Note: Descriptions are shown in the official language in which they were submitted.
CA 02333107 2000-11-23
WO 9.9/63972 PCT/US99/12772
1
PHARMACEUTICAL PRODUCT
AND METHODS AND APPARATUS FOR MAKING SAME
Cross Reference to Related Cases
The following U.S. patents are of interest: Pat. No. 5,669,973 issued 23-Sep-
97 to
Pletcher et al., APPARATUS FOR ELECTROSTATICALLY DEPOSITING AND RETAINING
MATERIALS UPONA SUBSTRATE; Pat. No. 5,714,007 issued 03-Feb-98 to Pletcher et
al.,
APPARATUS FOR ELECTRO~STATICALLY DEPQS'TIING A MEDICAMENT POWDER
UPON PREDEFINED REGIONS OFA SUBSTRATE; Pat. No. 5,788,814 issued 04-Aug-98
to Sun, CHUCKS AND METHODS FOR POSITIONING MULTIPLE OBJECTS ON.4
SUBSTRATE; Pat. No. 5,753,:302 issued 19-May-98 to Sun et al., ACOUSTIC
DISPENSER;
Pat. No. 5,846,595 issued 08-Dec-98 to Sun et al., ELECTROSTATIC CHUCKS; Pat.
No.
5,858,814 issued 12-Jan-99 to Sun et al., ELECTROSTATIC CHUCKS; Pat. No.
5,871,010
issued 16-Feb-99 to Datta et al., INHALER APPARATUS WITH MODIFIED SURFACES
FOR ENHANCED RELEASE ~OF DRYPOWDERS.
The following U.S. patent applications are of interest: S.N. 08/659,501 filed
06-Jun-
1996 by Pletcher et al., METh'OD AND APPARATUS FOR ELECTROSTATICALLY
DEPOSITING A MEDICAMENT POWDER UPON PREDEFINED REGIONS OF A
SUBSTRATE; S.N. 08/733,525 filed 18-Oct-96 by Pletcher et al., METHOD AND
APPARATUS FOR ELECTROSTATICALLY DEPOSITING A MEDICAMENT POWDER
UPON PREDEFINED REGIC)NS OFA SUBSTRATE; S.N. 08/956,348 filed 23-Oct-97 by
Loewy et al., DEPOSITED R~?AGENTS FOR CHEMICAL PROCESSES; S.N. 08/956,737
filed 23-Oct-97 by Loewy et ail., SOLID SUPPORT WITHATTACHED MOLECULES; S.N.
09/026,303 filed 19-Feb-98 bar Sun, BEAD TRANSPORTER CHUCKS USING REPLILSIVE
FIELD GUIDANCE; S.N. 09/047,631 by Sun, BEAD MANIPULATING CHUCKS WITH
BEAD SIZE SELECTOR; S.1\f . 08/083,487 filed 22-May-98 by Sun, FOCUSED
ACOUSTIC
BEAD CHARGERlDISPENSI;R FOR BEAD MANIPULATING CHUCKS; S.N. 09/095,425
filed 10-Jun-98 by Sun et al:, .AC WAVEFORMS BL4SING FOR BEAD MANIPULATING
CHUCKS, and S.N. 09/095,321 filed 10-Jun-98 by Sun et al., APPARATUS FOR
CLAMPING A PLANAR SUBSTRATE; S.N. 09/095,616 filed 10-Jun-98 by Chrai et al.,
PHARMACEUTICAL PRODUCT AND METHOD OF MAKING; and S.N. 09/095,246 filed
10-Jun-98 by Desai et al., DRYPOWDER DEPOSITIONAPPARATUS.
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
2
Field of the Invention
The present invention relates generally to unit dosage or unit diagnostic
forms and an
apparatus and method for making such unit forms.
Background of the Invention
In the pharmaceutical industry, pharmaceutical products including diagnostic.
products comprise a container (e.g., a bottle, a blister pack or other
packaging) containing a
plurality of "unit dosage forms" or "unit diagnostic forms." Each of such unit
forms
contains a pharmaceutically- or biologically-active ingredient or ingredients
and inert or
inactive ingredient(s).
The pharmaceutically-active ingredient typically forms a drug. The diagnostic
form
may comprise a reagent or the like for use in diagnostic tests, and may be
part of a set which
includes several different reagents or active ingredients. Moreover, the
diagnostic form may
comprise an antibody, an antigen, or labeled forms thereof and the like.
A pharmaceutically- or biologically-active ingredient for use in a unit form
may be
supplied as a powder comprising a plurality of active-ingredient particles.
Such active-
ingredient particles are combined with inert or inactive ingredient particles
to form a
plurality of "major particles." 'Che major particles are quite small, with
dimensions on the
order of microns. Such major particles are typically combined with one another
to create the
final unit dosage or diagnostic form (e.g., tablet, caplet, test strip,
capsule, etc.).
There may be significant variation in the amount of pharmaceutically- or
biologically-active ingredient in one major particle and the next. Since a
large number of
major particles are required to create a final unit form, the aforedescribed
particle-to-particle
variation may result in a substantial variation in the amount of active
ingredient between one
unit form and the next. Thus, any given final form may contain substantially
more or less
than a desired amount of active; ingredients.
Destructive analytical screening procedures are conventionally performed to
assess
the amount of active ingredients) in final unit forms. Since such procedures
destroy the
unit forms, a statistical sampling is performed whereby a relatively small
number of forms
per batch are actually sampled and tested. Such screening procedures
disadvantageously
provide no assurance that all forms in a given batch contain a desired amount
of the
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
3
pharmaceutically- or biologically-active ingredients. In fact, such
statistical methods
practically "guarantee" that a statistically determinable percentage of the
forms in each batch
will be out of specification.
As such, the art would benefit from a method and apparatus that provides
improved
control over the active-ingredient content of unit dosage and diagnostic
forms.
Suramarv of the Invention
In one embodiment, the present invention provides a product comprising a
plurality
of pharmaceutical unit dosage forms or unit diagnostic forms (collectively,
"unit fornns").
Each form includes at least one active ingredient that is present in an amount
that
advantageously does not vary lby more than about five percent from a
predetenmined target
amount.
In one embodiment, th.e unit form comprises a substrate, an active ingredient
deposited thereon, and a cover layer that covers the active ingredient and is
joined (e.g., via
I S welding, adhesives, etc. ) to the; substrate in the proxim ity of the
active ingredient.
In the illustrated embodiments, the product is made via a dry deposition
apparatus
that deposits powder/grains on the substrate. In one embodiment, the apparatus
comprises an
electrostatic chuck, a charged powder delivery apparatus, and an optical
detection system.
The substrate is engaged to the: electrostatic chuck for the dry deposition of
powder. The
chuck has at least one collection zone at which a powder-attracting electrical
field is
developed. The charged powder-delivery apparatus directs charged powder for
electrostatic
deposition to the substrate at the collection zone(s). The optical detection
system quantifies
the amount of powder deposited.
In some embodiments, the dry deposition apparatus also includes an electronic
processor for controlling depositions responsive to sensor inputs. Such sensor
inputs
advantageously include one or more deposition sensors that are disposed on or
adjacent to
the electrostatic chuck and that provide data pertaining to the amount of
powder deposited.
Responsive to sensor data, the electronic processor adjusts deposition
parameters, as
necessary. Controllable parameters include powder flux through the powder-
delivery'
apparatus and applied voltage at the collection zone(s).
In still other embodiments, the present dry deposition apparatus
advantageously
includes a variety of other elements that are described in detail later in
this Specification.
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
4
l3rief Description of the Drawings
FIG. 1 depicts an isometric view of a product comprising a strip package
containing
a plurality of unit forms in accordance with an illustrated embodiment of the
present:
invention.
FIG. 2 depicts a cover layer of a strip package partially separated from a
substrate.
FIG. 3 depicts a side view of an illustrative unit form in accordance with the
present
teachings.
FIG. 4 depicts a top view of the illustrative unit form of FIG. 3.
FIG. 5 depicts a packaging container for storing the product of FIG. I .
FIG. 6 is a figurative depiction of an apparatus for making the present
product.
FIG. 7 depicts a top view of a robotic platform in accordance with an
embodiment of
the present invention.
FIG. 8 depicts a side elevation of the robotic platform of FIG. 7.
FIG. 9 figuratively depicts, via side-elevation, an embodiment of a
robotically-
operated receiver and an electrostatic chuck for carrying a substrate upon
which the unit
forms are deposited.
FIG. 10 depicts a plan view of a first surface of an illustrative
electrostatic chuck.
FIG. 11 depicts a plan view of a second surface of an illustrative
electrostatic chuck.
FIGS. 12a -12c depict side cross-sectional views of embodiments of the
electrostatic chuck of FIGS. 10 and 11 near a collection zone.
FIG. 13 depicts a front elevation of the receiver and electrostatic chuck
shown in
FIG. 9, and further depicts an illustrative arrangement for electrically
connecting the
electrostatic chuck to a circuit: board in the receiver.
FIG. 14 depicts a sidc: view of an illustrative lower pin assembly useful for
connecting the electrostatic chuck to a circuit board in the receiver.
FIG. 15 depicts a gasket disposed between the electrostatic chuck and the
receiver.
FIG.16 depicts a top view of the illustrative lower pin assembly of FIG. 14.
FIG. 17 depicts the underside the illustrative receiver with the electrostatic
chuck
adhered thereto.
FIG. 18 depicts the underside the illustrative receiver without the
electrostatic chuck.
FIG. 19 depicts a recE;iver platform for supporting components that comprise
the
receiver.
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
FIG. 20 depicts the receiver platform supporting several electronic
components.
FIGS. 21 & 22 depict further details of the receiver and the manner in which
it is
engaged to the robotic transport element.
FIG. 23 depicts a lamination support block for laminating the substrate and
cover
layer together.
FIG. 24 depicts a deposition engine for electrostatically depositing powder on
a
substrate.
FIGS. 25 and 26 depict a rotatable baffle for use in dispersing the powder at
a
powder deposition station.
FIG. 27 depicts an illustrative powder trap for capturing powder that does not
deposit.
FIGS. 28 and 29 depic;t an alternative embodiment of a receiver, electrostatic
chuck
and deposition station in accordance with the present teachings.
FIG. 30 depicts a first alternative embodiment of a powder feed apparatus.
FIG. 31 depicts a second alternative embodiment of a powder feed apparatus.
FIG. 32 depicts powder measurement via a diffuse reflection methodology.
FIG. 33 depicts powder measurement via an optical profilometry methodology.
FIG. 34 depicts a first measurement apparatus capable of both diffuse
reflection and
optical profilometry based-measurements.
FIG. 35 depicts the operation of the apparatus of FIG. 34 operating according
to
diffuse reflection methodology.
FIG. 36 depicts the operation of the apparatus of FIG. 34 operating according
to
optical profilometry methodology.
FIG. 37 depicts a second measurement apparatus capable of both diffuse
reflection
and optical profilometry based-measurements.
FIG. 38 depicts a plot that was developed based on data obtained using diffuse
reflection measurements.
FIG. 39 depicts a sealiing head that is positioned over a substrate and a
cover layer in
preparation for laminating them together.
FIG. 40 depicts a first illustrative equivalent circuit diagram for AC-biased
charge
and deposition sensing for a collection zone.
CA 02333107 2000-11-23
WO 99/63972 PCTNS99/12772
6
FIG. 41 depicts plots of waveforms of voltages measured at a floating pad
electrode
and a collection zone.
FIG. 42 depicts a second illustrative equivalent circuit diagram for AC-biased
charge
and deposition sensing for a collection zone.
FIGS. 43a-43c depict an illustrative method based on blow-fill-seal technology
for
fabricating a final dosage forni.
FIG. 43d depicts an illustrative final dosage form produced from the method of
FIGS. 43 a-43 c.
FIGS. 44a-44b depict: a further illustrative method for fabricating a final
dosage
foam.
FIG. 44c depicts an illustrative final dosage form produced from the method
depicted in FIGS. 44a-44b.
FIG. 45a depicts an additional method for fabricating a final dosage form.
FIG. 45b depicts an illustrative final dosage form produced from the method
depicted in FIG. 45a.
FIG. 46 depicts an illustrative embodiment of a final dosage form suitable for
providing timed release of a plurality of unit forms contained within the
final dosage form.
FIG. 47 depicts a further illustrative embodiment of a final dosage form
suitable for
providing timed release of a plurality of unit forms contained within the
final dosage form.
FIG. 48 depicts a bi-l;~yer substrate.
FIG. 49 depicts a method for making the bi-layer substrate of FIG. 48.
Detailed Description
The following terms shall have the respective meanings set forth below for the
purposes of this description and the appended claims.
Dielectric or non-conductive refers to materials that are non-conductive to a
degree
that distinguishes them from conductive materials such as copper and the like.
The degree of
non-conductance can vary considerably with context.
Dry deposited refers to depositing a material without using a liquid vehicle.
Effective amount means an amount effective to ( 1 ) reduce, ameliorate or
eliminate
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
7
one or more symptoms of a subject disease; (2) induce a pharmacological change
relevant to
treating a subject disease; or (3) prevent or lessen the frequency of
occurrence of a subject
disease, or symptoms thereof.
Electro-attractive dry deposition refers to methods that use an
electromagnetic field,
or an electrostatically-charged surface to dry deposit charged powder.
Grains are aggregates of either molecules or particles, such as the particles
comprising a powder, or polymer structure that can be referred to as "beads."
Beads can be
coated, have adsorbed molecules, have entrapped molecules, or otherwise carry
other
substances. The particles or nnolecules of a powder have an average diameter
that is
typically at least about 1 nanometer (nm), and more typically in the range of
about 100 nm to
about 500 nm. Grains have a diameter that is in the range of about 100 nm to
about 5
millimeters (mm), and more typically at least about 500 nm or 800 nm in
average diameter.
Planar substrate denol:es a substrate having two major dimensions, such as a
tape or a
sheet. While in some embodiments, planar substrates are flat, they need not
be.
