JP2002517304A - Drug product and method and apparatus for manufacturing drug product - Google Patents

Abstract

(57) SUMMARY The present invention provides a product (1) having a pharmaceutical unit dosage form (6) of a medication or diagnostic agent. Product (1) of the present invention has at least one active prescription drug present in an amount not exceeding about 5% from a predetermined target amount. In one embodiment, the unit dosage form is joined to the substrate by a substrate (8), a deposit (14) disposed on the substrate, and a joint overlying and surrounding the deposit (14). A cover layer (9) surrounding the stack between the substrate and the cover layer. The deposit consists of a powder, at least some of which have at least one active prescription. The unit dosage form is formed by a dry powder deposition device that electrostatically deposits powder on a substrate using an electrostatic chuck and a charged powder supply.

Description

DETAILED DESCRIPTION OF THE INVENTION

Cross-References to Related Applications The following are related U.S. patents: "APPARATUS FOR" by Pletcher et al.
ELECTROSTATICALLY DEPOSITING AND RETAINING MATERIALS UPON A SUBSTRATE (
199 according to the name of "Apparatus for electrostatically depositing a substance on a substrate and related substances)"
U.S. Pat. No. 5,669,973, Sep. 23, 1995, "APPARATUS FOR ELECT" by Pletcher et al.
ROSTATICALLY DEPOSITING A MEDICAMENT POWDER UPON PREDEFINED REGIONS OF A
U.S. Pat. No. 5,714,007, Feb. 3, 1998, entitled "SUBSTRATE (Device for Electrostatically Depositing a Chemical Powder on a Predetermined Area of a Substrate)", Sun's "CHUCKS AND METHOD".
"ACOUSTIC DISPENSER" by Sun et al., US Pat. No. 5,788,814, issued Aug. 4, 1998, entitled "FOR POSITIONING MULTIPLE OBJECTS ON A SUBSTRATE". U.S. Patent No. 5,753,302 issued May 19, 1998, S.
U.S. Pat. No. 5,753,302, dated December 8, 1998, entitled "ELECTROSTATIC CHUCKS" by Un et al .; Jan. 12, 1999, entitled "ELECTROSTATIC CHUCKS", Sun et al. U.S. Patent No. 5,858,814,
And Datta et al., "INHALER APPARATUS WITH MODIFIED SURFACES FOR ENHANCED R
There is U.S. Pat. No. 5,871,010 filed Feb. 16, 1999, entitled "ELEASE OF DRY POWDERS".

Also, related US patent applications include the following: “METH by Pletcher et al.
OD AND APPARATUS FOR ELECTROSTATICALLY DEPOSITING A MEDICAMENT POWDER UP
US Patent Application No. SN08 / 659,501, Jan. 6, 1996, entitled "ON PREDEFINED REGIONS OF A SUBSTRATE", entitled "METHOD AND APPARATUS" FOR ELECTROSTATIC
ALLY DEPOSITING A MEDICAMENT POWDER UPON PREDEFINED REGIONS OF A SUBSTRA
U.S. Patent Application No. SN08 / 733,525, issued October 18, 1996, entitled "TE (Method and Apparatus for Electrostatically Depositing Drug Powders in Predetermined Areas of Substrates)", Loewy et al., DEPOSITED REAGENTS FOR CHEMICAL PROCESSES. US Patent Application No. SN08 / 9, Oct. 23, 1997, entitled "Deposited Reagents for Performing Processing"
U.S. Patent Application No. 56,348, Loewy et al., Entitled "SOLID SUPPORT WITH ATTACHED MOLECULES" on October 23, 1997.
SN08 / 956,737, Sun's `` BEAD TRANSPORTER CHUCKS USING REPULSIVE FIELD G
U.S. Patent Application No. SN09 / 026,303, Feb. 19, 1998, entitled "UIDANCE (Bead Transport Chuck Using Repulsive Field)", Sun's "BEAD MANIPU
US Patent Application No. SN09 / 047,631, entitled "LATING CHUCKS WITH BEAD SIZE SELECTOR" and Sun's "F
US Patent Application No. SN08 / 083,487, May 22, 1998, Sun et al., Entitled "OCUSED ACOUSTIC BEAD CHARGER / DISPENSER FOR BEAD MANIPULATING CHUCKS"
U.S. Patent Application No. SN09 / 095,425, filed June 10, 1998, entitled "C WAVEFORMS BLASING FOR BEAD MANIPULATING CHUCKS", and "APPARATUS FOR CLAMPING A PLANAR SUBSTRATE" by Sun et al.
No. SN09 / 095,321, filed Jun. 10, 1998, entitled "PHARMACEUTICAL PRODUCT AND ME", issued June 10, 1998, entitled "Apparatus for Clamping Flat Substrates".
THOD OF MAKING (drug and method of manufacturing drug) "
U.S. Patent Application No. SN09 / 095,616, filed December 10, and "DRY POWDER DE" by Desai et al.
POSITION APPARATUS (Dry Powder Deposition Equipment) "June 1, 1998
There is U.S. Patent Application No. SN 09 / 095,246, dated 0.

TECHNICAL FIELD [0003] The present invention relates generally to unit dosage forms or unit diagnostic forms and devices and methods for making such unit forms. About.

BACKGROUND OF THE INVENTION In the pharmaceutical industry, a pharmaceutical product containing a diagnostic agent is a container (eg, a bottle, a blister pack, or other package) containing a plurality of “unit dosage forms” or “unit diagnostic dosage forms”. have. Such unit dosage form contains the pharmaceutically or biochemically active ingredient (s) and the inactive ingredient (s).

[0005] Pharmaceutically active prescription drugs generally form a drug. A diagnostic dosage form can include reagents and the like used in diagnostic tests, and can include a portion of a collection containing several different reagents or active prescriptions. Further, the diagnostic drug form can include an antibody, an antigen, or a form in which these are labeled.

[0006] Pharmaceutically or biochemically active prescriptions used as unit dosage forms are supplied as a powder consisting of a plurality of active prescription drug particles. Such active prescription particles are combined with active or inactive prescription particles to form a plurality of "large particles."
Even large particles are very small with dimensions on the order of microns.
Such large particles are generally combined with one another to form a final unit dosage form or unit diagnostic dosage form (eg, a tablet, caplet, test strip, capsule, etc.).

[0007] Significant differences in the amount of a pharmaceutically or biochemically active prescription may occur between one large particle and the next. Because a large number of large particles are required to form the final unit dosage form, the particle-to-particle differences may reduce the amount of active prescription between one unit dosage form and the next. Large differences are caused. Thus, for any given final dosage form, there may be a significant over-deficiency in the desired amount of active prescription.

[0008] Disruptive analytical screening techniques are routinely used to evaluate the amount of active prescription (s) in the final unit dosage form. Since such an approach destroys the unit dosage form, static sampling is performed, thereby actually sampling and testing a relatively small number of dosage forms per unit batch. Such a screening approach has the disadvantage that it does not guarantee that all dosage forms in a given batch contain the desired amount of pharmaceutical or biochemical prescription. In fact, such a static method effectively "guarantees" that a satisfactory determined proportion of the dosage form of each batch will be out of specification.

[0009] Accordingly, there is a need for a method and apparatus that allows for excellent control of the active prescription content of unit dosage forms and unit diagnostic dosage forms.

In one embodiment, the present invention provides an article of manufacture comprising a plurality of pharmaceutical unit dosage forms or unit diagnostic dosage forms (hereinafter collectively referred to as “unit dosage forms”). Each dosage form has at least one active prescription drug present in a superior amount that does not differ by more than about 5% from a predetermined target amount.

[0011] In one embodiment, the unit dosage form comprises a substrate, an active prescription deposited on the substrate,
A cover layer covering the active prescription and bonded to the substrate (by fusing, adhesive, etc.) near the active prescription.

In an exemplary embodiment, the product is made by a dry deposition apparatus that deposits powder / grain on a substrate. In one embodiment, the apparatus includes an electrostatic chuck, a charged powder supply, and an optical detection system. The substrate is engaged with an electrostatic chuck that performs dry deposition of the powder. The chuck has at least one collection zone in which a powder suction electric field is formed. The charged powder supply device electrostatically deposits the charged powder on the substrate in the collection zone (s), directing the charged powder on the substrate. The optical detection system quantifies the deposited powder.

In one embodiment, the dry deposition device has an electronic processor that controls deposition in response to sensor input. Such sensor input preferably comprises one or more deposition sensors located on or adjacent to the electrostatic chuck and providing data regarding the amount of powder deposited. In response to the sensor data, the electronic processor adjusts the deposition parameters as needed. Controllable parameters include the powder flux through the powder feeder and the applied voltage at the collection zone (s).

[0014] In yet another embodiment, the dry deposition apparatus of the present invention includes various other elements described in detail herein below.

BEST MODE FOR CARRYING OUT THE INVENTION The following terms have the following meanings for the purpose of describing the present invention and describing the claims.

The dielectric or non-dielectric refers to a material having non-conductivity such as copper that can be distinguished from a conductive material. The degree of non-conductivity can vary greatly in that situation.

Dry deposition refers to depositing a substance without using a liquid vehicle.

An effective amount is (1) an amount effective to reduce, ameliorate, or eliminate one or more symptoms of the primary disease, (2) an effective amount to induce a pharmacological change associated with treatment of the primary disease. Or (3) an amount effective to eliminate or reduce the frequency of occurrence of the main disease or its symptoms.

[0019] Electro-attractive dry deposition refers to a method of dry-depositing a charged powder using an electromagnetic field or an electrostatically charged surface.

Grains are molecules or aggregates of particles, such as particles of polymer structure, which can be referred to as powders or “beads”. Beads include those coded, supporting adsorbed molecules, capture molecules or other substances. The particles or molecules of the powder are generally at least about 1 nanometer (nm),
More typically, it has an average diameter in the range of about 100-500 nm. Grain
Diameter of about nm to 5 millimeters (mm), more usually at least about 500 to 80
It has an average diameter of 0 nm.

A flat substrate refers to a substrate having two main dimensions, such as a tape or a sheet. In some embodiments, the flat substrate is flat, but need not be.

The unit dosage form (pharmaceutical dosage or diagnostic agent) is one or more separate active prescriptions, whether on separate substrates and whether the substrates are suitable for ingestion. Whether these prescription drugs are in capsules, can be packaged,
Alternatively, they can be used as pharmaceutical dosages or as element (s) for diagnostic purposes, whether or not they can be used for the intended purpose in unit dosage form. Product and Unit Dosage Form FIG. 1 shows a product 1 according to an exemplary embodiment of the present invention. The product 1 has a package 2 embodied as a strip 4 having an array of unit dosage forms 6. Strip 4 comprises a substrate 8 and a cover layer 9.

Each of the substrate 8 and the cover layer 9 comprises a substantially flat and flexible film or sheet. In some embodiments, either the substrate 8 or the cover layer 9 has an array of hemispherical bubbles, recesses, blisters, depressions (hereinafter “bubbles”) 12, which are rows and Preferably, they are arranged in rows. In the exemplary package shown in FIG. 1, the cover layer 9 has a 3 × 5 arrangement of such bubbles 12, but more or less bubbles can be provided as appropriate. Substrate 8 and cover layer 9 preferably have a thickness of about 0.001 inch (0.0254 mm) and generally comprise a thermoplastic material. Materials suitable for use as substrate 8 and / or cover layer 9 include, but are not limited to, polyvinyl acetate, hydroxypolymethylcellulose, and polyethylene oxide films. Polyvinyl acetate films suitable for use as a substrate and / or cover layer are available from Polymer Film, Inc. of West Haven, CT, Chri.
s Craft (Gary, Indiana), Aquafilm (Winston-Salem, North Carolina), Idroplast SpA (Montecatini Terme (PT), Italy), AICello Che
Commercially available from mical Co., Ltd. (Toyohashi, Japan).

As shown in FIG. 2 (showing the cover layer 9 partially “peeled off” from the substrate 8) and FIG. 3, the bubble 12 between the substrate 8 and the cover layer 9 Dry active prescription drug 1 in the form of powder (s) / grain (hereinafter referred to as powder)
Four deposits are arranged. In one embodiment, active prescription drug 14 is a pharmaceutical product, such as Drug II, and in other embodiments, active prescription drug 14 is a biochemical diagnostic laboratory or a diagnostic product useful for medical-related purposes. The method and means for depositing the active prescription 14 on the substrate 8 will be described later in this specification. As used herein, the term "powder" means a single (i.e., one type) powder as well as a plurality (i.e., different types) of powder.

As shown in the cross-sectional view of FIG. 3 and the plan view of FIG. 4 (each drawing shows only a single bubble 12), the substrate 8 and the cover layer 9 12 are integrated with one another via a joint or fusion joint surrounding the same. Joining is performed, for example, by heat or ultrasonic fusion or through a suitable adhesive. The unit dosage form 6 is composed of the active prescription drug 14, the bubble 12, and the area of the substrate 8 in the joint 7.

As shown in FIG. 5, the strip 4 containing the unit dosage form 6 can be placed in a packaging container such as a box 16 for the convenience of the user.

[0027] The unit dosage form 6 according to the present invention comprises various final dosage forms.
Can be used to form Exemplary final dosage forms incorporating one or more unit dosage forms 6 are described later herein after describing various embodiments of a device for making the unit dosage form 6. Apparatus for Producing the Product of the Present Invention FIG. 6 conceptually illustrates elements of a device 100 suitable for producing the product of the present invention. The device 100 comprises a platform 101 for creating the unit dosage form of the present invention.
have. Platform 101 is preferably configured for robotic operation as shown in the exemplary embodiment. However, in other embodiments, the platform 101 can be configured to be non-robotic. In such other embodiments,
The platform 101 includes, for example, a manual mechanism (a manual mechanism for taking out and transporting a substrate or the like).
Gantry and crane). Platform 101
The various operations, the primary one being the electrostatic deposition of a dry powder on specific discrete areas of the substrate, create a unit dosage form. Other tasks include some or all of material handling, alignment, dosimetry, and lamination.

The electrostatically charged powder is supplied to the robot platform 101 via a powder supply device 801. The processor 401 and the controller 403 control various electronic functions of the device 100, such as, for example, an electrostatic deposition operation, an operation of the powder supply device 801, an operation of a robot operatively associated with the platform 101, and a dose measurement operation. . A memory 405 is provided in the processor 401 and the controller 403.
Is connected.

In some embodiments, platform 101 and / or powder supply 801
Is isolated from the surrounding environment by an environmental enclosure. In such an environment, the environment controller 901 controls the robot platform 101 and the powder supply device 8.
01, temperature, pressure and humidity are controlled.

Next, the above elements of the device 100 will be described in detail. Platform and its operation 7 and 8 are respectively plan view and a front view of an exemplary platform 101. One support 104 is arranged at each corner of the platform 101. The support 104 lifts various structures associated with the support bench 110 and platform 101 above a table or the like. In addition, the support 104
Optionally, a frame or superstructure of the side mounted barrier 106 is preferably provided, as shown in FIG. The side-mounted barrier 106 can be formed of glass, polycarbonate, acrylic panels, or the like. Side-mounted barrier 10
6 cooperates with a top barrier (not shown) and a support bench 110 to form an environmental enclosure or chamber 102 that defines an area therein where air or inert gas is present. Isolate from the environment.

