DE19758730B4 - Electrostatic chuck for manufacturing pharmaceutical products e.g. tablets, inhaler substrate - Google Patents

Abstract

The electrostatic chuck (620) attracts an object (680) such as a pharmaceutical tablet or pharmaceutical particles. The chuck has a floating electrode thereby providing for charge imaging for the deposition particles in a selected image. A sensing electrode senses the number of particles attracted to the objects on the chuck thus ensuring that an accurate amount is deposited. The lower conductive layer (610) of the chuck is coated with a dielectric layer (630), on top of which is an upper conductive layer (640) with two electrodes (650, 660). A second dielectric layer (670) is placed on top of the upper conductive layer (640). A voltage between 200 and 2000 volts, either DC or AC, is applied across the two electrodes of the chuck

Description

The present application corresponds a continuation-in-part application of the US application with the serial number 08 / 630,050 ("Electrostatic Holders") on April 9th Was filed in 1996. Related and pending U.S. patent applications are "Inhaler Apparatus with Modified Surfaces for Enhanced Release of Dry Powders ", which coexists with the present application was submitted, "Inhaler Apparatus with an Electronic Means for Enhanced Release of Dry Powders ", which coexists with the present was submitted, serial no. 081630.049 ("Acoustic Dispenser", which was filed on April 9, 1996), and their simultaneous Continuation-in-part application 08 / 630,012 filed with the present application ("Holding devices and methods for positioning a plurality of objects on a substrate ", which was filed on April 9, 1996), 08 / 471,889 ("Methods and Apparatus for Electronically Depositing a Medicament Powder Upon Predefined Regions of a Substrate ", submitted on 6. June 1995 and their continuation-in-part registration, on June 6 1996) 08 / 467,647 ("Apparatus for Electro statically Depositing and Retaining Materials Upon a Substrate "on 6 Jun i 1995) and 08 / 506,703 ("Inhaler Apparatus Using a Tribo-Electric Charging Technique "on July 25, 1995 was submitted) and which among other things the electrostatic Deposition of objects, such as describing particles of a powder on a substrate. The foregoing patent applications are hereby incorporated by reference then included in its entirety in the present application.

The present invention is directed on electrostatic holding devices, methods for their Use, including the electrostatic deposition of particles on an object, and on the objects themselves that have been subjected to electrostatic deposition are. According to one Aspect, the present invention provides an electrostatic chuck for the electrostatically attracting an object or objects, the subject being a chemical or pharmaceutical Examination or control or control or manufacturing used becomes. Things can for example, pharmaceutical substrates, such as one pharmaceutical tablet or an inhalation substrate.

Additional embodiments the invention see holding devices and their use for electrostatic Attracting particles such as a pharmaceutically active one Component, on a substrate, such as a tablet. According to one Aspect, the electrostatic chuck has a floating Electrode on and is used to target particles to a substrate attract above the floating electrode, thereby creating a charge image for the Provide deposition of particles according to a selected image or pattern. additionally the invention provides an electrostatic holding device, the one sensing or sensor electrode for feeling of the number of particles attached to the holder have been attracted to thereby ensure the deposition of an exact Ensure amount of particles. Furthermore, the present invention provides objects the selected one Areas in which particles have an electrostatic device be applied to the object.

In the pharmaceutical industry become pharmaceutical compositions with an active ingredient by mechanically mixing the active ingredient with pharmaceutical suitable or acceptable carrier substances manufactured. A major disadvantage for this method lies in the inaccuracy of the distribution of the effective Component in the individual tablets of a batch. This problem becomes particularly clear when the active ingredient is in lower Dosage is present and the inaccuracy of the mechanical mixture can be made into individual tablets in a single batch or pack to lead, that have different dosages.

In addition, some contain pharmaceuticals Compositions, for example, a mixture of different carriers together with the active ingredient, the carrier itself not completely tolerates the active ingredient. For example, the effective ingredient in the carrier difficult to solve be or the carrier can bioavailability affect the active ingredient in a negative way.

