrhythmia, sinus congestion,
`region of the aerosol delivery article so as to further
`allergies, convulsions, anxiety, schizophrenia, hyperac
`disperse that aerosol and form second aerosol 50. The
`tivity, and the like. Examples of suitable drugs include
`second aerosol passes through a delivery portion 55
`50
`ephedrine; nicotinic compounds such as nicotine, substi
`which can be equipped to include a cooling region 85.
`tuted nicotine compounds and metanicotine; meta
`The construction and dimensions of the cooling region
`proterenol; ritaline; resperine; terbutaline; dopamine;
`can vary depending upon factors such as the tempera
`phenytoin; lipid molecules; propranolol; diazepam; di
`ture of the second aerosol upon exiting the heating
`phenhydramine; steroids, including cortico steroids
`region, and the desired temperature of that aerosol im
`55
`such as cortisone, prednisone, triamcinolone and pred
`mediately upon delivery to the user. The cooling region
`nisolone; peptide and polypeptide drugs such as are
`also can allow for condensation of vaporized aerosol
`described in Science, Vol. 260, p.912 (1993); synthetic
`forming material into aerosol particles. Typically, the
`pulmonary surfactants such as dipalmitoyl lecithin; and
`length of the cooling region ranges from about 1 cm to
`the like. Representative pharmaceutical materials are
`about 5 cm. For example, the cooling region can be
`60
`set forth in U.S. Pat. No. 5,145,861 to Ducep et al.; U.S.
`constructed so as to provide for sufficient cooling of
`Pat. No. 5,109,010 to Beight et al.; U.S. Pat. No.
`heated aerosol and thus provide that aerosol at a palat
`5,026,861 to Beight et al.; U.S. Pat. No. 4,999,431 to
`able temperature (i.e., at about 20' C. to about 40 C.).
`Cheng et al.; U.S. Pat. No. 4,990,519 to Cheng et al.;
`In use, the user places aerosol forming material 23
`U.S. Pat. No. 4,886,811 to Cheng et al.; U.S. Pat. No.
`into the reservoir 18 of the nebulizer 13, and provides
`65
`4,861,756 to Jackson; U.S. Pat. No. 4,748,274 to Creege
`electrical current (i.e., by using an on/off switch) to
`et al.; U.S. Pat. No. 4,650,872 to Wright; U.S. Pat. No.
`power the ultrasonic nebulizer head 60. Alternatively,
`4,622,422 to Creege; U.S. Pat. No. 4,435,420 to Doherty
`for other types of aerosol generators, the aerosol form
`
`35
`
`Philip Morris Products, S.A.
`Exhibit 1029
`Page 005
`
`

`

`10
`
`5,388,574
`7
`8
`tive ingredient has the form of a plurality of aerosol
`et al.; U.S. Pat. No. 4,405,635 to Dage et al.; and U.S.
`particles.
`Pat. No. 4,391,818 to Doherty et al.; as well as by Bow
`man et al., Textbook of Pharmacology, Second Edit.
`The aerosol forming material can have the form of an
`(1980). If desired, the active ingredient can be provided
`emulsion. See, U.S. Pat. No. 4,655,959 to Stopper and
`U.S. Pat. No. 5,145,604 to Neumiller; and Hiemenz,
`and delivered in a buffered or salt form. As such, fine
`Principles of Colloid and Surface Chemistry, p. 467-474
`aerosol particles of an active ingredient can be provided
`(1986); and Friberg, et al., Microemulsions: Structure and
`in a salt form during delivery, because the first stage
`Dynamics (1987). Such an emulsion typically includes a
`aerosol particles can be produced in such a manner
`continuous phase of active ingredient (e.g., active ingre
`(e.g., nebulized from an emulsion) such that the active
`dient in neat form or as a solution within a suitable
`ingredient can be provided in aerosol form in salt form,
`solvent) and a dispersed phase of a volatile material. If
`and the first stage aerosol can be further dispersed into
`desired, the emulsion can include surfactants (e.g., cati
`a plurality of smaller sized aerosol particles in a manner
`onic, anionic or nonionic surfactants), or other surface
`such that the salt nature of the active ingredient is main
`active agents capable of providing the desired proper
`tained.