Unit form (pharmaceutical dosage or diagnostic) includes one or more discrete
active
ingredients (whether or not on a separate substrate and whether or not the
substrate is edible)
that can be used as a dosage for pharmaceutical purposes or as an elements)
for diagnostic
purposes, whether or not encapsulated, whether or not capable of being
packaged or
otherwise available for end use as a unit.
Product and Unit Form
FIG. 1 depicts a product 1 in accordance with an illustrative embodiment
of'the
present invention. Product 1 comprises a package 2 that is realized as a strip
4 having an
array of unit dosage forms 6. Strip 4 comprises a substrate 8 and a cover
layer 9.
Substrate 8 and cover layer 9 each comprise a substantially planar, flexible
film or
sheet. In some embodiments, one of either substrate 8 or cover layer 9
includes an array of
semi-spherical bubbles, concavities, blisters or depressions (hereinafter
"bubbles") 12 that
are advantageously arranged in columns and rows. In the illustrative package
depicted in
FIG. 1, cover layer 9 comprise, a three-by-five array of such bubbles 12,
although more or
fewer bubbles may suitably be; provided. Substrate 8 and cover layer 9 are
advantageously
_ formed to have a thickness of about 0.001 inches (0.0254 mm) and typically
comprise a
thermoplastic material. Materials suitable for use as substrate 8 and/or cover
layer 9 include,
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
8
without limitation, polyvinyla.cetate, hydroxypropylmethylcellulose and
polyethylene oxide
films. Polyvinylacetate films suitable for use as the substrate and/or cover
layer are
commercially available from Polymer Films, Inc. of West Haven, CT; Chris Craft
of Gary,
IN; Aquafilm of Winston-Salem, NC; Idroplast S.p.A. of Montecatini Terme (PT),
Italy;
AICello Chemical Co., Ltd. of Toyohashi; Japan; and Soltec of Paris, France.
As depicted in FIG. ~! (showing cover layer 9 partially "peeled" back from
substrate
8) and FIG. 3, a deposit of a dry active ingredient 14, in the form of
powder(s)/grains
(hereinafter, "powder,") is disposed between substrate 8 and cover layer 9
within a bubble
12. In some embodiments, active ingredient 14 is a pharmaceutical product,
such as a drug;
in other embodiments, active ingredient 14 is a diagnostic product that is
useful for
biological diagnostic laboratory or medical related purposes. The method and
means by
which active ingredient 14 is deposited on substrate 8 is described later in
this specification.
As used herein, the term "pov~rder" signifies a single (i.e., one type of)
powder as well as
multiple (i.e., different types of) powders.
As depicted via a cross-sectional view in FIG. 3 and plan view in FIG. 4 (each
showing only a single bubble 12), substrate 8 and cover layer 9 are attached
to one another
via bonds or welds 7 that are near to and encircle bubble 12. Bonding can be
effected, for
example, via heat or ultrasonic welding or via suitable adhesives. Unit form 6
comprises a
deposit of active ingredient 14, bubble 12, and a region of substrate 8 within
bonds T.
As depicted in FIG. 5., strips 4 containing unit forms 6 can be provided, for
example,
in a box 16 or like packaging container, for the convenience of a user.
Unit dosage forms 6 in accordance with the present teachings can be used to
form a
variety of final dosage forms. Illustrative final dosage forms incorporating
one or more unit
dosage forms 6 are described :later in this specification after various
embodiments of an
apparatus for making unit dosage forms 6 are described.
Apparatus for Makin,~g the Present Product
FIG. 6 depicts, conceptually, the elements of an apparatus 100 suitable for
making
the present product. Apparatl.~s 100 comprises platform 101 wherein the unit
forms in
accordance with the present invention are created. Platform 101 is
advantageously adapted
for robotic operation, as depicted in the illustrative embodiments. In other
embodiments,
however, platform 101 is not robotic. In such other embodiments, platform 101
includes, for
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
9
example, manually-operated mechanisms (e.g., gantry and crane) for retrieval
and transit of
substrates, etc. Platform 101 creates such unit forms via a variety of
operations, chief of
which is the electrostatic deposition of dry powder on defined discrete
regions of a substrate.
Additional operations include; some or all of the following: materials
handling, alignment,
dose measurement and lamination.
Electrostatically-charged powder is delivered to robotic platform 101 via
powder
feed apparatus 801. Processor 401 and controller 403 control various
electronic functions of
apparatus 100, such as, for example, the application of voltage for the
electrostatic deposition
operation, the operation of powder feed apparatus 801, the operation of robots
that are
advantageously in conjunction with platform 101, and dose measurement
operations.
Memory 405 is accessible to processor 401 and controller 403.
In some embodiments., platform 101 and/or powder feed apparatus 801 are
isolated
from the ambient environment by an environmental enclosure. In such
environment:>,
environmental controller 901 provides temperature, pressure and humidity
control for robotic
platform 101 and powder feed apparatus 801.
A detailed description of the aforementioned elements of apparatus 100 is
provided
below.
The Platform and the Operation Thereof
FIGS. 7 and 8 depict a~ top view and a front elevational view, respectively,
of
illustrative platform 101. Four supports 104 are disposed one at each corner
of platform
101. Supports 104 elevate support bench 110 and various structures associated
with
platform 101 above a table or like surface. Additionally, supports 104
advantageously
provide a frame or superstructure for optional side-mounted barriers I06,
depicted in FIG. 7.
Side mounted barriers 106 ma;y be comprised of glass, polycarbonate or acrylic
panes and the
like. The side-mounted barriers, in conjunction with a top barrier (not shown)
and support
bench 110 define an environmental enclosure or chamber 102 that isolates the
region therein
from the ambient environment under air or inert gas.
Support bench 110 comprises five processing stations that perform various
operations advantageously used to produce the present product. Briefly, those
processing
stations include: input/output station 120, advantageously comprising three
substations
120A, 1208 and 120C, for storing substrates and cover layers; alignment
station 130 for
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
assuring that the substrate and cover layer are properly aligned to their
transport mechanism;
deposition station 150 where powder are deposited on the substrate; dose
measurement
station 140 for measuring the amount of powder that is deposited on the
substrate; and
lamination station 160 where the cover layer is laminated to the substrate.
5 In the illustrated embodiment, platform 101 is adapted for robotic operation
by way
of first robotic transport element 170 and second robotic transport element
180. A receiver
172 is attached to first robotic transport element 170. Receiver 172 is
operable, as discussed
in further detail later in this specification, to retrieve at least the
substrate from substation
120C and to move it to at least some of the various operational stations 130-
160 for
10 processing. A "bonding" headl 182 is attached to second robotic transport
element 180.
Bonding head 182 is operable, as discussed in further detail later in this
specification, to
join/seal the substrate and cover layer to one another.
Robotic transport elements 170 and 180 are movable (e.g., to access different
processing stations) along first: rails 190 that provide guides for motion in
one direction (e.g.,
along the x-axis). Additional rails (not shown) movably mounted on first rails
190 provide
guides/support for motion in a direction orthogonal (e.g., the y-axis) to
first rails 190, to
provide x-y motion. Drive means (not shown), such as x-y stepper motors, move
robotic
transport elements 170 and 180 along the rails. First and second robotic
transport elements
170 and 180 have telescoping .components under servo control (not shown) that
provide
movement along the z axis (i.e~., normal to the x-y plane). Such z-axis
movement allows
receiver 172 or bonding head 182 to move "downwardly" toward a processing
station to
facilitate an operation, and "upwardly" away from a processing station after
the operation is
completed. Robotic transport elements 170 and 180 advantageously include 8
control
components under servo control (not shown) that allow receiver 172 and bonding
head 182 to
be rotated in the x-y plane as may facilitate operations at a processing
station. Compressed
dry air or other gas is suitably provided, such as at a flow rate of 8 SCFM at
80 psi, to
operate the robotic transport elements. Robotic transport elements 170 and 180
can be based,
for example, on a Yaskawa Robot World Linear Motor Robot available from
Yaskawa
Electric Company of Japan.
The following disclosure provides a description of embodiments of various
elements
and features of apparatus 100. To provide perspective for such disclosure, a
summary of at
least one embodiment of the operation of apparatus 100 is first presented.
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
11
In operation, first robotic transport element 170 moves receiver 172 and an
engaged
electrostatic chuck 202 (used iEor powder deposition, see, FIGS. 9-11, etc.)
to input/output
station 120. At station 120, the electrostatic chuck engages substrate 80 and,
in some
embodiments, also engages a iFrame 81 that is joined to the substrate. In one
embodiment,
robotic transport element 170 then moves the engaged receiver 172,
electrostatic chuck 202,
substrate 80 and frame 81 to alignment station 130. At the alignment station,
frame 81 is re-
aligned to electrostatic chuck :Z02 via various alignment mechanisms, thereby
improving the
accuracy and consistency of .alignment of substrate 80 with electrostatic
chuck 202.
Robotic transport element 170 then moves engaged receiver 172, electrostatic
chuck
202, substrate 80 and frame 81 to dose measurement station 140. After aligning
with a
measurement apparatus at station 140, substrate $0 is scanned via a
measurement device and
distances from a reference point to substrate 80 at each of a plurality of
"collection zones"
CZ (see FIG. 10) are calculated and recorded to provide baseline data.
Robotic transport element 170 then moves engaged receiver 172, electrostatic
chuck
202, frame 81 and "virgin" substrate 80 to deposition station 150. At
deposition station 150,
the powder deposition engine (see FIGS. 23 - 29) is turned on and powder is
electro
deposited at collection zones ('_Z.
At the completion of the powder-deposition operation, robotic transport
element 170
returns substrate 80, with its complement of deposited powder, to dose
measurement station
150. At station 150, the measurement device again scans substrate 80 to
determine the
distance between the reference: point to the surface of the "deposit" of
powder accumulated at
each collection zone CZ. Frorn such distances, and the previously obtained
baseline data, the
amount (e.g., volume) of powder deposited at each collection zone is
calculated. If the
calculated amount is outside a desired range of a predetermined target amount,
such
information is displayed. An operator can then suitably adjust operating
parameters to bring
the process back into specification. In another embodiment, automatic feed
back is provided
to automatically adjust the process, as required. The "out-of spec" unit forms
may be
discarded.
Second robotic transport element 180 picks up cover layer 90 and frame 9I from
input/output station 120 and df;livers them to lamination station 160. After
measurements are
completed at dose measurement station 150, first robotic transport element 170
delivers
substrate 80 with its complement of powder to lamination station 160.
Substrate 80 is
CA 02333107 2000-11-23
WO 99/63972 PCT/IJS99/12772
12
placed, via first robotic transport element 170, on cover layer 90 such that
the deposits of
powder are properly aligned within the perimeter of the blisters or bubbles in
the cover layer.
After first robotic trmsport element 170 moves away, second robotic transport
element 180 returns and, by the operation of bonding head 182, welds the
substrate and cover
layer together, forming a plurality of unit forms on a strip (see, FIG. 1 ).
In an automated
system, the unit forms may bc; automatically transferred to a packaging
station wherein out-
of specification unit forms are screened out and in-spec unit forms are
appropriately
packaged.
The present method and apparatus provide a product containing a plurality of
pharmaceutical or diagnostic unit forms, each comprising at least one
pharmaceutically or
diagnostic active ingredient that advantageously does not vary from a
predetermined target
amount by more than 5%.
Having provided an overview of an embodiment of the present invention, further
detailed description of illustrative embodiments of various elements and
features of
apparatus 100 and the operation thereof are now provided.
The Receiver. Electrostatic Chuck and Substrate Assembly
In accordance with the present invention, powder comprising an active
ingredient is
electrostatically deposited at discrete locations on substrate 80 at
deposition station 150. In
the illustrated embodiments, accomplishing such deposition requires that,
among other
things, substrate 80 is transported to deposition station 150 from some other
location, and
that an electrostatic charge is developed that causes the powder to
electrostatically deposit on
substrate 80. Such transport and charging operations are facilitated, at least
in part, via
receiver 172 and electrostatic chuck 202. Before providing a detailed
description of such
elements, an overview of the cooperative relation between receiver 172,
electrostatic chuck
202 and substrate 80 is provided below in conjunction with FIG. 9.
FIG. 9 is a simplified representation that depicts receiver 172 engaged to
electrostatic
chuck 202. Illustrative receiver 172 comprises electronics housing 1610,
vacuum manifold
housing 1620, and gasket 1630, interrelated as shown. Electrostatic chuck 202
is engaged to
receiver 172 against gasket 1630. Substrate 80 (not shown in FIG. 9) is
releaseably secured
to electrostatic chuck 202. Electronics housing 1610 includes circuitry,
described in more
detail later in this specification, for controlling the operation of
electrostatic chuck 202.
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
13
Reduced pressure (e.l;., partial vacuum) is applied to passageways 1622 of
vacuum
manifold housing 1620 via inlet fitting 1621 and a passageway outlet (not
shown).
Passageways 1622 convey reduced pressure to "through holes" in electrostatic
chuck 202
(not shown in FIG. 9; see through holes ECH in FIGS. 10 and 11 ). Substrate 80
is in turn
exposed to such reduced pressure via openings in gasket 1630 (not shown in
FIG. 9, ,see slots
1631 in FIG. 15). The reduced pressure releaseably secures the substrate to
electrostatic
chuck 202. Further detailed description of receiver 172, electrostatic chuck
202 and substrate
80 and cover layer 90 is provided below.
In the illustrated embodiments, the substrate and cover layer are stored at
input/output substations 120A, 120B and 120C, and are advantageously mounted
on frames.
More particularly, substrates 80 are advantageously mounted on frames 81
forming substrate
assemblies 82, and cover layers 90 are advantageously mounted on frames 91
forming cover
assemblies 92. As depicted in FIGS. 2 and 3, substrate 80 is a planar film and
cover layer 90
is a substantially planar, flexible film having an array of semi-spherical
bubbles or blisters
that are advantageously arranged in columns and rows.
