Indian Patents
Title of Invention

DRY POWDER DOSE FILLING SYSTEMS AND RELATED METHODS.
Abstract Methods for flowably dispensing dry powders from a hopper having a dispensing port and a dry powder flow path can include: (a) generating a first non-linear vibration input signal, the first non-linear input signal comprising a plurality of different selected frequencies that correspond to a first dry-powder formulation; (b) applying the first non-linear vibration input signal to a dispensing hopper having at least one dispensing port while the first dry powder formulation is flowing therethrough; and (c) dispensing a first meted quantity of the first dry powder through the dispensing port to a receiving member. Related devices and computer program products for dispensing dry powders are also described.
Full Text DRY POWDER DOSE FILLING SYSTEMS AND RELATED METHODS
Related Applications
This application is a continuation-in-part of U.S. Application Serial No.
10/434,009, filed May 8, 2003, and claims priority to U.S. Provisional Application
Serial No. 60/392,671, filed June 27,2002, and U.S. Provisional Application.Serial
No. 60/440,513, filed January 16,2003, the contents of the above-referenced
applications are hereby incorporated by reference as if recited in full herein.
Field of the Invention
The present invention relates to the dispensing of dry powder substances such
as drugs, chemicals and toners and may be particularly suitable for dose-regulated
pharmaceutical products.
Background of the Invention
In the pharmaceutical industry, fine dry powders, particularly those intended
for inhalation products can be packaged or "filled" directly into inhalers or indirectly
into packages that can then be accessed by the delivery mechanisms of the inhalers at
the point of use. Generally described, known single and multiple dose dry powder
inhaler devices ("DPI's") use (a) individual pre-measured doses, such as capsules or
blisters containing the drug, which can be inserted into the device prior to dispensing,
or (b) bulk powder reservoirs which are configured to administer successive quantities
of the drug to the patient via a dispensing chamber which dispenses the proper dose.
See generally Prime et al., Review of Dry Powder Inhalers, 26 Adv. Drug Delivery
Rev., pp. 51-58 (1997); and Hickey et al., A new millennium for inhaler technology,
21 Pharm. Tech., n. 6, pp. 116-125 (1997).
Thus, depending on the filling container, the filling may be carried out to
generate multi-dose amounts or unit (single) dose amounts. To assure, dose

uniformity and regulatory compliance, the powders should be filled in a manner that
provides precisely meted or metered amounts so that an accurate active dose is
delivered to the patient. Presently, dry particle excipients or additives are added to the
active dry powder constituent(s) to attempt to allow for ease of filling. Present single
or unit dose powder quantities typically range from about 10-30mg. The lower range
of the filling dose amount may be limited by the filling protocols available. That is,
dry powders have relatively poor flow properties making precise filling problematic.
Many conventional filling methods use hoppers that have been modified to
attempt to aid the flow of powder from the hopper to the target fill device. The
metering of the dry powder during filling may be provided generally volumetrically,
as described in US Patent No. 6,226,962, and US 6,357,490. Additional examples of
volumetric metering systems are described in U.S Patent Nos. 5,865,012 and
6,267,155; these volumetric metering systems propose using an oscillating filling
head and/or vibration to aid powder fluidization of phannaceutically relevant
quantities. Others propose injecting a gaseous medium, such as compressed air, to
facilitate the filling process, such as described in U.S. Patent No. 5,727,607.
However, this filling process uses gravimetric metering that is typically not feasible
for pharmaceutical products that generally include reduced amounts (milligram
quantities or less) of dry powder. The above-referenced patents are incorporated by
reference as if recited in full herein.
Many pharmaceutical dry powder formulations employ small particles in the
dry powder drug mixture; these small particles can be subject to forces of
agglomeration and/or cohesion (i.e., certain types of dry powders are susceptible to
agglomeration, which is typically caused by particles of the drug adhering together),
which can result in poor flow and non-uniform dispersion, thus inhibiting reliable
filling. In addition, many of these dry powder drugs are hygroscopic in nature, a
characteristic that may also inhibit reliable filling. Further, fine or low-density dry
powders have a tendency to float or spontaneously aerosolize during dispensing,
inhibiting a uniform flow and/or making precision meted or metered dispensing
problematic. Hence, it is believed that conventional dispensing methods may have
about 15-20% variability, dose to dose.
Notwithstanding the above, there remains a need to provide improved and/or
accurate or precise dry powder dispensers and/or dispensing systems that can reliably
dispense small quantities of dry powders.
Summary of the Invention
The present invention provides methods, systems, apparatus and computer
program products that can promote a uniform fluid-like flow of dry powders. Certain
embodiments may be particularly suitable for dispensing flowable precision unit dose
amounts of low-density dry powders. Other embodiments are directed to medium
and/or unit density dry powders.
In certain embodiments, the operations can employ non-linear vibration input
energy transmitted to the dry powder during flow. The transmitted energy can be
configured or generated so as to flowably dispense accurate measures of dry powder
substances in a manner that inhibits or prevents aggregation, even in mass production
repeat fill environments. In certain embodiments, the non-linear vibration energy is
customized and comprises vibration input signals that correspond to selected
frequencies associated a particular formulation or drug to promote uniform dry
powder fluid flow (i.e., fluidizing the powder and/or simulating liquid flow
characteristics) without aggregation. The energy input may be generated by any
suitable means including, but not limited to, electrical means, mechanical means, or
combinations of same. The non-linear signal can be determined experimentally using
a floor of PVDF (known as KYNAR piezo-film or polyvinylidene fluoride) that
applies the non-linear signal to the powder and/or by evaluating flow characteristics
such as time between avalanches (measured in a rotating drum).
Certain particular embodiments are directed to dispensing relatively small
doses of low-density dry powders. The low-density powders may have densities that
are at about or less than 0.8 g/cm3. The dose amounts may be less than about 15mg,
and typically on the order of about 10µg to 10mg.
In certain embodiments, the non-linear vibratory input energy comprises a
plurality of predetermined frequencies that correspond to selected frequencies
associated with microflow of the dry powder. The frequencies can be selected
experimentally using a flow evaluation apparatus and/or using a property analysis that
characterizes certain flow parameters of that particular dry powder being dispensed.
Examples of microflow analysis parameters include those associated with the
dynamic angle of repose or time to avalanche, a fractal analysis of mass flow, or other
suitable analysis methodology known to those of skill in the art.
In particular embodiments, to establish the powder-specific energy signals, a
Fourier Transform power spectrum and/or phase space complexity analysis of data
associated with the angle of repose and/or time to avalanche can be employed.
During dispensing, the non-linear vibratory energy may be operated so that multiple
frequencies are transmitted concurrently via a single superimposed (weighted)
combination of selected frequencies. The transmitted energy signal may be generated
as a modulated multi-frequency input signal.
In certain embodiments, the energy input signal can comprise non-linear
signals such as amplitude modulated signals with carrier frequencies in the range of
between about 15kHz to 50kHz and a plurality of modulation frequencies in the range
of between about 10-500Hz. The systems may be adjustable to generate customized
non-linear signals matched to different ones of respective dry powders targeted for
dispensing to thereby be able to serially dispense multiple different types of dry
powders using predetermined different energy input signals.
In particular embodiments, the measured unit amount of fill can be
automatically carried out using a time-controlled based dispensing system as the dry
powder can be flowed in a fluid-like manner so as to cause the dry powder to simulate
substantially uniform fluid flow. Thus, the flow path associated with a particular
dispensing port can repeatedly open and then close in a predetermined time to mete
out desired quantities of the dry powder being dispensed.
In other embodiments, the mass of the dry powder can be dispensed by
measuring the change in an electrical parameter induced by the flexure in a
piezoelectric active material positioned on a receiving member. The flexure is caused
by a quantity or weight of dry powder being dispensed onto a tensioned piezoelectric
material. The dispensed weight creates a change in a detectable electrical property
that can be measured to determine the dispensed mass.
Certain embodiments of the present invention are directed to dispensing dry
powder drugs with accuracies of +/-10%, and typically about +/- 5% or less
variability, dose to dose, and may be carried out with requiring vacuums to dispense
the dry powder formulation.

Other embodiments of the present invention are directed to methods and
devices for increasing the bulk density without introducing cohesion or aggregation to
provide a more stable fluid flow of fine low-density dry powders. Thus, certain
embodiments of the dispensing systems contemplated by the present invention are
directed at increasing the apparent bulk density of the dry powder by compressing
portions of the powder bed in a dispensing path without evacuating the low-density
dry powder material during flow dispensing and without aggregating the particles of
the dry powder material.
In certain embodiments, apparatus for dispensing dry powders can include: (a)
an elongate flow channel having a width, length, and depth, the flow channel having
axially spaced apart inlet and outlet ports, wherein the elongate flow channel is
configured to extend in an angular orientation of between about 10-75 degrees relative
to the axial direction of flow; (b) a flexible piezoelectric layer configured to overlie
the flow channel so that, in operation, the piezoelectric layer is able to flex upwardly
away from the lowermost portion of the underlying flow channel; and (c) a signal
generator operatively associated with the piezoelectric layer, wherein, in operation,
the signal generator is configured to output a signal for flexing the piezoelectric layer
in the elongate flow channel.
Certain embodiments are directed to methods of flowably dispensing dry
powders from a hopper having a dispensing port and a dry powder flow path. The
methods include: (a) generating a first non-linear vibration input signal, the first non-
linear input signal comprising a plurality of different selected frequencies that
correspond to characteristic flow frequencies of a first dry powder formulation; (b)
applying the first non-linear vibration input signal to a dispensing hopper having at
least one dispensing port while the first dry powder formulation is flowing
therethrough; and (c) dispensing a first meted quantity of the first dry powder through
the dispensing port to a receiving member.
In particular embodiments, the computer program code includes a plurality of
predetermined different dry powder-specific flow enhancing vibration energy outputs,
each associated with a different dry powder that is flowably dispensable. The system
can be configured to dispense a plurality of different dry powders separately. The
control module can include computer program code that accepts user input to identify
the dry powder being dispensed, and computer program code that automatically