These disadvantages of the prior art are addressed by the present invention, by which electrostatic chucks along with their use provided in the chemical or pharmaceutical industry which, among other advantages, the exact separation of an effective Component guaranteed on or in a tablet.

SUMMARY THE INVENTION

The aforementioned drawbacks associated with the prior art are overcome by the inventive technique and the device for holding an object or a variety of objects, such as tablets without the use of mechanical force, for example for the deposition of a pharmaceutically active ingredient , overcome. The present invention provides advantages including cost effectiveness, efficiency and, for example, greater accuracy in applying a specified pharmaceutical dosage to or in a pharmaceutical substrate such as a tablet. Furthermore, the deposition of a pharmaceutically active component using static electricity is particularly expedient, for example, if the active component is immiscible or otherwise incompatible with the other components of the tablet or another substrate.

In one aspect, the present Invention an electrostatic chuck ready a conductive Layer which has at least one electrode for the electrostatic Has attracted an item, the item being for chemical or pharmaceutical control or manufacturing is used. For example, the article can be used with a pharmaceutically active Connection to be coated. The items can be numerous Types of substrates including for example of objects be that for are suitable for human consumption. The items can be pharmaceutical Substrates, such as an inhalation substrate, a pharmaceutical Tablet, capsule, sleeve, Suppository, preparation, bandage or pad. In certain embodiments the pharmaceutical substrate is not dielectric.

Certain embodiments see the use an electrostatic holding device for electrostatic tightening of objects, such as particles, to a pickup substrate. "Particles" are here as objects defined that is a size of less than about 1 mm in width or diameter. The electrostatic Holding devices according to the invention can used for example to remove particles of a powder, which has a pharmaceutically active ingredient to an absorbent to attract pharmaceutical substrate, the substrate being medically or can be pharmaceutically ineffective.

According to another aspect the present invention the use of an electrostatic Holding device for the tightening of an object in which the thickness of the object is preferred less than about 5 mm, and most preferably less than about 3 mm is.

In one embodiment of the invention the electrostatic chuck two electrodes in the top conductive Layer which for things are exposed and the two electrodes preferably grip like fingers each other. In other embodiments the holder has a single electrode in the upper conductive layer. The holding device can be used, for example, to hold an object to hold against the action of gravity or for example a variety of items to position on a substrate. See, for example, those at the same time pending US patent application with serial no. 08 / 630,012 on April 9th Was filed in 1996.

Certain aspects of the present Invention provide an electrostatic chuck that a has a floating electrode, the holding device being used is used to target objects, such as particles, to a substrate above the floating Electrode to attract a charge image for the deposition of particles after a selected one Provide image. additionally the invention sees a sensor electrode for detecting the number of objects such as the particles, which are on a receiving substrate have been deposited. In certain preferred embodiments is a sensor electrode on an electrostatic chuck arranged. The sensor electrode ensures the separation of one exactly measured amount of objects, such as particles. The particles deposited on a receiving substrate can, for example comprise a pharmaceutically active ingredient.

Furthermore, the present Invention objects ready the selected one Areas on which particles have an electrostatic device have been applied to the object.

In addition, the present sees Invention according to one Aspect of an electrostatic chuck that includes an inhalation substrate has, wherein the substrate has a conductive layer, the has at least one electrode to electrostatically particles for inhalation to attract. Preferably the particles have dry particles Powder containing a pharmaceutically active ingredient.

