United States Patent
`
`[191
`
`[11] Patent Number:
`[45]
`'Date of Patent:
`Feb. 14, 1995
`Ingebrethsen
`
`USOOS388574A
`
`5,388,574
`
`[54] AEROSOL DELIVERY ARTICLE
`
`[76]
`
`Inventor: Bradley J. Ingebrethsen, 3522 Kittery
`Ct., Winston-Salem, N.C. 27104
`
`[21] Appl. N0.: 99,015
`[22] Filed:
`Jul. 29, 1993
`
`Int. 01.6 ............................................. A61M 15/00
`[51]
`[52] US. Cl. .......................... 125/203.17;125/200.16;
`125/203.26
`
`[53] 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
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`.
`1,771,366 7/1930 Wyss et a1.
`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 Hum et a1.
`.. 128/175
`
`2,764,154 9/ 1956 Murai ............
`.. 128/201
`
`3,297,029 1/1967 Brinkman et a1.
`.. 128/188
`.
`3,820,540 6/1974
`.. 128/212
`3,859,398
`1/1975
`.. 261/141
`.. 219/301
`3,864,544 2/1975
`.. 128/193
`3,990,441 11/1976
`.. 128/212
`4,036,224 7/ 1977
`128/200
`4,190,046 2/1980
`.. 219/274
`4,214,146 7/ 1980
`.. 131/271
`4,303,083 12/1981
`128/203
`4,523,589 6/1985
`.. 131/273
`4,655,229 4/1987
`.. 252/305
`4,655,959 4/1987
`131/270
`4,715,387 12/1987
`.. 131/273
`.
`4,735,217 4/1988
`
`.
`...... 13 l/270
`4,765,347 8/ 1988
`
`4,832,012 5/1989 Raabc et a1.
`..............
`. 128/200.21
`
`.....
`4,922,901
`5/1990 Brooks et a1.
`128/203
`....... 131/194
`4,941,482 7/1990 Ridings et a1.
`
`..
`.. 128/200.18
`4,951,659 8/1990 Weiler et a1.
`
`
`4,963,367 10/1990 Beanow .............. 424/485
`5,145,604 9/1992 Neumiller ........................... 252/312
`
`
`
`OTHER PUBLICATIONS
`
`Paul C. I-Iiemenz; Principles of Colloid and Surface
`Chemistry; 1986; pp. 467—474.
`Anthony J. Hickey; Summary of Common Approaches
`
`to Pharmaceutical Aerosol Administration;
`255—288.
`
`(1992);
`
`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 a]; Generation of Monodis-
`perse Aerosol Standards; Environ Sci Technol 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
`
`ABSTRACT
`[57]
`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
`
`
`
` NJOY et a1.
`
`EXHIBIT 1006
`
`

`

`US. Patent
`
`Feb. 14, 1995
`
`5,388,574
`
`0.
`
` mmonmum?
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`\¢m
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`
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`_.o_.._«7%
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`

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`1
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`5,388,574
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`AEROSOL DELIVERY ARTICLE
`BACKGROUND OF THE INVENTION
`
`invention relates to aerosol delivery
`The present
`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
`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-
`tion of disease; and other substances and articles re-
`ferred to in 21 U.S.C. §321(g)(l). 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.
`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.
`Pat. No. 4,922,901 to Brooks et al.; and U.S. Pat. No.
`4,941,483 to Ridings et a1.; 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-
`cant numbers of particles of relatively large size (i.e.,
`greater than about 5 pm 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
`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
`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.
`
`SUMMARY OF THE INVENTION
`
`The present invention relates to an aerosol delivery
`article. The article includes an aerosol generating means
`
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`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 aerosol). 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.