selectively adjusts the output of the vibration energy generation source based on the
identified dry powder being dispensed.
In certain embodiments, the computer program code for the predetermined dry
powder-specific flow enhancing vibration energy output for the dry powder being
dispensed is based on data experimentally obtained from a flow analysis of the dry
powder.
Other embodiments are directed to computer program products for operating a
flowing dry powder dispensing system having an associated dry powder flow path
with a dispensing port and a vibration energy source associated therewith to facilitate
fluidic flow. The computer program product includes computer readable storage
medium having computer readable program code embodied in said medium. The
computer-readable program code includes: (a) computer readable program code that
identifies a plurality of different powder-specific flow enhancing vibration energy
signals, a respective one for each of the plurality of different dry powders, each of the
flow enhancing vibration energy signals corresponding to individually predetermined
flow property data of the plurality of dry powders; and (b) computer readable program
code that directs the dispensing system to operate using the powder-specific vibration
energy signal associated with the dry powder being dispensed as identified in the
plurality of different vibration energy signals.
The present invention contemplates providing systems similar to the methods,
and certain systems can be described by inserting "means for" in front of the
operations noted under any of the methods described above. These and other objects
and/or aspects of the present invention are explained in detail in the specification set
forth below.
Brief Description of the Drawings
Figure 1A is a schematic enlarged partial front view of a filling or dispensing
nozzle according to embodiments of the present invention.
Figure 1B is a flow diagram of examples of operations that can be used to
carry out embodiments of the invention.
Figure 1C is a flow diagram of examples of operations that can be used to
mete amounts of dry powder according to embodiments of the present invention.
Figures 2A-2C is a schematic illustration of the characterization and
generation of customized energy input signals for different dry powders according to
embodiments of the present invention.
Figures 3A-3E illustrate a series of operations that can be carried out to
determine a suitable signal according to embodiments of the present invention.
Figure 4 is a graph of the vibration amplitude as a function of frequency used
to disperse the dry powder used to vibrate the powder during filling according to
embodiments of the present invention.
Figure 5A is a partial section view of a dispensing system according to
embodiments of the present invention.
Figure 5B is a partial section view of a dispensing system according to
alternative embodiments of the present invention.
Figure 6 is a schematic front section view of a dispensing system according to
additional embodiments of the present invention.
Figure 7 is a schematic front partial section view of another embodiment of
the present invention.
Figure 8 is a side perspective view of an oscillating insert member according
to embodiments of the present invention.
Figure 9 is a schematic front perspective view of a dispensing system
according to additional embodiments of the present invention.
Figure 10A is a schematic illustration of a dispensing system according to
additional embodiments of the present invention.
Figure 10B is a graph illustrating a detectable alteration in an electrical
parameter that can be used to determine a dispensed mass or weight using a
dispensing system similar to that shown in Figure 10A according to embodiments of
the present invention.
Figure 11 is a block diagram illustrating a computer program module
according to embodiments of the present invention.
Figure 12 is a block diagram of operations that can be used to evaluate dry
powder dispensing parameters according to embodiments of the present invention.
Figure 13 is a perspective view of a dispensing mechanism according to
embodiments of the present invention.
Figure 14A is a front view of a flow channel member according to
embodiments of the present invention.
Figure 14B is a top view of the flow channel member shown in Figure 14A.
Figure 14C is a side view of the flow channel member shown in Figures 14A
and 14B.
Figure 15A is a front view of a cover member according to embodiments of
the present invention.
Figure 15B is a top view of the cover member shown in Figure 15A.
Figure 15C is a side view of the cover member shown in Figures 15A and
15B.
Figure 15D is a front view of the cover member shown in position overlying
the flow channel member of Figure 14A according to embodiments of the present
invention.
Figure 16A is a top view of a piezoelectric polymer member according to
embodiments of the present invention.
Figure 16B is a top view of a clamping brace that may be used to secure the
cover member (Figure 15A) and flow channel member (Figure 14A) according to
embodiments of the present invention.
Figure 17A is a perspective view of an alternate embodiment of a dispensing
and/or dry powder flow evaluation apparatus according to embodiments of the present
invention.
Figure 17B is a section view of the device taken along line 17B-17B in
Figure 17A.
Description of Embodiments of the Invention
The present invention will now be described more fully hereinafter with
reference to the accompanying figures, in which embodiments of the invention are
shown. This invention may, however, be embodied in many different forms and
should not be construed as limited to the embodiments set forth herein. Like numbers
refer to like elements throughout. In the figures, certain layers, components or
features may be exaggerated for clarity, and broken lines illustrate optional features or
operations, unless specified otherwise. The term "meted" is used interchangeably
with the term "metered." In addition, the sequence of operations (or steps) is not

limited to the order presented in the claims unless specifically indicated otherwise.
Where used, the terms "attached", "connected", "contacting", and the like, can mean
either directly or indirectly, unless stated otherwise. Further, the term "hopper" is
broadly used for ease of description to designate devices or a transient portion or
holding portion of the flow path in a dispensing system and can include, but are not
limited to, a dispensing head(S), a portion of the flow path, and/or a reservoir body
and the like. The figures are not necessarily shown to scale.
In the description of the present invention that follows, certain terms are
employed to refer to the positional relationship of certain structures relative to other
structures. As used herein, the terms "front" or "forward" and derivatives thereof
refer to the general or primary direction that the dry powder travels as it is dispensed;
these terms are intended to be synonymous with the term "downstream," which is
often used in manufacturing or material flow environments to indicate that certain
material traveling or being acted upon is farther along in that process than other
material. Conversely, the terms "rearward" and "upstream" and derivatives thereof
refer to the directions opposite, respectively, the forward and downstream directions.
As used herein, the term "non-linear" means that the applied vibratory action
or signal has an irregular shape and/or cycle, typically employing multiple
superimposed frequencies and/or a vibratory frequency line shape that has varying
amplitudes (peaks) and peak widths over typical standard intervals (per second,
minute, etc.) over time. In contrast to conventional systems, the non-linear vibratory
signal input operates without a fixed single or steady state repeating amplitude at a
fixed frequency or cycle. This non-linear vibratory input can, thus, transmit a variable
amplitude motion (as either a one, two and/or three-dimensional vibratory motion) to
the powder.
The devices and methods of the present invention may be particularly suitable
to dispense discrete measured or meted quantities of dry powders, including those
formulated as medicaments, and/or pharmaceutical agents for oral and/or inhalation
delivery. The dry powders may be those approved, by a regulatory agency for
dispensing as a pharmaceutical product, or may be dry powder used in a drug trial,
drug discovery, clinical, or pre-clinical evaluation or be the subject of other
commercial or non-commercial scientific, research and/or laboratory evaluation. The
dry powders may include one or more active pharmaceutical constituents as well as
biocompatible additives that form the desired formulation or blend.
Embodiments of the invention may be particularly suitable for dispensing low-
density dry powders. However, other embodiments include processing unit density
and/or medium density powders. The term "low-density dry powder" means dry
powders having a density of about 0.8 g/cm3 or less. In particular embodiments, the
low-density powder may have a density of about 0.5 g/cm3 or less. The term "unit
density dry powder" means dry powders having a density of about 1 g/cm3. The term
"medium density dry powder" means dry powders having a density greater than 0.8
g/cm3 and less than or equal to about 1.2 g/cm3.
In certain embodiments, during dispensing, the dry powder is formulated as
having substantially only one or more active pharmaceutical constituents,
substantially without additives, such as excipients. As used herein, "substantially
without additives" means that the dry powder is in a substantially pure active
formulation with only minimal amounts of other non-biopharmacologically active
ingredients. The term "minimal amounts" means that the non-active ingredients may
be present, but are present in greatly reduced amounts, relative to the active
ingredient(s), such that they comprise less than about 10%, and preferably less than
about 5%, of the dispensed dry powder formulation, and, in certain embodiments, the
non-active ingredients are present in only trace amounts.
In any event, individually or unit dose dispensable quantities of dry powder
formulations can be a single ingredient or a plurality of ingredients, whether active or
inactive. The inactive ingredients can include additives added to enhance flowability
or to facilitate aeorolization delivery to the desired systemic target. The dry powder
drug formulations can include active particulate sizes that vary. The device may be
particularly suitable for dry powder formulations having particulates which have
particle sizes that on average are less than about 50µm, and that are typically in the
range of about 0.5-50µm. In certain embodiments, the dry powder formulations have
particle sizes in the range of about 0.5µm -20.0µm, and more preferably in the range
of about 0.5 µm -8.0µm. The dry powder may be a respirable low-density dry
powder having average particle size diameters between about 0.5-0.8 µm.
The dry powder formulation can be dispensed alone or also be dispensed to
include flow-enhancing ingredients, which typically have particulate sizes that may be

larger than the active ingredient particulate sizes. In certain embodiments, the flow-
enhancing ingredients can include excipients having particulate sizes on the order of
about 50-100 µm. Examples of excipients include lactose and trehalose. Other types
of excipients can also be employed, such as, but not limited to, sugars which are
approved by the United States Food and Drug Administration ("FDA") as
cryoprotectants (e.g., mannitol) or as solubility enhancers (e.g., cyclodextrine) or
other generally recognized as safe ("GRAS") excipients.
Examples of diseases, conditions or disorders that may be treated with dry
powders dispensed according to embodiments of the present invention include, but are
not limited to, asthma, COPD (chronic obstructive pulmonary disease), influenza,
allergies, cystic fibrosis and other respiratory ailments, and diabetes and other related
insulin resistance disorders. In addition, dry powder inhalant administration may be
used to deliver locally acting agents such as antimicrobials, protease inhibitors, and
nucleic acids/oligionucleotides as well as systemic agents such as peptides like
leuprolide and proteins such as insulin. For example, inhaler-based delivery of
antimicrobial agents such as antitubercular compounds, proteins such as insulin for
diabetes therapy or other insulin-resistance related disorders, peptides such as
leuprolide acetate for treatment of prostate cancer and/or endometriosis and nucleic
acids or ogligonucleotides for cystic fibrosis gene therapy may be performed, See,
e.g., Wolff et al., Generation of Aerosolized Drugs, J. Aerosol. Med. pp. 89-106
(1994). See also U.S. Patent Application Publication No. 20010053761, entitled
Method for Administering ASP B28-Human Insulin and U.S. Patent Application
Publication No. 20010007853, entitled Method for Administering Monomeric Insulin
Analogs, the contents of which are hereby incorporated by reference as if recited in
full herein.
Typical unit dose amounts of the dry powder can vary depending on the
patient size, the systemic target, and the particular drug. Conventional exemplary dry
powder dose amounts of inhalation drugs (with excipients) for an average adult
(human) is about 10-30 mg and for an average adolescent pediatric subject is from
about 5-10 mg. Exemplary dry powder drugs include, but are not limited to,
albuterol, fluticasone, beclamethasone, cromolyn, terbutaline, fenoterol, ß-agonists,
salmeterol, formoterol, glucocorticoids, and steroids.
In certain embodiments, the administered bolus or dose can be formulated
with an increase in concentration (an increased percentage of active constituents) over
conventional blends. Further, the dry powder formulations may be configured as a
smaller administerable dose compared to the conventional 10-25 or 30 mg doses. For
example, each unit dry powder dose may be on the order of less than about 60-70% of
that of conventional doses. In certain particular embodiments, the unit dry powder
dose, such as those used in inhalers, an adult dose may be reduced to under about 15
mg, and may be between about 10µg-10mg, typically between about 50µg-10mg. The
active constituent(s) concentration may be between about 5-10%. In other
embodiments, active constituent concentrations can be in the range of between about
10-20%, 20-50%, or even larger. In particular embodiments, such as for nasal
inhalation, target dose amounts may be between about 12-100µg.
Turning now to Figure 1A, a portion of a dispensing system 10 is shown. The
system 10 comprises a dispensing hopper 25 with a dispensing port 25p. A quantity
of a dry powder 15 can be disposed in the hopper 25 for dispensing. As used herein,
the term "dry powder" is used interchangeably with "dry powder formulation" and
means the dry powder can comprise one or a plurality of constituents or ingredients
with one or a plurality of (average) particulate size ranges. The dry powder may be a
dry powder with cohesive or agglomeration tendencies. As is also shown, the
dispensing system 10 also comprises a non-linear signal generator 20 that is operably
associated with the hopper 25. The non-linear signal generator 20 is configured to
generate a vibratory signal 20s that facilitates the flowable dispensing of the dry
powder 15. The hopper 25 and port 25p define a flow path for the dry powder 15.
An axis 25a extends vertically axially through the port and hopper, 25p, 25,
respectively. The system 10 may include a valve 25v operably associated with the
port 25p to controllably and/or selectively open and close the port 25p (and, thus, the
dry powder flow path) during operation.
As shown, the signal generator 20 may be operably associated with a control
module 21. The signal generator 20 may be configured to transmit the vibratory
energy either locally to a limited site (shown as position "A" with lateral arrows
representing lateral movement) or distributed along a major portion of the length of
the hopper 25 (shown by space "B" with a plurality of distributed arrows along a
portion of the wall 25w of the hopper 25).

Figure 1B illustrates examples of operations that may be used to dispense dry
powder according to embodiments of the present invention. A powder-specific dry
powder vibratory energy signal can be generated (block 100) (corresponding to the
particular dry powder being currently dispensed). The system can be configured to
generate multiple different signals (block 115), and, as such, the signal generator can
be adjusted to output the particular signal corresponding to the dry powder then being
dispensed. The powder specific vibratory signal may be a non-linear signal
comprising a plurality of selected frequencies (block 110). The non- linear signal can
fiuidize the powder in such a way that a powder "flow resonance" is generated
allowing precision flowable dispensing and/or reducing, inhibiting and/or preventing
agglomeration.
In particular embodiments the signal generator 20 can include a transducer
that is driven by an amplifier to provide the vibratory input The transducer can be
driven to have relatively small amplitude output such as about 100 mm or less,
typically less than 10 mm, and in certain embodiments, about 1mm or less. In other
embodiments, the signal generator 20 can be configured to force the hopper or other
portion of the flow path (whether wall, outer perimeter of the device itself or other
component which transmits the vibratory energy to the dry powder) to move, deflect
and/or vibrate with relatively small amplitudes of less than about 1 mm. In certain
embodiments of systems that employ at least one transducer, the transducer may be
driven with low energy such as less than about 100 mW.
In particular embodiments, the signal can be configured to generate a
downwardly oriented force vector on the dry powder during flow that can increase the
apparent bulk density of the dry powder to simulate or cause the dry powder to flow
in a substantially uniform fluid-like manner.
Again referring to Figure 1B, successive meted quantities of dry powder can
be dispensed using the corresponding powder-specific signal (block 120). The
successive quantities of dry powder can be captured in a desired receiving member
(block 130). The vibratory signal may be a low energy signal. In the past, other
attempts for fluidization use either airflow or vibration with linear frequencies that
may cause aggregation. For example, in the past, others have proposed uniform
frequency systems (using vibrating orifices, ultrasonic systems, and the like) to
generate sinusoidal, square, or other uniform (period/cycle) signals.

