US 6,684,880 B2
`(10) Patent No:
`a2) United States Patent
`Trueba
`(45) Date of Patent:
`Feb.3, 2004
`
`
`US006684880B2
`
`(54) APPLICATOR FOR DISPENSING
`BIOACTIVE COMPOSITIONS AND
`METHODS FOR USING THE SAME
`.
`.
`Inventor: a E. Trueba, Philomath, OR
`(75)
`.
`(73) Assignee: Hewlett-Packard Development
`Company, L.P., Houston, TX (US)
`;
`;
`.
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`US.C. 154(b) by 0 days.
`
`;
`(*) Notice:
`
`.
`(21) Appl. No.: 10/007,133
`(22)
`Filed:
`Dec. 4, 2001
`
`(65)
`
`Prior Publication Data
`US 2003/0101991 A1 Jun. 5, 2003
`7
`
`.
`oo ecscseenseeeenee A61M 11/00; BOSB 17/06
`(52) Unt. C1?
`(52) U.S. Ch. eee ceneeeeees 128/200.16; 128/200.19;
`128/203.15; 128/203.12
`(58) Field of Search oo... eee 261/154, 130,
`261/104, 107, DIG. 65; 128/203.13, 203.15,
`203.17, 203.26, 203.27, 203.28, 200.16,
`200.14; 604/58
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
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`5,002,048 A *
`3/1991 Makiej, Jn... 128/200.23
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`6,190,326 Bl *
`2/2001 McKinnonetal. ......-.. 600/529
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`3/2001 Voges veces 128/200.14
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`3/2001 McKinnon etal. .... 128/200.23
`6,234,167 Bl *
`5/2001 Coxet al. cece 128/200.14
`6,325,062 B1 * 12/2001 Sosiak «00.0... 128/203.25
`6,325,475 Bl * 12/2001 Hayes et al. wo. 347/2
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`. 434/262
`6,358,058 Bl *
`3/2002 Strupat et al.
`.........
`6,390,453 B1 *
`5/2002 Fredericksonetal. ........ 261/26
`6,435,175 Bl *
`8/2002 Stenzler ese 128/200.14
`6,523,536 B2 *
`2/2003 Fugelsang et al.
`..... 128/200.14
`6,543,443 B1 *
`4/2003 Klimowicz etal. ..... 128/200.23
`.
`kos
`cited by examiner
`
`Primary Examiner—Weilun Lo
`4cicraiat Examiner_—Michael G Mendoza
`
`(57)
`
`ABSTRACT
`
`An applicator for delivering a bioactive composition
`includes a jet dispenser having an orifice for ejection of
`droplets from the dispenser. The jet dispenser further
`includes a main body. At least partially insertable through
`the main body isa replaceable fluid reservoir for holding and
`delivering the bioactive composition to the orifice for ejec-
`tion therethrough. A body orifice spacer
`is positioned
`between the orifice of the dispenser and a target during
`+
`gs
`.
`.
`oy
`ejection of the bioactive composition to the target.
`
`30 Claims, 2 Drawing Sheets
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`Sinclair Pharmaetal.
`EUNSUNG-1008
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`Sinclair Pharma et al.
`EUNSUNG-1008
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`1
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`

`

`U.S. Patent
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`Feb. 3, 2004
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`Sheet 1 of 2
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`US 6,684,880 B2
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`2
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`Sheet 2 of 2
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`US 6,684,880 B2
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`Feb. 3, 2004
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`U.S. Patent
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`US 6,684,880 B2
`
`1
`APPLICATOR FOR DISPENSING
`BIOACTIVE COMPOSITIONS AND
`METHODSFOR USING THE SAME
`
`FIELD
`
`This invention relates to administration of compositions
`(such as pharmaceutical compositions), including composi-
`tions administered topically or delivered to a mucous
`membrane, such as via inhalation. In particular, this inven-
`tion combinesthe unrelated technologies of pharmaceutical
`administration and inkjet technology.
`
`BACKGROUND
`
`Bioactive compositions, such as pharmaceuticals, provide
`effective treatments for a variety of illnesses. Unfortunately,
`administration of therapeutically effective doses of many
`medications can be difficult in some instances. For example,
`some drugs (particularly peptide based drugs, such as
`insulin) are partially or totally inactivated by the highly
`acidic environment of the stomach if orally ingested.