The support bench 110 has five processing stations that perform various operations that are effectively used to manufacture the product of the present invention. Briefly, these processing stations include an input / output station 120 (preferably three substations 120A, 120B, 120) for storing substrates and cover layers.
C), an alignment station 130 for ensuring that the substrate and the cover layer are properly aligned with the transport mechanism, and a deposition station 15 for depositing the powder on the substrate.
0, a dosing station 140 for measuring the amount of powder deposited on the substrate;
There is a lamination station 160 for laminating the cover layer to the substrate.

In the illustrated embodiment, platform 101 includes first robotic transport element 170
And the second robot transport element 180 enables robot work. The receiver 172 is attached to the first robot transport element 170. Receiver 172
Performs processing by removing at least a substrate from the substation 120C and moving the substrate to at least some of the various processing stations 130-160, as will be described in more detail later herein. The “joining” head 182 is attached to the second robot element 180. The bonding head 182 is operable to bond and seal the substrate and the cover layer to each other, as described in more detail later herein.

The robot transport elements 170, 180 can move along a first rail 190 forming a motion guide in one direction (eg, along the x-axis) (eg, have access to various processing stations). Another rail (not shown) movably mounted on the first rail 190 forms a guide / support that moves in a direction orthogonal to the first rail 190 (eg, along the y-axis). . Driving means (not shown) such as an xy stepper motor drives the robot transport elements 170, 180 along the rails. The first and second robotic transport elements 170, 180 have nested parts that are servo-controlled (not shown), and that have a z-axis (ie, x
-An axis perpendicular to the y-plane). Such z-axis motion is
Receiver 172 or bonding head 182 is “down” toward the processing station
To allow the work to be performed and to allow the work station to be "up" away after the work is completed. The robot transport elements 170, 180 are servo controlled θ control components (not shown) that allow the receiver 172 and the joining head 182 to rotate in the xy plane to facilitate work at the processing station.
It is preferred to have Compressed dry air or other gas is suitably supplied at 80 psi and a flow rate of 8 SCFM to operate the robotic transport element. The robot transfer elements 170 and 180 are, for example, Yaskawa Ro commercially available from Yaskawa Electric (Japan).
bot World Linear Motor Robot.

Embodiments and features of various elements of the device 100 are described below. To provide a perspective of such disclosure, at least one embodiment of the operation of the device 100 will first be summarized.

In operation, the first robotic transport element 170 moves the receiver 172 and the engaged electrostatic chuck 202 (used for powder deposition; see FIGS. 9-11) to the input / output station 120. At station 120, the electrostatic chuck engages the substrate 80 and, in some embodiments, also engages a frame 81 coupled to the substrate. In one embodiment, the robot transport element 170 then moves the engaged receiver 172, electrostatic chuck 202, substrate 80, and frame 81 to the alignment station 130. At the alignment station, the frame 81 is realigned to the electrostatic chuck 202 via various alignment mechanisms, thereby improving the accuracy and consistency of alignment between the substrate 80 and the electrostatic chuck 202.

The robot transport element 170 then moves to the engaged receiver 172, electrostatic chuck 20
2. Move the substrate 80 and the frame 81 to the dose measuring station 140. After being aligned with the measurement device at station 140, the substrate 80 is scanned through the measurement device and, at each of a plurality of "collection zones" (see FIG. 10), from the reference point to the substrate 80 The distance to is calculated and recorded to give baseline data.

The robot transport element 170 then moves on to the engaged receiver 172, electrostatic chuck 20
2. Move frame 81 and “virgin” substrate 80 to deposition station 150. At the deposition station 150, the powder deposition engine (see FIGS. 23-29) is energized and the powder is electrostatically deposited in the collection zone CZ.

At the completion of the powder deposition operation, robotic transport element 170 returns substrate 80 to be loaded with the deposited powder to dosing station 150. At station 150, the measurement device again scans substrate 80 to determine the distance between the reference point and the "deposited" surface of the powder accumulated in each collection zone CZ. From this distance and the previously obtained baseline, the amount (eg, volume) of the powder deposited in each collection zone is calculated. If the calculated amount is outside the desired range of the predetermined target amount, such information is displayed. The operator then adjusts the operating parameters appropriately to bring the process back to specification. In other embodiments, automatic feedback is provided to automatically adjust the process as needed. "Out-of-spe
c) The unit dosage form can be discarded.

The second robot transport element 180 picks up the cover layer 90 and the frame 91 from the input / output station 120 and supplies them to the stacking station 160. When the measurement is completed at the dosing station 150, the first robotic transport element 170 supplies the substrate 80 to which the powder is to be captured to the lamination station 160. The substrate 80 is placed on the cover layer 90 via the first robotic transport element 170 so that the powder deposition is properly aligned within the cover layer bulges or bubble boundaries.

As the first robotic transport element 170 moves away, the second robotic transport element 180 is returned, and the operation of the bonding head 182 fuses the substrate and cover layer together, resulting in multiple strips on the strip (see FIG. 1). Form a unit dosage form. In an automated system, the unit dosage form is automatically conveyed to a packaging station where non-standard unit dosage forms are filtered out and in-specification unit dosage forms are packaged as appropriate.

The methods and apparatus of the present invention provide a product containing multiple unit dosage forms of a drug or diagnostic agent, with each unit dosage form having no more than 5% error of a predetermined target amount.

Having described an overview of one embodiment of the present invention, various elements and features of the apparatus 100 and their operation will now be described in further detail. Receiver, Electrostatic Chuck, and Substrate Assembly According to the present invention, the powder containing the active prescription is electrostatically deposited at a deposition station 150 at discrete locations on the substrate 80. To perform such a deposition in the illustrated embodiment, the substrate 80 may be transported from some other location to the deposition station 150 under various conditions, and the powder may be electrostatically deposited on the substrate 80. It is necessary to generate an electrostatic charge for the deposition. Such transport and charging operations are facilitated, at least in part, by receiver 172 and electrostatic chuck 202. Prior to providing a detailed description of these elements, a cooperative relationship between the receiver 172, the electrostatic chuck 202, and the substrate 80 will be described below with reference to FIG.

FIG. 9 is a schematic diagram showing the receiver 172 engaged with the electrostatic chuck 202.
The exemplary receiver 172 includes an interconnected electronics housing 161 as shown.
0, a vacuum manifold housing 1620, and a gasket 1630. The electrostatic chuck 202 is engaged with the receiver 172 via the gasket 1630. Substrate 80 (not shown in FIG. 9) is releasably secured to electrostatic chuck 202. The electronic component housing 1610 includes an electrostatic chuck 202.
(Which will be described in more detail later in this specification).

A low pressure (eg, partial vacuum) is supplied to the passage 1622 of the vacuum manifold housing 1620 via an inlet fitting 1621 and a passage outlet (not shown). Passage 1622 directs low pressure to a “through hole” in electrostatic chuck 202. The substrate 80
Opening of gasket 1630 (not shown in FIG.
31) is exposed to such low pressure. The low pressure releasably secures the substrate to electrostatic chuck 202. Receiver 172, electrostatic chuck 20
2, the substrate 80 and the cover layer 90 will be described in more detail below.

In the illustrated embodiment, the substrate and cover layers are connected to the input / output substation 12.
0A, 120B, 120C and preferably attached to a frame.
New More specifically, the substrate 80 is mounted on a frame 81 forming a substrate assembly 82.
The cover layer 90 is attached to a frame 91 forming a cover assembly 92.
Preferably. As shown in FIGS. 2 and 3, the substrate 80 is a flat film.
The cover layer 90 has an arrangement of hemispherical bubbles or bulges (arranged in rows and columns).
(Preferably placed).

In the exemplary embodiment shown in FIG. 7, the first input / output substation 120 A contains the substrate assembly 82, the second input / output substation 120 B contains the cover assembly 92, and the third input / output substation 120 B The / output substation 120C houses the interlocked frames 81, 91 containing the bonded / laminated substrate 80 and cover layer 90.

As will be described further below, the frames 81, 91 allow the substrates 80, 90 to
It effectively helps to match the various elements of zero. Both frames are preferably made of a suitable material that is "lightweight" and strong, such as aluminum. A frame that is considered suitable for use in connection with the present invention is a rectangle having a short side of about 200 mm and a long side of about 300 mm, and all sides having a thickness of about 12.7 mm. ing.

FIG. 10 shows the first surface 204 of the electrostatic chuck 202. The electrostatic chuck 202 has a layer 203 of a dielectric material such as, for example, a Kapton® brand polyimide film commercially available from Dupont de Nemours (Wilmington, Del.). Electrostatic chuck is about 0.01 inch (0.25mm)
And thus have relatively high flexibility. Exemplary electrostatic chuck 2
02 has a "through hole" ECH implemented as a slot located around it. Other suitable shapes for "through holes" in electrostatic chucks are disclosed in U.S. patent application Ser.
No. 95,321. The first surface 204 further has a plurality of powder collection zones CZ. In the exemplary electrostatic chuck 202, collection zone CZ is organized into eight columns 207 _C! ~207 _C8 to each of the collection zone of 12 units, it is preferable to having a total of 96 collection zone CZ. As will be described later herein, each collection zone CZ corresponds to a powder deposition location on a substrate (see substrate 8 in FIG. 1). The collection zone CZ is formed in the electrostatic chuck 202 by the structure of the dielectric and conductive regions,
Some embodiments thereof are described later herein in connection with FIGS. 12A-12C.

FIG. 11 shows the second surface 206 of the electrostatic chuck 202. FIG. 12A
As shown in more detail in FIG. 12C, the collection zone CZ is
Is formed through. Such electrical contact pads 208 form contacts for connection to a controlled voltage source. The electrical contact pad 208 is electrically connected to another selected electrical contact via the address electrode 210.

The individual electrical contact pads 208 and a selected group of these contact pads (eg, pad 2 in a given row 207 _C! -207 _C8 of the exemplary chuck 202 of FIG. 11)
08 form an exemplary group), a first voltage is applied to the contact pads 208 of the column 207 _C! While a second voltage different from the first voltage is applied to the second electrode 207 _C! is applied to the contact pads 208 of the column 207 _C2, hereinafter, if desired, the voltage applied to the contact pads 208 on each column is changed. It will be appreciated that the application of such different voltages to such different rows will deposit different amounts of powder in the collection zone CZ of each such row. It will be appreciated that in other embodiments, the address electrodes have different configurations and form electrical interconnections between groups of differently configured contact pads 208. In the layout of contact pads 208 and address electrodes 210 shown in FIG. 11, the voltage is applied to a single unit in a given column 203 so that substantially the same static charge is formed on each contact pad in the column. Contact pad 208
It only needs to be applied to only one.

FIGS. 12A-12C illustrate some exemplary embodiments of structures suitable for forming a collection zone CZ in an electrostatic chuck, such as electrostatic chuck 202.
For clarity of illustration, FIGS. 12A-12C show structures associated with only a single collection zone CZ of the electrostatic chuck.

In the first embodiment shown in FIG. 12A, conductive material 305 is disposed through dielectric layer 303 in each region designed to be a collection zone CZ. The conductive material rests on portions of the first surface 304 and the second surface 306 of the electrostatic chuck. The portion of the conductive material 305 resting on the first surface 304 has a powder suction electrode 307A, while the portion of the conductive material 30 resting on the second surface 306.
Part 5 has an electrical contact pad 308A (similar to the previously described electrical contact pad, such as contact pad 208 shown in FIG. 11). A shield electrode 312 (also referred to as a “ground electrode” based on a priority bias) is disposed within layer 303.

When an electrode is applied to the electrical contact pad 308A, an electrostatic field is generated at the powder suction electrode 307A in the collection zone CZ. The electrostatic field causes the charged powder to be attracted to the substrate (eg, substrate 380), as described later herein. Also, the electrostatic field assists in holding the substrate 380 flat against the first surface 304 of the electrostatic chuck. Substrate 3
The low pressure created in the vacuum manifold housing 1620 (see FIG. 9) where the 80 is exposed also helps to adhere the substrate 380 to the electrostatic chuck. The firm attachment of the substrate 380 to the electrostatic chuck increases the reliability of the powder deposition in the collection zone.

FIG. 12B shows a through hole E in the electric contact pad 308B and the powder suction electrode 307B.
2 shows a second exemplary embodiment in which CH is formed. FIG. 12C shows a third exemplary embodiment in which the powder suction electrode 307C and the base substrate 380 are separated by an additional layer 314 of dielectric material. Electrical contact pads 308C are provided on second surface 30 of layer 303.
6 on.

The electrostatic chuck having the configuration shown in FIG. 12C is a “pad indent chuck (Pad
Indent Chuck), which is effective for performing a powder deposition of, for example, about 2 mg or less, and preferably about 100 μg or less per one collection zone CZ (for example, the collection zone is in the range of 3 to 6 mm). Assume that it has a diameter). The electrostatic chuck having the structure shown in FIG. 12A is called “Pad Forward Chuck”.
ard Chuck) ", which is, for example, one collection zone CZ
Suitable for carrying out about 20 μg of powder deposition per (again, assume that the collection zone has a diameter of about 3-6 mm). For high dose deposition, a pad forward chuck is more effective than a pad indent chuck.

From the foregoing, it is clear that the voltage source must be electrically connected to the powder suction electrode (commonly referred to by the reference numeral “307”). FIG.
Shows a configuration for making such a connection. FIG. 13 shows the receiver 172 engaged with the electrostatic chuck 202 as shown in FIG.
It is the perspective view seen from the direction.

The electrical connection to the powder suction electrode 307 is made via a connecting pin. Each articulated pin 1623 has a pin 1627 and a lower pin assembly 1624. Pin 1627 is valid for standard circuit boards. As shown in the side view of FIG.
The lower pin assembly 1624 has a slot 1625 for receiving a pin 1627. The pin 1627 is connected to a slot (not shown) of the pin connector board 1611. As will be described in further detail herein, the pin connector board 1611 is electrically connected to a controlled voltage source. Connecting pins 1623 pass through holes (not shown) in electronic component housing 1610, holes (not shown) in vacuum manifold housing 1620, and holes 1632 (see FIG. 15) in gasket 1630, and the Make contact with contact pads (not shown in FIG. 13). Such an electrical contact pad may be, for example, the second surface 20 of the electrostatic chuck 202.
11 as pads 208 located in FIG.
See also pads 308A-308C).

A conductive adhesive, such as conductive epoxy, is applied to the lower pin assembly 1624 so that the adhesive bonds the lower pin assembly to the electrical contact pads. The notch 1626 of the lower pin assembly 1624, as shown in the plan view of the lower pin assembly 1624 shown in FIG. 16, prevents excess conductive adhesive from flowing into the area where the lower pink contacts the electrical contact pads. To do.