In the illustrative embodiment depicted in FIG. 7, first input/output
substation 120A
contains substrate assemblies l32, second input/output substation 120B
contains cover
assemblies 92, and third input/output substation 120C contains interlocked
frames 81 and 91
containing substrates 80 and cover layers 90 after bonding/lamination.
As described further below, frames 81 and 91 advantageously aid in aligning
the
substrates 80, 90 to various elements of apparatus 100. The frames are made of
a suitably
strong material that is preferably "light weight," such as, for example,
aluminum. Frames
having a rectangular shape with the shorter sides measuring about 200 mm and
the longer
sides measuring about 300 mm~, and all sides having a thickness of about 12.7
mm have
found to be suitable for use in conjunction with the present invention.
FIG. 10 depicts a view of first surface 204 of electrostatic chuck 202.
Electrostatic
chuck 202 comprises a layer 203 of dielectric material such as, for example,
Kapton~ brand
polyimide film commercially available from Dupont de Nemours, Wilmington, DE.
'The
electrostatic chuck has a thickness of about 0.01 inches (0.25 mm), and, as
such, is relatively
flexible. Illustrative electrostatic chuck 202 has "through holes" ECH
implemented as slots
that are disposed at its periphery. Other suitable configurations for
electrostatic chuck
"through holes" are illustrated in U.S. Pat. App. No. 09/095,321. First
surface 204 further
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
14
includes a plurality of powder collection zones CZ. In illustrative
electrostatic chuck 202,
collection zones CZ are advantageously organized in eight columns 20701- C8 of
twelve
collection zones each for a total of ninety-six collection zones CZ. As will
be described
further later in this specification, each collection zone CZ corresponds to a
powder
deposition location on the substrate (see substrate 8 in FIG. 1). Collection
zones CZ are
formed within electrostatic chuck 202 by an arrangement of dielectric and
conductive
regions, several embodiments. of which are described later in this
specification in conjunction
with FIGS. 12a - 12c.
FIG. 11 depicts a view of second surface 206 of electrostatic chuck 202. As
depicted
in more detail in FIGS. 12a - 12c, collection zones CZ are formed via
electrical contact pads
208. Such electrical contact pads 208 provide contact points for connection to
a controlled
voltage source. Electrical contact pads 208 are electrically connected to
selected other
electrical contact pads via address electrodes 210.
By virtue of discrete Electrical contact pads 208, and address electrodes 210
that
electrically connect select groupings of such contact pads (e.g., the pads 208
within a given
column 20701- C8 of illustrFttive chuck 202 of FIG. 11 define an illustrative
grouping), a
first voltage can be applied to contact pads 208 in column 20701, while a
second voltage
different from the first voltage can be applied to contact pads 208 in second
column 20702,
and so forth varying the voltage applied to contact pads 208 on a column-by-
column basis as
desired. It will be understood that the application of such different voltages
to such different
columns results in depositing a different amount of powder at collection zones
CZ in each of
such columns. It will be appreciated that in other embodiments, address
electrodes are
arranged differently thereby creating electrical interconnects between
differently arranged
groupings of contact pads 208. For the layout of contact pads 208 and address
electrodes 210
depicted in FIG. 11, voltage need only be applied to a single contact pad 208
within a given
column 203 for substantially the same electrostatic charge to be developed at
each contact
pad 208 within that column.
FIGS. 12a -12c depict several illustrative embodiments of structural
arrangements
suitable for forming collection zones CZ within an electrostatic chuck, such
as electrostatic
chuck 202. For clarity of illustration, the structure associated with only a
single collection
zone CZ of an electrostatic chuck is depicted in FIGS. 12a - 12c.
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
In a first embodiment depicted in FIG. 12a, a conductive material 305 is
disposed
through layer 303 of dielectric at each region designated to be a collection
zone CZ. The
conductive material overlays a~ portion of first surface 304 and second
surface 306 of the
electrostatic chuck. The portion of conductive material 305 overlying first
surface 304
comprises a powder-attracting electrode 307A, while the portion of conductive
material 305
overlying the second surface 306 comprises electrical contact pad 308A
(equivalent to the
electrical contact pads previously described, such as contact pad 208 depicted
in FIG. 11 ). A
shield electrode 312 (also termed a "ground electrode" based on a preferred
bias) is disposed
within layer 303.
10 Applying a voltage to electrical contact pad 308A generates an
electrostatic field at
powder-attracting electrode 3~I7A at collection zone CZ. As described later in
this
specification, the electrostatic field attracts charged powder to the
substrate (e.g., substrate
380). Additionally, the electrostatic field aids in holding substrate 380 flat
against first
surface 304 of the electrostatic; chuck. The reduced pressure that is
developed in vacuum
15 manifold housing 1620 (see FIfG. 9) to which substrate 380 is exposed also
assists in adhering
substrate 380 to the electrostatic chuck. Tight adherence of the substrate 380
to the
electrostatic chuck increases the reliability of powder deposition at the
collection zones.
FIG. 12b depicts a second illustrative embodiment where through holes EC$ are
formed at electrical contact pad 308B and powder-attracting electrodes 307B.
FIG. 1.2c
depicts a third illustrative embodiment wherein an additional layer 314 of
dielectric material
separates powder-attracting electrode 307C from base substrate 3$0. Electrical
contact-pad
308C overlays second surface 306 of layer 303.
The electrostatic chuclk provided by the configuration depicted in FIG. 12c
can be
termed a "Pad Indent Chuck" which is useful, for example for powder
depositions of less
than about 2 mg, preferably less than about 100 pg, per collection zone CZ
(assuming, for
example, a collection zone having a diameter within the range of 3-6 mm
diameter). 'The
electrostatic chuck provided b;y the configuration depicted in FIG. 12a can be
termed a "Pad
Forward Chuck" which is useful, for example, for powder depositions of more
than about 20
p,g per collection zane CZ (ag;ain assuming a collection zone of about 3-6 mm
diameter). The
Pad Forward Chuck is more useful than the Pad Indent Chuck for higher dose
depositions.
It should be clear from earlier description that a voltage source must be
electrically
connected to the powder-attracting electrodes (hereinafter generically
identified by the call-
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
16
out "307"). An illustrative arrangement for providing such connection is
depicted in FIG. 13,
which depicts receiver 172 engaged to electrostatic chuck 202 as in FIG. 9,
but viewed from
the perspective indicated by the arrows identified as "13" in FIG. 9.
Electrical connection to powder-attracting electrodes 307 is effected via
coupled pins
1623. Each coupled pin 1623 comprises a pin 1627 and a lower pin assembly
1624. Pin
1627 is advantageously a standard circuit board pin. As depicted via side view
in FI(i. 14,
lower pin assembly 1624 has a slot 1625 for receiving pin 1627 (not shown).
Pins 1627
couple with slots (not shown) on pin connector board 1611. As described in
further detail
later in this specification, pin connector board 1611 is electrically
connected to a controlled
voltage source. The coupled pins 1623 pass through holes (not shown) in
electronics housing
1610, holes (not shown) in vacuum manifold housing 1620 and holes 1632 (see
FIG. 15) in
gasket 1630 to contact the electrical contact pads (not shown in FIG. 13) of
electrostatic
chuck 202. Such electrical contact pads are depicted, for example, in FIG. 11,
as pads 208
located on second surface 206 of electrostatic chuck 202 (see also, pads 308A-
3080 of FIGS.
12a-12c).
A conductive adhesive, such as conductive epoxy, is applied to a lower region
of
lower pin assemblies 1624 suclh that the adhesive adheres the lower pin
assemblies to the
electrical contact pads. Notch 1626 in lower pin assembly 1624, as shown in a
top view of
lower pin assembly 1624 depicted in FIG. 16, allows excess conductive adhesive
to be
displaced from the region at wlhich the lower pin assembly contacts the
electrical contact pad.
The above-described arrangement for providing electrical connection to powder-
attracting electrodes 307 advantageously avoids deforming electrostatic chuck
202, which in
most embodiments is relatively susceptible to deformation. It is advantageous
to avoid such
deformation because, if the electrostatic chuck deforms, then the substrate
adhered thereto
will likewise deform. Deformation of the substrate is undesirable because it
is preferable to
deposit powder on a "flat" substrate. Thus, while other arrangements for
providing electrical
connection to the powder-attracting electrodes, as may occur to those skilled
in the art in
view of the present teachings, may suitably be used, such arrangements will
advantageously
avoid deforming the electrostatic chuck.
Gasket 1630, depicted in FIG. 15, includes slots 1631 that allow reduced
pressure to
be transmitted to eleclxostatic chuck 202. Gasket 1630 further includes holes
1632 that allow
coupled pins 1623 to be inserted through the gasket 1630, as previously
described. Gasket
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
17
1630 preferably insulates at le;ast about 2,000 - 2,500 volts. In one
embodiment, gasket 1630
is coated on both sides with adhesive. A material suitable for use as gasket
1630 is a
graphics art paper having a thickness of 0.004 inches (0.1 mm) that is coated
on both sides
with an aggressive rubber-based adhesive. Such paper is commercially available
from Cello-
S Tak of Island Park, New York.
FIGS. 17 - 22 depict additional detail of an illustrative embodiment of
receiver 172,
and an arrangement for connecting the receiver to first robotic transport
element 170.
FIG. 17 depicts underside 1730 of receiver platform 1720 of illustrative
receiver 172
with electrostatic chuck 202 adhered thereto. Electrostatic chuck 202 has
alignment features
240, such as pins or holes, by which it is aligned to complementary holes or
pins 1629 in
receiver platform 1720 (see F'.IG. 18). Also depicted are alignment pins 1650
that are
received by complementary holes in support bench 110 for aligning receiver 172
to various
processing stations (e.g., deposition station 150). Height-adjustable vacuum
cups 1670 are
advantageously used to attach the substrate frame (not shown) to the receiver.
FIG. 18 depicts underside 1730 of receiver platform 1720 without electrostatic
chuck
202. FIG. 18 shows passageways 1622 for conveying reduced pressure to through
holes
ECH in electrostatic chuck 2CI2 (through holes ECH not shown in FIGS. 17 and
18; see
FIGS. 10 and 11 ) and to passageway outlet 1628. Pin conduits 1623A allow
passage of
coupled pins 1623 to electrical contact pads on electrostatic chuck 202.
Further shown are
alignment features 1629, which can be, for example, alignment pins or
alignment pin
receptacles for mating with alignment features 240 of electrostatic chuck 202.
FIG. 19 shows upper side 1710 of receiver platform 1720. Receiver platform
1720
includes passageway outlet 16.28, pin conduits 1623A and moldings that form
reinforcing
braces 1780. As illustrated in FIG. 20, braces 1780 on upper side 1710 support
processor
board 1614, addressing board 1615 and high-voltage board 1612 (i.e., bias-
generation board).
Electrical communication to <;lectronics located off of receiver 172 can be
accomplished via
port 1616. Tubing connectar :L627B connects receiver 172 to an external vacuum
source for
developing reduced pressure tlhrough vacuum manifold housing 1620, etc., for
adhering
substrate assembly 82 to electrostatic chuck 202.
FIG. 20 also depicts a substrate frame, such as substrate frame 81, engaged to
underside 1730 of receiver platform 1720 (electrostatic chuck not shown).
Substrate frame
81 includes alignment feature<.~ 52 that suitably engage complementary
alignment features at
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
18
alignment station 130.
FIGS. 21 and 22 depict an arrangement by which receiver 172 is engaged to
robotic
transport element 170 (depicted in FIG. 8), as well as showing additional
features associated
with receiver 172. FIG. 21 provides a "cutaway," along the indicated
perspective, of the
view indicated in FIG. 22.
In the illustrative embodiment depicted in FIGS. 21 and 22, receiver 172 is
mounted
to first robotic transport element 170 (not shown) via bearing housing 1120.
Bearing housing
1120 contains spline shaft 11:!1 and spline shaft bearings 1122. Bearing
housing 1120
allows receiver I72 to be moved along the z-axis. Bearing housing 1120 couples
to floating
bolt assembly 1640 via spring; loaded coupling 1130. Floating bolt assembly
1640 (see FIG.
22) mounts to receiver cover :1660 via bushings 1641, which may be visco-
elastic isolation
bushings 1641. Such visco-elastic isolation bushings can be made, for example,
from
Sorbothane~ brand isolation damping material commercially available from
Sorbothane, Inc.
of Kent, OH. The visco-elastiic isolation bushings 1641 advantageously allow
receiver 172 to
move slightly, as required, when receiver locating pins 1650 {see also FIG.
17) are inserted
into alignment holes located on support bench 110. In this manner, the
locating accuracy of
robotic head 170 (f2 mil) can be increased (to about X0.5 mil) when base
substrate 80 is
presented for dry deposition at deposition station 150. Floating bolt assembly
1640 allows
receiver 172 to comply with alignment actions acting in a direction along the
x, y or z axes.
In the embodiment depicted in FIG. 21, receiver I72 includes pin connector
board
1611, high-voltage board 161:E, high-voltage chip areas 1613 and processor
board 1614. In
other embodiments, processing is orchestrated via a processor located
elsewhere on robotic
platform 101. High-voltage barrier wall 1661 isolates the high voltage areas
of receiver 172.
Illustrative receiver 172 further includes vacuum tubing 1627, first tubing
connector 1627A
for connecting vacuum tubing;1627 to vacuum manifold housing inlet fitting
1621 (see FIG.
9), and second tubing connector 16278 previously described.
Substrate frame 81, on which substrate 80 is mounted, is depicted as adhered
to the
underside of the receiver 172 (electrostatic chuck 202 not shown). As
discussed further
below, the frame advantageously assures that the substrate is aligned with a
post-deposition
measurement device. Vacuum cup receiving fixtures 51, which are disposed on
substrate
frame 81, receive height adjustable vacuum cups 1670 in vacuum-facilitated
engagement.
Vacuum hose fittings 1671, which are connected to a vacuum system, are in
fluid
CA 02333107 2000-11-23
WO 99/63972 PCT/I1S99/12772
19
communication with vacuum .cups 1670.