`Another problem isthe “first pass” effect, which refers to the
`partial inactivation of orally ingested drugsin the liver after
`they have been absorbed from the gastrointestinal system
`and before they have exerted their full therapeutic effect. In
`addition to such physiological obstacles to administration,
`patients often fail to take their medications at the proper
`prescribed intervals or for the necessary period of time.
`In addition to oral ingestion, inhalational administration
`has been used as an alternative route of drug delivery.
`Inhaled drugs can be absorbed directly through the mucous
`membranes and epithelium of the respiratory tract, thereby
`minimizing initial inactivation of bioactive substances by
`the liver.
`Inhalational delivery also can provide drugs
`directly to therapeutic sites of action (suchas the lungs or the
`sinuses). This mode of administration has been particularly
`effective for the delivery of pulmonary drugs (such as
`asthma medications) and peptide based drugs (usually via
`intranasal administration), using metered dose inhalers
`(MDIs). However, MDIs often require coordinating inhala-
`tion with actuation of the MDI, and some patients are not
`able to masterthis technique. Moreover,patients often forget
`to take medications at prescribed times or with the pre-
`scribed frequency, and some patients inadvertently or inap-
`propriately use medications,
`leading to hospitalizations,
`permanent injury, and even death.
`
`SUMMARY
`
`An applicator for delivering a bioactive composition
`includes a jet dispenser having an orifice for ejection of
`droplets from the dispenser. The jet dispenser further
`includes a main body. At least partially insertable through
`the main bodyis a replaceable fluid reservoir for holding and
`delivering the bioactive composition to the orifice for ejec-
`tion therethrough. A body orifice spacer
`is positioned
`between the orifice of the dispenser and a target during
`ejection of the bioactive composition to the target.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`fragmented, and partially
`FIG. 1 is a perspective,
`schematic, view of one embodimentofthe applicator having
`a tubular body orifice spacer.
`FIG. 2 is an enlarged, side elevational view of the
`embodimentillustrated in FIG. 1, shown in place for use
`with a human subject as an oral inhaler.
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`FIG. 3 is an enlarged, front elevational view of the
`embodiment of FIG. 1, showing a container module
`removed from the applicator and an array of four dispenser
`orifices arranged in the spacer. This figure also schematically
`illustrates the applicator connected to a remote control
`device, such as a computer.
`
`DETAILED DESCRIPTION
`
`Unless otherwise noted, technical terms are used accord-
`ing to conventional usage. Definitions of common terms in
`pharmacology may be found in Remington: The Science and
`Practice of Pharmacy, 19” Edition, published by Mack
`Publishing Company, 1995 (ISBN 0-912734-04-3); different
`routes of delivery to mucous membrances is discussed in
`particular at pages 710 to 714.
`29 6
`The singular forms “a,”
`“an,” and “the” refer to one or
`more than one, unless the context clearly dictates otherwise.
`As used herein, the term “comprises” means “includes.”
`An “array” refers to a predetermined pattern, which can
`be either regular or irregular. Examples of arrays are linear
`distributions or two-dimensional matrices. As used herein, a
`group of individual members stated in the alternative
`includes embodiments relating to a single memberof the
`group or combinations of multiple members. For example,
`the term “antibiotic, bronchodilator, or vitamin,” includes
`embodiments relating to “antibiotic,” “bronchodilator,”
`“vitamin,” “antibiotic and bronchodilator,” “bronchodilator
`and vitamin,” “antibiotic and vitamin,” and “antibiotic,
`bronchodilator, and vitamin.”
`A “bioactive” composition, substance, or agent is a com-
`position that affects a biological function of a subject to
`which it is administered. An example of a bioactive com-
`position is a pharmaceutical substance, such as a drug or
`antibiotic, whichis given to a subject to alter a physiological
`condition of the subject, such as a disease. Bioactive
`substances, compositions, and agents also include other
`biomolecules, such as proteins and nucleic acids, or lipo-
`somes and other carrier vehicles that contain bioactive
`
`substances. Bioactive compositions also may include phar-
`maceutical carriers, adjuvants, andsalts.
`“Drug” includes any bioactive composition administered
`for a therapeutic (including diagnostic) purpose.
`“Mucosal”refers to the mucous membranes, the mucous-
`secreting membraneslining bodily passages opento the air,
`such as parts of the respiratory and digestive tracts.