`DETAILED DESCRIPTION OF THE
`PREFERRED EMBODIMENTS
`
`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 enclosure member 30
`for providing a passageway 35 which allows passage of
`
`

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`3
`a first aerosol 40 produced by the aerosol generator
`through the aerosol delivery article towards mouthend
`42 of that article; a heating unit 45, or other suitable
`means for providing a heating region 46 thus causing
`the aerosol particles to undergo further dispersion or a
`transformation to yield a second aerosol 50; and a deliv-
`ery portion 55, or other suitable means for providing
`delivery of the second aerosol orally and/or nasally to
`the user.
`The aerosol generator 13 produces a first aerosol 40
`from the aerosol forming material 23 contained in the
`reservoir 18 of that aerosol generator. Typically, the
`first aerosol 40 is mechanically produced using a nebu-
`lizer, or other suitable means for producing an aerosol.
`A representative nebulizer is available as Microstat
`Ultrasonic from Mountain Medical Equipment, Inc.,
`Littleton, Colo. Such a nebulizer 13 includes an electri-
`cally powered ultrasonic nebulizer head 60 powered by
`an electrical power source 62; a valve 64 for inlet of
`drawn atmospheric air; an inner valve 66 for allowing
`drawn air to pass near the reservoir 18 containing the
`aerosol forming material 23. A connection collar 65
`allows the nebulizer to be assembled and disassembled
`in order to load that nebulizer with aerosol forming
`material. The inner valve 66 can be adapted to provide
`for passage of drawn air containing nebulized aerosol
`forming material (i.e., the first aerosol 40) out of the
`aerosol generator through exit passage 70. As such, the
`inner valve can include a cyclone region (not shown) so
`as to provide for a fairly lengthy aerosol passage, and a
`collection cone (not shown) so as to provide for deposi-
`tion of overly large size aerosol particles back into the
`reservoir.
`The first aerosol 40 exits the aerosol generator 13 and
`enters a passageway 35. As a practical matter, the pas-
`sageway also can be provided by a region of the aerosol
`generator. The passageway can vary in terms of its
`length, cross-sectional dimensions, construction and
`format. The length of the passageway typically is quite
`short in order to keep the dimensions of the article small
`for ease of use and for ease of draw, and in order to
`avoid loss of aerosol by deposition so that the concen-
`tration of the drawn aerosol is not adversely affected.
`However, the length of the passageway typically is
`sufficiently long in order that the first aerosol is given
`sufficient ability to form without being adversely af-
`fected by other components of the aerosol delivery
`article. For example, for the type of aerosol delivery
`article shown in FIG. 1,
`the first aerosol can pass
`through a passageway of about 5 cm to about 10 cm
`from the reservoir 18 to the heating unit 45. As such, it
`is possible to construct the enclosure member 30 from a
`material (e.g., a heat resistant plastic material such as a
`polycarbonate or a polyimide) which is adapted so as to
`have a smooth inner surface in order to provide for
`ready transfer of aerosol through the passageway. In
`addition, it can be desirable to construct the enclosure
`member 30 from a material which has a low coefficient
`for thermal conductivity, in order that heat generated
`by the heating unit 45 does not adversely affect the
`aerosol generator 13 and the formation of the first aero-
`sol 40. The enclosure member 30 can have a variety of
`shapes, such as a generally tubular shape which is
`shown in FIG. 1. However, the cross-sectional shape of
`the enclosure member does not need to be consistent
`along its length, and can be fruscoconical or helical in
`shape. Although the cross—sectional area of the passage—
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`way can vary, such area typically ranges from about 7
`cm2 to about 10 m2.
`The enclosure member 30 then includes a heating unit
`45, or other suitable means for causing the first aerosol
`particles to undergo a further dispersion to yield a sec-
`ond aerosol 50. The heating unit typically includes a
`region within the enclosure number 30, and such a re-
`gion can be characterized as a heating region 46. That
`heating region can have the form of tubes, baffles, or the
`like. The heating unit provides for a heating region 46
`where the first aerosol is heated sufficiently to form the
`second aerosol, and as such, heat is exchanged between
`the heating unit and the first aerosol. Exemplary heat
`exchange units and technology are described in Perry’s
`Chemical Engineer’s Handbook, Section 11, Sixth Edit.