The above configuration for making an electrical connection to the powder suction electrode 307 effectively prevents deformation of the electrostatic chuck 202 that is relatively susceptible to deformation in most embodiments. When the electrostatic chuck is deformed, the substrate attached thereto is also deformed, so that it is effective to prevent such deformation. Since the powder is preferably deposited on a "flat" substrate,
Deformation of the substrate is not preferred. Thus, from the teachings of the present invention, those skilled in the art will be able to conceive other configurations for making an electrical connection to the powder suction electrode, but such configurations are effective in preventing deformation of the electrostatic chuck. is there.

As shown in FIG. 15, gasket 1630 has a slot 1631 that allows low pressure to be transmitted to electrostatic chuck 202. Gasket 1630 allows articulating pin 1623 to be inserted into gasket 1630, as described above. Preferably, gasket 1630 has a withstand pressure of at least about 2,000-2,500V. In one embodiment, gasket 1630 is coated on both sides with an adhesive. A suitable material for use as gasket 1630 is 0.004 inch (0.1 mm) thick graphic arts paper coated on both sides with a dry rubber-based adhesive. Such papers are commercially available from Cello-Tak (Island Park, NY).

FIGS. 17-22 show an exemplary embodiment of a receiver 172 and a structure for coupling the receiver to the first robotic transport element 170 in further detail.

FIG. 17 shows a lower surface 1730 of the receiver platform 1720 of the exemplary receiver 172 to which the electrostatic chuck 202 is adhered. The electrostatic chuck 202 has alignment means 240, such as pins or holes, which are aligned with complementary holes or pins 1629 (see FIG. 18) of the receiver platform 1720. Additionally, alignment pins 1650 received in complementary holes in support bench 110 to align receiver 172 with various processing stations (eg, deposition station 150).
Are also shown. An adjustable height vacuum cup 1670 is advantageously used to attach a substrate frame (not shown) to the receiver.

FIG. 18 shows lower surface 1730 of receiver platform 1720 with electrostatic chuck 02 removed. In FIG. 18, a low pressure is applied to the through hole ECH of the electrostatic chuck 202.
(The through hole ECH is not shown in FIGS. 17 and 18. FIGS. 10 and 11)
A passage 1622 and a passage outlet 1628 leading to the same. Pin conduit 1
623A allows articulating pins 1623 to be threaded through the electrical contact pads of electrostatic chuck 202. FIG. 18 further shows alignment means 1 that allows, for example, an alignment pin or alignment pin receiver to engage alignment means 240 of electrostatic chuck 202.
629 is shown.

FIG. 19 shows a top surface 1710 of the receiver platform 1720. The receiver platform 1720 has a passage outlet 1628, a pin conduit 1623A, and a molding forming a reinforcing brace 1780. As shown in FIG. 20, brace 1780 on top surface 1710 includes processor board 1614, address board 1615, and high voltage board 1612 (ie, a bias generation board).
And support. The electric communication to the electronic components arranged other than the receiver 172 is as follows.
This can be done via port 1616. Tube connector 1627B couples receiver 172 to an external vacuum source that generates low pressure, such as through vacuum manifold housing 1620, to bond substrate assembly 82 to electrostatic chuck 202.

FIG. 20 also shows a receiver platform 1720 (electrostatic chuck not shown).
A substrate frame, such as substrate frame 81, engaged with a lower surface 1730 of FIG. Substrate frame 81 includes alignment means 52 that suitably engages complementary alignment means of alignment station 130.

FIGS. 21 and 22 illustrate the structure in which the receiver 172 is engaged with the robot transport element 170 (see FIG. 8) and other features associated with the receiver 172. FIG. 21 is a sectional view taken along the section line shown in FIG.

In the exemplary embodiment shown in FIGS. 21 and 22, the receiver 172 is connected to the first robot transport element 170 (not shown here) via the bearing housing 1120.
Attached to. The bearing housing 1120 is connected to the spline shaft 112.
1 and a spline shaft bearing 1122. The bearing housing 1120 is connected to the floating bolt assembly 1 via a spring-loaded coupling 1130.
640 (see FIG. 22). The floating bolt assembly 1640 is attached to the receiver cover 1660 via a bush 1641, which can be comprised of a viscoelastic insulating bush. Such a viscoelastic insulating bush is made of, for example, So
It can be made of Sorbothane® brand insulation damping material commercially available from rbothane Inc. (Kent, Ohio). The viscoelastic insulating bush 1641
When the receiver locating pins 1650 (see FIG. 17) are inserted into the alignment holes provided in the support bench 110, they can be moved slightly as needed. Therefore, when the base substrate 80 is subjected to dry deposition at the deposition station 150, the mounting accuracy (± 2 mil) of the robot head 170 can be increased to ± 0.5 mil. Floating bolt assembly 1640 may be configured such that receiver 172 includes x, y or z
It follows an alignment action acting in the direction along the axis.

In the embodiment shown in FIG. 21, the receiver 172 is a pin connector board 1611
, A high-voltage board 1612, a high-voltage chip area 1613, and a processor board 1614. In another embodiment, the processing is coordinated by a processor located somewhere on the robot platform 101. High voltage barrier wall thickness 1
661 isolates the high voltage region of the receiver 172. The example receiver 172 further includes a vacuum tube 1627 and a first tube connector 1627A that connects the vacuum tube 1627 to an inlet fitting 1621 (see FIG. 9) of the vacuum manifold housing.
And the above-mentioned second tube connector 1627B.

The substrate frame 81 to which the substrate 80 is attached is shown to be bonded to the lower surface of the receiver 172 (the electrostatic chuck 202 is not shown). As will be described later, the frame is composed of a post-deposition measurement device.
To ensure that they are consistent with The vacuum cup receiving fixture 51 located on the substrate frame 81 receives an adjustable high vacuum cup 1670 with vacuum engagement. The vacuum hose fitting 1671 connected to the vacuum system includes a vacuum cup 1670
Is in fluid communication with

A portion of receiver 172 (eg, receiver cover 1660 in FIG. 22) is preferably made of a durable, non-conductive material, such as plastic. An example of a suitable plastic is Noryl® brand polymer, commercially available from GE Plastics (Pittsfield, Mass.). Noryl® engineering plastics include modified polyphenylene oxide or polyphenylene oxide and polyphenylene ether resins. Modifiers for these resins include blends with a second polymer such as polystyrene or mixtures of polystyrene and butadiene. By changing the blend ratio and other additives,
Various polymer grades can be made. These unmodified polymers are characterized by regularly spaced small ring structures of the main molecular chain (ie, phenyl groups). This feature, combined with strong intermolecular attraction, causes extreme stiffness and lack of mobility. The use of Noryl (R) brand plastic or its equivalent provides the receiver 172 with strength that assists in forming a strong, flat support for the electrostatic chuck 202. The surface of the receiver 172 on which the electrostatic chuck 202 is mounted is preferably machined to a flat surface, for example, to ± 0.001 inch (0.025 mm). In addition, the feature that the weight of the plastic is small keeps the weight load acting on the first robot transfer element 170 small. Electronic Control of Electrostatic Chuck As described above, the apparatus 100 preferably has a central processor 401 and a controller 403 for performing calculations, control functions, and the like (see, for example, FIG. 6). Processor 401 accepts performance inputs from a number of sources, including, for example, on-board sensors and historical data from dosing station 140, and uses this information to adjust operating parameters to maintain powder deposition within specifications. Decide if you should. Such inputs include, for example, data regarding the amount of powder flux entering and passing through the deposition engine (formed at powder feeder 801 and deposition station 150) and the degree to which powder is uniformly deposited on electrostatic chuck 202. There is. The "on-receiver" electronics described below, alone or in cooperation with the processor 401 and the controller 403, form a means for adjusting the device 100 during operation.

When the processor 401 has a main responsiveness to process a function, the receiver 1
Processor board 1614 located within 72 can function as a communication board that receives commands from processor 401 and relays such commands to address board 1615. In some embodiments, the processor board 1614 receives data from a sensor, such as a charge sensor 1690 located at or adjacent to the electrostatic chuck 202 (see FIG. 18, where the charge sensor 1690 is (Shown by dashed lines). Charge sensor 1690 is an on-the-receiver device that monitors the amount of powder deposited. The processor board 1614 includes a powder suction electrode 307 (e.g., the respective electrodes 307A to 307A of FIGS. 12A to 12C).
By appropriately adjusting the voltage applied to 7C), the data from the charge sensor 1690 is interpreted and responsive to the data. The charge sensor is described further below. It is also disclosed in US patent application Ser. No. 09 / 095,425.

After receiving the signal from the processor board 1614, the address board 1615 sends a bias control signal (eg, D) for controlling the voltage at the powder suction electrode 307.
C or AC signal). Depending on the addressing scheme (e.g., the structure in which the individual electrical contact pads 208 are interconnected via the address electrodes 210), the voltage can be regional (e.g., defining rows and columns) or individually the powder suction electrodes 307 Is applied to

The address board 1615 preferably has multiple channels of synchronous outputs (eg, square wave or DC). The signal sent to the address board is coded, for example, in the form of a square-wave voltage pulse having a variable amplitude,
Cooperating with the appropriate voltage supplied to 07, the powder suction electrode 307 or group of these electrodes can be identified.

The bias control signal is sent out through the high voltage board 1612. The high voltage board 1612 is preferably a high voltage converter (transformer or high voltage DC-DC) that generates a voltage of 200 V or 2,500-3,000 V with either polarity to energize the powder suction electrode 307. Converter). Such high voltages are preferably formed in receiver 172 such that other systems are isolated from receiver 172. Charge Sensor The charge sensor 1690 uses a pulsed (AC) potential waveform to bias an electrostatic chuck to collect powder on the substrate 80, as disclosed in U.S. patent application Ser. No. 09 / 095,425. Is preferred. This bias waveform solves the problem of collecting powder on a conductive substrate because the powder attraction electrostatic field quickly disappears after the application of any given bias potential to the electrostatic chuck.

The use of an AC bias waveform for the powder suction electrode also solves another long-standing problem during deposition detection. More specifically, during deposition detection, one or more collection zones CZ are closely monitored for powder accumulation so that the powder deposition process (eg, making accurate dosing) can be adjusted. Such monitoring is accomplished optically by measuring the accumulated charge using an "on-board" charge sensor in the collection zone where the sensor is located. The accumulated charge is related to the actual charged powder deposition by empirical data collection. With dry powder deposition, such monitoring is often a very difficult task, especially for doses below 1 mg.

The difficulty lies not in the accuracy of the measuring device, but in various practical environmental factors that reduce the magnitude of the measuring sensitivity by a few orders of magnitude. With a quasi-static DC biased transporter chuck, on-board charge detection is particularly difficult. Data obtained by depositing on a polypropylene film substrate at different potentials indicates that if this potential is above a certain threshold, the deposited dose has a linear relationship to the bias potential. The data indicates that at least for some transporter chucks, the threshold potential is about 100-200 VDC.

FIG. 40 shows one equivalent circuit diagram that can perform AC biased charge and deposition detection for at least one collection zone CZ with floating pad electrodes. The floating pad electrode is configured to create a powder attraction field emanating from the floating pad electrode by indirectly biasing the powder attraction electrode (e.g., the respective powder attraction electrodes 307A-307C shown in FIGS. 12A-12C). An isolated conductor designed to be connected to a powder suction electrode via a capacitor.

An exemplary electrostatic chuck / substrate structure consistent with the equivalent circuit of FIG. 40 has flat electrodes used to create a powder attraction field. The underside of this flat electrode
The first dielectric layer is attached to the upper surface so as to be parallel to the upper surface.
Suitable dielectric materials include Pyrex 7740, available from Corning, Inc., or about 1
There are polyimide resins having a thickness of 0-20 mils. The flat electrode and the flat first dielectric layer are attached to each other using various suitable methods, such as, for example, lamination, powder deposition or thin film deposition. A flat shield electrode is attached to the lower surface of the first dielectric layer. The shield electrode has a hole for accommodating the floating pad electrode so as to be coplanar with the shield electrode and surrounded by the shield electrode.

The one or more CZs are generally dedicated to detection only, or are not strictly monitored in broad applications. By measuring the decrease in the suction potential V _BCZ that occurs when the charged powder is deposited on the collection zone CZ, the deposited charge can be measured.
Knowing the average charge / mass ratio q / m of the deposited powder, the accumulated powder deposited mass can be determined. Although V _BCZ can be measured directly across the charge collector electrode, it is usually preferable to measure the potential across a coupling capacitor, such as the floating pad electrode described above.

The coupling capacitor, as embodied as the floating pad electrode, provides a reasonable and accurate reproduction of the potential at the collection zone CZ on the substrate surface. Such accurate reproduction is shown by _examining the waveform 3602 of V _BCZ and the waveform 3604 of V _{Pad F} shown in FIG. The waveforms 3602 and 3604 include an RC decay (RC decay).
) Clearly appears. Waveform 3606 represents the pulsed bias voltage V _g. Whether using a charge collector or a charge coupled capacitor, these are considered charge sensing electrodes.

In the equivalent circuit of FIG. 40, the charge collector / coupling capacitor CC is electrically connected to another detection capacitor SC. The voltage generated across the sensing capacitor SC is a reliable indication of the potential V _BCZ . Such voltages are, for example, as shown schematically in the drawings, Keithley model numbers 614, 6512, 6
It can be measured with an electrometer M, such as a 17, 642, 6512 or 6517A electrometer. In general, the coupling capacitor CC is any electrode that is capacitively connected to the powder collection zone on the contact surface.

Applying a DC bias can stabilize the drift of the potential reading across the detection capacitor. Such drift is primarily due to spontaneous leakage across the dielectric material of the sensing capacitor and leakage of charge in the powder accumulated on the substrate or chuck. Drift also includes shot noise, Johnson (1 /
f) Induced by noise factors such as white noise, thermal noise, Galvanic noise, triboelectric noise, piezoelectric noise, amplifier noise, and electromagnetically induced noise. Paul Horowitz and Winfield Hill, "Electronics Technology (The
art Electronics) "(2nd edition, Cambridge University Press, 1989).

If the drift is large compared to the actual charge collected in the collection zone CZ, the accuracy of the charge sensor as a measuring device is unacceptably low. The use of the AC bias type waveform disclosed in the present application can effectively reduce the introduction of drift. Such reduction is achieved in a manner similar to that described above, which prevents "drift" of charge dissipation in the powder collection zone and facilitates accurate measurement of collected charge.

In FIG. 40, the AC bias source B is the same source as described above, and has an AC bias potential applied or applied via the powder suction electrode. This AC bias source B
Is electrically connected to the floating pad electrode or the collection zone itself when connected directly to the sensing capacitor as shown.