Portions of receiver 1'72 (e.g., receiver cover 1660 in FIG. 22) are
advantageously
manufactured from a durable non-conductive material such as, for example,
plastic.
Examples of suitable plastics include Noryl~ brand polymers commercially
available from
GE Plastics of Pittsfield, MA. Noryl~ engineered plastics are modified
polyphenylene
oxide, or polyphenylene oxide; and polyphenylene ether, resins. Modification
of these resins
involves blending with a second polymer such as polystyrene or a mixture of
polystyrene and
butadiene. By varying the blend ratio and other additives, a variety of
polymer grades are
produced. Unmodified, these polymers are characterized by regular closely-
spaced ring
structures (i.e., phenyl groups) in the main molecular chain. This feature
along with strong
intermolecular attraction causes extreme stiffness and lack of mobility.
Use of Noryl~ brand plastics or equivalent imparts a strength to receiver 172
that
aids in providing a firm, flat support for electrostatic chuck 202. The
surface of receiver 172
on which electrostatic chuck 202 is mounted is advantageously machined flat,
for example to
~ 0.001 inches (0.025 mm). ll~Ioreover, the characteristic low weight of the
plastic assists in
keeping the weight burden low on first robotic transport element 170.
Electronic Control o1"the Electrostatic Chuck
As previously described, apparatus 100 advantageously includes central
processor
401 and controller 403 for performing calculations, control functions, etc.
(see, e.g., FIG. 6).
Processor 401 receives performance input from multiple sources, including, for
example, on-
board sensors and historical data from dose measurement station 140, and uses
such
information to determine if operating parameters should be adjusted to keep
powder
deposition within specification. Such input includes, for example, data
pertaining to the rate
of powder flux into and through the deposition engine (made up of powder feed
apparatus
801 and deposition station l5tl) and the degree to which powder is being
evenly deposited at
electrostatic chuck 202. The "on-receiver" electronics described below, either
alone or in
conjunction with processor 401 and controller 403, provide a means for
adjusting apparatus
100 during operation.
When processor 401 has primary responsibility for processing functions,
processor
board 1614 located in receiver 172 can function as a communications board that
receives
commands from processor 40:L and relays such commands to addressing board
1615. In
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
some embodiments, processor board 1614 receives data from sensors, such as
charge sensor
1690, that are positioned on or adjacent to electrostatic chuck 202 (see FIG.
18, wherein
charge sensor 1690 is represented figuratively by dashed lines). Charge sensor
1690 is an on-
the-receiver device for monitoring the amount of powder being deposited.
Processor board
1614 locally interprets and responds to data from charge sensor 1690 by
suitably adjusting
the voltage applied to the powder-attracting electrodes 307 (e.g., electrodes
307A - 307C in
FIGS. 12a - 12c, respectively) as appropriate. Charge sensors are described
further below
and in U.S. Pat. App. 09/095,425.
After receiving signals from processor board 1614, addressing board 1615 sends
bias
10 control signals, which can be, for example, DC or AC signals, for
controlling the voltage at
powder-attracting electrodes 307. Depending upon the addressing scheme (e.g.,
the
arrangement, if any, by which individual electrical-contact pads 208 are
electrically
interconnected via address electrodes 210), voltage is either regionally
(e.g., by columns,
rows, etc.) or individually applied to powder-attracting electrodes 307.
15 Addressing board 1615 preferably has multiple channels of synchronized
output
(e.g., square wave or DC). The signals sent to the addressing board can be
encoded, for
example, with a pattern of square wave voltage pulses of varying magnitudes to
identify a
powder-attracting electrode 307, or a group of such electrodes, together with
the appropriate
voltage to be applied thereto.
20 The bias control signals are sent via high voltage board 1612, which
advantageously
has multiple channels of high-voltage converters (transformers or HV DC-to-DC
converters)
for generating the voltages, such as 200 V or 2,500 V or 3,000 V (of either
polarity), that
energizes powder-attracting electrodes 307. Such high voltages are
advantageously formed
within receiver 172 so that otI»er systems are isolated therefrom.
The Charge Sensor
The charge sensor 1690, mentioned above, advantageously uses pulsed (AC)
electrical potential waveforms for biasing the electrostatic chuck to collect
powder on
substrate 80, as is described in U.S. Pat. App. No. 09/095,425. This form of
biasing
overcomes the problem of collecting powder on a conductive substrate, where
the powder-
attracting field can decay rapidly after any given application of a bias
potential to the
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
21
electrostatic chuck.
Using AC bias waveforms for the powder-attracting electrode also solves
anather
long-standing problem during deposition sensing. In particular, during
deposition sensing,
one or more collection zones C'Z are closely monitored for powder
accumulation, so as to
allow regulation of the powder deposition process (e.g., to produce precise
dosages). Such
monitoring can be performed optically or by measuring accumulated charge using
an "on-
board" charge sensor at a sensor-associated collection zone. Accumulated
charge can be
correlated to actual charged powder deposition by empirical data collection.
In dry powder
deposition, such dose monitoring is often a very difficult task, particularly
for dosages below
one milligram.
The difficulty lies not with the precision of the measuring devices, but
rather with
various practical and environmental factors that can deteriorate measurement
sensitivity by
two or three orders of magnitude. For quasi-static DC-biased transporter
chucks, on-board
charge sensing is particularly difficult. Data obtained by depositing on a
polypropylene film
substrate with different potentials indicates that the deposited dose is
linearly related to the
bias potential if that potential is above a certain threshold potential. Data
indicates that
threshold potential is about 100-200 volts DC, at least for certain
transporter chucks.
FIG. 40 shows one possible equivalent circuit diagram that provides AC-biased
charge and deposition sensing for at least one collection zone CZ, which zone
has a floating
pad electrode. The floating pad electrode is an isolated conductor which is
designed to be
capacitively coupled to a powder-attracting electrode (e.g., powder-attracting
electrodes
307A- 307C of FIGS. 12a-12c, respectively) such that the bias to the powder-
attracting
electrode indirectly creates a powder-attracting field emanating from the
floating pad
electrode.
An illustrative electrostatic chuck/substrate arrangement corresponding to the
equivalent circuit of FIG. 40 includes a planar electrode that is used to
provide a powder-
attracting field. A bottom face of the planar electrode is affixed to an upper
face of a planar
first dielectric layer such that such faces are parallel to one another.
Suitable dielectric
material includes Pyrex 7740 glass available from Corning, Inc., or polyimide
resin having a
thickness of about 10 to 20 mils. The planar electrode and planar first
dielectric layer can be
affixed to one another using a variety of suitable methods such as, for
example, lamination,
powder deposition or thin film deposition. A planar shield electrode is
affixed to a bottom
CA 02333107 2000-11-23
WO 99/63972 PCTNS99/12772
22
face of the first dielectric lays;r. The shield electrode comprises an
aperture to accommodate
a floating pad electrode, coplanar with and surrounded by the shield
electrode.
One or more collection zones CZ are typically dedicated solely for sensing or,
alternatively, are in general use, but closely monitored. By measuring the
lowering of the
attraction potential VBCZ than occurs as charged powder deposits on the
collection zone CZ,
a measure of the deposited charge can be obtained. Knowing the average
charge/mass ratio
q/m of the deposited powder, the accumulated powder deposition mass can be
determined.
VgCZ can be measured directly across a charge-collector electrode, but it is
usually
preferable to measure the potE,ntial across a coupling capacitor, such as the
floating pad
electrode described above.
The coupling capacitor, as embodied by the aforedescribed floating pad
electrode,
provides reasonably accurate :reproduction of the potential at the collection
zone CZ on the
substrate surface. Such accurate reproduction is shown by examining waveforms
3602 for
VBCZ and waveform 3604 far Vpad F depicted in FIG. 41. RC decay is evident in
waveforms 3602 and 3604. VfJaveform 3606 represents the pulsed bias voltage
Vg. Whether
a charge collector or charge coupling capacitor is used, they may both be
considered charge
sensing electrodes.
In the equivalent circuit of FIG. 40, charge collector/coupling capacitor CC
is
electrically connected to a separate sensing capacitor SC. The voltage
generated across
sensing capacitor SC can be a reliable indicator of the potential VgCZ. Such
voltage can be
measured, for example, with an electrometer M, such as a Keithley model no.
614, 6512,
617, 642, 6512, or 6517A electrometer, as shown schematically in the figure.
Generally the
coupling capacitor CC is any electrode that is capacitively coupled to a
powder collection
zone on the contact surface.
DC biasing can cause a steady drift in the reading of the potential across the
sensing
capacitor. Such drift is due predominantly to natural leakage across the
dielectric material in
the sensing capacitor, and to charge leakage in the substrate or powder that
has accumulated
on the chuck. Drift can also b~e induced by noise factors such as shot noise,
Johnson (1/f)
white noise, thermal noise, Galvanic noise, triboelectric noise, piezoelectric
noise, amplifier
noise, and electromagnetically-induced noise. See, The Art of Electronics, by
Paul Horowitz,
Winfield Hill, 2nd Edition, Cambridge University Press, D 1989.
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
23
If the drift is large compared to the actual charge collected at a collection
zone CZ,
the accuracy of the charge sensor as a measurement tool can be unacceptably
low. L7sing AC
biased waveforms as disclosed herein advantageously reduces the incidence of
drift. Such a
reduction is accomplished in a. manner similar to that described above for
avoiding the "drift"
of charge dissipation on the powder collection zone, facilitating precise
measurement of
charge collected.
In FIG. 40, an AC bias source B may be the same source as described above,
with the
AC bias potential applied or administered via the powder-attracting electrode.
This
electrically couples to the floating pad electrode or to the collection zone
itself, if it is
directly connected to the sensing capacitor as shown.
By way of example, if'sensing capacitor SC is chosen to be 0.1 pF, and the q/m
of
the powder is IOpC/g, then a 100 mV signal change on the charge
collector/coupling
capacitor CC corresponds to 1 mg of powder deposited on the collection zone.
If, fo:r
example, the linear correlation factor is 3, then 1 mg of powder on the sensor
corresponds to
I 5 3 mg of powder in the actual deposition dose. A 99 pg actual dose will
thus have a
detectable potential change of 3.3 mV. With a 5% error tolerance, the
corresponding
background unpredictable noise contribution cannot exceed 160 p.V. This is
achievable with
careful shielding and grounding design. Preferably the charge collector is
integrated with the
chuck design to assure a consistent correlation.
In effect, the same benefits obtained using the AC bias waveform for Vg to
avoid
charge dissipation in the substrate can be used to reduce drift in the charge
sensing circuit.
FIG. 42 depicts another possible equivalent circuit for providing AC-biased
charge
and deposition sensing. The illustrative circuit of FIG. 42 reduces noise by
separating the
AC bias source B from electrometer M, sensing capacitor SC or charge
collector/coupling
capacitor CC. All of those components have a sensitivity to noise that is
critical.
As depicted in FIG. 42, AC bias source B is connected to the primary of a
transformer T. In this manner, only the periodic magnetic field generated by
Vg, (not Vg
itself) is introduced into the "sc,nsitive" components on the right side of
the figure. The
secondary winding of transfornner T is connected across a stabilizing bleed
resistor R, with
one pole (i.e., biasing pole BP) connected to charge collector/coupling
capacitor CC, and the
other pole (i.e., the sensing capacitor pole CP) connected to sensing
capacitor SC. To further
reduce noise, sensing capacitor SC is connected to ground. Electrometer M can
then
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
24
measure the voltage change on sensing capacitor SC with respect to ground, as
shown.1'he
two grounding points can be combined to further reduce electromagnetic noise.
Transformer
T can be a step-up transformer so that complex AC bias waveforms supplied here
and to the
powder-attracting electrode ca.n be generated inexpensively. A step-up ratio
of 50, for
example, may suitably be used. Such an arrangement substantially reduces drift
and makes
accumulated charge sensing more accurate, where previously a coupling current
of 100 pico-
Amperes or less made drift and noise a problem.
In some embodiments., transformer T is an isolation transformer, where the
primary
and secondary windings are separated by a Faraday cage. This can prevent
coupling between
the primary and secondary windings, where the primary winding acts as one
capacitor plate,
and the secondary as the other capacitor plate.
As a result of the improved signal to drift ratio obtained in accordance with
the
present teachings, the amount ~of charge sensed can decrease substantially.
Measurements
can be made using a 1000 pico~F capacitor as the sensing capacitor instead of
the 0.1 ~F value
used previously. Also, AC bias source B used in the circuits depicted in FIGS.
40 and 42 can
be separate from the AC waveform bias Vg on the chuck, by delivering a
separate A(: bias
directly to charge collector/coupling capacitor CC via a dedicated wire,
electrode, bus, etc.
Such a separate AC bias can be; frequency matched or detuned with respect to
Vg to insure
consistent correlation of the behavior of the charge collector/coupling
capacitor CC to actual
depositions.
The aforedescribed arrangements advantageously allow Vg biasing with voltage
peaks much higher than previously possible. Using 8000 molecular weight
polyethylene
glycol as a substrate, bias peaks of 2 kV have been used. It should be
understood a wide
variety of transporter chucks can suitably be used, including those that
operate with bias
electrodes directly exposed to l:he powder contact surface (i.e., the
substrate), such as is
illustrated in FIGS. 12a and 12b.
The Alignment Station
As previously described, electrostatic chuck 202 (engaged to receiver 172 and
first
robotic transport element 170), engages frame 81 containing substrate 80 at
input/output
station 120A, and then delivers it to alignment station 130 (see, e.g., FIGS.
7, 8, 9 and 21 ).
CA 02333107 2000-11-23
WO 99/63972 PCTlUS99/12772
At alignment station 130, frame 81 is released from electrostatic chuck
202/receiver 172 so
that alignment features 52 of flame 81 (see FIG. 20) matingly engage
complementary
alignment mechanisms (not shown) at the alignment station. Such alignment
features may
be, for example, pins on frame; 81 that are received by holes at alignment
station 130. Frame
5 81 is then re-engaged by the electrostatic chuck and receiver, and, as a
result, substrate
assembly 82 is now aligned to within the accuracy of robotic transport element
170 (e.g., t
0.002 inches (0.05 mm)).