`“Mucosal delivery” means application to a mucous
`membrane, including pulmonary or nasal inhalation.
`Devices and methods are disclosed herein for improving
`the topical or inhalational application of drugs, or mucosal
`delivery of drugs, by using applicators based on inkjet
`technologies. Kits and systems for administrating drugs in
`this fashion also are described.
`
`In some embodiments, an applicator is used to deliver a
`bioactive composition to a mucous membrane through a
`body orifice, such as a mouth or nose. The applicator
`includes a piezoelectric or thermal jet dispenser having a
`fluid ejection head with an orifice for ejection of droplets
`from the dispenser, with the jet dispenser at least partially
`enclosed within a main body. A fluid reservoir, for holding
`and delivering the bioactive composition to the orifice for
`ejection therethrough,
`is fluidically connected to the jet
`dispenser. In certain embodiments,
`the fluid reservoir is
`replaceable, such as a removable fluid reservoir that is at
`least partially insertable through the body of the jet dis-
`penser. The applicator may include multiple fluid reservoirs
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`US 6,684,880 B2
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`3
`including
`containing the same or different compositions,
`bioactive compositions, carriers, solvents, flavoring agents,
`and surfactants. A conduit fluid tubing system connects a
`fluid ejection head with a fluid reservoir. In embodiments
`having multiple fluid ejection heads and reservoirs,
`the
`conduit fluid tubing system may be a system of independent
`conduits with a separate conduit connecting each reservoir
`to a different fluid ejection head.
`Some embodiments of the applicator also include a body
`orifice spacer positioned between the jet dispenser orifice
`and the target body orifice during ejection of the bioactive
`composition to the target. The spacer may be separate from
`or contiguous with the main body, such as a separate spacer
`mounted on an external surface of the body, and may be
`dimensioned in any appropriate manner, such as a tubular
`spacer sized for inhalation through the mouth or nose. In
`particular, non-limiting examples, the spacer is angled, or at
`least a portion of it extends transverse to the applicator body,
`to direct
`fluid transverse to the application body. For
`example, the fluids maybe delivered through the spacerat an
`angle of 30-120° to the central axis of the applicator body.
`In specific embodiments, the applicatoris an inhaler, such
`as a pulmonaryornasal inhaler.In alternative embodiments,
`a similar applicator is used for topical application of a
`bioactive composition to the surface of the subject, such as
`a patch of skin, rather than delivering the composition to a
`mucous membranevia a body orifice.
`The droplets of bioactive composition delivered by thejet
`dispenser maybeof a particular size. In some embodiments,
`the droplets are sized for respiratory inhalation or
`for
`delivery to bronchial airways. In other embodiments, the
`droplets are sized for delivery to nasal membranes or
`passages.
`The applicator also may include a programmable
`controller, such as a microprocessor, for controlling the jet
`dispenser. The controller may be programmed via a keypad,
`touch screen, connection to a remote computer, removable
`memory device, or other suitable device.
`Additionally, the applicator may be included as part of a
`kit for administering a bioactive composition to a subject.
`The present disclosure concerns an applicator for inhala-
`tional or mucosaldelivery of a bioactive composition using
`a jet dispenser, such as a piezoelectric or thermal jet dis-
`penser. The dispenser includes a container or reservoir for
`holding the bioactive composition and deliveringit to a fluid
`ejection head for ejection through a dispenserorifice, or an
`array of dispenserorifices contained on one or more ejection
`heads. The thermal or piezoelectric jet dispenser propels
`precise amounts of droplets from the dispenser toward a
`mucosal target. In some embodiments, such as the embodi-
`ment illustrated in FIGS. 1-3, a spacer also is provided
`between the dispenserorifice and a target bodyorifice (such
`as the mouth or nostril), to space the dispenser a desired
`distance away from the target body orifice during delivery of
`the bioactive agent. This spacer may be attached to the
`applicator, held in place in the orifice, or merely be inter-
`posed between them, to provide an interface across which
`the bioactive substance may be distributed from the dis-
`penser orifice, or from the array of dispenser orifices, to a
`target body orifice. The target body orifice may be any
`naturalor artificially created body orifice, such as an orifice
`created via surgery, such as via a tracheotomy.