`ties to that emulsion, Emulsions can be provided by
`15
`The other ingredient of the aerosol forming material
`contacting immiscible components, other ingredients
`can vary. That ingredient can have a solid or liquid
`such as surfactants, and shearing or otherwise mechani
`form. If desired, that ingredient can include two or
`cally agitating the mixture of components. Typically,
`more components, and combinations of solid and liquid
`the dispersed phase provides about 1 percent to about
`components can be employed. Most preferably, the
`50 percent, usually about 5 percent to about 40 percent,
`other ingredient does not act as a solvent for the active
`and often about 10 to about 30 percent, of the volume of
`ingredient (e.g., the active ingredient and other ingredi
`the emulsion. Typically, the active ingredient can be
`ent are essentially immiscible with one another). As
`non polar or hydrophobic in character, making a dis
`such, the active ingredient and other ingredient each are
`persed phase provided by a material having a polar
`localized in various locations throughout the first aero
`character particularly desirable. Exemplary materials
`25
`sol particles. The other ingredient most preferably does
`suitable for forming a dispersed phase include water,
`not chemically interact with the active ingredient and
`ethanol, and the like. It also is possible, for certain ac
`does not significantly alter the pharmacological activity
`tive ingredients, to disperse or dissolve the active ingre
`of the active ingredient during normal conditions of
`dient in a polar liquid (e.g., water) and to employ such
`storage and use. The other ingredient preferably is of a
`a mixture as a continuous phase, and to employ a nonpo
`30
`nature, and is used in an amount, such that the other
`lar liquid (e.g., a hydrocarbon or a halogenated hydro
`ingredient is essentially pharmacologically inactive rel
`carbon) as a dispersed phase component.
`ative to the active ingredient. However, it is possible
`The aerosol forming material can be provided as a
`that both the active ingredient and other ingredient can
`first stage aerosol by separately providing immiscible
`provide pharmacological effects. The active ingredient
`ingredients, separately mechanically dispersing the in
`35
`is of a nature and character such that aerosol particles
`gredients (e.g., by nebulizing those separated ingredi
`can be generated from the multi-component material
`ents at the same time), and allowing the components of
`incorporating that ingredient. That ingredient is such
`the dispersed mixture to coagulate within the aerosol
`that when aerosol particles incorporating that ingredi
`delivery article to form multi-component aerosol parti
`ent are subject to certain conditions (e.g., the applica
`cles. These first stage aerosol particles later can be sub
`tion of heat), those aerosol particles are further dis
`jected to heat so as to further disperse the coagulated
`persed into aerosol particles of smaller size.
`components within the individual first stage aerosol
`The aerosol forming material can have the form of
`particles.
`microcapsules containing a volatile material dispersed
`The multi-component aerosol forming material also
`within a continuous phase of active ingredient (e.g.,
`can contain a reactive component (e.g., a blowing agent
`45
`active ingredient in neat form or as a solution within a
`which produces carbon dioxide or other gas) when
`suitable solvent). As such, when an aerosol provided
`subjected to certain conditions within the aerosol deliv
`from such a dispersion is provided and subjected to
`ery article. The production of gaseous material by com
`conditions (e.g., heat) sufficient to volatilize the mate
`ponents within the aerosol particles have the capability
`rial within the microcapsules, the microcapsules decom
`of causing first stage aerosol particles containing such
`50
`pose (e.g., explode) thereby causing the dispersion of
`blowing agents to be destroyed, and hence cause disper
`the aerosol particles of the active ingredient which was
`sion of active ingredient.
`incorporated within such microcapsules. If desired,
`The multi-component aerosol forming material is
`other ingredients can be incorporated into the micro
`such that it can readily generate an aerosol. As such, the
`capsules in order to ensure that the active ingredient is
`physical form preferably is such that the multi-compo
`55
`disp