As an example, if the detection capacitor SC is selected as 0.1 μF and the q / m of the powder as 10 μC / g, a signal change of 100 mV at the charge collector / coupling capacitor CC will be deposited on the collection zone. 1 mg of powder. For example, if the linear correlation factor is 3, 1 mg of powder on the sensor corresponds to the actual deposited dose of 3 mg of powder. Thus, a working amount of 99 μg has a detectable 3.3 mV potential change. Even if the allowable error is 5%, the effect of the corresponding unpredictable background noise is 160
Never exceed μV. This can be achieved by careful shielding and grounding design. The charge collector is preferably integrated with the chuck design to ensure a consistent correlation.

In fact, the drift of the charge detection circuit can be reduced with the same benefits obtained using a Vg AC bias waveform that prevents charge loss on the substrate.

FIG. 42 shows another possible equivalent circuit for AC biased charge and deposition detection. The example circuit of FIG. 42 includes an AC bias source B, an electrometer M, and a detection capacitor SC.
Alternatively, noise can be reduced by separating it from the charge collector / coupling capacitor CC. All these components are also sensitive to marginal noise.

As shown in FIG. 42, the AC bias source B is connected to the primary side of the transformer T. In this embodiment, the periodic magnetic field generated by Vg (not Vg itself)
Introduced to the "sensitive" part on the right side of the drawing. A stabilizing bleed resistor R is connected across the secondary winding of the transformer T, one of its poles (ie the bias pole BP) is connected to the charge collector / coupling capacitor CC. , The other pole (that is, the detection capacitor pole CP) is connected to the detection capacitor SC. To further reduce noise, the detection capacitor SC is grounded. Electrometer M
Measures the voltage change of the detection capacitor SC with respect to the ground as shown. To further reduce electromagnetic noise, the two ground points can be combined. The transformer T can be constituted by a step-up transformer, whereby the composite AC bias waveform supplied to the transformer and the powder suction electrode can be generated at low cost. For example, a setup ratio of 50 is suitable for use. Conventionally, a coupling current of 100 picoamps or less has caused the problem of drift and noise, but such a configuration significantly reduces the drift and enables more accurate detection of the accumulated charge.

In one embodiment, the transformer T is an insulated transformer in which the primary winding and the secondary winding are separated by a Faraday cage. This prevents the coupling between the primary winding and the secondary winding. The primary winding functions as one capacitor plate, and the secondary winding functions as the other capacitor plate.

As a result of the excellent signal / drift ratio obtained with the teachings of the present invention, the amount of charge detected can be significantly reduced. The measurement was performed using a 1000 picoF capacitor as the detection capacitor instead of the conventionally used 0.1 μF capacitor. Also, the AC bias source B used in the circuits shown in FIGS. 40 and 42 supplies another AC bias to the collector / coupling capacitor CC directly through a dedicated wire, electrode, bus, or the like, so that the chuck can be chucked. From the AC waveform bias Vg. Such another AC bias frequently matches or mismatches Vg to ensure a consistent correlation of the behavior of the charge collector / coupling capacitor CC to the actual deposition.

The above structure preferably allows Vg to be biased at much higher voltage peaks than previously possible. A 8000 molecular weight polyethylene glycol was used as the substrate and a bias peak of 2 kV was used. It should be understood that a wide range of transporter chucks that operate with bias electrodes exposed directly on the powder contact surface (ie, the substrate) can be used, as shown in FIGS. 12A and 12B. Alignment Station As described above, the electrostatic chuck 202 (the electrostatic chuck engaged with the receiver 172 and the first robotic transport element 170) engages the frame 81 containing the substrate 80 at the input / output station 120A, and then Supply the frame 81 to an alignment station 130 (eg, FIGS. 7, 8, 9 and 21). At the alignment station 130, the frame 81 is released from the electrostatic chuck 202 / receiver 172 so that the alignment means 52 of the frame 81 (FIG. 20) complementarily engages an alignment mechanism (not shown) at the alignment station. I do. Such alignment means may comprise, for example, pins of the frame 81 that are received in the holes at the alignment station 130.
The frame 81 is then re-engaged with the electrostatic chuck and receiver, so that
The substrate assembly 82 is aligned within the accuracy of the robot transport element 170 (ie, ± 0.002 inches (mm)).

In one embodiment, a viscoelastic pad (not shown), such as a foam rubber pad, is provided at the alignment station 130. When the substrate assembly 82 is re-engaged, the substrate 80
Is pressed against the pad to remove any air pockets formed between the substrate 80 and the electrostatic chuck 202. When the substrate 80 is pressed against the pad, the substrate-bonding vacuum of the receiver 172 is energized, and the powder suction electrode 307 is also energized to assist in adhering the substrate to the electrostatic chuck 202.

The alignment station 130 improves the alignment of the substrate with respect to the electrostatic chuck, especially in the presence of an environment that causes misalignment. One such environment occurs when a substrate frame (eg, substrate frame 81 or 91) is overlaid on another frame at an input / output substation. It will be appreciated that as the frames are successively superimposed, the frames will deviate from the proper alignment. The robot transport element (eg, element 170 or 180) is a vacuum cup 1670 (FIG. 22).
Misalignment may occur when engaging the frame via clamping means (see, eg, US Pat. Using the alignment station 130, the alignment accuracy is improved within the positioning accuracy of the robotic transport element (at the alignment station 130), and the substrate 80 is positioned with the required accuracy, for example, during a deposition operation. The alignment station 130 advantageously provides the second benefit that the viscoelastic pad facilitates intimate contact between the electrostatic chuck 202 and the substrate 80.

The second robot transport element 180 engages the frame 91 containing the cover layer 90 and uses the alignment station 130 in the manner described above to localize the frame 91 (lo).
calization). The second robot transport element 180 moves the cover assembly 92 to a stack support block 1901 (see FIG. 23; the frame 91 is not shown) and places it on the block 1901.

The alignment means is suitable for processing substrates in batch or piece form, as shown in the exemplary embodiment. Alignment issues are effectively addressed in different ways in the context of continuous machining operations. For example, if the substrate is placed on a tape in a continuous process, the frame will periodically lock onto the tape as the substrate is processed through a portion of the apparatus of the present invention where alignment issues are particularly important. Is done. To give such a process the ability to adjust, a small amount of loosely attached tape can be used between the locked frames, which allows the spacing between the frames to be adjusted based on alignment considerations. .

The deposition station 150 and the dosing station 1 where alignment is particularly important
Framing and alignment considerations for 40 are discussed further herein. In one embodiment of the deposition engine , after the substrate assembly 82 is aligned at the alignment station 130,
The first robot transport element 170 moves the substrate assembly to the deposition station 150. In another embodiment, the substrate assembly 82 is initially
, Whereby the baseline optical data is recorded prior to the powder deposition operation, and then the robotic transport element 170 moves the substrate assembly 82 to the deposition station 150.

The robot transport element 170 is rotated 90 ° at the deposition station 150 to align the frame 81 of the substrate assembly 82 with the deposition opening 158 (see FIG. 7). Locating pins 1650 (FIGS. 17 and 22) are used to establish alignment between receiver 172 / electrostatic chuck 202 / substrate assembly 82 and deposition opening 158.

FIG. 24 illustrates an exemplary deposition engine 800. Deposition engine 800
Has a deposition station 150 and an exemplary powder supply 801. Deposition engines have a variety of problem handling capabilities. Such problems include, for example, powder compaction, non-uniform powder flux, powder loading, operational stability and powder size limitations, among others. In some applications, such problems can be addressed by modifying the powder. However, the present invention is particularly useful for applications such as drugs where little or no modification of the powder is possible without causing regulatory problems. Therefore, the deposition engine itself must be designed to avoid such difficulties. Various components of the exemplary deposition engine 800 can improve the deposition operation, thereby reducing powder compaction and providing a more uniform powder without modifying the powder surface as is often the case in other applications. Flux, ease of powder loading, excellent work stability, possibility of using a wide range of powder particle sizes, and powder flow are obtained.

The illustrated powder supply device 801 includes an auger rotation motor 804, a hopper 806, a vibrator 808, an auger 810, a clean gas source 814,
An improved venturi feeder valve 812, a powder charging supply tube 816, a powder discharge tube 818, a powder trap 820, a high efficiency particle air (High Efficienc).
y Particulate Air (HEPA) filter 822. Powder supply device 80
1 is substantially disposed within an enclosure 802 shown in dashed lines for clarity.

In operation, auger 810 is rotated by auger rotation motor 804 to supply powder to Venturi feeder valve 812. Satisfactory rotational speeds for such purposes are in the range of about 10-80 rpm. An improved Venturi feeder valve 812 with a Venturi well supplying powder in a substantially linear path from the auger feed (ie, hopper 806) to the powder charging supply tube 816 was used. Such an improved valve prevents powder compaction, which tends to occur when powder falls to the bottom of a standard structure venturi well. The venturi well should be accessible to periodically evacuate, for example, by loosening the screws.

The vibrator 808 is preferably used to maintain a free flow of the powder, and the vibration intensity is set to a level that does not cause substantial agglomeration of the powder. Although the vibrator is shown acting on the hopper 806, it can be mounted on a shaft that drives a mechanical powder drive such as the auger 810.

When gas from a clean gas source 814, such as nitrogen, flows into a modified Venturi feeder Venturi 812, powder is withdrawn from the auger 810.
Such a gas also serves to extrude the powder through the powder charging supply tube 816. An improved venturi suitable for use in powder feeder 801 is
Commercially available from Vaccon Company, Inc., through Air Oil Systems (Mainland, PA) or Berendsen Fluid Power (Rahway, NJ).

Instead of the Venturi, the powder is supplied by a gas source into the powder charging supply tube 81.
6 can also be propelled. In one embodiment, gas source 814 directs gas pressure to the outlet of a mechanical device that supplies the powder. The gas jet can be oriented and adjusted so that the powder does not agglomerate at this outlet.

In order to perform electrostatic deposition, the powder must be charged. In one embodiment, the powder charging supply tube 816 is made of a material that can impart an appropriate charge to the powder by tribocharging by periodic collision with the inner surface of the tube as the powder passes through the tube. As is known in the art, TEFLON® and perfluoropolymers can be used to impart a positive charge to the powder (powder material can be suitable), and to impart a negative charge to the powder. Nylon (amide based polymer) can be used. When the powder is so charged, the tube generates a charge that is discharged by arcing when not needed. Therefore, the powder charging supply tube 8
The outer surface of 16 is provided with a conductive wrap or coating and is grounded. The tube 816 can be wrapped with, for example, aluminum or copper foil, or
Colloidal graphite product coatings such as Aquadag®, commercially available from oid Co. (Port Huron, Minn.). Alternatively, the powder charge supply tube 816 comprises a composition comprising graphite or other conductive particles such as copper or aluminum, an adhesive polymer, and a carrier solvent mixed in an amount that adequately maintains the "stickiness" of the adhesive polymer. It can also be coated with an object. One example of such a composition is 246 g of trichlorethylene, 30 g of polyisobutylene and 22.5 g of graphite powder.

The charge removed by the above grounding procedure can be monitored to measure the powder flux through the powder charging supply tube 816. This data is advantageously sent to a processor for analysis. As a result of this analysis, the deposition operation parameters can be modified appropriately to maintain in-spec operation. An example structure suitable for performing such monitoring will be described later.

In one embodiment, a capacitor is placed in series with the powder charging supply tube 816. The capacitor reduces the potential generated by the charge collected in tube 816. A 1 μF capacitor generates a voltage of 1 V when charged at 1 μC. The other pole of the capacitor is grounded. The capacitor brings the potential of the powder charging supply tube 816 close to the ground potential. The electrometer connected to the capacitor
Make an accurate measurement of the collected charge. For a powder charged to 50 μC / g, 1 μC corresponds to 20 mg of powder. The powder charging supply tube 816 can be biased. With a bias of 500 V, a noise of 10 pA is expected, creating 3 nC uncertainty at 3 minute intervals. Even with such a bias, such a system would have an error in measuring 20 mg of powder as small as 0.3%.
Controlling the conductivity of the ground wrap or coating results in a drop in potential along the powder charge supply tube 816, creating an electric field that facilitates the attraction of charged powder through the tube, while at the same time providing a great opportunity to pick up charge. Give to charged powder.

Another method of imparting charge to the powder is “inductive” charging. Induction charging 1
One way is to incorporate an inductive-charging region in the powder charging supply tube 816. More specifically, at least a portion of the powder charging supply tube 816 is made of a material such as stainless steel, which is biased by one pole from a power supply and the other pole is grounded. By applying an appropriate bias, an electric field is created in the inductive-charged area so that powder passing through the inductive-charged area can pick up the charge. The length of the induction-charge zone can be adjusted to the length needed to impart the desired amount of charge to the powder. In one embodiment, induction charging is used in combination with the tribocharging.

The powder charging supply tube 816 supplies the charging powder to the deposition station 150 via the nozzle 152. The deposition station 150 is surrounded by an enclosure 154 made of, for example, an acrylic panel. Advantageously, the nozzle 152 is provided with a rotating baffle 153 that enhances the uniformity of the powder cloud generated within the deposition station 150. The rotary baffle 153 is driven by the nozzle motor 151.

An example nozzle 152 with a rotating baffle 153 is shown in more detail in FIGS. 25 (plan view) and 26 (side view). The rotating baffle 153 has a baffle disk 1552, which is supported by three radially extending baffle supports 1551 that are spaced apart from one another. The baffle disk 1552 has a baffle outlet 1553 through which the powder passes. In the embodiment shown in FIG. 26, which is drawn to substantially full scale, the height BH of the rotating baffle 153 is about 0.72 inches (18 mm).

The powder is supplied through nozzle 152, for example, by a gas supplied at a pressure of about 20 psi and at a flow rate of about 2.5 liters / minute. The gas is preferably substantially free of moisture, oils and other impurities, and is preferably a chemically inert gas such as nitrogen or helium. The baffle 153 is about 1/4 to 1/2
It is useful to place the powder charging supply tube 816 above the outlet by an amount in the range of inches. Further, the baffle 153 preferably has a larger diameter or cross section than the outlet of the powder charging supply tube 816. For example, if a 1/4 inch diameter powder charging supply tube 816 is used, the diameter cross section of the baffle 153 can be 1/2 inch. To obtain the desired high uniformity of the powder cloud, the baffle 153 should rotate at a speed in the range of about 5-25 rpm.

Referring again to FIG. 24, the substrate assembly 82 and the electrostatic chuck 202 (FIG. 24)
Are not shown), a gasket 159 forming a deposition opening 158
Abut. The powder moving toward the collection zone CZ of the electrostatic chuck 202
It passes through the control grid 157. Control grid 157, from the collection zone downward, for example in polarity about 1/2 to 1.0 is arranged at a distance d _grid inch, and intended to powder, the distance d 1/2 per about 500V of _grid Preferably, a bias is applied. Thus, the control grid 157 "points" the powder cloud (in the direction of the charge on the control grid) that attracts the oppositely charged powder.

The control grid 157 can be formed, for example, by a “switchback” of a single wire or a series of parallel conductive lines formed from a grid of wires. The spacing between the parallel sections of wire is preferably in the range of about 5 to 15 mm.