`In certain embodiments, the dispenser includes the bio-
`active agent in the reservoir. Examples of agents that can be
`included in the reservoir include pharmaceutical composi-
`tions that are capable of mucosal delivery. Such agents
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`include drugs having sufficient permeability to move
`through a particular mucous membrane, such as a nasal
`membranes,intestinal epithelium, alveoli, and/or bronchial
`passages, into the bloodstream. Certain of these agents are
`designed to reach the microvasculature of the lungs for
`subsequent systemic absorption and distribution, or may be
`directed to a site of infection within the lungs. For example,
`an antibiotic composition may be designed to reach the
`lungs of a patient suffering pneumonia or other microbial
`infection of the lungs, while a psychogenic composition may
`be designed to be absorbedinto the bloodstream through the
`lungs of a patient suffering some psychological disorder.
`Non-limiting examples of agents that are suitable for
`mucosal delivery include: bronchodilators, such as anti-
`cholinergic drugs, calcium antagonists, sympathomimetic
`drugs, corticosteroids, and xanthine drugs; antibiotics, such
`as natural and synthetic penicillin, cephalosporins, and ami-
`noglycosides; analgesics, including natural semisynthetic,
`and synthetic opiates; antihistamines; psychogenic drugs,
`such as psychostimulants and psychopharmacologic agents;
`and vitamins and other nutritional supplements. Non-
`limiting examples of particular drugs may be found in
`Remington: The Science and Practice of Pharmacy, 19"
`Edition (1995) on page 1583, for example in Chapter 56
`(respiratory drugs).
`Many analogues of these drugs retain their biological
`activity and are also suitable for mucosal delivery. Although
`the disclosed dispenser is particularly suited for mucosal
`delivery of drugs, it can also be used for topical surface
`application of certain bioactive compositions, such as
`antibiotics, corticosteroids, minoxidil or retinoids, (such as
`Retin A), by spraying a bioactive composition onto a patch
`of skin.
`
`The reservoir holding the bioactive composition may be a
`fixed part of the applicator, for example, in a single-use,
`disposable applicator. However, in some embodiments, the
`reservoir is replaceable. In particular embodiments, one or
`more bioactive compositions are contained within multiple
`replaceable reservoirs. A replaceable reservoir allows
`greater flexibility in choosing particular drugs, or other
`bioactive compositions, for use with the applicator. For
`example, a series of replaceable reservoirs could contain a
`single drug in sequentially increasing or decreasing
`concentrations, or a series of different, but related, drugs for
`the treatment of a particular condition. Additionally, the use
`of replaceable reservoirs provides a more cost-effective
`alternative than fixed reservoirs, since only the empty
`reservoirs—andnotthe entire applicator—would need to be
`thrown away and replaced. In alternative embodiments, the
`replaceable reservoirs may be exchanged with minimal
`manipulation of the applicator. For example, as described in
`further detail below, the reservoirs of the embodimentillus-
`trated in FIGS. 1-3 may be exchanged without breaking
`open the main bodyof the applicator. In such embodiments,
`exchanging or replacing the reservoirs may be less compli-
`cated than if the reservoirs were accessible only by opening
`the main bodyof the applicator. An easier to use applicator
`may enhance user adherence to a particular regimen and
`allow physicians greater flexibility in choosing andtailoring
`treatment regimens. Additionally, if the replaceable reser-
`voirs are insertable through the main body of the applicator,
`mechanismsallowing easy accessto the interior of the main
`body(e.g., a hinged opening) are not necessary, thus elimi-
`nating some manufacturing costs.
`The dispenser also may include a controller for manually
`or automatically dispensing the bioactive substance from the
`dispenserat selected times. The controller may take the form
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`US 6,684,880 B2
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`5
`of an actuator that is manually depressed to activate the
`dispenser and dispense the agent. Alternatively, the control-
`ler may be a programmable device, such as
`a
`microprocessor, that is programmed to dispense the bioac-
`tive agent at predetermined intervals, for example several
`times a day. In some embodiments, the controller includes a
`audible or visible cue, such as a tone or light, to alert the
`subject that a dose of the bioactive composition is ready to
`be dispensed. Alternatively, the controller may be used to
`adjust the dosage of an administered drug for a particular
`circumstance, such as a particular time of day, an event (such
`as an activity that will require a dosage modification), or
`detection of a physiological condition (such as an adverse
`drug reaction that requires reduction or cessation of drug
`administration). Complex administration protocols may be
`followed, for example applying different drugs at different
`times throughout the day or for longer periods, such as a
`week, a month, or even longer.