The powder can be dispensed into suitable receiving members, whether bulk
reservoirs, unit dose blister packages or capsules, and the like. The dry powder can be
a low-density pharmacologically active dry powder (block 122). The meted quantity
can be unit dose amounts of less than about 15mg, with a dose-to-dose variability of
less than about 5-10% (block 124). In certain embodiments, the variability can be
less than about 2%. The amount of dispensed dry powder can be dispensed in a time-
controlled manner (block 131) rather than requiring volumetric dispensing as with
conventional protocols.
Figure 1C illustrates one method of controllably filling meted amounts of
low-density dry powder. The dry powder flows through a dispensing port (block 160)
and the dispensing port is selectively opened and closed at predetermined times to
control the amount of time the flow path is open and, thus, the amount of dry powder
dispensed (block 165). The dispensing port may be configured to yield unit dose
amounts of less than about 15mg (block 166). The time-controlled dispensing port
may be operated to yield precision-meted amounts of dry powder in doses under
10mg, and in certain embodiments between about l0µg-lmg. The term "precision"
means less than about 5% variation from a planned dose amount, and/or dose to dose,
and may be less than about 2% variation.
The dispensing head may be held in a static position with respect to an
underlying dispensing location. As such, the underlying receiving member may be on
a moving surface (such as a conveyor with a controlled conveyor speed) that causes a
different receiving member or location to be placed under the dispensing port at each
open interval for successive automated filling. In other embodiments, the dispensing
port can be placed on a moveable head with the receiving member(s) static, and the
head can be translated to overlie different receiving regions at different dispensing
times.
Figures 2A-2C illustrate three different dry powders 151, 152,153, each of
which can be analyzed and/or characterized (20ch1, 20ch2, 20ch3, respectively).
Custom or corresponding individual (non-linear) input signals with frequencies
selected from the corresponding characterization that are specifically targeted to that
dry powder to facilitate fluidic flow during dispensing can be determined for each dry
powder 151, 152, 153. The drug-specific signals are shown by the signals 20s1-20s3.
The signal generator 20 (Figure 1A) may be programmed with a plurality of
predetermined different signals 20s, or if a manufacturing apparatus dispenses only a
single dry powder, the signal generator 20 may be programmed with a single signal
20s. Appropriate powder-specific signals can be determined experimentally and/or
computationally at an OEM or evaluation site and forwarded to be input onto
dispensing systems at selective use sites (via computer program code that direct the
generation of the fluidic flow promoter signal).
Figures 3A-3E illustrate an example of operations that may be carried out to
generate a dry powder-specific signal. A microflow analysis of the dry powder to be
dispensed can be performed to assess avalanching flow profiles and/or other suitable
mass/time flow profiles. The.analysis can be carried out to select predominant
oscillatory frequencies for a particular dry powder that, when applied to the powder
during flowable dispensing, can promote uniform mass flow to achieve a fluid-like
flow, even for low-density dry powders.
Methods and devices for analyzing rapid powder flow measurement are
described in Crowder et al., Signal Processing and Analysis Applied to Powder
Behavior in a Rotating Drum, Part Part. Syst, Charact. 16, 191-196 (1999); Crowder
et al, An instrument for rapid powder flow measurement and temporal fractal
analysis, Part Syst Charact 16, pp. 32-34, (1999); and Morales-Gamboa, et al., Two
dimensional avalanches as stochastic Markov processes, Phys Rev. E, 47 R2229-
2232 (1993), the contents of which are hereby incorporated by reference as if recited
in full herein. See also, Ditto et al., Experimental control of chaos, Phys. Rev. Lett.,
65: 3211-3214 (1990); B. H. Kaye, Characterizing the Flow of Metal and Ceramic
Powders Using the Concepts of Fractal Geometry and Chaos Theory to Interpret the
Avalanching Behaviour of a Powder, in T.P. Battle, H. Henein (eds.), Processing and
Handling of Powders and Dusts, The Materials and Metals Society, 1997; B. H.
Kaye, J. Gratton-Liimatainen, and N. Faddis. Studying the Avalanching Behavior of a
Powder in a Rotating Disc, Part. Part. Syst. Charact. 12:232-236 (1995), and Ott et
al., Controlling Chaos, Phys. Rev. Lett. 64: 1196-1199 (1990), the contents of each of
these articles are also incorporated by reference as if recited in full herein. Using the
principals and relationships described in one or more of these articles with signals
derived from analyses of mass flow and/or microflow, one can determine custom
powder specific signals that may be able to achieve uniformly flowing dry powders.

As shown in Figure 3A, the time between avalanches, for a particular dry
powder of interest, may be evaluated experimentally using a rotating drum. This time
information may be converted to frequency space (frequency domain) as shown in
Figure 3B. Figure 3C illustrates that a distribution of frequencies 20f can be
determined (computationally or via computer models). Then, a desired number of
selected frequencies can be identified. The frequencies selected may span a desired
statistically significant percentage of the distribution or be the frequencies most
observed in the analysis spectrum. The term "most observed" means those
frequencies occurring the greatest number of times in the distribution. For example,
the number of different frequencies selected may be at least the three most observed
different frequencies and/or sufficient frequencies to represent at least about 50% of
the distribution. In certain embodiments, the number can be at least about 5, and
typically about 6, or a number sufficient to represent at least about 75% of the
frequency distribution. To select the number, two, three or four or more of the most
observed frequencies can be used to form the vibration signal. The results can be
analyzed experimentally and additional frequencies may be added to the combined
non-linear signal to improve fluidic flow performance.
Figure 3D illustrates that six of the most observed frequencies 20f1- 20f6, in
the distribution plot 20f can be selected. Figure 3E illustrates that the selected
frequencies can be superimposed to generate a single superposition signal (that may
also include weighted amplitudes for certain of the selected frequencies or
adjustments of relative amplitudes according to the observed frequency distribution).
Thus, Figure 3E illustrates a derived non-linear oscillatory or vibratory energy signal
that may be used to dispense a particular dry powder.
Referring again to Figure 3D, the signal can be created digitally by computer
code means employing mathematical or numerical computation techniques and
relevant equations. For example, for a signal 20s having representative frequencies
"f1-n," the cumulative signal x signal (20s, Figure 3D) can be generated include a
plurality of signal components, xf1-xfn (shown as 20f1-20fn in Figure 3D) at each
desired frequency, fn, each component having an amplitude "a" at its frequency as
described below. Using the spectrum shown in Figure 3D noting that the most
observed frequency in Figure 3D is 20f3, the following equations may be used to
generate the non-linear signal.

For an index, "n" ranging from 0-15,999, used to generate the digital signal:
n= [0:15999] Equation (1)
xf3= sin (2pn/16000) Equation (2)
xf2=af2 sin (2pn (f2)/l6000(f3)) Equation (3)
xf4= af4 sin (27pn (f4)/16000(f3)) Equation (4)
This evaluation can be continued for a desired number of frequencies to render
a representation of a sufficient number of frequencies /spanning a sufficient portion of
the spectrum. The powder-specific, non-linear signal can be generated by summing
the selected individual frequency components.
Xsignal =xf3 + xf4c + xf4.... Equation (5)
In certain embodiments, the overall power in the signal, xSignal, can be
increased by adding a phase shift to one or more of the summed components. For
example, for component xf2, the associated signal contribution can be adjusted by the
following equation:
xf2=af2 sin (2pn (f2)/16000(f3) + mp/nf) Equation (6)
Where "m" is the number at this frequency and nf is the total number of
frequencies contained in the signal.
Figure 4 illustrates an example of an amplitude-modified vibratory signal of a
dry powder that can include a kHz carrier frequency (such as between about 5kHz-
50kHz) modified by low modulating frequencies (typically between about 10-200Hz)
that may be generated by certain embodiments of the present invention. The vibration
signal may include a plurality of frequencies (applied serially or concurrently in a
superimposed manner) that are selectively applied to the dry powder formulation
flowing through a hopper and/or nozzle so that it is modified to match or correspond
to the flow characteristics of the dry powder formulation to reliably induce a fluid
flow state to promote uniform non-aggregated flow.

An example of a commercially available rotating drum is the TSI Amherst
Aero-Flow™ (TSI Inc. Particle Instruments/Amherst, Amherst, MA). This device
provides powder flow information by detecting the occurrence of and recording the
time between avalanches. The Aero-Flow™ has been utilized to demonstrate
correlation between powder flow and tableting performance for like materials. The
instrument uses a photocell detebtor for its avalanche detection mechanism. A light
shines through the Plexiglas drum and is obscured from the detector to varying
degrees by powder contained in the drum. As the drum rotates, the powder heap rises
with the rotation and the photocell detector is uncovered. When an avalanche occurs
in the powder heap, the light is again blocked by the cascading powder. The change
in light intensity striking the photocell is interpreted by the data collection software as
the occurrence of an avalanche. In other embodiments, the powder can be evaluated
to determine and/or measure avalanches using a sensitive microphone/accelerometer
that can be mounted on the rotating drum. Avalanches can be determined acoustically
from the sound generated by the avalanching powder. This evaluation technique may
allow for reduced amounts of the dry powder that is desired for use during the
avalanche evaluation to milligram quantities, such as about 10 mg or less. In any
event, statistics of the time between avalanches can be determined and an avalanche
time phase space plot can be generated.
A useful method of presenting data to discover the dynamics of a system is the
Poincare phase space plot. This phase space approach is one in which variables
sufficient to describe a system are contained in a single vector. The state of the n
variables at an instant in time is a point in phase space. Plotting the time evolution of
the system in phase space can map its dynamics. As an example, a simple harmonic
oscillator can be pictured in phase space by plotting the position versus the velocity,
variables that completely describe the system. The phase space plot of the harmonic
oscillator is a circle reflecting the periodic, but 90-degrees out of phase, exchange of
maximum position and velocity. A damped harmonic oscillator would appear as a
simple attractor with the trajectory encircling and eventually collapsing to the origin
as the position and velocity reach zero. The correlation dimension provides a measure
of the space filling properties of the phase space representation. A hypersphere of
dimension D and radius r is centered on each data point. The number of data points
falling within that sphere as a function of the radius may be displayed in a log-log
plot. The slope of the resulting line may be termed the correlation dimension.
To determine an appropriate vibration signal, a suitably sized dry powder
sample can be disposed in the drum (such as about 60 ml of powder). The drum can
be allowed to rotate through a single revolution before data collection begins so that
initial conditions over several powders are similar. The drum can be rotated at 0.5
revolutions per minute for 6 minutes. The photocell voltage signal can be sampled at
25 Hz using a PC based data acquisition board (DI-170, Dataq Instruments, Akron
OH). Time between avalanches and the voltage change upon avalanching can be
acquired from the voltage signal. A video camera can be situated perpendicular to the
drum can record the powder as it rotates in the drum. A grid can be placed behind the
drum, without obscuring the photocell, to facilitate determination of the angle of the
powder relative to the horizontal. Upon viewing the video, the base and height of the
powder heap can be recorded and the angle can be determined using the trigonometric
relation, ? = arctan(height/base). Determinations of the instantaneous powder angle
can be performed at 200 millisecond intervals. This rate corresponds to every sixth
frame of the video, determined previously by recording the counting of a stopwatch.
Angle data time series can comprise at least about 500 data points or 100
seconds. Computation of a Fourier power spectrum can be performed using the
Welch method with a 128 point Kaiser window and zero padding to 1024 data points
for the FFT calculation. Other suitable methods can be employed as is known to
those of skill in the art.
The avalanche statistics can be presented in terms of the mean and standard
deviation of time between avalanches. A phase space plot can be generated by
plotting the nth time to avalanche against the (n-1)th time to avalanche. For the angle
of repose, phase space plots consist of the instantaneous deviation from the mean
angle versus the first time derivative of the angle. The rate of change of the angle at
each data point can be approximated from the preceding and subsequent data points
using Newton's method.
The uniformity of flow can be discerned by examining the frequency and the
amplitude of the oscillations. Certain dry powder signals may exhibit a higher degree
of variability in frequency and in amplitude relative to others. By use of the Fourier
transform (FT) power spectrum, energy distributions can be obtained. Energy