The speed of the powder cloud can be monitored by measuring the light decay between light emitter 155 (eg, a laser light emitter) and light detector 156. This value is
1 can be transmitted.

The powder not used in the deposition station 150 is supplied to the powder suction tube 818.
Is sucked back into the powder trap 820 by the pressure difference FIG. 27 shows internal details of a powder trap 820 according to an example embodiment. The powder is supplied to the trap inlet 21
04 enters the powder trap 820. The powder trap 820 includes a series of conductive firsts.
The first baffle 2101 has a conductive second baffle 21.
02 is inserted. To obtain the required conductivity, the first and second baffles are formed of a metal such as copper, stainless steel or aluminum. The first and second baffles 2101 and 2102 are attached to a first trap conductor 2107 and a second trap conductor 2109, respectively. First and second conductors 2
107 and 2109 are attached to the trap body 2103. The trapping body 2103 is formed of, for example, an acrylic polymer (for example, plexiglass).

The first baffle is biased to, for example, + 2000V via a first trapping conductor 2107 that is in electrical communication with the first electrical inlet 2106. The second baffle
It is biased, for example, to -2000V via a second trapping conductor 2109 which is in electrical communication with the second electrical inlet 2108. The powder returned from the deposition station 150 is collected on a reverse charging baffle. If the powder is not charged,
Charge is imparted by a first collision with one baffle, and the powder is drawn into the oppositely charged baffle encountered downstream. Powder trap 8 through powder trap outlet
The gas leaving 20 is a HEPA filter 822 (not shown in FIG. 27; see FIG. 24).
Supplied to The HEPA filter 822 generally contains 0.3 μm powder particles for 99 days.
. It captures with an efficiency of 97%, which allows a relatively small amount of powder to be released into the environment, which is harmful (without dose control) as a bioactive agent.

The deposition process has to be stopped at some point. Such an outage is defined, for example, by a schedule (eg, the amount of powder deposited is controlled by the operating time) or in response to analysis of feedback data from the charge sensor. The amount of voltage drop required for shutdown is varied in relation to the substrate and powder specifications and the amount of powder applied to the substrate. Generally, such a voltage drop is selected to maintain adhesion of the powder to the substrate 80 without causing adhesion of the substrate to the electrostatic chuck 202 and substantial accumulation of powder. For example, to keep the powder but not to attract excess powder, it is sufficient to gradually reduce the 2000V deposition voltage (or the magnitude of the voltage if a pulsed voltage is used) to 400V. is there.

It will be appreciated that other structures or configurations of the deposition station 150 as well as many other elements of the powder deposition apparatus 100 disclosed herein may be suitably used in connection with the present invention. For example, a first variation of the receiver, electrostatic chuck and nozzle (included in the deposition station 150) is the side view of FIG. 28 and the plan view of FIG. In the first variant shown, the receiver 572 is configured as a rotating drum. A similarly configured electrostatic chuck 502 is engaged with the receiver 572. As in the previous embodiment, the substrate 580 contacts the electrostatic chuck 502. Shaft 501 transmits rotation to receiver 572 and (eg, through an internal conduit or the like).
The vacuum and potential are effectively transferred to a collection zone (not shown) of the electrostatic chuck 502. In one embodiment, the shaft 501 has four radially arranged nozzles 552.
(Only two of which are shown in FIG. 28).
Can be actuated to move "up and down". Grid 557 restricts improperly charged powder from accessing the collection zone. Changes in the deposition pattern are minimized by the rotating receiver 572.

It should be understood that the various elements of the powder feeder shown in FIG. 24 can be interchangeably or interchangeably with elements that perform equivalent functions. For example, the hopper and auger structure shown in FIG. 24 can be replaced with a rotating drum that temporarily stores and supplies the powder to a movable belt. In this case, the movable belt conveys the powder to means for removing the powder from the belt. As an example of such means, a powder charging supply tube 816 (FIG. 2)
4) Or there is a thin, high-speed gas jet that blows the powder into a conduit that communicates with the tube.

Alternatively, the powder supply device can be configured in a substantially different manner from the device 801 shown in FIG. Two such other configurations suitable for use in connection with the present invention are shown in FIGS.

FIG. 30 shows that the hopper 907 supplies powder to the gear wheel 9 driven by the motor 903.
5 shows a powder supply device 901 that was supplied to supply the powder supply device 05. Gas stream 909 directs the powder to deposition station 150. The electrostatic chuck 202, electrically connected to the high voltage source HV, is used for the deposition station 1 for receiving the powder in the collection zone.
The position at 50 is shown.

FIG. 31 shows a powder supply apparatus 1001 provided with a fluidized bed 1003. Gas flow 1
009 directs the powder to deposition station 150 through four powder charging supply tubes 1016. Although such four tubes are shown in FIG. 31, more or less tubes can be used as appropriate.

In some embodiments, particularly in embodiments where a dose of about 2-100 μg is applied to a 3-4 mm diameter area, it is preferred to feed the powder using a jet mill. For example, when a potential of 1,800 V is applied to the jet mill, charges can be introduced into the powder by induction charging. As a jet mill suitable for such work, Plastome
Commercially available from the Products Division of Coltec Industrial Products Inc. (Newton, PA) under the TROST® Air Impact Pulverizr trademark. Jet mills operate countercurrently with compressed gas and operate effectively at a flow rate of about 2.0 to 2.2 liters / minute. After the dosing station powder deposition is completed, the first robotic transport element 170 moves the substrate assembly 82 containing the powder support substrate 80 to the dosing station 140 (see, for example, FIGS. 7 and 8). The robot transport element 170 is rotated 90 ° and the frame 81
And the measurement aperture 146 (see FIG. 8). Receiver positioning pin 1650
The receiver 172 and the measurement aperture 146 are adjusted to about ± 0.00 (see FIG. 22).
Align with an accuracy of 05 inches (0.013 mm). Such alignment accuracy ensures that dose measurements are made at the proper location on the substrate 80 (ie, where the powder is deposited).

In embodiments that do not use a frame, such as frame 81 or 91, or a mechanism that ensures consistency of alignment at the deposition station and the dosing station,
Preferably, the dosimetry system has a mechanism for identifying the powder deposition location. In one embodiment, such a mechanism has a video camera that collects the data, and also has appropriate electronics to analyze the video data to determine the boundaries of the deposition. The video camera can be composed of, for example, a CCD.

The dosing station 140 includes a device that measures the thickness (ie, amount) of the powder deposited on the substrate 80. Either of the two (ie, both) optical measurement methods can be used, the diffuse reflection method and the optical profilometer method. Diffuse reflection has been used for many years and characterizes powders using a light source that emits light in the range that is absorbed by the powder. In connection with this technology, a theory for diffuse reflection using unabsorbed radiation has been developed. This theory has its origin in terms for powder layer thickness. Despite such practicality, to the applicant's knowledge, no product based on this theory has yet been developed commercially. Applicants have determined that measurements obtained based on the diffuse reflection method using non-absorbing radiation provide a strong correlation with the amount of powder deposited in unit dosage form, at least to some extent. It is believed that the limiting amount varies with the properties of the powder and corresponds to the amount of powder that prevents light from penetrating into the layer below.

The diffuse reflection method is based on reflecting or scattering a probe beam such as a laser beam from a powder surface in a direction not parallel to the specular reflection direction. Such scattered light is uniformly dispersed throughout. Dose deposits exhibiting this property or behavior are called "Lambert Radiators". This behavior ("Lambertian scattering") is an important property for dose weight measurements. Defined by

As noted above, non-absorbing radiation is used to create diffuse reflection. Common radiation is the visible red line obtained by common gas / 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 relationship: That is,

[0127]

Sd = R / (1-R) [1] where S is the scattering parameter defined by the properties of the particles in the dose stack, d is the thickness of the dose stack, and R is the minimum specular diffusion The measured diffuse reflection of the dose material on a substrate with reflectivity (assuming R _substrate = 0).

Equation [1] is rewritten as the following equation [2].

[0129]

D = (1 / S) [R / (1-R)] [2] where S is assumed to be a constant for a given particle size distribution.

Thus, the thickness of the dose deposit is directly related to the measured diffuse reflectance. If the dose deposit is a Lambert radiator as described above, a measurement of R can be obtained.

FIG. 32 schematically shows the diffuse reflection method for characterizing a dry powder. The light source 3102, for example, a low energy laser, is preferably focused through a beam splitter 3104. Light source 3102 can direct the beam to substrate 80. The substrate 80 is wider than the individual "mounds" of powder deposited on the radiator because there is no powder in the remainder that causes Lambert scattering. Reference beam detector 31
06 assists in determining the quality and intensity of the focused beam.

When light strikes powder 3114 deposited on plate 80, the powder scatters light in all directions. The scattered light SLHT is captured by the detector 3108. Preferably, an array of two or more detectors 3108 is used. Preferably, an amplifier (not shown) is used in connection with the detector. The output from the detector (s) 3108 is then connected to a commercially available A / D converter (not shown). The resulting digital signal is scanned using a computer controlled scanning mechanism 3110. Scanning mechanism 3110 is in communication with processor 401 (not shown in FIG. 32). Processor 401 generates a measurement of the powder thickness profile, and thus the dose weight of the deposit.

In one embodiment, the powder can be deposited on a substrate having a mirror surface where the contribution of the surface of the substrate 80 to the diffuse reflection factor is acceptably small. Also, the substrate 80 should be such that the measurements are not sensitive to diffuse reflections from the back of the substrate or the surface of the receiver 172.
It preferably has light absorbency.

Diffuse reflection in the non-absorbing region gives good accuracy in measuring dose deposition in the range of 50-400 μg, or as large as 750 μg, for 3 or 7 mm deposition dots, depending on the properties of the powder. . Diffuse reflection can detect layers much smaller than a single layer of powder. If the deposition is larger than a single layer, the probe light beam is
The upper layer must be partially penetrated so that reflections from the lower layer affect the upper layer so that accurate measurements can be taken. However, there is a practical limit on the thickness of the deposit (based on the powder) in order to exhibit Lambertian properties. Diffuse reflection is also a measure of the physical uniformity of dose deposition in the above ranges.

The optical profilometer method is effective in obtaining a measured value larger than the range accurately measured by the diffuse reflection method. FIG. 33 is a schematic diagram showing one embodiment of the optical profilometer method. Light such as laser light is emitted from the light source 3202 to the deposited powder 3.
When struck at 214, light is reflected at an angle representing the height of the deposited layer. Height can be easily calculated by triangulation. To improve the coherence of the reflected light, such reflected light is received by a profile meter lens 3212 before being captured by one or more position sensitive detectors 3208. Output data from the detector (s) 3208 is scanned using a scanning mechanism 3210 to generate a contour of the powder surface.

The profile meter can be composed of, for example, a confocal profile meter. In a confocal profilometer, light is directed to a substrate through a lens system, and the returned light is generally reflected to a detection location, but is at least partially passed through the same lens system. Confocal profilometers suitable for use in connection with the present invention are available from Keyence (Keyence Corporation, Japan) or Keyence Corporation of America (Woodcliff Lake, NJ). This model focuses the light of the light source through the pinhole, and a similar focusing of the return light through the pinhole helps to establish focus. 1 of lens
The anterior-posterior dithering of the two assists in establishing a focus oscillation that helps identify the optimal focus.

In one embodiment, a slit is used in place of a pinhole and a charge coupled device (CCD) is used to simultaneously retrieve data for multiple points along a linear region of the substrate 80.
A photodetector having a spatial resolution such as Certain features of the powder suction electrode 370 or receiver 172 can create a strong reflection that can overwhelm the effort to establish a reference plane for the substrate 80. Since the substrate 80 is preferably uniform, such reflections can be standardized. Once the material is deposited on the substrate 80, clean reflections are obtained if the substrate is sufficiently transparent.

The substrate 80 is scanned before the deposition operation and post-deposition scans
It is preferable to improve the accuracy of (2). The beam is scanned across the surface and the height of the surface from the reference position is established by triangulation. Differences in height from baseline before and after deposition can contribute to dose weight.

For the exemplary embodiment, a height difference is calculated for each row of collection zones CZ and for each collection zone CZ. Such values are stored in memory 405, and the differences are displayed as measured doses for each dosage unit. If any of the individual unit doses exceed the predetermined amount by a value of 5%, these unit doses are later identified and 100% tested by non-destructive testing of the actual amount of each unit dose. Go and be selectively discarded.

Since dry powders are generally good diffuse reflectors, it is also possible to use an optical triangulation system that is optimal for diffuse reflection. Pre-dose surface profile
Preferably, the surface of the substrate 80 is a diffuse reflector to determine the height of the substrate to be tested during a post-dose measurement. Further, it is effective that the substrate 80 has absorptivity so that reflection from the black surface of the substrate 80 or reflection from the receiver 172 is prevented.

For the sake of clarity, the measurement systems of FIGS. 32 and 33 have a single light source 3102 /
One with only 3202 is shown. However, more than one light source can be used in such a system.

In some embodiments, the deposition sites are continuously excited and the powder profile is scanned by moving the scanner, eg, from a first site to a second site, until all deposition sites have been characterized. Characterized after excitation of each light source through 3110 or 3210. In other embodiments, one or more deposition sites are excited at once and data is obtained by scanning these sites simultaneously. In such other embodiments, it is desirable to optimize conditions that reduce interference from nearby features that are simultaneously characterized. This can be achieved by optimizing the spacing between deposition sites or by varying the excitation of different sites.

Preferably, light sources 3102/3202 can move 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 comprised of an industrial solid state laser such as model LAS-200-635-5 available from LaserMax Inc. (Rochester, NY). The laser is preferably mounted on the detection platform 144 (see FIG. 8). Detectors 3108/3208 are available from USD Sensors, Inc. (H
awthone, California), any suitable detector,
Preferably, it can be composed of silicon. Alternatively, large area solar cells can be used.

Advantageously, the dosing station 140 incorporates both types (ie, diffuse reflectance and optical profilometer) of the dosimetry system. Thus, by choosing either one of the dosimetry systems, accurate dosing is not limited to either low or high dose deposition. FIG. 34 shows an arrangement operable to obtain two dosing modes using a single light source 3302 and a striped substrate 3380. The illustrated substrate 3380 with streaks attached to the electrostatic chuck 202 / receiver 172 has surface streaks 3381 running in one direction. Such a creased substrate is particularly useful for performing both contour measurements and diffuse reflectance measurements. The configuration shown in FIG.
In addition to 0, a detector 3308a for the diffuse reflectance measurement mode, a position sensitive detector 3308b for the profile meter measurement mode, and a profile meter lens 3
313.

The diffuse reflection measurement is performed in a plane such as a plane P including a streak as shown in FIG. The profilometer measurement is performed by positioning a triangulation system having an incident beam and a reflected beam in a plane such as a plane O orthogonal to the muscle direction, as shown in FIG. Thus, the streaks 3381 act like a diffusion surface in a profilometer measurement.