`In certain embodiments, the container may carry multiple
`container modules, such as removable and replaceable mod-
`ules that contain a bioactive agent. A container module may
`contain some other composition, such as a carrier,
`surfactant, solvent, or flavoring agent. Several modules may
`contain the same or different bioactive compositions, or
`some other composition, for example different compositions
`that combine beforeor at the time of delivery to modify one
`or both of the agents, or to produce a desired bioactive effect.
`An example of a modifying substance that may be com-
`bined at the point of ejection is a penetration enhancer that
`improves mucosal penetration of the other bioactive sub-
`stance. Penetration enhancers that may be mixed with a
`bioactive agent at the time of delivery include solvents such
`as water; alcohols (such as methanol, ethanol and
`2-propanol); alkyl methyl sulfoxides (such as dimethyl
`sulfoxide, decylmethyl sulfoxide and tetradecylmethyl
`sulfoxide); pyrrolidones (such as 2-pyrrolidone, N-methyl-
`2-pyrroloidone and N-(2-hydroxyethyl)pyrrolidone); lauro-
`capram; and miscellaneous solvents such as acetone, dim-
`ethyl acetamide, dimethyl
`formamide, and
`tetrahyrdofurfuryl alcohol. Other penetration enhancers
`include amphiphiles such as L-amino acids, anionic
`surfactants, cationic surfactants, amphoteric surfactants,
`nonionic surfactants, fatty acids, and alcohols. Additional
`penetration enhancers are disclosed in Remington: The Sci-
`ence and Practice ofPharmacy, 19Edition (1995) on page
`1583. Of course agents such as penetration enhancers also
`may be premixed with the bioactive agent prior to the point
`of ejection, for example the bioactive agent and modifying
`substance can be mixed together in the container.
`The bioactive agent may be any flowable fluid (for
`example a liquid, gel or powder), although liquids are used
`in particular embodiments of the dispenser.
`In some
`embodiments, at
`least one of the reservoirs contains a
`bioactive agent
`in powder or other dry form, such as
`ipratropium bromide powder. The powder or other agent is
`dispensed from the container, and may in someinstances be
`combined with a liquid (such as a penetration enhancer, or
`solvent) en route to the target body orifice or mucosal
`delivery site. The interface provided by a spacer between the
`dispenserorifice and the target body orifice allows chemical
`reactions to occur, as well as phase changesto stabilize (such
`as a change from a solid to a liquid state). This interface also
`may provideflexibility in the distribution of the drug across
`a larger target area or volume, as compared to application of
`the agent from a dispenserorifice that abuts the target body
`orifice. The spacer can also provide a flow pathway, external
`to the main body ofthe applicator, in which the droplets can
`be entrained in respiratory flow during inhalation.
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`Using existing inkjet technology, distribution of the drug
`to the target may be carefully controlled and exact dosing of
`the drug may be achieved. Controllers may be used to
`dispense simple or complex drug regimens, which is of
`particular advantage in patients who require numerousdaily
`medications. Computerized control of medication dosing,
`which may be programmed by medical personnel for sub-
`sequent automated delivery, can help avoid toxic drug
`interactions, overdoses, and deaths.
`The applicatoris suitable for use in a variety of ways. For
`example, the applicator may be intermittently used to intro-
`duce an agent into a target body orifice, such as the mouth,
`for administration of the bioactive agent. Alternatively, the
`applicator may be used to apply the agent to an area of skin
`for topical application of a bioactive composition, or used to
`transdermally introduce the bioactive agent.
`In another embodiment, the applicator may beselectively
`retained in prolonged contact with the target bodyorifice, for
`example by securing the applicator to the subject’s body
`with an attachment member, such as a strap or adhesive. In
`this manner, the active agent may be administered from the
`dispenser for a prolonged period of time. For example, the
`applicator may be included as a part of a maskorrespirator,
`which may be of particular use in a hospital setting. A
`replaceable reservoir may be removed from the applicator
`and replaced to avoid the necessity of removing the appli-
`cator from the patient.