In some embodiments, a visco-elastic pad (not shown), such as a foam rubber
pad, is
included at alignment station 1t30. When substrate assembly 82 is re-engaged,
substrate 80 is
10 pressed against the pad to remove any air pockets that are formed between
substrate 80 and
electrostatic chuck 202. With substrate 80 pressed against the pad, the
substrate-adhering
vacuum of the receiver 172 is activated, and powder-attracting electrodes 307
can also be
activated to aid in adhering they substrate to electrostatic chuck 202.
Alignment station 130 may improve substrate alignment to the electrostatic
chuck,
15 especially when misalignment-causing circumstances are present. One such
circumstance
arises when a substrate frame I;e.g., substrate frame 81 or 91) is stacked on
other frames at an
input/output substation. It will be appreciated that as frames are
successively stacked, the
frames may deviate from a properly aligned position. When a robotic transport
element (e.g.,
elements 170 or 180) engages the frame with a clamping feature, such as vacuum
cups 1670
20 (see, FIG. 22), misalignment may occur. Using alignment station 130,
alignment accuracy is
improved to within the placement accuracy of the robotic transport element (at
alignment
station 130) so that substrate 80, for example, can be positioned with the
requisite accuracy
during the deposition operation. Alignment station 130 advantageously provides
a secondary
benefit whereby the visco-elastic pad facilitates intimate contact between
electrostatic chuck
25 202 and substrate 80.
Second robotic transport element 180 engages frame 91 containing a cover layer
90
and uses alignment station 130, in the manner described above, to confirm
localization of
frame 91. The second robotic 'transport element 180 moves cover assembly 92 to
lamination
support block 1901 (see FIG. 23, frame 91 not shown) and deposits it thereon.
The alignment features described above are suitable for processing substrates
in
batch or piece-wise fashion, as in the illustrated embodiments. Alignment
issues are
advantageously addressed in a different manner in the context of continuous
processing
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
26
operations. For example, if, in a continuous process, the substrate is
deployed on a tape, then
frames can be periodically locked to the tape as it is processed through
portions of the
present apparatus where alignment issues are particularly important. To
provide adjustment
capability for such a process, a small amount of loosely fitting tape can be
employed between
the locked frames, thereby allowing the spacing between the frames to be
adjusted based on
alignment considerations.
Framing and alignmer,~t considerations are described further later in this
specification
with reference to deposition station 150 and dose measurement station 140,
where alignment
is particularly important.
Deposition Engine
In one embodiment, after substrate assembly 82 is aligned at alignment station
130,
first robotic transport element 170 moves the substrate assembly to deposition
station 150. In
another embodiment, substrate assembly 82 is first moved to dose measurement
station 140
so that baseline optical data can be recorded before the powder-deposition
operation, and
then robotic transport element 170 moves substrate assembly 82 to deposition
station 150.
Robotic transport element 170 is rotated 90° to align frame 81 of
substrate assembly
82 with deposition opening 158 (see FIG. 7) at deposition station 150.
Locating pins 1650
(FIGS. 17 & 22) are used to establish the alignment of receiver 172 /
electrostatic chuck 202
/ substrate assembly 82 with deposition opening 158.
An illustrative deposition engine 800 is illustrated in FIG. 24. Deposition
engine 800
includes deposition station 150 and illustrative powder feed apparatus 801. A
deposition
engine presents the possibility for a variety of processing problems. Such
problems include,
for example, powder compaction, non-uniform powder flux, powder loading,
operating
stability and powder size limitations, among others. In some applications,
such problems can
be addressed by modifying the powder. The present invention, however, is
intended to be
useful for applications, such as pharmaceuticals, in which there is often
little or no ability to
modify powder without raising regulatory issues. As such, the deposition
engine itself
should be designed to avoid such difficulties. Various components of
illustrative deposition
engine 800 can improve the deposition operation, resulting in: decreased
powder
compaction, more uniform powder flux, ease of powder loading, improved
operating
stability, the ability to use a wide variety of powder particle sizes, and
improved powder flow
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
27
without the powder surface modifications that are often performed in other
applications.
Illustrative powder feed apparatus 801 includes auger rotation motor 804,
happer
806, vibrator 808, auger 810, ;,lean gas source 814 feeding modified venturi
feeder valve
8I2, powder charging feed tube 816, powder evacuation tubes 818, powder trap
820, and
High Efficiency Particulate Air (HEPA) filter 822, interrelated as shown.
Illustrative powder
feed apparatus 801 is disposed substantially within enclosure 802, which is
depicted in
phantom for clarity of illustration.
In operation, auger 810 is rotated, via auger rotation motor 804, to feed
powder into
venturi feeder valve 812. A rotational rate within the range of about 10 to
about 80 rotations
per minute is satisfactory for such purpose. Modified venturi feeder valve 812
having a
venturi well that delivers powder in a substantially straight path from the
auger feed (i.e.,
hopper 806) to powder charging feed tube 816 was used. Such a modified device
avoids
powder compaction that may be experienced when powder fall to the bottom of
the venturi
well in standard arrangements. The venturi well should be accessible, for
example, by an
1 S unscrewing action, so that it can be periodically vacuumed.
Vibrator 808 is advanl:ageously used to keep the powder free-flowing, with
vibration
intensity set at a level that does not cause substantial aggregation of the
powder. The vibrator
is illustrated as acting on the hopper 806, but can likewise be applied to a
shaft driving a
mechanical powder-moving appliance such as auger 810.
When a flow of gas, such as, for example, nitrogen, from clean gas source 814
is
admitted to modified venturi feeder valve 812, powder is pulled from auger
810. Moreover,
such gas acts to push the powdler through powder charging feed tube 81b. A
modified
venturi suitable for use in the powder feed apparatus 801 is commercially
available from
Vaccon Company, Inc. through Air Oil Systems, Mainland, PA, or Berendsen Fluid
Power,
Rahway, NJ.
In place of a venturi, a gas source can be provided to propel powder through
powder
charging feed tube $16. In one; embodiment, gas source 814 directs gas
pressure towards the
outlet of a mechanical device that feeds powder. The gas jet can be directed
and adjusted to
act to deagglomerate powder at that outlet.
For electrostatic deposition, the powder must be charged. In one embodiment,
powder charging feed tube 8lbi is made of a material that imparts, by
triboelectric charging,
the appropriate charge to the powder as it transits the tube making periodic
collisions with
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
28
the sides thereof. As is known in the art, TEFLON~, a perfluorinated polymer,
can be used
to impart a positive charge to the powder (where appropriate for the powder
material) and
Nylon (amide-based polymer) can be used to impart a negative charge. In so
charging the
powder, the tube builds up ch:~rge which can, if not accommodated, discharge
by arcing.
S Accordingly, a conductive wrap or coating is applied to the exterior of
powder charging feed
tube 816 and grounded. Tube 816 can be wrapped, for example, with aluminum or
copper
foil, or coated with a colloidal graphite product such as Aquadag~, available
from Acheson
Colloids Co. of Port Huron, NfI. Alternatively, powder charging feed tube 816
can be coated
with a composition comprising graphite or another conductive particle such as
copper or
I O aluminum, an adhesive polymer, and a carrier solvent, mixed in amounts
that suitably
preserves the "tackiness" of the adhesive polymer. An example of such a
composition is 246
g trichloroethylene, 30 g polyisobutylene and 22.5 g of graphite powder.
The charge relieved b;y the grounding procedures outlined above can be
monitored to
provide a measure of powder iFlux through powder charging feed tube 816. This
data is
15 advantageously sent to process>or 401 for analysis. As a result of such
analysis, deposition
operating parameters can be modified, as appropriate, to maintain an on-
specification
operation. An illustrative arrangement suitable for providing such monitoring
is described
below.
In one embodiment, a capacitor is placed in series with powder charging feed
tube
20 816. The capacitor lowers the potential generated by the charges collected
in the tube 816.
A I p,F capacitor will build up 1 V for a I wC charge. The other pole of the
capacitor is
connected to ground. The capacitor acts to bring the potential of the powder
charging feed
tube 816 closer to ground. An electrometer connected to the capacitor provides
an accurate
measure of collected charge. With powder charged to 50 p,C/g, 1 pC corresponds
to 20 mg
25 of powder. Powder charging feed tube 816 can be biased. With an applied
bias of SOOV,
noise of 10 pA can be anticipated, creating an uncertainty of 3 nC over 3
minute intervals.
Even with such biasing, such a. system provides errors as low as 0.3% on
measurement of 20
mg of powder. By controlling the conductivity of the grounding wrap or
coating, a potential
drop along powder charging feed tube 816 can be established, creating an
electric field that
30 favors drawing charged powder through the tube while giving uncharged
powder greater
opportunity to pick up charge.
Another way to impart charge to the powder is by "induction" charging. One way
to
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
29
implement induction charging is to incorporate an induction-charging region in
powder
charging feed tube 816. More particularly, at least a portion of powder
charging feed tube
816 comprises a material such as a stainless steel, which is biased by one
pole from a power
supply, with the opposite pole grounded. With an appropriate bias, an electric
field is created
in the induction-charging region such that powder passing through it picks up
a charge. The
length of the induction-charging region can be adjusted as required to impart
the desired
amount of charge to the powder. In one embodiment, induction charging is used
in
conjunction with the tribochar~ging features described above.
Powder charging feed tube 816 feeds charged powder into deposition station 150
via
nozzle 152. Deposition station 150 is enclosed by enclosure 154, comprising,
for example,
acrylic panels. Nozzle 152 advantageously includes rotating baffle 153 that
increases the
uniformity of the powder cloud developed in deposition station 150. Nozzle
motor 151
drives rotating baffle 153.
An illustrative nozzle :152 with rotating baffle 153 is shown in more detail
in FIGS.
1 S 25 (plan view) and 26 (side vie;w). Rotating baffle 153 comprises baffle
disk 1552 that is
supported by three spaced, radiially-extending baffle supports 1551. Baffle
disk 1552
includes baffle outlets 1553 through which the powder passes. In the
embodiment depicted
in FIG. 26, which is drawn approximately to scale, the height BH of rotating
baffle 153 is
about 0.72 inches (18 mm).
Powder is fed through the nozzle 152 with, for example, a gas that is at a
pressure of
about 20 psi and fed at a rate o:f about 2.5 liters per minute. The gas is
preferably
substantially free of water, oil and other impurities, and is preferably a
chemically inert gas
such as nitrogen or helium. Baffle 153 is advantageously disposed above the
outlet of
powder charging feed tube 816 by an amount in the range of about one-quarter
to one-half
inch. Moreover, baffle 153 advantageously has a larger diameter or cross-
section than the
outlet of powder charging feed tube 816. For example, baffle 153 may have a
one-half inch
diameter cross section when a one-quarter inch diameter powder charging feed
tube 816 is
used. Baffle I53 should be rotated at a rate within the range of about 5 to
about 25 rotations
per minute to obtain the desired increase in uniformity of the powder cloud.
Referring again to FIG. 24, substrate assembly 82 and electrostatic chuck 202
(both
not shown) abut gasket 159 that frames deposition opening 158. Powder moving
towards
collection zones CZ of electrostatic chuck 202 pass through control grid 157.
Control grid
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
157 is advantageously disposed a distance dgt.id, for example about one-half
to about 1.0
inch, below the collection zones, and is biased at about SOOV per one-half
inch of distance
dgrid at the polarity intended ifor the powder. Control grid 157 thus
"collimates" the powder
cloud attracting powder having an opposite charge (to the charge on the
control grid).
Control grid 157 can be, for example, a series of parallel electrical wires,
such as can
be formed from "switchbacks" of one wire, or, alternatively, a grid of wires.
Spacing
between parallel sections of wire is advantageously within the range of about
5 to about I 5
mm.
The rate of powder cloud flux can be monitored by measuring light attenuation
10 between light emitter 155 (e.g., a laser emitter) and light detector 156.
This value can be
transmitted to processor 401.
Powder that is not utilized at deposition station 150 are drawn back by a
pressure
differential through powder evacuation tubes 818 to powder trap 820. FIG. 27
depicts
internal detail of an illustrative embodiment of powder trap 820. Powder
enters powder trap
15 820 via trap inlet 2104. Powder trap 820 includes a series of conductive
first baffles 2101
interleaved with conductive second baffles 2102. To provide the requisite
conductivity, the
first and second baffles can be formed of materials such as copper, stainless
steel or
aluminum baffles, for example;. The first and second baffles 2101 and 2102 are
affixed to
respective first trap electrical conduit 2107 and second trap electrical
conduit 2109. First and
20 second trap electrical conduits 2107 and 2109 are affixed to trap body
2103. Trap body 2103
is formed, for example, of acr!~lic polymer (e.g., plexiglass).
First baffles are biased at, for example, +2000V, via first trap electrical
conduit 2107,
which is in electrical communication with first electrical inlet 2106. The
second baffles are
biased, for example, at -2,000V, via second trap electrical conduit 2109,
which is in electrical
25 communication with second electrical inlet 2108. Powder returning from
deposition station
150 are collected on oppositely charge baffles. When powder is uncharged, a
first collision
with one baffle can impart a charge, allowing the powder to be attracted to an
oppositely-
charged baffle that it encounters downstream. Gas exiting powder trap 820
through powder
trap outlet 2105 is delivered to HEPA filter 822 (not shown in FIG. 27, see
FIG. 24). I-iEPA
30 filter 822 is typically 99.97 percent efficient in capturing 0.3 micron
powder particles,
thereby assuring that no morethan a relatively insignificant amount of powder,
which
powder can be detrimental as bioactive agents (without dosing control), is
released into the
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
31
environment.