Ideally, the streaks 3381 do not scatter light in parallel directions, so that all scattered light acts on the powder on the surface. In both methods, it is advantageous to dye the substrate so that reflections from the back surface of the substrate or the receiver 172 do not interfere with the profilometer or diffuse reflectance measurements.

FIG. 37 shows a configuration of dose measurement using two measurement modes as in the configuration of FIG. However, in the configuration of FIG. 37, each measurement mode uses each light source. An exemplary detection array 3400 is disposed on a support 3402,
The support 3402 is a detection platform 144 (not shown in FIG. 37; see FIG. 8).
Is placed on top. The detection array includes the diffuse reflection light source 3404A and the detection zone 3
It has a diffuse reflection system with 408A-3408F. The profilometer system has a profilometer lens 3413 that is part of the confocal system so that the return light passes through the same lens. The diffuse reflection light source 3404A is, for example, offset from the center point of the configuration where the lens 3413 can be seen. This results in specular reflections in areas 342 remote from detector zones 3408A-3408F.
Occurs at the center of the region, such as 0. Such a detector zone preferably comprises detectors that are tilted and arranged to receive only light from the appropriate direction.

The powder deposited in the collection zone CZ is measured both in area and thickness, and the deposition in each collection zone gives a volumetric measurement representing the amount of powder. Although the diffusion and profilometer measurements have been described in terms of thickness, they are also measured in terms of the area determined by the scanning beam.

More specifically, adjacent measurement beams are closely spaced, for example, by about 1 mm, so that the lateral area occupied by the collection zone CZ is also measured and the amount of powder present at each deposition location Considered in calculations. Preferably, the beam has a diameter of about 6 microns. For a deposition zone of about 4-7 mm, each powder "dot" is scanned 4-7 times, respectively. Such a scan is then used to calculate the dose in each collection zone CZ. The system stores the calculated results in each zone of the memory for future selective screening of unit dosage forms of substandard drugs or diagnostic agents. EXAMPLE On a Mylar substrate, dots of polyethylene glycol (PEG) powder having a diameter of about 3 mm were deposited. Laser-based Keyence instrument operating at 670 nm in "strong" mode (K
eyence Corporation of America) was used to obtain diffuse reflectance data. The data was obtained using various, usually larger, portions of the diffusely scattered light.
The analytical properties of the measurements do not appear to be very sensitive to some of the collected light (ie, measurements in this category are usually coarse and ideal for use as industrial measurement processes). Target).

The data presented in Table 1 below was obtained using the diffuse reflection method and is the basis for the plot 3500 shown in FIG. 38 for the four points in this data set. The first three data points are highly correlated, with a least squares fit of .0.
An 999 correlation criterion R value (R = 1 if perfect correlation) was given. The fourth data point showed a change and a least squares fit of the dataset as a whole gave an R value of 0.98. Both R values were well within the acceptable norms of the analytical procedure for determining the dry powder dose weight.

[0151]

[Table 1] Table 1. Experimental diffuse reflectance and dose weight data

Subsequent measurements showed a high correlation between the diffuse reflectance measurements and the dose weights of the various dose samples. Based on such data, the degree of correlation is believed to be closely related to the structure of the dose (ie, more specifically, whether the dose structure exhibits Lambertian properties). After mounting dose measurements cover material, the first robotic transfer element 170 moves the receiver 172 and the substrate assembly 82 to the laminating station 160. As described above, collection zone C
At Z, a holding signal is provided to the electrostatic chuck 202 to hold the deposited powder on the substrate 80 and the substrate on the electrostatic chuck.

At lamination station 160, substrate assembly 82 (ie, frame 81 and substrate 80) is moved to cover assembly 92 (ie, frame 91 and cover layer 90).
Placed on top of The cover assembly 92 is shown in FIG. 39 (here, frames 81 and 91).
Is not shown. As shown in FIG. 23), it is engaged with the laminated support block 1901. The laminated support block 1901 has dimples 1902 into which the depressions of the cover layer 90 fit, and further forms a support against which the cover layer and the substrate are pressed together. The alignment mechanism in the frames 81, 91 and the laminating station 160 is such that the position where the powder is deposited on the substrate is, as shown in FIGS.
To match the depressions, bubbles, etc. After the cover layer and the substrate are engaged, the holding signal is stopped.

After the first robot transfer element 170 is separated, the second robot transfer element 180 moves to a location above the stacking support block 1901. The second robot transport element 180 has a vacuum cup 1870 (see FIG. 8), a bonding head 182, and pads 1880 that press the substrate 80 against the cover layer 90 before and during the bonding operation. . Once in place, the second robotic transport element 180 operates the bonding head 182 to seal all deposits between the cover layer and the substrate, thereby comprising a dosing or diagnostic active formulation. Those consisting of drugs also form unit dosage forms. As will be appreciated by those skilled in the art, "bonding" or lamination can be accomplished in a variety of ways including, for example, ultrasonic, thermal techniques or adhesives. A suitable ultrasonic bonding head is a 900M-Series ™ ultrasonic welder available from Branson Ultrasonic Corporation (Danbury, Connecticut).

Once fusion is complete, the second robotic transport element 180 moves to its idle position and the final package of dosage forms is removed from the final process as appropriate.

[0156] If it is desired to keep the deposited powder from mixing with other factors in the film polyethylene art, the exemplary bonding method is effective, even though this could be achieved in other ways. It should be noted that the exemplary lamination process creates a junction that "circles around" the area where the material is to be deposited, but more uniform lamination methods can also be applied.

In one embodiment of the present invention, the placebo (
placebos), on which inert material is dried and deposited. Various Considerations In particular, a number of additional features that are useful with the deposition apparatus of the present invention are described. For example, using one method of aligning the substrate with the deposition station 150 and the dosing station 140 provides very favorable results. The exemplary embodiment uses a frame to facilitate such alignment. One of ordinary skill in the art will recognize that many features described herein are not available in other devices, such as frameless deposition devices.

In some embodiments, the electrostatic chuck can be configured to repeat the process and be reused earlier than in the illustrated embodiment. For example, in embodiments where the substrate is a film advanced on a roller, the electrostatic chuck used for deposition is contacted with the film as the film advances to the deposition station and removed shortly thereafter. If necessary, other chucks can be used to ensure that the film is smooth and flat (in most embodiments) when fed to the dosing station. Such embodiments using roller fed film generally do not use frames, even though the frames are optional as described above.

Due to the small variation in dosage level (ie, the amount of active prescription) of unit dosage forms made in accordance with the teachings of the present invention, such dosage forms and the methods and devices for making them are well controlled. It is effectively used to treat unique medical conditions that require different dose regimens. Such well-managed dose regimens are necessary, for example, for overlapping doses of components and narrow therapeutic windows. Such a narrow therapeutic window is necessary for avoiding toxic effects, or for changing disease states, as a function of patient size / metabolism, or for changing patient conditions.
Some examples of narrow treatment windows are described below. Example I-Levothyroxine Adult Dose (microgram-μg): 25, 50, 75, 88, 100, 112
, 125, 137, 150, 175, 200 and 300. The recommended pediatric dose (μg) for congenital hypothyroidism is as follows:

Age Dose / Dav daily dose / kg body weight 0 to 6 months 25 to 508 to 106 to 12 months 50 to 756 6 to 8 1 to 5 years 75 to 100 5 to 66 6 to 12 years 100 to 150 4 ５5 Example II-Digoxin adult dose (μg): 125, 250 and 500.

[0161] Patients with renal failure require smaller doses than the usual maintenance dose of digoxin. Digoxin toxicity occurs more frequently and lasts longer because patients with impaired renal function have a reduced ability to excrete digoxin. Newborns show significantly different tolerance for digoxin. Preterm or premature babies are particularly sensitive and must be individually defined according to their degree of development, as well as at lower doses. Example III-Warfarin Adult Dose (mg): 1, 2, 2.5, 3, 4, 5, 6, 7.5 and 1
0. Example IV-Nitroglycerin Adult Dose (μg): 300, 400 and 600 Other Final Dosage Forms As mentioned above, unit dosage forms such as the unit dosage forms of FIGS. 1-5 are effective for a variety of applications. It can be used to create various final dosage forms. In one embodiment, the final dosage form is a well-known “blow-fill-fill” as shown in FIGS. 43A-43D.
It is made by placing one or more unit dosage forms 6 in an outer shell using a "sealing" technique.

First, a pharmaceutically acceptable polymer 4308p is injected into the mold 43 by compressed gas.
02, the polymer 4308p is kept in contact with the inner wall 4304 of the mold 4302. Upon curing, polymer 4308p provides final dosage form 431
0 (see FIG. 43D) outer shell 4308 is formed. Although illustrated in a "peanut" shape, the mold 4302 can be appropriately shaped to create a final dosage form having any one of a number of desired shapes.

As shown in FIG. 43B, after curing of the polymer 4308p, one or more unit dosage forms 6 that need to achieve the desired dosage level are introduced into the mold 4302. After introducing the desired number of unit dosage forms 6 and any optional fillers, the “mouth” 43 of the mold 4302
06 is sealed as shown in FIG. 43C. For example, a polymer 4308p can be used to seal the mouth 4306. Next, when the mold 4302 is opened, the final dosage form 4310 as shown in FIG. 43D is taken out.

In another embodiment, a pharmaceutical film of sufficient thickness (eg, a derivative from starch, cellulose, and polyethylene glycol, etc.) is used in one or more unit dosage forms 6
Used as a “container” for As shown in FIG. 44A, a first film 4402 receives one or more unit dosage forms 6 in one or more depressions 4404 thereof. On the first filter 4402, a second film 4406 is placed as shown in FIG. 44B to seal the depression 4404. Next, the film is cut into dices to form depressions 440.
Separation of 4 results in a plurality of final dosage forms 4410 as shown in FIG. 44C.

In a third embodiment of the collection dosage form, the strip 4 comprises two strips as shown in FIG. 45A.
Sandwiched between two films 4502 and 4504. The elements of the strip 4 are as described above (see FIG. 1 and its associated description) and have a substrate 8 and a cover layer 9. Substrate 8 has a plurality of deposits deposited by the methods and apparatus described herein. Each deposit contains an active prescription. The cover layer 9 has a plurality of bubbles and blisters 12 that are consistent with the deposition on the substrate 8. The bubble 12, the “underlying” portion of the substrate 8 and the associated volume form the unit dosage form 6. Thus, it can be said that the strip 4 has a plurality of unit dosage forms 6.

The two films 4502, 4504 are bonded to each other or bonded to the strip 4, sandwiching the unit dosage form 6 between them and the second
Creating a package. Information about the unit dosage form is printed or copied on the second package. The second package and the strip 4 contained therein are cut into dices to form a "stamp" shaped final dosage form 4510, one of which is shown in FIG. 45B. In embodiments where the second package is configured for ingestion, a "stamp" shaped dosage form 4510 may be ingested. In embodiments where the second package is not suitable for ingestion, the unit dosage form 6 must be removed for dosing.

In another embodiment, there is provided a final dosage form comprising a plurality of unit dosage forms 6 having the same or different active prescriptions and capable of timed release. Such final dosage forms have an isolation layer that separates or isolates each unit dosage form within the final dosage form.
An exemplary embodiment of such a final dosage form is shown in FIGS. 46 and 47.

FIG. 46 is an exploded view for clarity of the drawing, showing four unit dosage forms 6 a-6 d within the final dosage form 4610. In the first embodiment, the unit dosage forms 6a to 6d
Are the same (ie, the same active prescription and the same amount of active prescription). In a second embodiment, unit dosage forms 6a-6d have the same active prescription, but the active prescription is present in different amounts. In a third embodiment, unit dosage forms 6a-6d have different active prescriptions.

The final dosage form 4610 has an “overcoat” or “overlap” film that isolates the unit dosage forms 6a-6d from each other. In the exemplary final dosage form 4610 shown in FIG. 46, each overlapping film 4604a-4604d has a respective "dimple" 4606a-4606d to facilitate receipt of one of the unit dosage forms 6a-6d. The final dosage form 4610 is spread with a desired number of overlapping films (eg, overlap films 4604a-4604d) and a strip (eg, strip 4) containing a plurality of unit dosage forms 6 between adjacent overlap films. It can be made by sandwiching.
Strip 4 can be made according to the teachings of the present invention.

[0170] The overlap films are aligned such that the dimples of each overlap are aligned with each other. The unit dosage form containing strips are aligned with the overlap film such that the unit dosage form from each strip is located within the perimeter of the adjacent overlap film dimple. The various overlapping layers and sandwiched strips are “punched” in a single operation and the final dosage form 4610
To form

[0171] The overlap films 4604a to 4604d can be joined before or during the punching operation. Outermost overlap film 4
From 604d to the innermost overlap film 4604a, the dimple diameter decreases and the dimples are "overlaid", as if a set of cookware were overlaid on each other. In another embodiment (not shown), a second group of superimposed dimples and unit dosage forms is disposed on a second side of the base film 4602.

In another embodiment, the final dosage form 4610 is manufactured in a multi-overlap operation in which the first overlap encapsulates the first unit dosage form and then the second overlap The film and the second unit dosage form are disposed on the first overlap, and so on, to form a final dosage form 4610 for each layer.

FIG. 47 shows another embodiment of the final dosage form containing multiple unit dosage forms 6. Similar to the final dosage form 4610, the unit dosage forms 6a-
6d can be identical to one another, be in different amounts with the same active prescription, or be composed of different active prescriptions.

The final dosage form 4710 may be a “diffusion barrier” (eg, 47
04a) is attached to unit dosage form 6a (eg, by bonding and bonding, etc.), then additional unit dosage forms (eg, 6b-6d) and additional diffusion barriers (eg, 4704b-
4704c). In connection with applicable standards, in some embodiments, an overcoat surrounds the unit dosage form and the assembly of the diffusion barrier. Similarly, in some embodiments, additional overlap layers or diffusion barriers 4702 and 4708 are attached to the first material and the final dosage form (eg, unit dosage forms 6a and 6d).

A description of the overlap layer, diffusion barrier, and additional description of the base substrate and cover substrate will be provided in the next section. Substrates for Specific Use Dosage Forms Using the method and apparatus of the present invention, the same active prescription can be obtained by appropriate selection of the base substrate and / or cover substrate, (1) rapid release, (2) It can be made up in unit dosage form for delayed release, (3) timed release, (4) post-gstric release, or (5) colonic release. More specifically, to make such a dosage form, the same active prescription is deposited on a substrate or has the following respective properties: (1) fast water solubility, (2) slow water solubility, (3) water-insoluble but water-swellable; (4) insoluble in acid but soluble in alkali; or (5)
A cover layer is deposited that has properties such as being insoluble but sensitive to degradation by an anaerobic attack.

Some generalizations can be made regarding the desired properties of the various substrates, overlays and diffusion barriers described above. Such properties and candidate materials having such properties are listed and described below. Substrate As mentioned above, the substrate functions as a deposition substrate on which the powder is electrostatically deposited.
Materials suitable for use as a substrate have the following properties: electrical resistivity (40
% Or less relative humidity, minimum 5 × 10 ¹¹ ohm / area) to have it high strength, it is dimensionally stable, that moisture absorption is low, have a non-soluble (here, non It is effective to have a solubility that does not include safety issues), a dark color that is optically diffusive, and that it is sealable.