`One particular embodiment of the device includes a
`piezoelectric or thermal jet dispenser that includes a plural-
`ity of removable modules in fluid communication with one
`or more dispenser orifices (such as an array of orifices)
`ejecting and directing a fluid from the dispenser orifices
`toward a target body orifice. A spacer may be carried by the
`dispenser and positioned to be disposed against the target
`body orifice while the dispenser ejects the pharmaceutical
`fluid from the dispenser. A programmable microprocessorin
`the dispenser may control ejection of the fluid from the
`dispenser orifice at pre-selected intervals, such as once or
`twice a day, every one to eight hours, or even every few
`minutes or seconds, or ejection can be triggered by a manual
`actuator, a sensor, or a feedback mechanism.
`In some
`particular embodiments, the applicator includes a sensor that
`detects a pressure drop in the spacer during inhalation. The
`sensor then triggers the controller to release a dose of the
`bioactive composition without further action by the subject.
`In this manner, a subject may trigger a dose of a bioactive
`composition simply by positioning the spacer against the
`mouth or nose and inhaling. In some embodiments an air
`intake vent is provided in the space to facilitate circulation
`of air through the spacer. Thus, the composition may be
`ejected by the dispenser orifice and dispersed into an air-
`stream.
`
`The pressure sensor also may be used to monitor the
`amount of composition released by the device during inha-
`lation. For example, the sensor may measure the difference
`in pressure and duration of the pressure drop, and the
`controller (such as a microprocessor) may use this informa-
`tion to calculate an amount of composition released by the
`device. The controller may stop the release of the compo-
`sition from the dispenser orifice prior the end of inhalation
`by the subject, if a sufficient amount of the composition has
`been released, or if the amount of composition released
`during inhalation is less than the programmed dosage, the
`controller may cause the device to emit a signal indicating
`that the subject should inhale another dose of the composi-
`tion.
`
`The device may further include a programming module,
`such as a keypad or touch screen for entering dosage
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`US 6,684,880 B2
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`7
`information, a display screen for showing what information
`has been entered, and indicators (such as one or morelights
`or a display screen on the exteriorof the device) that provide
`information about how much drug remains in the device.
`Display screens and touch screens also may provide infor-
`mation about medications in the device, and provide an
`interface through which other information about the medi-
`cations or
`their administration can be entered and/or
`obtained.
`
`The dispensers disclosed herein may be similar to liquid
`dispensers knownas inkjet printheads used in inkjet printing
`mechanisms, such as printers, plotters, facsimile machines
`and the like, some of which are described, for example, in
`Durbeck and Sherr, Output Hardcopy Devices, Academic
`Press Inc., 1987 (SBN 0-12-225040-0), particularly in
`chapter 13, pages 311-370. These technologies have in
`commonthe extraction of a small quantities of a fluid from
`a reservoir that is converted into fine droplets and trans-
`ported through the air to a target medium by appropriate
`application of physical forces. This technology has been
`implemented in a variety of ways, but one of the common
`approaches has been thermal inkjet technology, in which
`liquids are heated using resistors to form drops and propel
`them from a chamber through an orifice toward a target.
`Another approach is piezoelectric inkjet
`technology,
`in
`which movement of a piezoelectric transducer changes a
`chamber volumeto generate the drop.
`A typical jet printing mechanism uses cartridges (often
`called “pens”) which shoot drops of liquid colorant
`(generally referred to as “ink”) onto a page. Each cartridge
`is a printhead formed with very small nozzles through which
`the ink drops are fired. Most often, the printhead is held in
`a carriage which slides back and forth along a guide rod in
`a reciprocating printhead system, with a target or print
`media, such as paper, being advanced in steps between each
`pass of the printhead. To print an image on media,
`the
`printhead is scanned back and forth across the page, shoot-
`ing drops of ink in a desired pattern as it moves. Other
`printing systems known as “page-wide array” printers,
`extend the printhead across the entire page in a stationary
`location and print as the media advances under the print-
`head. Theparticular liquid ejection mechanism within either
`type of printhead may take on a variety of different forms,
`such as the piezoelectric or thermal printhead technology.
`For example, two thermal ink ejection mechanismsare
`shown in U.S. Pat. Nos. 5,278,584 and 4,683,481, both
`assigned to the Hewlett-Packard Companyandherein incor-
`porated by reference. In a thermal system, a barrier layer
`containing fluid channels and vaporization chambers is
`located between a nozzle orifice plate and a substrate layer.