At some point, the deposition process must be shutdown. Such shutdown may be
dictated, for example, by schedule (e.g., where the amount of powder that is
deposited is
controlled by the period of operation) or in response to the analysis of
feedback data from a
charge sensor. Shutdown involves reducing the voltage (or the amplitude in the
case of a
pulsed voltage profile) directed to powder-attracting electrodes 370, and
shutting down
powder feed apparatus 801. The amount of voltage reduction required for
shutdown will
vary as a function of the substrate and powder specifics, as well as the
amount of powder
applied to the substrate. Generally, such voltage reduction is selected to
maintain substrate
adherence to electrostatic chuck 202, and powder adherence to substrate 80
without causing
substantial further powder accumulation. By way of example, stepping down a
2000V
deposition voltage (or voltage amplitude where pulsed voltage is utilized) to
400V should be
sufficient to retain powder but not attract additional powder.
It should be appreciated that other arrangements or configurations for
deposition
1 S station 150, as well as for many of the other elements of powder
deposition apparatus 100
described herein, may suitably be used in conjunction with the present
invention. For
example, a first alternate embodiment of a receiver, an electrostatic chuck,
and a nozzle (as
included at deposition station :150) is depicted via side view in FIG. 28 and
via top view in
FIG. 29. In the depicted first .alternate embodiment, receiver 572 is
configured as a rotatable
drum. Similarly configured electrostatic chuck 502 is engaged to receiver 572.
As in
previous embodiments, substrate 580 abuts electrostatic chuck 502. Axle 501
imparts
rotation to receiver 572 and advantageously conveys (e.g., through internal
conduits, etc.)
vacuum and electrical potential to collection zones (not shown) on
electrostatic chuck 502.
In some embodiments, axle 5(Il is also operable to move receiver 572 "up and
down"
relative to four radially-arranged nozzles 552 (only two of which are depicted
in FIG.. 28).
Grids 557 limit access by improperly charged powder to the collection zones.
Variations in
the deposition pattern can be rr~inimized by rotating receiver 572.
It should be understood that various elements of the powder feed apparatus
depicted in
FIG. 24 may be suitably interclhanged or replaced by elements performing
equivalent
functions. For example, the hopper and auger arrangement depicted in FIG. 24
can be
replaced with a rotating drum that temporary stores powder and delivers it to
a movable belt.
The movable belt then transports the powder to a means for removing the powder
from the
CA 02333107 2000-11-23
WO 99/63972 PCT/U899/12772
32
belt. An example of such a means is a thin, high velocity, jet of gas that
blows the powder
into powder charging feed tube 816 (FIG. 24) or a conduit in communication
therewith.
Alternatively, the powder feed apparatus may be configured in a substantially
different manner from the apparatus 801 depicted in FIG. 24. Two such
alternative
S configurations that are suitable for use in conjunction with the present
invention are depicted
in FIGS. 30 and 31.
FIG. 30 depicts powder feed apparatus 901, in which hopper 907 directs powder
to
gear wheel 905 that is driven by motor 903. Gas flow 909 directs powder to
deposition
station 150. Electrostatic chu<;k 202, electrically connected to high voltage
source HV, is
depicted in position at deposition station 150 receiving powder at its
collection zones.
FIG. 31 depicts powdc;r feed apparatus 1001 comprising fluidized bed 1003. Gas
flow 1009 directs powder to deposition station 150 through four powder
charging feed tubes
1016. While four such tubes acre depicted in FIG. 31, more tubes, or as few as
one tube may
suitably be used.
1 S In some embodiments, particularly wherein doses such as about 2 p.g to
about 100 pg
are applied to an area of 3 to 4 mm diameter, a jet mill can be favorably
employed to deliver
powder. Charge can be introduced to the powder by induction charging by
applying a
potential to the jet mill itself, such as applying a 1,800V potential to the
jet mill. A jet mill
suitable for such service is available from Plastomer Products Division of
Coltec Industrial
Products Inc. (Newton, PA) under the mark TROST~ Air Impact Pulverizer. That
jet mill
utilizes directly opposing streams of compressed gas, and is usefully operated
at a flow rate
of about 2.0 to 2.2 liters per minute.
Dose Measurement Station
2S After completing powder deposition, first robotic transport element 170
moves
substrate assembly 82 containing powder-bearing substrate 80 to dose
measurement station
140 (see, e.g., FIGS. 7 and 8). Robotic transport element 170 is rotated
90° to align frame 81
with measurement opening 141i (see FIG. 8). Receiver locating pins 1650 (see
FIG. 22) are
used to align receiver 172 with measurement opening 146 to an accuracy of
about X0.0005
inches (0.013 mm). Such alignment accuracy assures that the dose measurements
are taken
at the proper locations on substrate 80 (i.e., the locations at which the
powder is deposited).
In embodiments that do not use frames, such as frames 81 or 91, or another
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
33
mechanism for assuring consistency of alignment at the deposition station and
the dase-
measurement station, the dose-measurement system advantageously includes a
mechanism
for identifying the positions o;f the powder depositions. In one embodiment,
such a
mechanism includes a video camera that collects data and further includes
suitable
electronics for analyzing the video data to determine the boundaries of the
depositions. The
video camera can be, for exarr~ple, a CCD.
Dose measurement sW tion 140 includes an apparatus for measuring the thickness
(i.e., the amount) of powder deposited on substrate 80. Either of two (or
both) optical
measurement methods may be. used: diffuse reflection and optical profilometry.
Diffuse
reflection has been used for many years to characterize powder using light
sources that emit
in a range that is absorbed by the powder. In conjunction with that
technology, a theory was
developed for diffuse reflection using non-absorbing radiation. The theory
derives a term for
the thickness of a powder layer. In spite of such utility, to the applicants'
knowledge, no
products based thereon have been commercially developed. Applicants have
discovered that
measurements obtained based on diffuse reflection using non-absorbing
radiation provide a
strong correlation with the deposited amount of powder in a unit form, at
least up to a certain
amount. The limiting amount varies with the character of the powder and is
believed to
correspond to an amount of powder that prevents light penetration into lower
layers.
The diffuse reflection method is based on reflecting or scattering a probe
light beam,
such as a laser beam, off of thc; powder surface in directions that are not
parallel to the
specular reflection direction. :iuch scattered light is generally uniformly
distributed. Dose
depositions that exhibit this property or behavior are said to be "Lambert
Radiators." This
behavior ("Lambertian scattering") is an important property for dose weight
measurements.
The relation between Lambertiian scattering and the optical properties of
powder are defined
by a scattering model developed by Kubelka and Munk.
As described above, non-absorbing radiation is used to create diffuse
reflection.
Typical radiation is the visible red lines provided by common gas and diode
lasers such as
632.8, 635 and 670 nm. When non-absorbing radiation is used and when the dose
deposition
has a finite thickness, d, the Kubelka-Munk model gives the following
relation:
I ] Sd = R/( 1-R)
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
34
where: S is a scattering parameter defined by the properties of the particles
of the
dose aleposition;
d is the dose deposition thickness; and
R is the measured diffuse reflection for dose material on substrates with
mininnal specular diffuse reflectance wherein Rsubstrate = d is
assumed.
Expression [ 1 ] can be rewritten as:
(2J d = ( 1 /S) [Rl( 1-R)]
where: S is assumed to be a constant for a given particle size distribution.
Thus, the thickness of the dose deposition is directly related to the measured
diffuse
reflectance. If the dose deposition is a Lambertian radiator, as previously
defined, the
measurement of R is available..
FIG. 32 depicts, figur,~tively, the diffuse reflection method for
characterizing dry
powder. Light from light source 3102, which can be, for example, a low-energy
laser, is
preferably focused through beam splitter 3104. Light source 3102 can direct a
beam toward
substrate 80 that is wider than the individual "mounds" of deposited powder
since the rest of
substrate 80 will not have powder that gives rise to Lambertian scattering.
Reference beam
detector 3106 assists in detern~ining the quality and intensity of the focused
beam.
When light impinges on powder 3114 that is deposited on substrate 80, the
powder
scatter light SLHT in all directions. Scattered light SLIEIT is captured by
detector 3108.
Preferably, an array of two or more detectors 3108 are used. Amplifiers (not
shown) are
advantageously used in conjunction with the detectors. The output from the
detectors) 3108
is then connected to a commercial A/D converter {not shown). The resulting
digital signal is
scanned, such as by using a computer-controlled scanning mechanism 3110.
Scanning
mechanism 3110 communicates with processor 401 (not shown in FIG. 32).
Processor 401
generates a powder thickness profile and, thus, the dose weight measurements
of the
depositions.
In one embodiment, the powder can be deposited on a substrate that has a
specular
surface so that the contribution of the surface of substrate 80 to the diffuse
reflected
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
component is kept acceptably low. Moreover, substrate 80 is advantageously
absorptive so
that the measurement will not be sensitive to diffuse reflections from its
back surface or from
the surface of receiver 172.
Diffuse reflection in a non-absorbing region provides good accuracy in
measuring
S dose deposition amounts ranging from 50-400pg, or even as high as 750 pg to
1 mg, for a 3-
or 7 mm deposition dot, depending on the characteristics of the powder. The
diffuse
reflection method can detect substantially less than a monolayer of powder. If
the deposit is
more than a monolayer, the probe light beam must partially penetrate the upper
layers so that
it can be affected by the reflection off of the lower layers to provide an
accurate
10 measurement. There tends, however, to be a practical limit (dependent upon
the powder) to
deposition thickness for it to e:rchibit Lambertian characteristics. Diffuse
reflection is also a
measure of the physical uniformity of the dose deposits at the above-listed
ranges.
Optical profilometry is useful for obtaining dose measurements that are above
the
ranges that can be accurately measured by the diffuse reflection method. FIG.
33 depicts,
15 figuratively, an embodiment off the optical profilometry method. When
light, such as laser
light, from light source 3202 is. delivered to deposited powder 3214, light is
deflected at an
angle that is indicative of the height of the deposition layer. That height
can be readily
calculated by triangulation. To improve the coherence of deflected light, such
deflected light
is received by profilometer lens 3212 before being captured by one or more
position sensitive
20 detectors 3208. The output dales from detectors) 3208 is scanned using a
scanning
mechanism 3210 to generate a profile of the powder surface.
The profilometer can be, for example, a confocal profilometer. In a confocal
profilometer, light is directed t~o the substrate through a lens system, and
returned light passes
at least in part through the same lens system, though typically the returned
light is reflected
25 to a detection site. A confocal profilometer suitable for use in
conjunction with the peesent
invention is available from Keyence (Keyence Corp., Japan, or Keyence
Corporation of
America, Woodcliff Lake, NJ) as Model LT8105. That model focuses source light
through a
pinhole, and a similar focusing through a pinhole of the return light helps
establish focus.
Applying back-and-forth dithering movement to one of the lenses aids in
establishing
30 oscillations in the focus that help identify the optimal focus point.
In one embodiment, a slit is used in place of a pin hole, and a spatially
resolvable
light detector, such as a charge-coupled device (CCD), is used to
simultaneously retrieve data
CA 02333107 2000-11-23
WO 99/63972 PCT/LTS99/12772
36
for multiple points along a linE;ar area of substrate 80. There exists a
possibility that
poweder-attracting electrodes 370 or some feature of receiver 172 will create
strong
reflections that can overwhelrr~ efforts to establish the baseline surface of
substrate 80. Since
substrate 80 is preferably uniform, such reflections can be normalized. Once
material is
deposited on substrate 80, or v~rhere the substrate is sufFciently opaque,
clean reflections are
obtainable.
Substrate 80 is advant;~geously scanned before the deposition operation to
increase
the accuracy of the post-deposition scans. The beam is scanned across the
surface and the
height of the surface from a reference location is established by
triangulation. The difference
in height from the reference before and after deposition is attributable to
the dose weight.
For the illustrated embodiments, the difference in height is calculated for
each
column of collection zones C2:, and for each collection zone CZ. Such values
are stored in
memory 405, and the differences are displayed as a measure of the dosage
amount for each
dosage unit. When any of the individual unit dosage amounts are beyond the
predetermined
amount by the preferred five percent value, those units can be later
identified and selectively
discarded providing 100 percent inspection with non-destructive testing of the
actual
amounts of each unit dosage.
Since dry powder is typically a good diffuse reflector, it is also possible to
use an
optical triangulation system that is optimized for diffuse reflection. To
determine the pre-
dose surface profile, and to establish the height of the substrate under
examination during the
post-dose measurement, it is preferred that the surface of substrate 80 is a
diffuse reflector.
Moreover, substrate 80 is advantageously absorptive so that reflections off of
the baclk
surface of substrate 80 or off of receiver 172 are avoided.
For clarity of illustration, the measurements systems of FIGS. 32 and 33 were;
depicted with only a single light source 3102/3202. More than one light source
can,
however, be used in such systems.
In some embodiments, the deposition sites are excited in succession and the
powder
profile is characterized after each light source excitation through scanning
mechanism 3110
or 3210 by moving the scanner, for example, from a first site to a second site
and so an until
all of the deposition sites are characterized. In other embodiments, more than
one deposition
site is excited at a time and data is obtained by scanning the sites
simultaneously. In such
other embodiments, it is desirable to optimize conditions for reducing the
interference from
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
37
nearby sites that are being simultaneously characterized. This can be
accomplished by
optimizing the spacing between the deposition sites or by alternating the
excitations of
different sites.
It is desirable that light source 3102/3202 be movable in different
directions. An
industrial process grade (x,y) stage 142 (see FIG. 8) provides movement in the
x and y
directions. Light source 3102/:3202 can be a solid state laser suitable for
industrial
applications such as, for example, model LAS-200-635-S available from LaserMax
Inc. of
Rochester, NY. The laser is advantageously mounted on detection platform 144
(see FIG. 8).
Detectors 3108/3208 can be any suitable detector, preferably silicon, such as
those sold by
UDT Sensors, Inc. of Hawthorne, CA. Alternatively, large-area solar cells can
also be used.
It is advantageous to incorporate both types of the dose measurement systems
(i.e.,
diffuse reflectance and optical profilometry) into dose measurement station
140. By doing
so, accurate dose measurements are not limited to one of either low dose or
high dose
depositions due to the selection of one or the other of the dose measurement
systems. FIG. 34
depicts an arrangement that is operable to provide the two modes of dose
measurement using
a single light source 3302 and a~ striated substrate 3380.