As candidate materials for the base substrate having the above desired properties, ethyl cellulose, cellulose acetate phthalate, water-soluble acrylic copolymer, paper (characteristics when oral administration is permitted), crosslinked poly (vinylpyrrolidinone), crosslinked gelatin and nonwoven fabric However, the present invention is not limited to these. Example Base substrate is an aqueous dispersion of ethyl cellulose (FMC Company (Philadelphia)
Commercially available as Aquasol ECD from Pennsylvania). The film formation temperature of the as supplied ethylcellulose was undesirably high. The film forming temperature can be lowered by adding, for example, a plasticizer or the like. In one embodiment, about 15-40% by volume, preferably 25-30% by volume
Is added to the ethylcellulose. The triacetin additive produced a cohesive flexible film formed at low temperatures (e.g., 50-60 <0> C). Table II below shows the relative humidity (relative humidity:
RH).

[0178]

TABLE 2 TABLE II triacetin plasticized electrical properties 20% RH 30% RH 40% RH 60% RH the surface of the film made from the ethylcellulose dispersion sheet resistance ^{1.0 × 10 12 7.9 × 10 11} 4.1 × 10 ¹¹ 1.8 × 10 ¹¹ (Ohm / Area) Volume resistivity (Ohm-cm) 1.0 × 10 ¹² 7.9 × 10 ¹¹ 4.1 × 10 ¹¹ 1.8 × 10 ¹¹ As described above, the substrate used in connection with the present invention and The cover layers are joined together to form a unit dosage form. In the embodiment shown in FIG. 48, the substrate 4880 has a two-layer film having a hydrophobic layer 4882 and a hydrophilic layer 4884. The hydrophobic layer 4882 maintains high electrical resistance and mechanical stability under a wide range of conditions (eg, temperature, humidity, etc.). The hydrophilic layer 4884 swells and becomes "tacky" when exposed to high humidity. The two-layer substrate 4880 can be exposed to high humidity or directly attached to a small drop of water (eg, by ink jet printing or a micropipette) and bonded to the cover layer.

In one embodiment, the two-layer substrate comprises a triacetin plasticized ethyl cellulose dispersion (ECD) as the hydrophobic layer 4882,
Hydroxypropyl cellulose as the hydrophilic layer 4884
ulose: HPC). The electrical properties of the HPC-ECD base substrate in relation to relative humidity (RH) are shown in Tables III and IV below.

[0180]

TABLE III Electrical properties test of multi-layer film composed of HPC type LFP cast on ECD Surface 20% RH 30% RH 40% RH 60 % RH Surface sheet resistance * HPC 1.5 × 10 ¹² 8.0 × 10 ¹¹ 5.8 × 10 ¹¹ 1.4 × 10 ¹¹ Surface sheet resistance EPC 3.0 × 10 ¹² 1.7 × 10 ¹¹ 1.3 × 10 ¹² 3.2 × 10 ¹¹ Volume resistivity ** HPC 1.9 × 10 ¹³ 9.2 × 10 ¹³ 7.0 × 10 ¹² 2.4 × 10 ¹² (* Is ohm / area, ** is ohm-cm)

[0181]

[Table 4] Table IV Electrical properties of multi-layer film made of HPC type JFNT cast on ECD Property test surface 20% RH 30 % RH 40% RH 60 % RH Surface sheet resistance * HPC 1.0 × 10 ¹² 4.7 × 10 ¹¹ 2.3 × 10 ¹¹ 1.0 × 10 ¹¹ Surface sheet resistance EPC 2.6 × 10 ¹² 1.2 × 10 ¹² 6.8 × 10 ¹¹ 3.8 × 10 ¹¹ Volume resistivity ** HPC 1.1 × 10 ¹² 9.5 × 10 ¹² 5.7 × 10 ¹² 2.2 × 10 ¹² (* is ohm / area, ** is ohm-cm) Another candidate material for the hydrophobic layer 4882, which is commercially available as an aqueous dispersion, is cellulose acetate phthalate and a water-soluble acrylic copolymer. Other candidate materials that are suitable but require more complex processing include, but are not limited to, unmodified cellulose, unmodified starch, cytin, and other materials described above as candidate materials for the base substrate. Not something.

Other readily available hydrophilic layer candidate materials include hydroxypropylmethylcellulose, methylcellulose, modified starch, maltodextrin, natural and synthetic gums, poly (vinyl alcohol), poly (vinylpyrrolidinone), and the like. And hydrogels derived from other similar substances.

A method 4900 for forming such a two-layer film is shown in FIG.
The illustrated method includes two main operations: a casting of the hydrophobic layer (step 49).
10) and a casting operation of the hydrophilic layer (Step 4920). The hydrophobic layer is cast, for example, by applying a suitable material (eg, a plasticized ethyl cellulose dispersion) to the cast substrate, as shown in operation 4910a. As a cast substrate, a plastic film (eg, Mylar (trademark), stainless steel) which is smooth and lacks adhesiveness is effective. Next, the applied material is dried under controlled temperature and humidity conditions according to operation 4910b. A temperature of 55 ° C. and a relative humidity of 35% have been found to be suitable for performing the drying operation 4910b. Other temperature and relative humidity conditions can be used as appropriate.

Next, at work block 4920a, a hydrophilic layer is cast by applying a solution to the hydrophobic film. The applied solution is dried under controlled temperature and humidity conditions in operation 4920b. To perform the drying operation 4920b, 28
A temperature of ° C. and a relative humidity of 45% have proven suitable. Other temperature and relative humidity conditions can be used as appropriate.

After the hydrophobic and hydrophilic layers have been cast, in a final operation 4930, the formed two-layer film is removed from the cast substrate. Such removal can be accomplished by stripping the two-layer film from the cast substrate.

In another embodiment, rather than casting a hydrophobic layer, a commercially available pre-form pharmaceutically certified hydrophic film can be used. Next, a hydrophilic layer is cast over the hydrophobic layer. Cover Layer As described above, a cover layer is used in electrostatic deposition processes that cover the substrate, thereby trapping the deposited active prescription between it and the substrate. Materials suitable for use as the cover layer preferably have the following properties. That is, it dissolves immediately at all pH and temperature conditions, etc., can be modified to accept a range of doses, and is easily dyed for color coding.

[0187] Candidate materials for the cover layer having the above desirable properties include, but are not limited to, commercially available hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, poly (vinylpyrrolidinone), poly (vinylalcohol), and poly (ethyleneoxide). It is not something to be done. Diffusion Barrier Diffusion barriers are used in final dosage forms, for example, containing a number of unit dosages, such as final dosage form 4710. Materials suitable for use as a diffusion barrier include:
Having the following properties: equal swelling over the entire pH range, controlled diffusion of water, crosslinked water-soluble polymer, active drug delivery rate controlled by material thickness or degree of crosslink density. Is preferred.

As a candidate material for the diffusion barrier, poly (methacrylic acid), acrylic hydrogel (
For example, loosely crosslinked polymers of hydroxyethyl, hydroxypropyl acrylate or methacrylate), polysaccharides (eg, starch, agar, maltodextrin, etc.), gums (eg, gum arabic, gelling agents, etc.) and carboxymethyl cellulose. However, the present invention is not limited to this. Overcoat film for example, the secondary package layer, the final dosage form 4310,4410,4510,
An overcoat (overlap) film is used to surround the unit dosage form, such as certain embodiments of 4610 and 4710. The properties of the overcoat film are determined according to the desired properties of the final dosage form (eg, rapid release, delayed release, post-gastric release, etc.).

More specifically, for release in the stomach, it is desirable that the overcoat film be dissolved in an acid. Suitable acid-soluble materials include, but are not limited to, poly (vinyl pyridine) and amine-substituted acrylic copolymers.
For release in the small intestine, the overcoat film preferably has alkali solubility and / or enzymatic attack. Suitable alkali-soluble materials include, but are not limited to, carboxyl-substituted acrylic copolymers and polymer derivatives of alginic acid. Suitable enzyme erodible materials include proteins (
Examples include, but are not limited to, casein, gluten, albumin, etc.), lipids, starch, polylactide and poly (lactide-co-glycolide).

For release in the colon, it is effective that the overcoat film has slow overall water solubility and is digested by anaerobic bacteria. Suitable water-soluble materials include ultrahigh molecular weight poly (ethylene oxide), high molecular weight poly (ethylene glycol) blended with poly (vinylpyrrolidinone) or poly (vinyl alcohol), shellac, completely (> 98%) or slightly (25% or less) hydrated poly (vinyl alcohol), poly (styrene-co-maleic anhydride), and high molecular weight acrylate and methacrylate copolymers containing high amounts of acidic monomers such as acrylic acid and methacrylic acid Is not limited to these. Adhesive In some embodiments, an adhesive is used to bond the substrate and cover layer together and to bond the various overcoat / overlap layers to other layers. cheek,
For those used for gingival and nasal sites, the adhesive preferably has excellent adhesion and is non-toxic. Suitable adhesives include, but are not limited to, synthetic rubber, pressure sensitive acrylic adhesives, temporary dental adhesives, and maltodextrins. For skin, the adhesive preferably has excellent adhesiveness and is non-allergic. Suitable adhesives include those of the type used for adhesive bandages. For those used in the vagina and rectum, the adhesive preferably has low adhesive strength and is non-allergic. Suitable adhesives are "in situ swelling" materials such as polysaccharides.

All patents and patent applications cited herein are hereby incorporated by reference in their entirety. All patent applications for which this application claims priority are also incorporated by reference in their entirety.

It will be appreciated by those skilled in the art that modifications of the illustrated apparatus and methods may be used as appropriate in connection with the present invention, and that the present invention may be practiced in other ways than those specifically described. Thus, it is intended that the present invention cover all modifications that come within the spirit and scope of the invention as defined by the appended claims.

[Brief description of the drawings]

FIG. 1 is a perspective view illustrating a product having a strip package containing a plurality of unit dosage forms according to an exemplary embodiment of the present invention.

FIG. 2 is a perspective view showing a cover layer of a strip package partially separated from a substrate.

FIG. 3 is a side sectional view showing an exemplary unit dosage form according to the present invention.

FIG. 4 is a plan view showing the unit dosage form of FIG. 3;

FIG. 5 is a perspective view showing a packaging container for storing the product of FIG. 1;

FIG. 6 is a schematic view showing an apparatus for manufacturing the product of the present invention.

FIG. 7 is a plan view illustrating a robot platform according to an embodiment of the present invention.

FIG. 8 is a side sectional view showing the robot platform of FIG. 7;

FIG. 9 is a schematic side view illustrating one embodiment of an electrostatic chuck supporting a robot-operated receiver and a substrate on which a unit dosage form is deposited.

FIG. 10 is a plan view illustrating a first surface of an exemplary electrostatic chuck.

FIG. 11 is a plan view illustrating a second surface of the exemplary electrostatic chuck.

FIG. 12A is a side cross-sectional view illustrating an embodiment near the collection zone of the electrostatic chuck of FIGS. 10 and 11;

FIG. 12B is a side cross-sectional view illustrating an embodiment near the collection zone of the electrostatic chuck of FIGS. 10 and 11;

FIG. 12C is a side cross-sectional view illustrating an embodiment near the collection zone of the electrostatic chuck of FIGS. 10 and 11;

FIG. 13 is a front view of the receiver and the electrostatic chuck shown in FIG. 9, showing an exemplary structure for electrically connecting the electrostatic chuck to a circuit board of the receiver.

FIG. 14 is a side view of an exemplary lower pin assembly useful for connecting an electrostatic chuck to a receiver circuit board.

FIG. 15 is a plan view showing a gasket disposed between the electrostatic chuck and the receiver.

FIG. 16 is a plan view showing the exemplary lower pin assembly of FIG.

FIG. 17 is a diagram illustrating a lower surface of an exemplary receiver to which an electrostatic chuck is adhered.

FIG. 18 is a diagram illustrating the lower surface of an exemplary receiver without an electrostatic chuck.

FIG. 19 is a plan view showing a receiver platform that supports components constituting the receiver.

FIG. 20 is a plan view showing a receiver platform that supports some electronic components.

FIG. 21 is a diagram illustrating the receiver and the manner in which the receiver engages the robot transport element in further detail.

FIG. 22 shows the receiver and the manner in which the receiver engages the robot transport element in further detail.

FIG. 23 is a cross-sectional view showing a laminated support block for integrally laminating a substrate and a cover layer.

FIG. 24 is a schematic diagram illustrating a deposition engine for electrostatically depositing a powder on a substrate.

FIG. 25 illustrates a rotating baffle used to disperse powder at a powder deposition station.

FIG. 26 illustrates a rotating baffle used to disperse powder at a powder deposition station.

FIG. 27 illustrates an exemplary powder trap that captures non-deposited powder.

FIG. 28 illustrates another embodiment of a receiver, electrostatic chuck, and deposition station according to the present invention.

FIG. 29 illustrates another embodiment of a receiver, electrostatic chuck, and deposition station according to the present invention.

FIG. 30 is a drawing showing a first embodiment of a powder supply device.

FIG. 31 is a view showing a second embodiment of the powder supply device.

FIG. 32 is a view showing a powder measuring method by a diffuse reflection method.

FIG. 33 is a drawing showing a powder measuring method by an optical profilometer method.

FIG. 34 is a drawing showing a first measuring device capable of performing a measuring method based on both the diffuse reflection method and the optical profilometer method.

FIG. 35 shows the operation of the device of FIG. 34 operating according to the diffuse reflection method.

FIG. 36 illustrates the operation of the apparatus of FIG. 34 operating according to the optical profilometer method.

FIG. 37 is a drawing showing a second measuring device capable of performing a measuring method based on both the diffuse reflection method and the optical profilometer method.

FIG. 38 is a drawing showing a plot displayed based on data obtained by using the diffuse reflection method.

FIG. 39 illustrates a sealing head disposed over a substrate and a cover layer in preparation for laminating them together.

FIG. 40 illustrates a first exemplary equivalent circuit diagram for performing AC biased charge and deposition detection for a collection zone.

FIG. 41 is a diagram showing waveforms of voltages measured at a floating pad electrode and a collection zone.

FIG. 42 illustrates a second exemplary equivalent circuit diagram for performing AC biased charge and deposition detection for a collection zone.

FIG. 43A illustrates an exemplary method for producing a final dosage form based on blow fill seal technology.

FIG. 43B illustrates an exemplary method for producing a final dosage form based on blow fill seal technology.

FIG. 43C illustrates an exemplary method for producing a final dosage form based on blow-fill-seal technology.

FIG. 43D illustrates an exemplary final dosage form made from the method of FIGS. 43A-43C.

FIG. 44A illustrates another exemplary method of making a final dosage form.