spectrums that are dispersed over a range of frequencies can indicate more irregular
flow. The mean time to avalanche can be subtracted from the instantaneous time to
avalanche to deconvolute relevant frequency data in angle phase space plots.
Identifying the predominant frequencies and selectively combining and/or using those
identified frequencies as the basis of the transmitted vibration energy excitation signal
may induce resonance in the dry powder during dispensing.
Other analysis methods and apparatus can be employed. For example, as
shown in Figure 13, an example of one apparatus that is configured to allow
adjustment of the excitation signal and/or angle of flow for a powder under
evaluation, can be used and the adjustments altered until reliable fluidic flow is
output. The operational parameters determined in that manner can be used to define
the non-linear customized fluidic flow signal for dispensing that powder. The
apparatus shown in Figure 13 may also be used during active dispensing using one or
more of the devices (depending on the desired delivery capacity). This apparatus will
be discussed further below.
Referring back to Figure 1A, the vibratory energy signal 20s can be generated
and applied to the dry powder 15 so that the dry powder is exposed to a force vector
having a downward orientation Fv as it travels through a portion of the hopper 25 and
exits the dispensing port 25p (in the same direction as Fg). During dispensing, the
apparent bulk density of the dry powder can be temporarily increased over its real
bulk density without (irreversibly) aggregating the dry powder thereby allowing the
dry powder to flow in a more uniform fluid like manner. The non-linear vibration
energy signal may be supplemented by other vibration energies as will be discussed
further below.
In certain embodiments, the signal 20s and/or the vibration of the energy
transmitting surfaces in the channel 25 may concurrently or successively rapidly
vibrate the dry powder at a plurality of different frequencies (at similar or different .
amplitudes) in the range of between about 10 Hz-1000 kHz. In certain embodiments,
the frequencies are between about 10-200 Hz, such as 10-60 Hz. In other
embodiments, they may be in the range of between about 7kHz-100 kHz, such as
7.5kHz or more such as frequencies between about 15 kHz to 50 kHz.
The vibration signal 20s can be generated by any suitable vibratory source,
including electrical means, mechanical means, and/or electro-mechanical means.

That is, at least a portion of the hopper 25 can be (physically) translated by and/or in a
predetermined non-linear vibration imparting motion to impart a downwardly oriented
force vector Fv using powder specific signals. Examples of vibratory sources include,
but are not limited to, one or more of: (a) ultrasound or other acoustic or sound based
sources (above, below or at audible wavelengths) that can be used to instantaneously
apply non-linear pressure signals onto the dry powder 15; (b) electrical or mechanical
deflection of the sidewalls of the hopper or dispensing port 25p; (c) movement of the
hopper 25 or portions thereof (such as, but not limited to, physically moving and/or
deflecting portions such as solenoids, piezoelectrically active portions and the like)
non-linearly about the axis 25a (comprising one or more of selectably controllable
amounts of travel in the horizontal, vertical, and/or diagonal directions relative to the
flow path axis 25a); and (d) oscillating or pulsed gas (airstreams), which can
introduce changes in one or more of volume flow, linear velocity, and/or pressure.
Examples of mechanical and/or electro-mechanical vibratory devices are described in
U.S. Patent Nos. 5,727,607, 5,909,829 and 5,947,169, the contents of which are
incorporated by reference as if recited in full herein.
Referring again to Figure 1C, in certain embodiments, at least a portion of the
length of the hopper walls 25w (either an inner, outer or intermediate surface) may be
formed of a piezoelectrically active material so that application of a (non-linear)
powder specific voltage signal generates (non-linear) flexure of the wall 25w which
can be transmitted to the dry powder 15 during dispensing. The piezoelectric material
may be ceramic or an elastomeric (such a polymer and/or copolymer based) material.
If the piezoelectric material is located on an outside or inner surface, the surface may
be configured to transfer the energy to the dry powder while inhibiting loss of the
strength of the signal. In other embodiments, the inner surface may be configured to
actually amplify the signal while in yet other embodiments, the signal takes into
account the loss of the transmission through intermediate mediums and materials.
Figure 5A illustrates that a major portion of the length of the walls 225w that
define the interior chamber of the hopper 25 can be piezoelectrically active. In other
embodiments selective portions (illustrated by the cross hatch markings in Figure 5A)
can be formed to be piezoelectrically active. The selective portions may be
continuous or segmented and spaced apart along the hopper 25. In certain
embodiments, a series of radially and/or longitudinally spaced apart portions, other

flow channel portions, or substantially the entire perimeter of a flow channel, can be
made to be piezoelectrically active.
In addition, to increase the piezoelectric active surface area, at least one
interior component 225a that comprises piezoelectric material can be disposed in the
flow path. The interior component 225a may have a planar, spherical, cylindrical, or
any other desired configuration.' It may be fixed in the cavity of the hopper so that it
is held in a static vertically position or may be dynamically mounted in the cavity.
The entire perimeter of the interior component 225a may be active and able to flex, or
selective portions or sides may be configured to flex. The interior component 225a
may be rotatable or translatable (up, down, angularly, and the like) while also being
able to flex in response to applied voltage or current. The interior component 225a
and the walls 225w may be controlled by a single signal generator. Different signals,
including signal line shapes, amplitudes of voltages, and the like may be applied at
different locations so that the non-linear vibratory energy is cumulatively effectively
transferred to the dry powder to facilitate fluid flow. In other embodiments,
reciprocating voltage signal patterns or signals may be used (on opposing wall
segments or between the intermediate component and a facing wall) to amplify the
vibratory signal.
The signal 20s can be influenced by the amount of active surface and the
excitation voltage pulses applied thereto as well as the channel geometry. During
dispensing, the hopper channel can be vibrated by providing a voltage across the
piezoelectric layer. In certain embodiments, the voltage provided may be at about
100-200 volts peak-to-peak. In other embodiments, the voltage can be applied at a
different level and at other various frequencies, such as at a higher frequency of
between about 25kHz to about 2MHz.
In certain embodiments, the piezoelectric material, shown generally as
element 225w in Figure 5A can be formed from a piezoelectrically active material
such as PVDF (known as KYNAR piezo film or polyvinylidene fluoride) and its
copolymers or polyvinylidene difluoride and its copolymers (such as PVDF with its
copolymer trifluoroethylene (PVDF-TrFe)). The piezoelectric material can be a thin
flexible layer or film. The term "thin film" typically means that the layer has a
thickness that is less than about 200 microns thick, and more typically less than about
100 microns thick (such as about 28 microns).

Non-vibratory insulating material (such as neoprene) can be disposed to hold
the polymer and/or copolymer which can increase the interchange between the dry
powder and the piezoelectric material; this may increase the amount of energy
transferred to the dry powder from the oscillating or vibrating active pie2oelectric
polymer film so as to cause the dry powder to vibrate at a frequency that is at or near
a resonant frequency thereof. In certain embodiments, laminates of one or more
layers of PVDF and other material layers can be used. Suitable laminates include, but
are not limited to, thin film layers of PVDF united to thin layers of one or more of
aluminum, PVC and nylon films. The aluminum may help the channel hold its
desired shape. The PVDF may form the bottom, top or intermediate layer of the
laminate, structure. For intermediate layer configurations, vias and/or edge
connections can be used to apply the electric excitation signal.
In other embodiments, the piezoelectrically active material can be a ceramic.
Examples of piezo-ceramic materials and elements are available from EDO
Corporation, Salt Lake City, Utah. Generally described, piezoceramic materials can
produce motion by receiving electric potential across their polarized surfaces. See
Mostafa Hedayatnia, Smart Materials for Silent Alarms, Mechanical Engineering, at
www. Memagazine.org/contents/current/fearures/alarms.html (© 1998 ASME). Other
piezo-electric materials can also be employed as long as they have sufficient structural
rigidity or strength (alone or applied to another substrate) to provide the desired
vibratory motion for the dry powder.
In certain embodiments, the hopper 25 can be shaped and/or sized to define a
resonant chamber or cavity to generate a desired frequency of oscillation of the
piezoelectric material and/or a particular dry powder formulation. That is, each blend
or formulation of dry powder may exhibit different flow characteristics that can be
accounted for in the geometry design of the hopper 25 and/or the applied signal. The
height, depth, length, or width of the hopper flow path channel may be adjusted based
on the particular drug or dry powder being administered.
Metal trace patterns, where used, can be provided by applying a conductive
pattern onto one or more of the outer faces of the piezoelectric substrate layer. For
depositing or forming the metal, any metal depositing or layering technique can be
employed such as electron beam evaporation, thermal evaporation, painting, spraying,
dipping, or sputtering a conductive material or metallic paint and the like or material

over the selected surfaces of the piezoelectric substrate (preferably a PVDF layer as
noted above). Of course, alternative metallic circuits, foils, surfaces, or techniques
can also be employed, such as attaching a conductive mylar layer or flex circuit over
the desired portion of the outer surface of the piezoelectric substrate layer.
Generally described, for piezoelectric polymer materials, inner and outer
surface metal trace patterns can be formed on opposing sides of the piezoelectric
polymer material in a manner that provides separation (the opposing traces do not
connect or contact each other). For example, conductive paint or ink (such as silver
or gold) can be applied onto the major surfaces of the package about the elongated
channels and associated metal traces such that it does not extend over the perimeter
edge portions of the piezoelectric substrate layer, thereby keeping the metal trace
patterns on the top and bottom surfaces separated with the piezoelectric substrate
layer therebetween. This configuration forms the electrical excitation path when
connected to a control system to provide the input/excitation signal for creating the
electrical field that activates the deformation of the piezoelectric substrate layer
during operation. The excitation circuit configuration can be suchthat the upper
trace operates with a positive polarity while the lower trace has a negative polarity or
ground, or vice versa (thereby providing the electric field/voltage differential to excite
the piezoelectric substrate). Of course, the polarities can also be rapidly reversed
during application of the excitation signal (such as + to -, or + to -) depending on the
type of excitation signal used, thereby flexing the piezoelectric material in the region
of the receptacle portion. For a more complete discussion of the active excitation path
or configuration as used in forming blister packages, see U.S. Provisional Application
Serial No. 60/188,543 to Hickey et al., and corresponding International PCT
publication WO 01/68169, the contents of which are incorporated by reference herein.
In addition, the piezoelectric polymer material may be configured as two sandwiched
piezoelectric polymer film layers separated by an intermediately positioned pliable
core, all of which are concurrently defonnable by the application of voltage
thereacross.
Figure 5B illustrates an alternate embodiment of the present invention. In this
embodiment, the bulk density of the dry powder is (temporarily) increased along the
flow path during the flowing dispensing operation. As shown, the hopper 25 includes
a permeable member 325 that forms a portion of the wall segment in the flow path.