Striated substrate 3380., shown attached to electrostatic chuck 202/receiver
172, has
surface striations 3381 running in one direction. Such a striated substrate is
particularly
useful for providing both profile and diffuse reflection measurements. The
arrangement of
FIG. 34 includes, in addition to light source 3302 and striated substrate
3380, detectors
3308a for diffuse reflection measurement mode and position sensitive detectors
3308bfor
profilometry measurement mode, and profilometer lens 3313.
The diffuse reflection measurements are made in a plane that contains the
striations,
such as plane P, as depicted in '.FIG. 35. Profilometry measurements are made
by positioning
the triangulation system with incident and reflected beams in a plane, such as
plane O, that is
orthogonal to the striation direction, as depicted in FIG. 36. Striations 3381
thus act like a
diffuse surface for the profilometry measurement.
Ideally, striations 3381 do not scatter light in a parallel direction, so that
any
scattered light is attributable to powder on the surface. For both
measurements, the substrate
is advantageously dyed so that reflections from the substrate's back surface
or from receiver
172 do not interfere with profilometry or diffuse reflection measurements.
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
38
FIG. 37 depicts an arrangement for dose measurement using two measurement
modes, like the arrangement of FIG. 34. In the arrangement of FIG. 37,
however, each
measurement mode utilizes its own light source. Illustrative detection array
3400 is disposed
on support 3402, which support is disposed on detection platform 144 (not
shown in FIG. 37,
S see FIG. 8). The detection array has a diffuse reflectance system comprising
diffuse
reflectance light source 3404A and detection zones 3408A - 3408F. A
profilometry system
comprises profilometry lens 3413 that is part of a confocal system so that
returned light
passes through the same lens. 'Diffuse reflectance light source 3404A is, for
example, offset
from a center point of the arrangement where lens 3413 is found. As a result,
specular
reflections will be centered in an area such as area 3420 away from detector
zones 3408A -
3408F. Such detector zones include detectors that are preferably angled and
arranged to only
accept light from an appropriate direction.
It should be understood that the powder deposited at a collection zone CZ are
measured both in area and thickness to provide a volume measure manifesting
the amount of
powder with a deposit at each collection zone. The above diffuse and
profilometer
measurements, while described in terms of thickness, are also measured in
conjunction with
areas that are determined by the scanning beams.
In particular, adjacent measurement beams are closely spaced, for example 1 mm
apart, so that the transverse region occupied by a collection zone CZ is also
measured and
considered in the calculations of the amount of powder present at each
deposited location.
The beams are advantageously about 6 microns in diameter. For a deposition
zone of about
4-7 mm, each powder "dot" will be scanned with four to seven scans,
respectively. Such
scans are then used to calculate; the amount of dosage at each collection zone
CZ. The
system stores the calculations for each zone in memory for future selective
screening of out-
of specification pharmaceutical or diagnostic unit dosage forms.
EXAMPLE
Polyethylene glycol (PEG) powder in an about 3 mm diameter dot has been
deposited onto a Mylar substrate. Diffuse reflectance data was obtained using
a laser-based
Keyence instrument (Keyence Corporation of America) operating at 670 nm in the
"intensity" mode. Data was otrtained using different, usually larger,
fractions of the diffusely
scattered light. The analytical properties of the measurement did not appear
to be very
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
39
sensitive to the fraction of collected light (i.e., the measurement is, in
this context, unusually
robust and ideal for use as an industrial measurement process).
The data set forth in Table 1 below was obtained using the diffuse reflection
method,
and is the basis for the plot 3500 depicted in FIG. 38, for the four points of
this data set. The
first three data points were highly correlated and the least squares fit gave
an R value, which
is a measure of correlation, of 0.999 (for perfect correlation, R = 1). The
fourth data point
showed variation and the least squares fit for the data set as a whole gave an
R value of 0.98.
Both R values were well withiin accepted norms for analytical procedures to
determine dry
powder dose weights.
Table 1. Experimental diffuse reflectance and dose wei h~ t data
PEG Dose Weight, Calculated R/(1-R)
Microgri~ms, by Assay _
108.6 0.35
86.6 0.312
50.6 0.254
36.6 0.201
Subsequent measurements showed that a high degree of correlation existed for
the
1 S diffuse reflection measurements and dose weight for various types of dose
samples. Based
on such data, the degree of correlation is thought to be closely related to
the structure of the
dose (i.e., in particular whether the structure exhibits Lambertian
characteristics).
Apwlication o!a Covert Material
After dose measurement, first robotic transport element 170 moves receiver 172
and
subtrate assembly 82 to lamination station 160. As previously mentioned, a
holding signal is
applied to electrostatic chuck :Z02 at collection zones CZ to hold the
deposited powder to
substrate 80 and the substrate to the electrostatic chuck.
At lamination station 160, substrate assembly 82 (i.e., frame 81 and substrate
80) is
deposited on top of cover assembly 92 (i.e., frame 91 and cover layer 90),
which assembly 92
is engaged to lamination support block 1901 as depicted in FIG. 39 (frames 81
and 91 not
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
shown; see also FIG. 23). Lamination support block 1901 has dimples 1902 into
which the
indentations of cover layer 90 fit, and further provides support to allow the
cover layer and
substrate to be pressed together. Alignment mechanisms on frames 81 and 91 and
at
lamination station 160 assure that the locations with deposited powder on
substrate 80 are
5 matched with the indentations, bubbles, etc. in cover layer 90, as
illustrated in FIGS. 23 and
39. After the cover layer and substrate are engaged, the holding signal is
withdrawn.
After the first robotic 'transport element 170 moves away, second robotic
transport
element 180 moves into place above lamination support block 1901. Second
robotic transport
element 180 has vacuum cups 1870 (see FIG. 8), bonding head 182, and a pad
1880 that
10 compresses substrate 80 against cover layer 90 before and during the
bonding operation.
Once in position, second robotic transport element 180 manipulates bonding
head 182 to seal
all the depositions between thf; cover layer and substrate thereby forming the
unit forms,
whether comprising dosage or diagnostic active ingredients. As will be
appreciated by those
skilled in the art, "bonding" or lamination can suitably be performed using a
variety of
15 methods, including, for example, ultrasonics, thermal techniques, or via
adhesives. A
suitable ultrasonic bonding head is the 900 M-SeriesTM ultrasonic welder
available from
Branson Ultrasonics Corporation in Danbury, CT.
When welding is completed, second robotic transport element 180 moves to its
idle
position and the final package of dosage forms is removed for final processing
as
20 appropriate.
The illustrated bonding method is useful when one desires to keep the
deposited
powder free of admixture with other components such as film polymers, though
it will be
recognized that this can be achieved in other ways. The illustrated lamination
process
provides bonds that "ring" the area on which material is deposited, but it
will be recognized
25 that more uniform lamination processes are also applicable.
In one embodiment of the invention, placebos are produced by laminating a
substrate
sans deposit, or on which an inactive substance was dry deposited.
30 Miscellaneous Considerations
Many ancillary features that are useful in conjunction with the present
deposition
apparatus are described herein with particularity. For instance, very
favorable results are
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
41
obtained using one method of Maligning the substrate with the deposition
station 150 and with
the dose measurement station :L40. The illustrated embodiments utilize frames
to facilitate
such alignment. Those skilled in the art will recognize that many of the
features described
herein are useful without others that are described, such as a deposition
apparatus that does
not use frames.
In some embodiments.. the electrostatic chuck will be cycled out of the
process and
reused sooner than in the illustrated embodiments. For example, in embodiments
where the
substrate is a film that is advanced on rollers, the electrostatic chuck used
in deposition can
be brought in contact with the film when the film advances to the deposition
station, and
removed immediately thereafter. If necessary, another chuck can be used to
assure that the
film is smooth and flat (in most embodiments) when presented to a dose-
measurement
station. Such an embodiment with a roller-fed film will typically not use
frames, though
frames are an option as discussed above.
Using the techniques and apparatuses described herein, uniform depositions of
t5%,
and as precise as t3% of a target amount are obtained. Such depositions can
include, for
example, depositions onto 4 mm diameter collection zones of amounts ranging
from 2 p,g to
50 mg.
In view of the low variability in dosage levels (i.e., the amount of active
ingredient)
of unit dosage forms produced in accordance with the present teachings, such
dosage forms,
and the methods and apparatus by which they are made, are advantageously used
for treating
a unique set of disease conditions that require a well-controlled dose
regimen. Such well-
controlled dose regimens may be required, for example, for compounds with
overlapping
doses and narrow therapeutic windows. Such narrow therapeutic windows may be
necessary
to avoid toxic side effects, or due to changes in disease state, or as a
function of the
size/metabolism of the patient, or due to changes in the patient's condition.
Several
examples of narrow-therapeutic-window products are described below.
EXAMPLE I - Levothvroxine
Adult doses (micrograms - pg ;): 25, 50, 75, 88, 100, 112, 125, 137, 150, 175,
200 and 300.
Recommended pediatric doses (p,g) for Congenital Hypothyroidism:
CA 02333107 2000-11-23
WO 99/63972 PC1'/US99/12772
42
Age Dose/Dav Daily Dose/Krt body
wt.
0-6mo. 25-SO 8- 10
6- l2mo. 50-75 6-8
1-Syr. 75-100 S-6
6- l2yr. 100- 150 4-5
EXAMPLE II - Digoain
Adult doses (p,g): 125, 250 and 500.
Patients with renal insufficiency require a smaller than usual maintenance
dose of
Digoxin. Digoxin toxicity develops more frequently and lasts longer in
patients with renal
impairment because of decreased excretion of Digoxin. Newborn infants display
considerable variability in their tolerance to Digoxin. Premature and immature
infants are
particularly sensitive, and dosage must not only be reduced but must be
individualized
according to their degree of maturity.
EXAMPLE III - Warfarin
Adult doses (milligrams- mg): 1, 2, 2.5, 3, 4, 5, 6, 7.5 and 10.
EXAMPLE IV - Nitroglycerin
30
Adult doses (fig): 300, 400 and 600.
Additional Final Dosage Forms
As previously noted, unit dosage forms, such as unit forms 6 of FIGS. 1-5, can
be
used to create a variety of final dosage forms useful for different
applications. In one
embodiment, a final dosage form is produced by disposing one or more unit
dosage forms 6
within an outer shell via well-known "blow-fill-seal" technology, as depicted
in FIGS. 43a-
43d.
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
43
First, a pharmaceutically-acceptable polymer 4308p is "blown," such as with
compressed gas, into mold 4302 such that polymer 4308p remains against inner
wall 4304 of
mold 4302. Upon cure, polymer 4308p will form outer shell 4308 of a final
dosage form
4310 (see FIG. 43d). AlthouF;h depicted with a "peanut" shape, it should be
understood that
mold 4302 can be suitably formed to provide a final dosage form having any one
of a
multiplicity of desired shapes.
As illustrated in FIG. 'I3b, one or more unit forms 6, as is required to
obtain a desired
dosage level, is introduced into mold 4302 after polymer 4308p has cured.
After introducing
the desired number of unit forms 6, and any additional fillers, etc., "mouth"
4306 of mold
4302 is sealed, as depicted in I~LG. 43c. Polymer 4308p, for example, can be
used to seal
mouth 4306. Mold 4302 is then opened, and final dosage form 4310 is removed,
as depicted
in FIG. 43d.
In another embodiment, pharmaceutical films (e.g., starch-derived, cellulose-
derived,
polyethylene glycol-derived, etc.) having sufficient thickness are used as a
"container" for
one or more unit forms 6. As depicted in FIG. 44a, a first film 4402 receives
one or more
unit forms 6 in one or more wells 4404. Second film 4406 is placed over first
film 4402 to
seal the wells 4404, as depicted in FIG. 44b. The films can then be diced to
separate the
wells 4404 providing a plurality of final dosage forms 4410, as illustrated in
FIG. 44c.
In a third embodiment of a final dosage form, a strip 4 is sandwiched between
two
films 4502 and 4504, as depicted in FIG. 45a. The elements of strip 4 have
been previously
described (see FIG. 1 and the accompanying description), and include a
substrate 8 and a
cover layer 9. Substrate 8 includes a plurality of depositions that have been
deposited in
accordance with the methods, and via the apparatus, described herein. Each
deposit includes
an active ingredient. The cover layer 9 includes a plurality of bubbles or
bumps 12 that are
aligned with the deposits on substrate 8. A bubble 12, an "underlying" portion
of substrate 8
and an associated deposit define a unit form b. Strip 4 thus comprises a
multiplicity of unit
forms 6.
Films 4502 and 4504 are bonded to one another, or to strip 4, thereby
sandwiching
unit forms 6 therebetween and creating a secondary package therefor.
Information pertaining
to unit forms, etc., is advantagt;ously printed or otherwise reproduced on the
secondary
package. The secondary package and included strip 4 can be diced producing a
plurality of
"postage stamp" final dosage forms 4510, one of which is depicted in FIG. 45b.
In
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12'772
44
embodiments in which the sec;ondary package is edible, dosage form 4510, in
its "postage
stamp" form, may be ingested.. In embodiments in which the secondary package
is not
edible, unit form 6 must be removed for administering.
In a further embodiment, a final dosage foam comprising a plurality of unit
forms 6
having the same or different active ingredients and capable of timed release
is provided.
Such final dosage forms have segregating layers that separate or segregate
each ofthe unit
forms within the final dosage form. Illustrative embodiments of such a final
dosage form are
depicted in FIGS. 46 and 47.
FIG. 46 depicts four unit forms 6a-6d within final dosage form 4610, shown in
an
exploded view for clarity of illustration. In a first embodiment, unit forms
6a-6d are
identical (i.e., same active ingredient and same amount of said active
ingredient). In a
second embodiment, unit forrr~s 6a-6d comprise the same active ingredient, but
that active
ingredient is present in differing amounts. And in a third embodiment, unit
forms 6a-6d
comprise different active ingredients.