FIG. 44B illustrates another exemplary method of making a final dosage form.

FIG. 44C shows the final dosage form produced from the method shown in FIGS. 44A and 44B.

FIG. 45A illustrates another method of manufacturing a final dosage form.

FIG. 45B shows a final dosage form produced from the method shown in FIG. 45A.

FIG. 46 illustrates an exemplary embodiment of a final dosage form suitable for providing timely release of a plurality of unit dosage forms contained within the final dosage form.

FIG. 47 illustrates another exemplary embodiment of a final dosage form suitable for providing timely release of a plurality of unit dosage forms contained within the final dosage form.

FIG. 48 is a perspective view showing a two-layer substrate.

FIG. 49 is a view illustrating a method of manufacturing the two-layer substrate of FIG. 48.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY , CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, GH, GM, HR, HU, ID, IL, IS, JP, KE, KG , KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW (72) Inventor Chrysius S.S. Inventor Disai Nitin Vitalbuhay, New Jersey, United States 08550 Princeton Junction Amherst Way 7 (72) Inventor Hummer Lawrence Harrison, United States of America New Jersey 08536 Plainsboro Aspen Dora Eve 507 (72) Inventor Keller David, United States of America Pennsylvania 18940 Newton Cambridge Lane 353 (72) Inventor Kumar Narrin, United States of America New Jersey 08003 Cherry Hill Longston Drive 413 (72) Inventor Lar Prince, United States of America New Jersey 08003 Cherry Hill Filmer Ave 304 (72) Inventor Levin Aaron William, United States of America New Jersey 08648 Lawrence Ville Springwood Drive 6 (72) Inventor Murray Lamaswamy, New Jersey, USA 08876 Hillsborough Wesley Road 39 (72) Inventor, Omara Kelly Dennis, United States New Jersey 08530 Mercer Hopewell Township Lynbrook Driving 7, (72) Inventor, Polinique Eugene Samuel United States of America New Jersey 08046 Wheelingboro Grover 13 (72) Inventor Levenberg Howard Christopher United States of America New Jersey 08540 Princeton Fontaine Court 16 (72) Inventor Loke William Ronald United States of America New Jersey 08853 Rocky Hill Hickory Coat 70 (72) Inventor Rosati Dominique Steven United States 08620 Hamilton Amsterdam Road 44 (72) Inventor Sing Bawa United States 08043 New Jersey 08043 Woolheath Wise Drive 12 (72) Inventor Southgate Peter David United States New Jersey 08852 Monmouth Junction Ridge Road 958 (72) Invention Sun Hoi Cheon United States New Jersey 08852 Monmouth Junction Wildwood C G 3402 (72) Inventor Zandszie Peter John New Jersey, USA 08648 Lawrenceville Jill Drive 13 F-term (reference) 4C076 AA42 BB01 EE06 EE10 EE12 EE16 EE32 EE33 EE36 EE38 EE41 EE48 FF22 FF23 FF27 FF28 FF29 FF28 FF29 A BB28

Claims (76)

[Claims] 1. An electrostatic chuck having one or more collection zones, each collection zone being operable in conjunction with a bias power supply to generate a powder attraction electrostatic field, and being attached to and detached from the electrostatic chuck. A substrate operably engaged and lying over the collection zone; a charged powder supply device for directing the charged powder to the substrate; and an optical detection device for obtaining data indicative of the amount of powder deposited in each collection zone. A dry powder deposition apparatus for depositing powder on a substrate, further comprising: 2. The electrostatic chuck is moved to an input / output station to engage with a substrate, moved to a deposition station to receive charged powder, and moved to a dose measuring station to measure by an optical detection device. The apparatus of claim 1, further comprising a transport element operable to obtain data. 3. The apparatus of claim 1, further comprising a frame for receiving said substrate, said frame comprising first alignment means. 4. A deposition sensor for obtaining data indicative of an amount of deposited powder, a controller operable to receive data indicative of the amount of deposited powder, and a controller for adjusting deposition parameters in response to the received data. The apparatus of claim 1, further comprising a processor operable in association therewith. 5. The apparatus of claim 4, wherein said processor is further operable to receive from said optical detection device data indicative of an amount of deposited powder. 6. An input / output station for storing a substrate, a deposition station for electrostatically depositing powder on the substrate, and obtaining data indicative of the amount of powder deposited on the substrate. A dry powder deposition apparatus for depositing powder on a substrate, comprising: a platform having a dose measuring station according to claim 1 and a lamination station for laminating a cover layer on the substrate after the powder is deposited. 7. The system of claim 6, further comprising a first transport element operable to engage the substrate at the input / output station and transporting the substrate to a deposition station, a dosing station, and a lamination station. Equipment. 8. The apparatus of claim 7, further comprising a second transport element having a bonding head operable to permanently bond a cover layer to the substrate at the laminating station. 9. The apparatus of claim 7, further comprising an alignment station for aligning the substrate with a first transport element. 10. The system further comprises a receiver coupled to the first transport element, and an electrostatic chuck having a plurality of collection zones, each collection zone associated with a bias power supply to generate an electromagnetic field. The apparatus of claim 7, operable, wherein an electrostatic chuck is removably engaged with a receiver within the electromagnetic field. 11. The apparatus of claim 10, wherein said receiver further comprises an electronic element for controlling operation of the electrostatic chuck. 12. The apparatus according to claim 6, further comprising a powder supply for supplying said powder to a deposition station. 13. The apparatus of claim 12, wherein said powder supply device comprises a tube for supplying powder to a deposition station. 14. The apparatus according to claim 13, further comprising a mechanical device for extracting the powder from a supply hopper. 15. A venturi well and a venturi feeder valve operable to withdraw powder from the mechanical device and to supply powder to the tube in connection with the gas flow, wherein the gas flow further comprises a tube flow. A venturi feeder valve configured to be operable to propel the powder through a gas source; 15. The apparatus of claim 14, further comprising at least one of: 16. The method of claim 15, wherein the venturi well is physically positioned to pass the powder from the mechanical device to the tube in a substantially straight path. apparatus. 17. A drum for temporarily storing the powder, a movable belt for receiving the powder from the drum, means for extracting the powder from the movable belt, and receiving the extracted powder and directing the powder to the tube. 14. The apparatus of claim 13, further comprising: 18. The apparatus according to claim 13, further comprising a baffle provided at an outlet of said tube to enhance the uniformity of a cloud of powder directed to said deposition station. 19. The apparatus according to claim 13, further comprising a powder trap for collecting powder that has not been electrostatically deposited at said deposition station. 20. The apparatus of claim 6, further comprising a wall separating the platform and the first transport element from a surrounding environment. 21. Deposition means for electrostatically depositing an active prescription at an individual location on a substrate, and measuring means for non-destructively measuring the amount of active prescription deposited at said individual location. An apparatus comprising: 22. Laminating means for bonding the cover layer to the substrate, said laminating means forming a joint individually surrounding the active prescription deposited at each of said individual locations. 22. The device according to claim 21, wherein: 23. The apparatus of claim 23, further comprising alignment means for facilitating the deposition of the active prescription at each of the individual locations and for measuring the amount of active prescription deposited at each of the individual locations. 23. The device according to 21 or 22. 24. The apparatus according to claim 21, further comprising means for storing the substrate. 25. The apparatus according to claim 21, further comprising a transport unit for transporting the substrate to a deposition unit and a measurement unit. 26. Apparatus according to any of claims 21 to 25, further comprising sensor means for monitoring the electrostatic deposition of the active prescription. 27. The apparatus according to claim 26, further comprising processor means and controller means for receiving input from said sensor means, analyzing the received input, and controlling deposition means in response to said analysis. The described device. 28. The apparatus according to claim 21, wherein said measuring means comprises a diffuse reflection optical detection device. 29. The apparatus according to claim 21, wherein said measuring means comprises an optical profilometer. 30. The apparatus according to claim 21, wherein said measuring means comprises an integrated diffuse reflection / profile meter device. 31. A product comprising a unit dosage form of a therapeutic or diagnostic agent, the unit dosage comprising a substrate comprising a first polymer and an active prescription deposited on a first surface of the substrate. An article of manufacture comprising a stack and a cover layer comprising a second polymer, wherein the cover layer is bonded to the first surface of the substrate by a bond covering the stack and surrounding the stack. 32. A plurality of unit dosage forms, the plurality of unit dosage forms comprising a first unit dosage form of a substrate.
32. The product of claim 31, comprising a plurality of deposits disposed on a surface, wherein the plurality of deposits are covered by a cover layer. 33. The product of claim 32, wherein said active prescription is present in a unit dosage form having an amount not exceeding about 5% by weight from the target amount. 34. The article of claim 32, wherein said substrate comprises a flat film. 35. The article of claim 32, wherein said cover layer comprises a flat film. 36. The cover layer has a shape with a plurality of hemispherical bubbles,
35. The product of claim 34, wherein each pile is disposed within a perimeter of one hemispherical bubble. 37. The substrate according to claim 35, wherein the substrate has a shape with a plurality of hemispherical bubbles, each deposition being disposed within a perimeter of one hemispherical bubble.
The product described. 38. One or more of the deposits has a substantially circular shape and is about 3-1.
38. The method according to claim 31, having a size within a range of 0 mm.
Product described in the section. 39. The product according to claim 31, wherein the first and second polymers are the same. 40. The product according to claim 31, wherein the substrate and the cover layer are suitable for ingestion into the body. 41. The product according to claim 31, wherein the substrate has electric resistance and low hygroscopicity. 42. The article of claim 41, wherein said substrate has insolubility and optical diffusion. 43. The product of claim 41, wherein said substrate is soluble and transparent. 44. The substrate is selected from the group consisting of ethyl cellulose, cellulose acetate phthalate, water-insoluble acrylic copolymer, paper, crosslinked poly (vinylpyrrolidinone), crosslinked gelatin, nonwoven, soy protein, rice protein and whey protein. The product according to any one of claims 31 to 38 and 40 to 43. 45. The product according to claim 31, wherein the substrate has an additive for lowering a film forming temperature. 46. The product of claim 45, wherein said additive is a plasticizer. 47. The product of claim 46, wherein said substrate comprises ethyl cellulose and said plasticizer is triacetin. 48. The product according to claim 31, wherein the substrate comprises a two-layer film. 49. The article of claim 48, wherein said two-layer film comprises a hydrophobic layer and a hydrophilic layer. 50. The article of claim 49, wherein said hydrophobic layer comprises a material selected from the group consisting of an ethylcellulose dispersion, a cellulose acetate phthalate dispersion and a water-soluble acrylic copolymer dispersion. 51. The hydrophilic layer as claimed in claim 1, wherein the hydrophilic layer comprises hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, modified starch, maltodextrin, natural and synthetic gums, poly (vinyl alcohol), poly (vinylpyrrolidinone) and derivatives thereof. 50. The product of claim 49, comprising a material selected from the group consisting of a hydrogel. 52. The product according to any one of claims 31 to 38 and 45 to 49, wherein the cover substrate does not melt at a specific pH and a specific temperature. 53. The cover substrate is made of a material selected from the group consisting of hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, poly (vinylpyrrolidinone), poly (vinyl alcohol) and poly (ethylene oxide). Claims 31-38 and 45-49
A product according to any one of the preceding claims. 54. The product is a final dosage form, the product further comprising first and second overlayers integrally joined together, wherein the unit dosage form comprises a first overlayer and a second overlayer. 54. The product according to any one of claims 31 to 53, wherein the product is arranged between the product. 55. At least one of said first and second overlayers includes:
55. The product according to claim 54, wherein product information is described. 56. A plurality of drug unit dosage forms, each unit dosage form comprising a substrate comprising a first polymer, and a deposit comprising an active prescription, wherein the deposit is disposed on a first surface of the substrate. A cover layer comprising a second polymer, the cover layer being joined to the first surface of the substrate by a joint covering and surrounding the stack, the cover layer further comprising a plurality of isolating layers, each isolating layer comprising: 1 from at least one adjacent unit dosage form
A product characterized by isolating two unit dosage forms. 57. The product of claim 56, wherein said isolation layer is an overlap film with dimples for receiving a unit dosage form. 58. The isolation layer is arranged in an overlapping manner from an innermost overlap with dimples having a minimum diameter to an outermost overlap with dimples having a maximum diameter. 58. The product of claim 57, wherein: 59. The article of claim 56, wherein said isolation layer is a diffusion barrier that joins adjacent adjacent unit dosage forms. 60. The article of claim 59, further comprising an overcoat covering the unit dosage form and the diffusion barrier. 61. The unit dosage form according to claim 56, wherein the unit dosage form is the same.
60. The product of any one of claims 60. 62. The unit dosage form comprising the same active prescription, wherein the active prescription differs in at least some of the unit dosage forms.
61. The product according to any one of claims 60. 63. A product according to any one of claims 56 to 60, wherein at least some of the unit dosage forms consist of different active prescription drugs. 64. The product of any one of claims 57, 58 and 60, wherein said overcoat is acid soluble. 65. The article of claim 64, wherein said overcoat is selected from the group consisting of poly (vinyl pyridine) and an amine-substituted acrylic copolymer. 66. The article of claim 57, wherein the overcoat has alkali solubility. 67. The article of claim 66, wherein said overcoat is selected from the group consisting of a carboxyl substituted acrylic copolymer and a polymer derivative of alginic acid. 68. The product of claim 57, wherein the overcoat is enzymatically erodable. 69. The product of claim 68, wherein said overcoat is selected from the group consisting of proteins, lipids, starch, polylactide and poly (lactide-co-glycolide). 70. The product of claim 57, wherein the overcoat has a slow water solubility. 71. The overcoat comprises a high molecular weight poly (ethylene glycol) blended with ultra-high molecular weight poly (ethylene oxide), poly (vinyl pyrrolidinone) or poly (vinyl alcohol), shellac, 98% or more aqueous (
hydrolyzed) selected from the group consisting of poly (vinyl alcohol), up to 25% aqueous poly (vinyl alcohol), poly (styrene-co-maleic anhydride), and high molecular weight acrylate and methacrylate copolymers containing acidic monomers. 71. The product of claim 70, wherein: 72. The article of claim 59, wherein the diffusion barrier swells evenly according to pH and is capable of controlling the diffusion of water. 73. The article of claim 72, wherein said diffusion barrier comprises a material that is a cross-linked water-soluble polymer. 74. The article of claim 72, wherein the diffusion barrier is selected from the group consisting of poly (methacrylic acid), acrylic hydrogel, polysaccharide, gum, and carboxymethylcellulose. 75. A charged powder comprising a substrate having a plurality of deposits of an active prescription, wherein the deposits are disposed in discrete areas on a first surface of the substrate and generate an electrostatic force in the discrete areas. Further comprising a cover layer, wherein the cover layer overlies the plurality of stacks and individually surrounds each stack by a joint that individually surrounds each stack. A product characterized by being bonded to one surface. 76. The cover layer has a flat shape with a plurality of recesses,
77. The product of claim 75, wherein each recess is overlying the stack and is individually sealed.