`(1984). A case 71 or other means for housing other
`components of the heating unit 45, typically is provided
`outside of the enclosure member 30. The case 71 pro-
`vides a convenient and aesthetic holder or chamber for
`0 components of the heating unit which are suited to be
`positioned outside of the enclosure member 30. Typi-
`cally, the heating unit generates heat as a result of an
`electrical resistance heating element 72 and an electrical
`power source 74. The power source can be a battery
`power supply having one or more batteries (as shown in
`FIG. 1) or provided by normal household current
`stepped down by an appropriate transformer. The resis—
`tance heating element 72 and vary in terms of size,
`composition and configuration. For example, the resis-
`tance heating element can be provided by graphite
`yarns, graphite fabrics, Nichrome film or wire, metal
`screens, metal or ceramic resistance heating materials,
`or the like. The resistance heating element also can be in
`thermal contact with a conducting agent 77 (e.g., an
`aluminum metal sheet) which is configured so as to
`distribute heat over a desired region of the aerosol de-
`livery article. As shown in FIG. 1, the resistance heat-
`ing element 72 is provided by winding a resistance heat-
`ing wire 72 around a coiled length of metal tubing 77
`which acts as a conducting agent for electrically gener—
`ated heat. It is desirable that the surface temperature of
`that portion of the heating unit be sufficiently high, the
`residence time of the aerosol be sufficiently long, and
`the surface configuration be such to provide a suffi-
`ciently high surface area, in order that the aerosol can
`be adequately heated. The heating region can have the
`form of a tubular passageway, a coiled passageway, an
`annular tube, a baffled passageway, passageways having
`resistance heating screens positioned thereacross, or the
`like. Typically, the effective length of the passageway
`of the heating region (i.e., the average distance travelled
`by the aerosol during heating) is less than about 30 cm,
`often less than about 25 cm and occasionally less than
`about 20 em; but most often is at least about 10 cm.
`Insulating material 79 (e.g., glass fiber or ceramic fiber)
`can be positioned within enclosure member 30 so as to
`surround the tubular conducting agent 77, and hence
`ensure that heat generated by resistance heating is effi—
`ciently used to heat the aerosol.
`The manner in which the heat is provided by the
`heating unit can vary. Typically, the heating unit in—
`cludes a current regulating means 82 to control the
`temperature of the heating element, and representative
`current regulating means are described in US. Pat. No.
`4,922,901 to Brooks et 8.1., which is incorporated herein
`by reference. The current regulating means can be time-
`based in that a particular current can be passed through
`a particular resistance heating element for a controlled
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`

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`5
`period of time in order that a predetermined tempera-
`ture can be reached and maintained by a time-based
`on/off switching mechanism which provides sufficient
`current over controlled intervals of time to maintain a
`controlled, essentially constant temperature. Current
`regulating means which modulate current flow through
`the heating element can be employed in place of on/off
`time-based circuits. In addition, on/off and current
`modulating means can be connected to temperature
`sensors or other sensing means, rather than to a time-
`based circuit, in order to control the passage of current
`through the resistance heating element. Such sensors
`can be temperature sensors such as infrared sensors,
`piezoelectric films or the like, or thermostats such as
`bimetallic strips. Such temperature sensors can sense
`either the temperature of the resistance element directly
`or the temperature of the aerosol passing the heating
`element. Alternatively,
`the temperature sensors can
`sense the temperature of a second “model” resistance
`heating element having a heating and cooling character
`related to that of the resistance heating element. An-
`other type of sensor which can be employed is a dy-
`namic resistance sensor which senses the change in
`electrical resistance of the heating element during the
`heating period.
`The heating unit can include a switch (not shown) for
`turning that heating unit on prior to use, and for turning
`that heating unit off after use. However, the heating unit
`can be activated an deactivated by a pressure activated
`switch (not shown); which is actuated to allow current
`flow and hence heat generation upon draw, and is deac-
`tuated to prevent current flow and hence heat genera-
`tion when draw ceases. A representative pressure actu-
`ated switching mechanism and method for operation in
`a draw controlled aerosol delivery article are set forth
`in U.S. Pat. No. 4,922,901 to Brooks et al.