Final dosage form 46110 comprises "overcoat" or "overwrap" films 4604a-4604d
that
segregate unit forms 6a-6d from one another. In illustrative final dosage form
4610 depicted
in FIG. 46, each overwrap film 4604a-4604d comprises respective "dimple" 4606a-
4606d
that facilitates receipt of one of the unit forms 6a-6d. Final dosage form
4610 can be made
by layering a desired number of overwrap films (e.g., overwrap films 4604a-
4604d), and
sandwiching a strip (e.g., strip 4) that contains a plurality of unit forms 6
between adjacent
overwrap films. The strips 4 a;re produced in accordance with the present
teachings.
The overwrap films are aligned such that dimples on each overwrap film are
aligned
with one another. The unit form-containing strips are aligned with the
overwrap films such
that a unit form from each strip is positioned within a perimeter of a dimple
of an adjacent
overwrap film. The various overwrap layers and sandwiched strips are "punched"
in a single
operation, yielding final dosage form 4610.
Overwrap films 4604a-4604d may be bonded to a base film 4602 before or during
the punching operation. Moving from outermost overwrap film 4604d to innermost
overwrap film 4604a, the diarr~eter of the dimple decreases such that the
dimples "nest" in
the manner in which pots in a ;>et of cookware nest one within another. In an
additional
embodiment (not depicted), a ;second grouping of nested overwrap dimples and
unit fbnms
are disposed on a second side of base film 4602.
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
In an alternate embodiment, final dosage form 4610 can be manufactured via a
multi-step overwrapping operation wherein a first overwrap encapsulates a
first unit form, a
second overwrap film and a second unit form are then positioned over the first
overwrap, etc.
building up final dosage form 4610 layer by layer.
5 FIG. 47 depicts a funther embodiment of a final dosage form containing
multiple
unit forms 6. Like final dosage form 4610, unit forms 6a-6d of final dosage
form 4710 of
FIG. 47 may be identical to one another, may comprise the same active
ingredient but in
different quantities, or may comprise different active ingredients.
Final dosage form 47:10 can be manufactured by attaching (e.g., bonding,
adhering,
10 etc.) a "diffusion barrier" (e.,g., 4704a) to a unit form 6a and then
sequentially attaching
additional unit forms (e.g., 6b-6d) and additional diffusion barriers (e.g.,
4704b-4704c),
seriatim. As a function of application specifics, in some embodiments, an
overcoat 4706
encompasses the collection of unit forms and diffusion barriers. Similarly, in
some
embodiments, additional overwrap layers or diffusion barriers 4702 and 4708
are attached to
15 the first and last unit form (e.F;., unit forms 6a and 6d).
Description of the ove;rwrap layers and diffusion barriers, as well as
additional
description of the base and cover substrates, are provided in the following
section.
Substrates or Specific-Delivery Dosage Forms
20 Utilizing the present methods and apparatus, the same active ingredient can
be made
as a (1) prompt-release; (2) delayed release; (3) timed release; (4) post-
gastric release; or (5)
colonic-release unit form by suitable selection of the base and/or cover
substrates. In
particular, to produce such dosage forms, the same active ingredient is
deposited on a
substrate or laminated with a <;over layer that has the following respective
properties; (1)
25 rapidly water-soluble; (2} slovvly water-soluble; (3) insoluble but water-
swellable; (4) acid-
insoluble but alkaline-soluble; or (5) insoluble but sensitive to degradation
by anerobic
attack.
Certain generalization can be made concerning desirable properties of the
various
substrates, overlayers and diffusion barriers previously described. Such
properties, and
30 candidate materials possessing such properties, are listed and described
below.
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
46
Substrate
As previously described, the substrate serves as a deposition substrate upon
which
powder is electrostatically deposited. Materials suitable for use as a
substrate
advantageously possess the following properties: electrically resistive
(minimum 5 x 1011
ohm/sq. at a relative humidity _< 40%); strong; dimensionally stable; low
moisture uptake;
insoluble (where insolubility does not pose a safety issue); optically diffuse
and darkly
colored; and sealable.
Candidate materials for a base substrate possessing the above-listed desirable
properties include, without limitation, ethyl cellulose, cellulose acetate
phthalate, water-
insoluble acrylic copolymers, paper (specialty if oral approval is sought),
cross-linked
polyvinyl pyrrolidinone), cro:>s-linked gelatin, and non-woven fabric.
Example
A base substrate was produced from an aqueous dispersion of ethyl cellulose
(commerically available from FMC Company of Philadelphia, PA. as Aquasol
ECI~). The
film- formation-temperature of the as-supplied ethyl cellulose was undesirably
high. Film-
formation-temperature can be :reduced with additives, such as, for example, a
plasticizer. In
one embodiment, triacetin is added to the ethyl cellulose in an amount in the
range of about
15 to about 40 volume percent, and preferably between 25 and 30 volume
percent. Triacetin
additive produced coherent, supple films that formed at low temperatures
(e.g., 50" - 60° C).
Table II lists the electrical properties of such films as a function of
relative humidity (1tH).
Table II
Electrical Properties of Films
Produced from Ethyl Cellulose Dispersion
Plasticized with Triacetin
20% RH 30% RH 40% RH 60% RH
Surface Sheet Resistance,
<ohm/square>: 1.0 x 1012 7.9 x 1011 4.1 x 1011 1.8 x 1011
Volume Resistivity,
<ohm-cm>: 1.0 x 1012 7.9 x 1011 4.1 x 1011 1.8 x 1011
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
47
As previously described, the substrate and cover layer utilized in conjunction
with
the present invention are bonded to one another to form a unit dosage form. In
an
embodiment depicted in FIG. 48, substrate 4880 comprises a bi-layer film that
includes
hydrophobic layer 4882 and hydrophilic layer 4884. Hydrophobic layer 4882
maintains high
electrical resistance and mechanical stability under a wide range of
conditions (e.g.,
temperature, humidity, etc.). lHydrophilic layer 4884 swells or becomes
"tacky" upon
exposure to high humidity. Bii-layer substrate 4880 can be bonded to a cover
layer by
ultrasonic welding, exposure to high humidity, or directed application (e.g.,
by ink jet
printing or micropipette) of small droplets of water.
In one embodiment, bi-layer substrate 4880 comprises an ethyl cellulose
dispersion
("ECD") plasticized with triacetin as hydrophobic layer 4882 and hydroxypropy)
cellulose
("HPC") as hydrophilic layer 4884. Electrical properties of the HPC-ECD base
substrate are
provided below in Tables III and IV as a function of relative humidity (RH).
Table III
Electrical Properties of Multi-Layer Films
Comprising HPC Type LFP Cast on ECD
Surface
Property _ Tested 20% RH 30% 40% RH 60% RH
_ RH
Surf. Sht. Resistance*HPC 1.5 x 8.0 x 5.8 x 1.4 x
1012 1011 1011 1011
Surf. Sht. ResistanceEPC 3.0 x 1.7 x 1.3 x 3.2 x
1012 1012 1012 1011
Volume Resistivity**HPC 1.9 x 9.2 x 7.0 x 2.~4
1013 1013 1012 x 1012
Table IV
Electrical Properties oJMulti Layer Films
Comprising HPC Type JFNF Cast on ECD
Surface
Property Tested 20% RH 30% RH 40% RH 60% RH
Surf. Sht. Resistance*HPC 1.0 x 10124.7 x 2.3 x 1.0 x
1011 1011 1011
Surf. Sht. ResistanceEP(: 2.6 x 10121.2 x 6.8 x 3.8 x
1012 1011 1011
Volume Resistivity**HP(: 1.1 x 10129.5 x 5.7 x 2.2 x
1012 1012 1012
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/I2772
48
(*<ohm/square>, **<ohm-cm>)
Other candidate materials for hydrophobic layer 4882 that are commercially-
available as aqueous dispersions are cellulose acetate phthalate and water-
insoluble acrylic
copolymers. Additional candidates that are suitable, but require more complex
processing
include, without limitation, unmodified cellulose, unmodified starch, chitin
and other
materials previously identified as candidates for the base substrate.
Other candidate materiials for hydrophilic layer 4884 that are readily
available
include hydroxypropylmethyl cellulose, methylcellulose, modified starches,
maltodextrins,
natural and synthetic gums, polyvinyl alcohol), polyvinyl pyrrolidinone), and
the like, and
hydrogels derived from these a.nd other similar materials.
A method 4900 for forming such a bi-layer film is depicted in FIG. 49. The
illustrative method involves two primary operations: casting the hydrophobic
layer (step
4910) and casting the hydrophilic layer (step 4920). The hydrophobic layer is
cast, for
example, by applying a suitable material (e.g., plasticized ethyl cellulose
dispersion) on a
casting substrate, as depicted in operation 4910a. A smooth, poorly adherent
plastic film
(e.g., MylarT"', stainless steel) is advantageously used as the casting
substrate. The applied
material is then dried under conditions of controlled temperature and humidity
as per
operation 4910b. A temperature of SS°C and relative humidity of 35%
have been found to
be suitable for performing drying operation 4910b. Other conditions of
temperature and
relative humidity may suitably be used.
The hydrophilic layer is then cast from a solution applied to the hydrophobic
elm in
operation block 4920a. The applied solution is dried under conditions of
controlled
temperature and humidity in operation 4920b. A temperature of 28°C and
relative humidity
of 45% have been found to be suitable for performing drying operation 4920b.
Other
conditions of temperature and relative humidity may suitably be used.
After the hydrophobic payer and the hydrophilic layer have been cast, the
resulting
bi-layer film is then removed from the casting substrate in a final operation
4930. Such
removal can be effected by peeling the bi-layer film from the casting
substrate.
In an alternate embodiment, rather than casting the hydrophobic layer, a
commerically-available pre-fonmed pharmaceutically-approved hydrophic film may
be used.
The hydrophilic layer is then cast over the hydrophobic film.
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/1Z772
49
Cover Laver
As previously described, the cover layer is used in the electrostatic
depositian
process to cover the substrate thereby trapping the deposited active
ingredient therebetween.
Materials suitable for use as a cover layer advantageously possess the
following properties:
immediately soluble in all conditions of pH, temperature and the like;
deformable to accept a
range of doses; and easily dyed for color coding.
Candidate materials for a cover layer possessing the above-listed desirable
praperties
include, without limitation, commerical hydroxypropylmethyl cellulose, methyl
cellulose,
hydroxypropyl cellulose, polyvinyl pyrrolidinone), polyvinyl alcohol),
polyethylene
oxide).
Diffusion Barrier
A diffusion barrier may be used, for example, in final dosage forms containing
multiple unit dosages, such as final dosage form 4710. Materials suitable for
use as a
diffusion barrier advantageously possess the following properties: swollen
equally across
full pH range; control diffusion of water; cross-linked water-soluble polymer;
active
ingredient delivery rate controllable by material thickness or by degree of
cross-linking
density.
Candidate materials for the diffusion barrier include, without limitation,
poly(methacrylic acid), acrylic hydrogels (e.g., mildly cross-linked polymers
of hydroxyethyl
or hydroxypropyl acrylate or methacrylate), polysaccharides (e.g., starches,
agar,
maltodextrin, etc.), gums (e.g., acacia, gellan, etc.), and carboxymethyl
cellulose.
Overcoat Films
An overcoat (overwrap) film is used, for example, where a secondary packaging
layer surrounds the unit forms, such as for final dosage forms 4310, 4410,
4510, 4610, and
some embodiments of 4710. Properties of the overcoat films are defined as a
function of the
desired characteristic (e.g. prompt-release; delayed release; post-gastric
release, etc.) of the
final dosage form.
In particular, for release in the stomach, the overcoat film is advantageously
acid
soluble. Suitable acid-soluble materials include, without limitation,
polyvinyl pyridine), and
amine-substituted acrylic copolymers. For release in the small intestine, the
overcoat film is
CA 02333107 2000-11-23
WO 99/63972 PCT/US99/12772
alkaline soluble and/or enzyme erodable. Suitable alkaline-soluble materials
include,
without limitation, carboxyl-substituted acrylic copolymers and polymeric
derivatives of
alginic acid. Suitable enzyme-erodable materials include, without limitation,
protein (e.g.,
casein, gluten, albumin, etc.), lipid, starch, polylactide and poly(lactide-co-
glycolide).
5 For colonic release, th<; overcoat film is advantageously universally but
slowly water
soluble and digestible by anero~bic bacteria. Suitable water-soluble materials
include,
without limitation, ultra-high molecular weight polyethylene oxide), high
molecular weight
polyethylene glycol)s blended with polyvinyl pyrrolidinone) or polyvinyl
alcohol), shellac,
fully (>_ 98%) or slightly (_< 25'%) hydrolyzed poly(vinly alcohol), and
polystyrene-co-
10 malefic anhydride), high molecular weight acrylate and methacrylate
copolymers containing
significant amounts of acidic monomers such as acrylic acid and methacrylic
acid.
Adhesives
15 Adhesives are used, in some embodiments, for bonding the substrate and
cover layer
together, and for bonding various overcoatloverwrap layers to other layers.
For buccal,
gingival and nasal locations, the adhesive advantageously provides good
adhesion and is
non-toxic. Suitable adhesives include, without limitation, synthetic rubber,
acrylic pressure-
sensitive adhesives, dental temporary, and maltodextrin. For dermal
applications, the
20 adhesive advantageously proviides good adhesion and is non-allergenic. A
suitable adhesive
is the type used for adhesive bandages. For vaginal and rectal applications,
the adhesive
advantageously exhibits poor adhesion and is non-allergenic. A suitable
adhesive is a
"swell-in-place" material such as polysaccharide.
25 All patents and patent applications cited in this specification are
incorporated herein
by reference in their entirety. Any patent application to which this
application claims
priority is also incorporated heorein by reference in its entirety.
It will be understood by those skilled in the art that variations in the
illustrated
devices and methods may suit~~bly be used in conjunction with the present
invention and that
30 the invention may be practiced otherwise than as specifically described.
Accordingly, this
invention includes all modifications encompassed within the spirit and scope
of the invention
as defined by the claims that fellow.