The bulk density 15pl of the dry powder 15 above this segment is reduced (shown by
fewer numbers of spaced apart particles) to the bulk density below or at this segment
15p2 (shown by a condensed or increased concentration of particles). The permeable
member 325 is configured to receive pressurized gas at a first wall inlet region 325i
and expel it at an egress portion 325e across from the receiving region 325i so that the
forced gas travels across the dry powder and flow path as the dry powder is dispensed
vertically at the port 25p. The pressure of the forced gas flow is higher at the inlet
region than at the egress or outlet region 325e. This cross-travel provides a pressure
drop that slightly compresses the dry powder to increase the apparent bulk density
(making it heavier with a larger downwardly oriented Fv) to facilitate meted
dispensing. In certain embodiments, the permeable member 325 is configured to
direct an exogenous pressurized gas (such as air) to flow at substantially 90 degrees
across the flow path while the dry powder is flowing downwardly in a manner that
inhibits aggregation. This can temporally compress the dry powder to increase the
bulk density of the dry powder.
The permeable member 325 can define a portion of the wall 325w of the flow
path to provide a substantially continuous contour inner wall. The inlet region 325i
and outlet region 325e may be horizontally symmetrically disposed about the axis of
the flow path 25a (as shown) or may be vertically offset (not shown), such as with the
egress portion below the inlet portion. In any event, the permeable member 325 is
configured to generate a predominantly cross-flow forced air pattern. The desired
entry pressure and pressure drop can be selected as a function of particle size, size
distribution, porosity, and apparent density. In certain embodiments, the pressure can
be provided at between about 1.10-5 atm and the pressure drop across the flow path
(measured at the exit or egress region) can be less than 10-20%. In certain
embodiments, the bulk density may be increased by about 10-100%.
In certain embodiments, the permeable member 325 can be a filter or stainless
steel frit that is sized and configured to allow gas or air flow thereacross with a pore
size that inhibits dry powder from exiting from same when exposed to the pressurized
gas cross-flow. Other suitably configured materials and structures may also be used.
Preferably, the permeable member 325 and the components defining the dry powder
contact surfaces in the flow path of the dispensing system 10 are configured to
dispense in vivo biocompatible, formulations and to withstand periodic sterilization

cleaning procedures. In other embodiments, portions of the flow path may be
disposable after dispensing a suitable number of doses to promote anti-aggregation
improved flow and/or reduced-maintenance systems.
In certain embodiments, multiple vibratory inputs can be employed
concurrently, alone or in combination with the non-linear sources. Thus, for example,
the hopper and dispensing port have an associated axis extending along the gas flow
path and the system can include a translation mechanism that moves at least a portion
of the hopper in a desired motion, such as an eccentric motion, so that at least a
portion of the hopper oscillates relative to the axis and, in operation, generates a force
with a downward force component or vector that is transmitted to the dry powder
during dispensing. In other examples, a portion of the hopper 25 (and/or each
individual dispensing head 425h, see Figure 9) may be exposed to centrifugal
acceleration or other suitable motion to impart an angular velocity onto the dry
powder held therein, thereby introducing downward force vectors, Fv, onto the dry
powder during flow to compress the powder bed to increase the apparent bulk density
and inhibit aggregation without requiring evacuation of the flowing (low density)
powder.
Figure 6 illustrates that the dispensing system 10 can be configured to operate
with both non-linear vibration energy and centrifugal motion 20m (represented by the
arrows dispersed about the axis 25a). The motion may be accomplished by moving,
or oscillating, the hopper 25 about its axis 25a. In operation, the motion 20m can
generate a force with a downward force component or vector that is transmitted to the
dry powder during dispensing.
Figure 7 illustrates one embodiment whereby local non-linear vibration
energy can be applied to the dry powder 15. As shown, the hopper 25 includes a head
portion 25h with an insert 31 held therein. The insert 31 can be configured as an
elongated insert that is held in the flow path in the hopper 15 such that the insert 31 is
pivotally and/or floatably held in the flow path and extends a distance out of the
dispensing port 25p and rotates relative to the hopper 25 and the axis 25a during
dispensing to transmit directional acceleration to particles of the dry powder 15. The
dry powder 15 may be dispensed through the end portion of the insert 31. Figure 8
illustrates that the insert 31' can be configured to define a flow path 25f and a
dispensing port that is translated in a predetermined motion 20s about the axis 20a,

during operation. In other embodiments, the insert 31,31' may comprise outwardly
extendable members that move up and down corresponding to their speed of
translation (not shown).
In any event, the insert 31, 31' can be translated and/or oscillated with a
selected motion that has an associated non-constant period or periods, or may have a
cyclical constant period or periods. The insert 31, 31' may be oscillated relative to
the axis 25a to generate a force with a downward component or vector Fv that is
transmitted to the dry powder 15 during dispensing. The insert 31,31' may also
comprise portions formed of piezoelectrically active material that can be excited to
generate vibration energy.
Figure 9 illustrates yet another embodiment of a dispensing system 10. As
shown, the system 10 includes a hopper 25 that is sized and configured as a central
hopper 425 that feeds a plurality of dispensing heads 425h. Vibration energy can be
applied to a rack of heads, filling from a single hopper 425h. The central hopper can
be translated back and forth in non-linear or linear manner to vibrate the contents
thereof (the motion shown by arrows and element number 425m). The individual
heads 425h can also be translated (rotated about the axis or moved up, down,
diagonally, or otherwise) in a desired linear or non-linear manner. In particular
embodiments, the heads 425h may be translated to generate an angular velocity that is
sufficient to give directional acceleration to the particles. The extremes of motion or
travel of the hopper 425 and/or the heads 425h may be very small, particularly when
carried out at high frequencies. Thus, it is contemplated that the vibration generation
energy output can employ a high frequency motion applied onto a selected portion of
the hopper 425, with the outer bounds of the physical motion of the hopper being
small. The term "high frequency" means frequencies in the range of between about 1
kHz-1000 kHz, typically at between about 10-100 kHz with the small bounds of travel
including movement in the range of between about 50-500 mm, and typically about
10-100 mm, or even less.
Figure 10A illustrates a dispensing system 10 that cooperates with a sheet of
receiving substrate material 500 that employs elastomeric piezoelectrically active
material that can be used to measure small meted quantities of dry powders 15. As
described for the piezoelectric material for the hopper 25 above, the piezoelectrically
active substrate 500 can include a PVDF material. The PVDF material' can be treated

to have a metallic pattern 500e that can detect changes in a desired electrical
parameter. One unitary sheet can be used with electrically isolated individual dose
regions 500d or separate sheets can be used for each dose (not shown). The sheet 500
can be held in tension (along the length and/or width of the sheet) while a quantity of
dry powder 15 is dispensed thereon. The tensioning may be provided by wrapping
opposing end portions about tensioning bars that can be adjustably rolled to provide
the desired tension. In other embodiments, the tensioning can be provided by tenting
end portions of the sheet 500 over spaced apart structural members that may include a
center support member (not shown). The sheets may have self-tensioning members
that are portable therewith or tensioning members that are affixed to a conveying
surface. Other tensioning mechanisms can also be employed as will be appreciated by
one of skill in the art. Standard weighing techniques well known to those of skill in
the art may also be used to determine the weight of the dispensed dose(s).
An alteration in a selected monitored electrical parameter that is induced by
the weight residing on a dose region can be detected and a meted mass calculated by
the amount of shift. The shift may be measured in a relative (pre and post change) or
absolute amount (defining a pre-amount by a calibration number).
A detection system 510 can be configured to serially engage the dose regions
on the sheet 500 or to simultaneously engage all of the dose regions and selectively
activate the detection to measure the desired location. The detection system 510 can
be in communication with the dispensing system control system to provide dynamic
real-time feedback data regarding the meted quantity that can be used to control the
operation of the dispensing system. The data may be used to control the open time of
gated flow paths that can be controlled to mete the desired amount. Over or under
amounts, or departures from predetermined variability levels, may be indicated when
detected.
The detection system 510 may be configured to detect a change in capacitance
or to obtain a plurality of voltage values (which may be transient) over time, during
dispensing. Alternatively, the detection system 510 may be configured to detect after
the dispensing. The induced change in the selected parameter or parameters is
generated by the flexure or strain associated with the downwardly generated force
associated with the weight of the dry powder on the stretched (tensioned)
piezoelectrically active foil region 500d. Thus, the capacitance change and the like

correspond to the deposited weight. The signal may be used to weigh or measure
masses in the range of under about 30mg, and preferably under about 15mg, and still
more preferably in the range of between about 10µm-10mg. Other electrical
parameters may also be used such as, but not limited to, resonant frequency, and the
like. Using the resonant frequency and/or capacitance parameter may provide
increased sensitivity or resolution.
Figure 11 is a block diagram of exemplary embodiments of data processing
systems that illustrates systems, methods, and computer program products in
accordance with embodiments of the present invention. The processor 410
communicates with the memory 414 via an address/data bus 448. The processor 410
can be any commercially available or custom microprocessor. The memory 314 is
representative of the overall hierarchy of memory devices containing the software and
data used to implement the functionality of the data processing system 405. The
memory 414 can include, but is not limited to, the following types of devices: cache,
ROM, PROM, EPROM, EEPROM, flash memory, SRAM, and DRAM.
As shown in Figure 11, the memory 414 may include several categories of
software and data used in the data processing system 405: the operating system 452;
the application programs 454; the input/output (I/O) device drivers 458; the powder
specific (vibratory) signal generator module 450; and the data 456. The data 456 may
include a plurality of dry powder data 451 corresponding to particular or target signal
parameters for each dry powder, which may be obtained from an operator or stored by
the dispensing system 420 and/or timing data that defines the meted dose amounts,
flow rates, and open time for the dispensing port (allowing automatic control of the
dispensing operation, dependent on the dry powder being dispensed). As will be
appreciated by those of skill in the art, the operating system 452 may be any operating
system suitable for use with a data processing system, such as OS/2, ADC, OS/390 or
System390 from International Business Machines Corporation, Armonk, NY,
Windows CE, Windows NT, Windows95, Windaws98 or Windows2000 from
Microsoft Corporation, Redmond, WA, Unix or Linux or FreeBSD, Palm OS from
Palm, Inc., Mac OS from Apple Computer, LabView, or proprietary operating
systems. The I/O device drivers 458 typically include software routines accessed
through the operating system 452 by the application programs 454 to communicate
with devices such as I/O data port(s), data storage 456 and certain memory 414
components and/or the dispensing system 420.
The application programs 454 are illustrative of the programs that implement
the various features of the data processing system 405 and preferably include at least
one application which supports operations according to embodiments of the present
invention. Finally, the data 456 represents the static and dynamic data used by the
application programs 454, the operating system 452, the I/O device drivers 458, and
other software programs that may reside in the memory 414.
While the present invention is illustrated, for example, with reference to the
powder-specific signal generator module 450 being an application program in Figure
11, as will be appreciated by those of skill in the art, other configurations may also be
utilized while still benefiting from the teachings of the present invention. For
example, the module 450 may also be incorporated into the operating system 452, the
I/O device drivers 458 or other such logical division of the data processing system
405. Thus, the present invention should not be construed as limited to the
configuration of Figure 11, which is intended to encompass any configuration
capable of carrying out the operations described herein.
In certain embodiments, the powder-specific signal generator module 450
includes computer program code for automatically determining the type of vibratory
input desired to generate a non-linear vibratory energy signal directing the selective
operation of the vibratory energy in and/or along the flow path according to the dry
powder being dispensed.
The I/O data port can be used to transfer information between the data
processing system 405 and the dispensing system 420 or another computer system or
a network (e.g., an intranet and/or the Internet) or to other devices controlled by the
processor. These components may be conventional components such as those used in
many conventional data processing systems which may be configured in accordance
with the present invention to operate as described herein.
While the present invention is illustrated, for example, with reference to
particular divisions of programs, functions and memories, the present invention
should not be construed as limited to such logical divisions. Thus, the present
invention should not be construed as limited to the configuration of Figure 11 but is
intended to encompass any configuration capable of carrying out the operations
described herein.
The flowcharts and block diagrams of certain of the figures herein illustrate
the architecture, functionality, and operation of possible implementations of dry
powder-specific dispensing and/or vibratory energy excitation means according to the
present invention. In this regard, each block in the flow charts or block diagrams
represents a module, segment, or portion of code, which comprises one or more
executable instructions for implementing the specified logical function(s). It should
also be noted that in some alternative implementations, the functions noted in the
blocks may occur out of the order noted in the figures. For example, two blocks
shown in succession may in fact be executed substantially concurrently or the blocks
may sometimes be executed in the reverse order, depending upon the functionality
involved.
In certain embodiments, the system 10 can accept user input regarding the
type of dry powder being dispensed. The system 10 can be configured to accept
manual or electronic input and production batches (with the desired drug to be
dispensed) can be identified over a selected period of time and saved for automatic
interrogation by the control module upon each new batch, shift, or other desired time
interval.
In certain embodiments, the present invention can provide computer program
products for operating a flowing dry powder dispensing system having an associated
dry powder flow path with a dispensing port and a vibration energy source associated
therewith to facilitate fluidic flow. The computer program product can include a
computer readable storage medium having computer readable program code
embodied in the medium. The computer-readable program code can include: (a)
computer readable program code that identifies at lease one, and typically, a plurality
of different, powder-specific vibration energy signals, (where a plurality of signals is
used, there is a respective one for each of the plurality of different dry powders), each
of the vibration energy signals corresponding to individually predetermined flow
property data of the plurality of dry powders; and (b) computer readable program
code that directs the dispensing system to operate using the powder-specific vibration
energy signal associated with a target dry powder (which can be selected from a
library of pre-identified selectable versions of the plurality of different vibration
energy signals).
In certain embodiments, the powder specific vibration energy signals are non-
linear. The computer program code can accept user input to identify the dry powder
being dispensed, and computer program code that automatically selectively adjusts
the output of the vibration energy signal based on the identified dry powder being
dispensed. The vibration energy output signals for the dry powders being dispensed
are based on data obtained from a fractal mass flow analysis or other suitable analysis
of the different dry powders. The dispensing system and computer controller may be
particularly suited to dispense low-density dry powder.
The output signals may be include at least two, and typically a plurality of at
least three, superpositioned modulating frequencies and a selected carrier frequency.
The modulating frequencies can be in the range noted herein (typically between abou
10-500 Hz), and, in certain embodiments may include at least three, and typically
about four superpositioned modulating frequencies in the range of between about 10-
100Hz, and more typically, four superpositioned modulating frequencies in the range
of between about 10-15Hz.
The computer program code can controllably dispenses meted quantities of
dry powder independent of volumetric evaluations by considering flow rate of the dry
powder out of the dispensing port and controlling the amount of time the dispensing
port is open during dispensing.
Figure 12 illustrates operations that can be carried out to evaluate or selected
desired dispensing signals and/or system configuration parameters that can then be
used to dispense target dry powders according to embodiments of the present
invention. These operations can be used to determine the powder specific (vibratory)
signal(s) of different target dry powders, the powder specific signal can then be
implemented in a vibratory signal generator computer module for operating signal
generators for dispensing a dry powder of interest
As shown in Figure 12, a flow channel housing having an angularly
adjustable elongate flow channel therein is provided (block 600). The orientation of
the flow channel is adjusted so that the flow channel is angularly offset (with the
dispensing port located lower than the input port) in the axial direction with respect to
the horizontal and vertical axis (block 610). In certain embodiments, the flow