`The resistance heating element 72,
`the electrical
`power source 74, the current regulating means 82, the
`switching mechanism, and other electronic components
`of the heating unit 45 are connected together using
`known techniques by electrically conductive wires (not
`shown). As such, one skilled in the an of electronics can
`provide the circuitry capable of producing heat neces-
`sary to cause further dispersion of the first stage aerosol
`particles 40.
`The heat provided by the heating unit acts to alter the
`character of the first aerosol 40 passing through that
`region of the aerosol delivery article so as to further
`disperse that aerosol and form second aerosol 50. The
`second aerosol passes through a delivery portion 55
`which can be equipped to include a cooling region 85.
`The construction and dimensions of the cooling region
`can vary depending upon factors such as the tempera-
`ture of the second aerosol upon exiting the heating
`region, and the desired temperature of that aerosol im-
`mediately upon delivery to the user. The cooling region
`also can allow for condensation of vaporized aerosol
`forming material into aerosol particles. Typically, the
`length of the cooling region ranges from about 1 cm to
`about 5 cm. For example, the cooling region can be
`constructed so as to provide for sufficient cooling of
`heated aerosol and thus provide that aerosol at a palat-
`able temperature (i.e., at about 20° C. to about 40° C.).
`In use, the user places aerosol forming material 23
`into the reservoir 18 of the nebulizer 13, and provides
`electrical current (i.e., by using an on/off switch) to
`power the ultrasonic nebulizer head 60. Alternatively,
`for other types of aerosol generators, the aerosol form-
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`ing material is correspondingly placed into the aerosol
`generator, and prepared for aerosol generation and
`delivery. For aerosol forming materials in the form of
`emulsions which can be characterized as stable, the
`emulsions can be used as such. However, emulsions
`which can be characterized as unstable may require
`agitation prior to use. Meanwhile, the heating unit 45 is
`turned on so as. to generate heat in the heating region of
`the aerosol delivery article. When the heating unit is
`capable of generating a sufficient amount of heat, the
`aerosol delivery article is drawn upon at the extreme
`mouth end 42. However, the heating unit also can be
`draw controlled in order that current is provided to the
`resistance heating element immediately upon draw and
`during the draw period. As such, drawn air entering the
`aerosol generator through valve 64 is used to provide
`the first aerosol 40 from the aerosol forming material 18.
`The first aerosol 40 passes from the aerosol generator 13
`through the passageway 35 and is heated in the heating
`region 46 to provide the second aerosol 50. The second
`aerosol then passes into the mouth of the user. As such,
`the finely dispersed particles of the second aerosol 50
`can be drawn into, and hence delivered to, the respira-
`tory system (e.g., the nose and/or mouth, throat, and
`lungs) of the user. As such, fine particles of the active
`ingredient can be delivered to the respiratory system of
`the user.
`The aerosol forming material is a multi-component
`material, and as such, includes at least one active ingre-
`dient and at least one other ingredient. The active ingre-
`dient can include at least one flavoring agent. The fla-
`voring agent can provide fruit, coffee, tobacco, spice
`flavor or any other desired flavor, to the aerosol. The
`flavor can be an artificial flavor or natural flavor (e.g.,
`as provided by fruit or tobacco extracts). Ingredients
`such as glycerine,
`triethylene glycol and propylene
`glycol can be ingredients within the multi-component
`material. The active ingredient most preferably includes
`at least one pharmaceutical material.
`Pharmaceutical materials useful herein most prefera-
`bly are those which can be administered in an aerosol
`form directly into the respiratory system of the user.