`The substrate layer typically contains linear arrays of heater
`elements, such as resistors, which are energized to heat ink
`within the vaporization chambers. Upon heating, an ink
`droplet is ejected from a nozzle associated with the ener-
`gized resistor. By selectively energizing the resistors as the
`printhead movesacross the page, the ink is expelled in a
`pattern on the print media to form a desired image (e.g.,
`picture, chart, or text).
`In piezoelectric inkjet technology, an activating pulse is
`applied to a piezoelectric plate or member attached to a
`plate, which then respondsby flexing to propel an ink drop
`out of a nozzle. Several examples of piezo-electric inkjet
`printheads are described in U'S. Pat. Nos. 4,992,808; 6,186,
`619; and 6,149,968 (assigned to Xaar Technology Ltd.) and
`USS. Pat. No. 6,193,343 and WO 00/16981 (assigned to
`Seiko Epson Corporation), herein incorporated by reference.
`Someprinthead designs use “snapper” reservoir systems,
`in which permanent or semi-permanentprintheads are used
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`in conjunction with a detachable reservoir carrying a fresh
`liquid supply, with the reservoir being snappedinto place on
`the printhead. Another design uses permanent or semi-
`permanentprintheads in what is knownin the industry as an
`“off-axis” printer. In an off-axis system, the printheads carry
`only a small liquid supply reciprocally back and forth across
`the printzone, with this on-board supply being replenished
`through tubing that delivers liquid from an “off-axis main
`reservoir” placed at a remote, stationary location within or
`near the printhead. In both the snapperand off-axis systems,
`rather than purchasing an entire new cartridge which
`includes a costly new printhead, the consumer buys only a
`new supply of liquid for the main reservoir.
`In striving to duplicate the quality of photographic film
`images, the inkjet industry has focused on decreasing the
`size of ink droplets ejected from the nozzles, as well as
`accurately placing these droplets on the print media. For
`instance, some of the more recent inkjet print cartridges are
`able to deliver droplets about 3-6 picoliters in volume,
`although larger droplets also may be generated, for example
`droplets of 10, 50, 100, or more picoliters. The resolution
`within which currently commercially available inkjet print-
`ing mechanisms may place ink droplets on a page is on the
`order of 1200-2400 dots per inch (knownin the industry as
`a “dpi” rating). Thus, while striving to achieve photographic
`print quality, inkjet printing technology has become very
`adept at accurately metering and dispensing fluids. This
`ability to dispense very small and accurate amounts of fluids
`(including liquids and powders) is a part of the application
`systems illustrated herein. For example, the jet dispenser
`may emit droplets sized for respiratory inhalation, for deliv-
`ery to bronchial airways, or for delivery to otherparts of the
`respiratory system, such as the throat or nasal passages. In
`particular embodiments, the droplets sizes are about 10 wm
`or less, such as about 2 um to about 8 um.
`Additionally, differently sized droplets may be emitted for
`distribution for multiple parts of the respiratory system, such
`as distributing larger droplets throughout the bronchi and
`smaller droplets deeper into the lungs, such as to the
`bronchioles or the alveoli. These differently sized droplets
`maybe of the same or different compositions (e.g., droplets
`of a first composition may be sized for distribution to the
`bronchi, while droplets of a second composition may be
`sized for delivery deeper into the lungs).
`While these inkjet printheads may be used in the mucosal
`application systems illustrated here, rather than using a
`printing analogy, the printhead will instead be referred to in
`a more general nature as a “dispenser” or “dispenser head.”
`FIGS. 1-3 illustrate one particular embodiment of a
`mucosal or inhalational application system 20 for adminis-
`tering a bioactive composition to a subject, such as a
`pulmonary inhaler for the mouth 22 of a person 24. In
`alternative embodiments,
`the mucosal application system
`may bea different type of inhaler, such as a nasal inhaler, or
`a different type of applicator, such as a topical applicator.
`The mucosal application system 20 illustrated in FIG. 1
`includes applicator 30(also referred to herein as a dispenser
`30), which is illustrated as an applicator for dispensing a
`fluid (such as powder) chemical composition to a body
`orifice, such as a mouth 22. The applicator 30 includes main
`body 32 (also referred to herein as a body 32 and an
`applicator body 32), which may be coupled to body orifice
`spacer 35. While the illustrated applicator 30 includes a
`main body 32