channel is adjusted to be at different selected angles during the evaluation to consider
the impact that the angle may have on the dispensing flow.
A dry powder of interest is introduced into the elongate flow channel (block
614). The dry powder can be a low-density dry powder (block 616). The flow
channel can be vibrated to thereby vibrate the dry powder to cause the dry powder to
fluidly flow out of the channel via an exit port (block 615). The flow channel can
include a flexible piezoelectric polymer over which the dry powder flows; the
piezoelectric polymer can be electrically stimulated to flex upwardly to cause it to
vibrate the powder as the powder travels along and through the flow channel. As
described above, the vibration can carried out using a non-linear excitation signal
having a carrier frequency and a modulation frequency (block 617). In certain
embodiments, the carrier frequency can be between about 2.5kHz-50kHz and
modulation frequency may be between about 10-500Hz. In any event, flow
characteristics can be evaluated, typically over several different input signals at
different frequencies, and at least one frequency (and/or angular orientation of the
flow path) selected for its ability to generate reproducible fluidic flow of dry powder
based on the flow characteristics exhibited during the vibrating step (block 620).
To generate sufficient flow in the flow channel to allow evaluation and/or
reliable dispensing, a dry powder mass input of between about 2-50 mg or greater
may be used to provide fluid flow through the dispensing port.
The apparatus can be configured to generate a reproducible flow rate (less than
about +/-10% variation) for dispensing reliable amounts of dry powders. The
average flow rate generated for certain low-density dry powders may be in the range
of between about 0.001-5 mg/sec. In certain embodiments, the flow rate may be
about 0.028 mg/sec. In other embodiments, typically for unit density and/or medium
density powders, the flow rates may be greater, such as greater than 5 mg/sec and up
to about 50 mg/sec, typically between about 10-30 mg/sec.
Several parameters can influence the dispensing flow rate, such as, but not
limited to, the amount (mass) of dry powder input into the flow channel, the angle of
the flow channel, the size of certain components, such as the surface area of the
piezoelectric material that contacts the dry powder, the channel and/or orifice
volumetric size (particularly the depth and width of the channel), the dry powder
itseif, as well as the vibratory signal input to excite the powder to move it through the
flow channel can influence.
Figure 13 illustrates a dry powder dispensing apparatus 700 that can be used
to dispense dry powders. The apparatus 700 can be used at a laboratory and/or
research site using flow parameters or signals that can generate fluidic flow for a dry
powder of interest. In other embodiments, the apparatus 700 can be used in a
scientific, research or small-scale academic and/or commercial program. For
example, the device 700 can be used in a drug discovery program or clinical trial
application where it is desired to provide or dispense reliable dose amounts without
need for mass production ranap-up for scaled commercialization. Thus, the apparatus
700 may be used to provide discrete doses in desired reliable amounts (typically in the
50µg-10mg range), but larger or smaller doses can also be provided, typically for drug
evaluation, without requiring relatively expensive equipment costs and/or in a manner
that is not labor intensive. In other embodiments, the apparatus 700 can be used to
develop signals that are matched to a particular dry powder. The signal(s) can then be
implemented using the same oi a different dispensing apparatus, such as those
described above, at any desired dispensing location.
Referring back to Figure 13, the apparatus 700 includes a channel member
710, a cover member 720, and an intermediately positioned flexible piezoelectric
polymer layer 730. The channel member 710 holds an elongate powder flow channel
710f that has a depth, width, and length. The piezoelectric polymer layer 730 can be
positioned to overlie the channel 710f and the sidewalls to hold the dry powder as it
moves through the flow channel 710f. Suitable materials for forming the flexible
piezoelectric polymer layer 730 can be obtained from Measurement Specialties, Inc..
located in Fairfield, NJ. One example of a suitable material is a 28 micron
piezoelectric film sheet, silver ink metallized PVDF, identified as Part No. 1-100-
4346-0. The piezoelectric polymer layer can include additional material layers
attached thereto and/or coatings disposed thereon.
Figures 14A-14C illustrate one embodiment of a channel member 710. As
shown in Figure 14A, the flow channel 710f has two opposing sides 710wi, 710w2
and may be configured with declining sides (each side converging toward the bottom
of the channel from top to bottom). In particular embodiments, the flow channel 710f
may have a sectional profile that is substantially a "V" shape, with the walls 710w1,

710w2 angling to meeting at a common center located at a lowermost portion of the
channel 710b. The depth of the channel can be less than about 5 cm, typically about
3.6 cm, or even less. Other configurations of the flow channel can be used, such as,
but not limited to, concave, semi-circular, partial oval or partial elliptoid,
frustoconical, and the like. Other channel depths may also be employed, depending
on the scale, size of components, dry powder being dispensed and/or analyzed, and
input used to carry out the vibration. The cover member 720 may be adjusted
accordingly.
The channel member 710 may be configured with an open top portion 7l0t
and opposing side edge portions 710si, 710s2. Figure 14C illustrates that the flow
channel has a depth D that varies along the length of the flow channel 710f. As
shown, the deepest portion of the flow channel D1 is positioned proximate the dry
powder intake (inlet port), while the more shallow depth D2 is positioned proximate
the dispensing port 725p (Figure 13). The depth of the flow channel 710f can vary in
a gradual manner, such as linearly (in a straight line) with a predefined slope.
In particular embodiments, the channel 710f can have a depth D1 that is about
17 mm at the inlet portion 710i of the member 710 and terminates at a depth D2 that is
about the same at the exit portion 710e. The channel 710f may have a length that is
less than about 20 cm. In certain embodiments, the channel has a length of about 13.1
cm. The width may be less than about 5 cm, and typically about 2 cm.
Figures 15A-15C illustrate one embodiment of a cover member 720. As
shown in Figure 15D, the cover member 720 is sized and configured with a tip
portion 720t that, when assembled to the flow channel member 710, enters a distance
"L" into the flow channel 710f of the channel member 710. As such, the tip portion
720t is sized and shaped to be able to be received into the flow channel 71 Of. As
shown, the tip portion 720r includes sidewalls 720si, 7l0s2 that decline at the same
angle as that of the walls 710w1, 710w2 of the channel member 710. Because the
cover member 720 has a flange 720f of substantially constant thickness that sits on the
upper portion of the flow channel member 710, the length of the tip portion 720t
defines its penetration depth into the flow channel 710f. The tip portion 720t can be
sized so that, in position, its lowermost portion does not contact the bottom 710b of
the flow channel 710f so as to provide an open flow orifice and inhibit pinching the
piezoelectric layer 730 between the two members 710, 720.

As shown in Figure 15D, the cover member 720 includes a bottom portion
720b that is configured to reside on the upper side edge portions 710s1, 710s2 of the
channel member 710 to position the tip portion 720t of the cover member the desired
distance into the depth of the flow channel 710f. The space extending between the tip
portion 720t of the cover member 720 and the piezoelectric layer 730 extending over
the bottom 710b of the flow channel 710f can be defined as the flow orifice 750.
Thus, when assembled, the open flow orifice 750 proximate the dispensing outlet or
port (or dispensing end of the device) can vary a desired amount. In certain
embodiments, the variation is from about 2 mm-7 mm, and in other embodiments
about 2-5 mm.
Figure 15D illustrates the cover member 720 positioned over the flow channel
member 710 with the piezoelectric layer 730 held therebetween. The assembled
members 710, 720 define a gap distance (or flow orifice) between the lowermost
portion of the tip portion 720r of the cover member 720 and the lowermost portion of
the flow channel 710b. This gap distance can be adjusted by sliding the cover
member 720 forward or rearward in the flow channel member 710.
As shown in Figure 15C, the vertical or inward projection length of the tip
portion 720t can vary over the axial length of the cover member 720. This allows for
the device to adjust the size of the reservoir defined by the coupling of the cover
member 720 to the flow channel member 710.
As shown in Figures 15D and 17B, the piezoelectric material layer 730 can be
tensioned across opposing sides of the flow channel 710b so that its center portion is
free to flex in response to the applied excitation (vibratory) signal. The outer edge or
perimeter portions of the piezoelectric material 730 can be pinched or clasped .
between the overlying members 710, 720.
In operation, the piezoelectric layer 730 flexes upwardly in response to the
input excitation signal(s) to vibrate the powder positioned above the piezoelectric
layer 730. When non-conductive cover members are employed (such as those formed
of DELRIN polymer), aluminum foil can be positioned over the tip portion 720t 6f
the cover member 720 to inhibit static build up in the dry powder. In other
embodiments, the cover member 720 may be formed of a pharmaceutically
compatible conductive material, such as stainless steel, and/or the appropriate surfaces
can be coated with a desired metallic coating, such as gold. In certain embodiments,

an ionizer bar can be placed at one or more positions in the flow channel to decrease
the static charge, suitable ionizer bars are available from NRD, LLC, located in Grand
Island, NY.
Figure 15B illustrates that the cover member 720 can have an elongate dry
powder input region 721 that is open to the channel member 710 below. Thus, in
operation, the dry powder can be input at desired locations over the channel 710f even
if the cover member 720 is slid (rearward or forward) a distance over the flow channel
710f for adjustment of the flow orifice size. The length of the input region 721 (slot
721s) may be at least about 2.9 cm. As shown in Figures 17A and 17B, the flow
channel 710f can be divided into a reservoir length L1 and an adjacent flow channel
length Lf. The reservoir length is that portion of the flow channel in the inlet region
721 that is defined between two inserts 792, 793. The inserts 792, 793 are sized to
extend through the cover member slot 721s a depth into the channel. As shown in
Figure 17B, the first or upstream insert 792 has a greater length than the downstream
insert 793 and is configured to extend to contact or force the piezo-layer 730 to move
closer to the bottom of the channel 710f and inhibit backfiow of the powder in the
reservoir so as to hold a dry powder material supply in the inlet region 721 and
gradually feed the dry powder into the flow channel length Lf. The flow channel
length Lr can be described as that portion of the flow channel 710f that is located
downstream of the reservoir (downstream of a major portion of the input region 721,
shown as downstream of the first bracket 746).
Figure 16A illustrates one embodiment of a configuration of a piezoelectric
layer 730 that may be a piezoelectric polymer layer. It is noted that the term
"piezoelectric polymer layer" is used for ease of description, but the term "polymer"
as used herein, can also include co-polymers and blends, mixtures and derivatives
thereof. As shown, one long side 7301 of the layer 730 has a flap portion 730f with
cut outs 730n1, 730n2 which are configured to allow upwardly extending attachment
members 742, 743 (Figure 13) to extend therethrough. The other side 73012 can be
substantially straight and configured to be substantially flush between the aligned
portions of the cover member 720 and flow channel member 710. The attachment
members 742, 743 can be used to attach upper and lower bracket pairs 746,747,
which clamp the cover member 720 and flow channel member 710 together. The
cover member 720 can be formed with sufficient weight to obviate the need for