`Typical of such materials are drugs or other types of
`medicaments which are used in the treatment of asthma,
`pneumonia, influenza, emphysema, bronchitis, epilepsy,
`depression, shock, respiratory stress in adults and pre-
`mature infants, hypertension, Alzheimer’s disease, Par-
`kinson’s disease, cardiac arrhythmia, sinus congestion,
`allergies, convulsions, anxiety, schizophrenia, hyperac-
`tivity, and the like. Examples of suitable drugs include
`ephedrine; nicotinic compounds such as nicotine, substi-
`tuted nicotine compounds and metanicotine; meta-
`proterenol; ritaline; resperine;
`terbutaline; dopamine;
`phenytoin; lipid molecules; propranolol; diazepam; di-
`phenhydramine; steroids,
`including cortico steroids
`such as cortisone, prednisone, triamcinolone and pred-
`nisolone; peptide and polypeptide drugs such as are
`described in Science, Vol. 260, p.912 (1993); synthetic
`pulmonary surfactants such as dipalmitoyl lecithin; and
`the like. Representative pharmaceutical materials are
`set forth in U.S. Pat. No. 5,145,861 to Ducep et al.; U.S.
`Pat. No. 5,109,010 to Beight et al.; U.S. Pat. No.
`5,026,861 to Beight et al.; U.S. Pat. No. 4,999,431 to
`Cheng et a1.; U.S. Pat. No. 4,990,519 to Cheng et a1.;
`U.S. Pat. No. 4,886,811 to Cheng et al.; U.S. Pat. No.
`4,861,756 to Jackson; U.S. Pat. No. 4,748,274 to Creege
`et al.; U.S. Pat. No. 4,650,872 to Wright; U.S. Pat. No.
`4,622,422 to Creege; U.S. Pat. No. 4,435,420 to Doherty
`
`

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`5,388,574
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`7
`et al.; US. Pat. No. 4,405,635 to Dage et a1.; and US.
`Pat. No. 4,391,818 to Doherty et a1.; as well as by Bow-
`man et al., Textbook of Pharmacology, Second Edit.
`(1980). If desired, the active ingredient can be provided
`and delivered in a buffered or salt form. As such, fine
`aerosol particles of an active ingredient can be provided
`in a salt form during delivery, because the first stage
`aerosol particles can be produced in such a manner
`(e.g., nebulized from an emulsion) such that the active
`ingredient can be provided in aerosol form in salt form,
`and the first stage aerosol can be further dispersed into
`a plurality of smaller sized aerosol particles in a manner
`such that the salt nature of the active ingredient is main-
`tained.
`The other ingredient of the aerosol forming material
`can vary. That ingredient can have a solid or liquid
`form. If desired, that ingredient can include two or
`more components, and combinations of solid and liquid
`components can be employed. Most preferably,
`the
`other ingredient does not act as a solvent for the active
`ingredient (e.g., the active ingredient and other ingredi-
`ent are essentially immiscible with one another). As
`such, the active ingredient and other ingredient each are
`localized in various locations throughout the first aero-
`sol particles. The other ingredient most preferably does
`not chemically interact with the active ingredient and
`does not significantly alter the pharmacological activity
`of the active ingredient during normalconditions of
`storage and use. The other ingredient preferably is of a
`nature, and is used in an amount, such that the other
`ingredient is essentially pharmacologically inactive rel-
`ative to the active ingredient. However, it is possible
`that both the active ingredient and other ingredient can
`provide pharmacological effects. The active ingredient
`is of a nature and character such that aerosol particles
`can be generated from the multi-component material
`incorporating that ingredient. That ingredient is such
`that when aerosol particles incorporating that ingredi-
`ent are subject to certain conditions (e.g., the applica-
`tion of heat), those aerosol particles are further dis-
`persed into aerosol particles of smaller size.