clamping, or other attachment means can be used to provide the desired holding force
to keep the layer 730 in position. The flexible piezoelectric layer 730 can be
preformed or formed in situ to substantially conform to the shape of the underlying
channel 710f . The position of the cover member 720 and the length of the associated
tip projection 720t can influence the size of the flow orifice provided by the
cooperation of the layer 730 and the cover and flow channel members 720, 710,
respectively.
As shown in Figure 13, the layer 730 is pinched or securely held about its
perimeter portion. However, the layer 730 is held in the channel 710f so that its
primary surfaces are able to flex upwardly. The piezoelectric layer 730 is held so that
the portion of the layer 730 in the flow channel 710f is forced to vibrate in the upward
direction. As shown in Figure 13, the signal(s) can be applied directly to the
piezoelectric layer 730 from a signal generator 20 via a signal lead 775.
Referring again to Figure 13, an amplifier 20A can be operatively associated
with the signal generator 20 and used to modulate the signal before transmitting to the
layer 730, as desired. The signal generator 20 can be any suitable signal generator. In
certain embodiments, the signal generator 20 is a wave signal generator that can
incorporate or be operatively associated with an amplifier. The signal generator 20
may be combined into a signal processor or provided by other configurations of
electronic circuitry. In certain embodiments, the ground connection can be via the top
surface of the polymer layer 730 with the positive contact via the bottom surface. The
metallization can be removed from the region to which the ground connects.
Positioning the ground connection on the top surface (where the dry powder resides)
can act to inhibit the dry powder being exposed to voltage during operation. The
electrical contacts can be made via a central portion of the flap 730f, although other
locations may also be used.
Valves or other "on-off" configurations can be used to dispense discrete
amounts of the dry powder. In certain embodiments, the flow dispensing can be
controlled by terminating and/or electrically decoupling the input signal from to the
piezoelectric layer 730 such as by using a timer 20t (which feature is shown for
example in Figure 13) that can be in communication with the layer 730 and/or valve
member (not shown). As described above for other embodiments, the receiving
containers may be translated under the dispensing orifice at a timed rate to provide the

desired dose amounts. In certain embodiments, a plurality of elongate flow channels
can be arranged to concurrently and/or serially dispense (the same or different) dry
powder (not shown).
As shown in Figure 13, the apparatus 700 may include an angle adjustment
mechanism 780. As shown, the angle adjustment mechanism includes a bracket 780b
upon which a portion of the underside of the flow channel member 710 can rest. The
apparatus 700 can include a hinge bracket member 745 that is pivotably attached to a
portion of the flow channel member 710 (and/or cover member 720). In operation,
the bracket 780b can be raised and lowered and the flow channel member 710 pivots
accordingly to adjust the angle of inclination of the flow channel 710f. As will be
appreciated by one of skill in the art, other angle adjustment configurations can be
employed. The angle adjustment mechanism 780 can include a protractor or other
angular scale to allow a user to be able to ascertain the angle without undue
measurement. Typically, during evaluation of a powder, when the apparatus 700 is
used to ascertain flow parameters, the flow channel 710f will be positioned at several
different angles. In certain embodiments, the angles evaluated can be proximate to
but under the static angle of repose (under or over 90 degrees), and may, in certain
embodiments, be between about 10-75 degrees.
The frequency of the signal generated to cause the selected vibration to obtain
the desired fluidic flow is typically influenced by the voltage amount per frequency
per given capacitance. As the polymer layer defines the capacitance, the size of the
layer or sheet will influence this parameter. In addition, the amplifier selected may
also limit the operational frequency of the wave signal generator employed. Off the
shelf units (such as a 200V amplifier) may limit the amplitude modulated (carrier)
frequency output to between about 2500-7800Hz, while customized signal processors
may not be so limited (capable of generating increased carrier frequencies in the range
of between about 15kHz-50kHz, or more as described above). An example of a
suitable waveform generator is Part No. 33120A from Agilent, located in Palo Alto,
CA, and an example of an amplifier is Part No. EPA-104 from Piezo Systems, located
in Cambridge, MA.
The apparatus 700 can include a stationary mounting frame 790 that holds the
angle adjustment mechanism 780, the hinge bracket member 745, and the flow
channel and cover members 710, 720, respectively.

As shown in Figure 13, the apparatus 700 may include a hopper 25 with a
hopper outlet port 25p that is in fluid communication with the cover member port 721
that can continuously or episodically feed dry powder into the flow channel 710f.
Although particularly suitable for pharmaceutical dry powders, the methods,
systems and devices contemplated by the present invention may be used to dispense
any desired dry powder, such as toners and the like.
The invention will now be described in more detail in the following non-
limiting examples.
EXAMPLE 1
The data in Tables 2 and 3 were obtained using the apparatus illustrated in
Figure 13. The signal generator was a 200V amplifier. The carrier frequency
selected for the Inhalac 230 dry powder (a dry powder from Meggle Gmbh, •
Wasserburg, Germany, that has a 230 mesh size when sieved by the manufacturer)
was 7500 Hz. The signal (identified as arb 2 signal) used to vibrate the piezoelectric
polymer layer may be selected and/or expressed using one or more of Equations 1-6
herein. The exemplary excitation signal includes the superposition of four modulating
frequencies ranging from 10-15 Hz.
The foregoing is illustrative of the present invention and is not to be construed
as limiting thereof. Although a few exemplary embodiments of this invention have
been described, those skilled in the art will readily appreciate that many modifications
are possible in the exemplary embodiments without materially departing from the
novel teachings and advantages of this invention. Accordingly, all such modifications
are intended to be included within the scope of this invention as defined in the claims.
In the claims, means-plus-function clauses, where used, are intended to cover the
structures described herein as performing the recited function and not only structural
equivalents but also equivalent structures. Therefore, it is to be understood that the
foregoing is illustrative of the present invention and is not to be construed as limited
to the specific embodiments disclosed, and that modifications to the disclosed
embodiments, as well as other embodiments, are intended to be included within the
scope of the appended claims. The invention is defined by the following claims, with
equivalents of the claims to be included therein.
WE CLAIM :
1. A method of f lowably dispensing dry powders from a hopper having a dispensing port and
a dry powder flow path, comprising :
generating a first non-linear vibration input signal, the first non-linear input signal
comprising a carrier frequency modulated by a plurality of different selected frequencies
that correspond a first dry powder formulation;
applying the first non-linear vibration input signal to a dispensing hopper having a dry
powder flow path and at least one dispensing port while the first dry powder formulation is
flowing therethrough; and
dispensing a first meted quantity of the first dry powder through the dispending port to a
receiving member.
2. A method according to claim 1, wherein the selected frequencies of the non-linear signal
correspond to known and/or predetermined flow characteristic frequencies of the first dry
powder, and wherein the generating step is carried out to cause the dry powder to flow in a
substantially uniform fluidic manner without aggregation.
3. A method according to claim 1, wherein the dispensing step is carried out by
synchronizing the dispensing port to open for a predetermined amount of time, the time
corresponding to the dry powder flow rate and amount of meted dry powder desired.
4. A method according to claim 1, wherein the first meted quantity is a single unit dose
amount that is less than about 15 mg.
5. A method according to claim 1, wherein the first meted quantity is a single unit dose
amount that is between about 10µg-10mg.
6. A method according to claim 1, wherein the dispensing step is carried out to successively
dispense a plurality of meted quantities, the plurality of meted quantities being between
about 10µg-10mg, and wherein each of the plurality of.............
meted quantities are in substantially the same amount with a variation dose to dose of
less than about 10%.
7. A method according to Claim 6, wherein the dose to dose variation is
less than about 5%.
8. A method according to Claim 1, wherein the non-linear input signal
has a plurality of superpositioned modulating frequencies.
9. A method according to Claim 1, wherein the dry powder formulation is
a low-density dry powder formulation.
10. A method according to Claim 1, wherein the input signal is derived
from an evaluation of observed frequencies of time between avalanches as detected in
a mass flow analysis of the dry powder formulation.
11. A method according to Claim 10, wherein the derivation of the input
signal converts time to frequency space to render frequency distribution data of the
mass flow analysis of the dry powder formulation.
12. A method according to Claim 1, further comprising generating a
second non-linear vibration input signal, the second non-linear input signal
comprising a plurality of different selected signal frequencies that correspond to
predetermined flow characteristics of a second dry powder formulation;
adjusting the non-linear input signal to apply a second non-linear vibration
input signal to the dispensing hopper while the second dry powder formulation is
flowing therethrough, the second input signal being different from the first input
signal; and
dispensing a first meted quantity of the second dry powder through the
dispensing port to a receiving member.
13. A method according to Claim 1, wherein the applying step is carried
out at a localized portion of the. hopper.

14. A method according to Claim 1, wherein the applying step is carried
out by applying the non-linear vibration energy along a major portion of the length of
the hopper, the length of the hopper extending in the direction of flow.
15. A method according to Claim 12, wherein the non-linear input signal
comprises a plurality of superimposed frequencies that are selected to represent a
desired number of the most observed frequencies in a flow analysis frequency
distribution.
16. A method according to Claim 1, wherein the applying step is carried
out to concurrently apply vibrational energy at multiple selected frequencies.
17. A method according to Claim 1, further comprising increasing the
apparent bulk density of the first dry powder during the dispensing step without
evacuating the flow path.
18. A method according to Claim 17, wherein the hopper and dispensing
port define a dry powder flow path, and wherein the increasing the apparent density
step comprises directing a gas at a first pressure to enter, flow across, and exit the
flow path at a second lesser pressure, proximate the dispensing port as the dry powder
moves downwardly in the hopper during the dispensing step.
19. A method according to Claim 1, wherein the hopper has an associated
axis extending along the gas flow path, said method further comprising moving the
hopper in a centrifugal motion so that it oscillates relative to the axis and generates a
force with downward component or vector that is transmitted to the first dry powder
formulation during the dispensing step.
20. A method according to Claim 1, wherein the hopper has an associated
axis extending along the gas flow path, said method further comprising moving the
hopper in an eccentric motion so that it oscillates relative to the axial center line and
generates a force with downward component or vector that is transmitted to the first
dry powder formulation during the dispensing step.
21. A method according to Claim 1, wherein the non-linear input signal
comprises frequencies in the range of between about 10Hz to 1000kHz.
22. A method according to Claim 1, wherein the non-linear input signal
comprises carrier frequencies in the range of between about 15kHz to 50kHz.
23. A method according to Claim 1, wherein the hopper comprises an
insert configured to reside in the flow path in the hopper such that it downwardly
extends a distance out of the dispensing port, said method further comprising
translating the insert during the dispensing step to accelerate the particles of the dry
powder formulation.
24. A method according to Claim 23, wherein the translating step is carried
out to oscillate the insert with a selected motion that has an associated non-constant
period or periods.
25. A method according to Claim 1, wherein the vibration energy input
signal is based on electrical stimulation of the hopper.
26. A method according to Claim 1, wherein the vibration energy input
signal is generated by mechanical stimulation of the dry powder.
27. A method according to Claim 1, wherein the vibration energy input
signal is generated by electro-mechanical stimulation of the hopper and/or dry
powder.
28. A method according to Claim 1, wherein the vibration energy input
signal comprises imparting a high frequency motion onto a selected portion of the
hopper, with the outer bounds of the motion of the hopper being small.
29. A dry powder dispensing system, comprising.'
a hopper configured to hold a dry powder therein, the hopper having at least
one dispensing port and a wall with an inner surface and outer surface;
a quantity of a dry powder disposed in the hopper;
at least one vibration energy generation source operably associated with the
hopper, wherein, in operation, the at least one vibration energy generation source is
configured to output a desired non-linear vibratory energy sufficient to impart an
angular velocity with downward force vectors to the dry powder as the dry powder
flows downwardly to the dispensing port; and
a control module operably associated with the hopper and the vibration
energy generation source, the control module comprising'.
computer readable program code configured to direct the vibration
energy source to output the vibration energy corresponding to the dry powder
in the system.
30. A system according to Claim 29, the control module further
comprising:
computer readable program code configured to select the output of the
vibration energy generation source from a library of non-linear energy outputs
associated with a plurality of different dry powders, based on a desired predetermined
dry powder specific vibration energy output associated with the dry powder being
dispensed.
31. A system according to Claim 30, wherein the system is configured to
dispense a plurality of different dry powders separately, and wherein the control
module comprises computer readable program code that accepts user input to identify
the dry powder being dispensed, and computer program code that automatically
selectively adjusts the output of the vibration energy generation source based on the
identified dry powder being dispensed.
32. A system according to Claim 29, wherein the computer program code
for the predetermined dry powder-specific vibration energy output for the dry powder
being dispensed defines an output signal that is derived from flow data experimental
obtained from a flow analysis of the dry powder in the system.
33. A system according to Claim 30, wherein the computer program code
for the library of predetermined dry powder-specific vibration energy outputs for the
dry powders are derived from data obtained from a mass flow analysis of the dry
powders.
34. A system according to Claim 29, wherein the dry powder is a low-
density dry powder, and wherein the system is configured to serially dispense a
plurality of single unit doses.in amounts less than about 15mg.
35. A system according to Claim 34, wherein the single dose amount is
between about 10µg-10mg.
36. A system according to Claim 29, wherein the system is configured to
dispense a plurality of meted quantities, the plurality of meted quantities being
between about 10µg-10mg, and wherein each of the plurality of meted quantities are
in substantially the same amount with a variation, dose to dose, of less than about
10%.
37. A system according to Claim 30, wherein the computer program code
of predetermined vibration generation source output signals is derived from selected
parameters of a mass flow analysis of the dry powders.
38. A system according to Claim 37, wherein the derivation converts time
space data of the mass flow analysis of the dry powders to frequency space data.
39. A system according to Claim 29, wherein, in operation, the vibration
energy generation source is configured to deliver the output signal and cause the dry
powder to flow in a substantially uniform fluidic manner without aggregation.
40. A system according to Claim 29, further comprising a valve operably
associated with the at least one dispensing port and in communication with the control
module, the valve being configured to open and close the flow path across the
dispensing port to controllably dispense meted quantities of dry powder by permitting
flow of the dry powder out of the dispensing port for a predetermined time at a
substantially uniform flow rate, the flow rate and open time of the valve during the
valve operation cycle corresponding to the desired dispensed dose amount.
41. A system according to Claim 29, wherein the vibration generation
source is configured to output high frequency vibration energy.
42. A system according to Claim 29, wherein the hopper comprises a
piezoelectric material that is operably associated with the dry powder in the hopper,
and wherein the vibration energy generation source comprises a power source that can
supply a selected electrical input signal to the piezoelectric material, wherein, in
operation, the piezoelectric material outputs the desired vibration energy to the dry
powder.
43. A system according to Claim 29, wherein the vibration generation
source is configured to increase the apparent bulk density of the dry powder in the
hopper during dispensing in the absence of evacuation.
44. A system according to Claim 43, further comprising:
a permeable member attached to the hopper and positioned proximately above
the dispensing port and defining a portion of the dry powder flow path; and
a forced gas source configured to direct gas to enter a first side of the
permeable member at a first pressure, flow across the gas flow path, and exit the
permeable member at a different location at a second pressure to generate a pressure
differential across the width of the gas flow path proximate the permeable member.
45. A system according to Claim 44, wherein the permeable member is a
stainless steel filter or frit.
46. A system according to Claim 44, wherein the hopper, the permeable
member, and the dispensing port define an axially extending dry powder flow path,
and wherein, in operation, the apparent bulk density of the dry powder is increased as
the dry powder moves downwardly in the hopper due at least in part to the
transversely generated pressure differential.
47. A system according to Claim 29, wherein the hopper and associated
dispensing port have an associated axis extending along the gas flow path, said system
further comprising a translation mechanism that moves at least a portion of the hopper
in a centrifugal motion so that the hopper and/or dispensing port oscillates relative to
the axis and, in operation, generates a force with a downward component or vector
that is transmitted to the first dry powder during dispensing.
48. A system according to Claim 29, wherein the hopper and dispensing
port have an associated axis extending along the gas flow path, said system further
comprising a translation mechanism that moves at least a portion of the hopper in an
eccentric motion so that at least a portion of the hopper oscillates relative to the axis
and, in operation, generates a force with a downward component or vector that is
transmitted to the dry powder during dispensing.
49. A system according to Claim 29, wherein the vibration energy
generation source outputs a non-linear input signal comprising vibration excitation
frequencies in the range of between about 10 Hz to 1000 kHz.
50. A system according to Claim 29, wherein the vibration energy
generation source outputs a non-linear input signal comprising at least one carrier
frequency in the range of between about 15kHz to 50kHz and a plurality of
modulation frequencies in the range of between about 10-500Hz.
51. A system according to Claim 29, further comprising an elongated
insert configured to reside in the flow path in the hopper such that the insert
downwardly extends a distance out of the dispensing port and eccentrically rotates
relative to the axis of the flow path of the hopper during dispensing to transmit directional
acceleration to particles of the dry powder.
52. A system according to claim 51, wherein, in operation, the insert is oscillated with a
selected motion that has an associated non-consiant period.
53. A system according to claim 29, wherein the vibration generation energy output
comprises a high frequency motion applied onto a selected portion of the hopper, with the
outer bounds of the motion of the hopper being small.
54. A system according to claim 29, further comprising a computer program product
controlling the dispensing of dry powders, the computer program product configured to
control the activation of a valve that opens and closes the flow path of the dispensing
system to control the amount of dry powder dispensed in unit dose amounts of less than
about 15 mg.
55. A flowing dry powder processing and/or dispensing system having an associated dry
powder flow path with a dispensing port and a vibration energy source associated therewith
to facilitate fluidic flow, and a computer program product for operating said
processing/dispensing system, said computer program product comprising:
a computer readable storage medium having computer readable program code embodied in
said medium, said computer-readable program code comprising:
computer readable program code that identifies a plurality of powder-specific vibration
energy signals, each corresponding to an individual flow analysis; and
computer readable program code that directs the dispensing system to operate using the
powder-specific vibration energy signal associated with a target dry powder.
56. The system according to claim 55, wherein the powder specific vibration energy signals
are non-linear.
57. The system according to claim 55, further comprising computer program code that
accepts user input to identify the dry powder being dispensed, and computer program code
that automatically selectively adjusts the output of the vibration energy signal based on the
identified dry powder being dispensed.
58. The system according to claim 55, wherein the vibration energy output signals for the
dry powders being dispensed are based on data obtained from a flow analysis of different
dry powders.
59. The system according to claim 55, wherein the dispensing system is configured to
dispense low-density dry powder.
60. The system according to claim 55, further comprising computer program code that
controllably dispenses meted quantities of dry powder independent of volumetric
evaluations by considering flow rate of the dry powder out of the dispensing port and
controlling the amount of time the dispensing port is open during dispensing.
61. The system according to claim 60, and wherein the computer program is configured to
controllably dispense a plurality of single unit doses of low density dry powders in amounts
less than about 15mg.
62. The system according to claim 61, wherein the single dose amount is between about
10µg-10mg.
63. The system according to claim 62, wherein the computer program product is configured
to controllably dispense a plurality of meted quantities of low-density dry powder, the
plurality of meted quantities being between about 10µg-10mg, and wherein each of the
plurality of meted quantities are in substantially the same amount with a variation, dose to
dose, of less than about 10%.
64. The system according to claim 55, further comprising computer program code that
automatically repeatedly actuates a valve operably associated with the dispensing port to
open and close the dispensing port according to the desired meted quantities and filling
protocol.
65. A method of measuring doses of dry powder formulations, comprising:
tensioning an elastomeric piezoelectric material with metallic conductive
portions thereon;
dispensing a quantity of a dry powder onto the piezoelectric material about a
predetermined location proximate at least one of the metallic conductive portions, the
dispensing causing the flexing of the piezoelectric material;
measuring an alteration in a selected electrical parameter associated with the
flexure of the piezoelectric material; and
determining the mass of the dispensed dry powder based on the measured
alteration.
66. A method according to Claim 65, wherein the piezoelectric material is
PVDF, and wherein the step of measuring is carried out by sensing the voltage
generated by the piezoelectric film responsive to the weight of the dry powder
positioned thereon.
67. A method according to Claim 65, wherein the step of measuring is
carried out by sensing a change in capacitance generated by the piezoelectric material
due to the applied force associated with the weight of the dry powder positioned
thereon.
68. A method according to Claim 65, wherein the step of measuring is
carried out by sensing a change in the resonant frequency in the piezoelectric material
due to the applied force associated with the weight of the dry powder positioned
thereon.
69. A method according to Claim 65, wherein the dispensing is carried out
for single dose amounts about 30mg or less.
70. A method according to Claim 65, wherein the dispensing is carried out
for single dose amounts between about 10µg-10mg.
71. A method according to Claim 65, wherein the dry powder is a low
density dry powder.
72. A system for measuring doses of dry powder formulations, comprising:
means for tensioning an elastomeric piezoelectric material with metallic
conductive portions thereon; .
means for dispensing a quantity of a dry powder onto the piezoelectric
material about a predetermined location proximate at least one of the metallic
conductive portions to cause the flexing of the tensioned piezoelectric material by
dispensing the dry powder thereon during the dispensing;
means for measuring an alteration in a selected electrical parameter associated
with the flexure of the piezoelectric material; and
means for determining the mass of the dispensed dry powder based on the
measured alteration.
73. A system of flowably dispensing dry powders from a hopper having a
dispensing port and a dry powder flow path, comprising:
means for generating a first non-linear vibration input signal, the first non-
linear input signal comprising a plurality of different selected frequencies that
correspond to a flow analysis of a first dry powder formulation;
means for applying the first non-linear vibration input signal to a dispensing
hopper having at least one dispensing port while the first dry powder formulation is
flowing therethrough; and
means for dispensing a first meted quantity of the first dry powder to a
receiving member.
Methods for flowably dispensing dry powders from a hopper having a dispensing port and a dry powder flow path
can include: (a) generating a first non-linear vibration input signal, the first non-linear input signal comprising a plurality of different
selected frequencies that correspond to a first dry-powder formulation; (b) applying the first non-linear vibration input signal to
a dispensing hopper having at least one dispensing port while the first dry powder formulation is flowing therethrough; and (c)
dispensing a first meted quantity of the first dry powder through the dispensing port to a receiving member. Related devices and
computer program products for dispensing dry powders are also described.

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Patent Number 223379
Indian Patent Application Number 01896/KOLNP/2004
PG Journal Number 37/08
Publication Date 12-Sep-2008
Grant Date 10-Sep-2008
Date of Filing 10-Dec-2004
Name of Patentee ORIEL THERAPEUTICS, INC.
Applicant Address 630 DAVIS DRIVE, SUITE 120, DURHAM, NC
Inventors:
# Inventor's Name Inventor's Address
1 CROWDER, TIMOTHY, M. 4208 THETFORD ROAD DURHAM, NC 27707
2 HICKEY, ANTHONY, J. 1208 KILLINGTON COURT CHAPEL HILL, NC 27514
PCT International Classification Number G06F 17/00
PCT International Application Number PCT/US03/020842
PCT International Filing date 2003-06-26
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/440, 513 2003-01-16 U.S.A.
2 60/392, 671 2002-06-27 U.S.A.
3 10/434, 009 2003-05-08 U.S.A.