`The aerosol forming material can have the form of
`microcapsules containing a volatile material dispersed
`within a continuous phase of active ingredient (e.g.,
`active ingredient in neat form or as a solution within a
`suitable solvent). As such, when an aerosol provided
`from such a dispersion is provided and subjected to
`conditions (e.g., heat) sufficient to volatilize the mate-
`rial within the microcapsules, the microcapsules decom-
`pose (e.g., explode) thereby causing the dispersion of
`the aerosol particles of the active ingredient which was
`incorporated within such microcapsules. If desired,
`other ingredients can be incorporated into the micro-
`capsules in order to ensure that the active ingredient is
`dispersed into a plurality of aerosol particles of small
`Size.
`
`The aerosol forming material can have the form of
`microsponges containing a volatile material dispersed
`within a continuous phase of active ingredient (e.g.,
`active ingredient in neat form or as a solution within a
`suitable solvent). As such, when an aerosol provided
`from a dispersion of such microsponges is provided and
`subjected to conditions (e.g., heat) sufficient to volatil—
`ize and release the volatile material held within the
`microsponges, the resulting volatilized material causes
`the dispersion of the active ingredient which was incor-
`porated within such microsponges. The dispersed ac-
`
`8
`tive ingredient has the form of a plurality of aerosol
`particles.
`The aerosol forming material can have the form of an
`emulsion. See, US. Pat. No. 4,655,959 to Stopper and
`US. Pat. No. 5,145,604 to Neumiller; and Hiemenz,
`Principles of Colloid and Surface Chemistry, p. 467-474
`(1986); and Friberg, et a1., Microemulsions: Structure and
`Dynamics (1987). Such an emulsion typically includes a
`continuous phase of active ingredient (e.g., active ingre-
`dient in neat form or as a solution within a suitable
`solvent) and a dispersed phase of a volatile material. If
`desired, the emulsion can include surfactants (e.g., cati-
`onic, anionic or nonionic surfactants), or other surface
`active agents capable of providing the desired proper-
`ties to that emulsion. Emulsions can be provided by
`contacting immiscible components, other ingredients
`such as surfactants, and shearing or otherwise mechani-
`cally agitating the mixture of components. Typically,
`the dispersed phase provides about 1 percent to about
`50 percent, usually about 5 percent to about 40 percent,
`and often about 10 to about 30 percent, of the volume of
`the emulsion. Typically, the active ingredient can be
`non polar or hydrophobic in character, making a dis-
`persed phase provided by a material having a polar
`character particularly desirable. Exemplary materials
`suitable for forming a dispersed phase include water,
`ethanol, and the like. It also is possible, for certain ac-
`tive ingredients, to disperse or dissolve the active ingre-
`dient in a polar liquid (e.g., water) and to employ such
`a mixture as a continuous phase, and to employ a nonpo-
`lar liquid (e.g., a hydrocarbon or a halogenated hydro-
`carbon) as a dispersed phase component.
`The aerosol forming material can be provided as a
`first stage aerosol by separately providing immiscible
`ingredients, separately mechanically dispersing the in-
`gredients (e.g., by nebulizing those separated ingredi-
`ents at the same time), and allong the components of
`the dispersed mixture to coagulate within the aerosol
`delivery article to form multi-component aerosol parti-
`cles. These first stage aerosol particles later can be sub-
`jected to heat so as to further disperse the coagulated
`components within the individual first stage aerosol
`particles.
`The multi-component aerosol forming material also
`can contain a reactive component (e.g., a blowing agent
`which produces carbon dioxide or other gas) when
`subjected to certain conditions within the aerosol deliv-
`ery article. The production of gaseous material by com-
`ponents within the aerosol particles have the capability
`of causing first stage aerosol particles containing such
`blowing agents to be destroyed, and hence cause disper-
`sion of active ingredient.
`is
`The multi-component aerosol forming material
`such that it can readily generate an aerosol. As such, the
`physical form preferably is such that the multi-compo-
`nent material is relatively stable, and can be stored for
`reasonable periods of time prior to use. The individual
`components of the aerosol forming material are such
`that there is not experienced adverse affect upon the
`active ingredients by the other ingredients during stor-
`age.
`The aerosol delivery article includes an aerosol gen-
`erator which provides a first st