• (a) Bereitstellen einer elektrostatischen Halteeinrichtung und
• (b) elektrostatisches Anziehen eines Gegenstandes an die Halteeinrichtung,

wobei der Gegenstand bei der chemischen oder pharmazeutischen Herstellung verwendet wird. Zusätzlich zu einem Verfahren der Herstellung sieht die vorliegende Erfindung die Verwendung einer elektrostatischen Halteeinrichtung vor, um einen Gegenstand an ein Substrat elektrostatisch anzuziehen, wobei der Gegenstand ein Träger für eine chemische Reaktion ist, die bei einer chemischen Überprüfung bzw. Kontrolle oder bei der Herstellung von Chemikalien oder Medikamenten bzw. pharmazeutische Produkten verwendet wird.The present invention also provides methods using an electrostatic chuck. For example, the invention provides a method of chemical or pharmaceutical manufacture, which comprises:

• (a) providing an electrostatic chuck and
• (b) electrostatically attracting an object to the holding device,

the article being used in chemical or pharmaceutical manufacture. In addition to a method of manufacture, the present invention provides for the use of an electrostatic chuck to electrostatically attract an article to a substrate, the article being a vehicle for a chemical reaction that occurs during a chemical check or manufacture Chemicals or medication or pharmaceutical products is used.

The invention also provides for the use of an electrostatic chuck to hold a Ge object or several objects electrostatically attract to a substrate, the thickness of the object being less than about 3 m. In addition, the invention provides for the use of an electrostatic holding device which has a bias potential for attracting an object to a substrate, the bias potential being less than the breakdown potential or the breakdown voltage of the materials which form the holding device.

The methods according to the present invention can with numerous objects including an edible Substrate, a pharmaceutical substrate, such as an inhalation substrate, a tablet, a capsule, a sleeve, one Suppository, a treatment agent, a bandage and one Pad used, and optionally also when the substrate is not dielectric. additionally can the methods according to the invention can be used with particles that are pharmaceutically active Include component and the methods according to the invention include their Use for coating an object, such as a tablet, with a pharmaceutically active composition.

The invention also provides a procedure ready for putting on a selected one Number of particles on a substrate, with:

• (a) Providing an electrostatic chuck with a sensor electrode,
• (b) applying multiple electrostatically charged particles the holding device, and
• (c) sensing the number of particles that have been attracted to the holder are.

This method can, for example can be used with particles of a dry powder, the Process is used to measure the amount of on a substrate which deposited powder is attracted to the holding device determine.

Another aspect of the invention sees a method for depositing particles on selected areas a substrate, the method using an electrostatic Holding device with floating electrodes in areas of the holding device which provides the selected Correspond to areas of the substrate. In addition, the invention provides a method of making a pharmaceutical composition ready with (a) providing a pharmaceutical substrate, and (b) electrostatically depositing particles on the substrate, the deposition preferably using an electrostatic Has holding device. Preferably, the electrostatic Hold up a floating electrode and the particles will essentially deposited on an area of the substrate which corresponds to the floating electrode, and the electrostatic holding device preferably also has a sensor electrode for the determination the amount of particles deposited on the substrate.

See another aspect the present invention a method of making a dosage form before, with: (a) providing an electrostatic chuck, the one area has that over an X or Y coordinate is addressable, (b) contacting the Holding device with objects, which have a pharmaceutically active ingredient, wherein things adhere to the holding device essentially in the areas, the regarding X or Y coordinates are addressable, and (c) releasing the objects a pharmaceutical carrier, with the areas of the holding device on which the objects adhere, is aligned. The holding device preferably has several surfaces, which are X- or Y-addressable, with each surface or area one separate pharmaceutical carrier equivalent. Furthermore, the objects are preferably essentially deposited simultaneously on a plurality of pharmaceutical carriers. This method can be used, for example, to differentiate Dosage units form when at least two of the pharmaceutical carrier pick up a different number of items. This method is particularly useful for pharmaceutical effective ingredients, such as hormones, in different Dosages are administered and it is desirable to have a pharmaceutical Packaging to form more than one type of dosing unit contains.

SHORT DESCRIPTION THE FIGURES

1 is a cross-sectional view of a schematic representation of an electrostatic chuck with interdigitated electrodes according to the invention.

2 FIG. 12 is a top plan view of a schematic representation of the interdigitated electrodes of FIG 1 ,

3A and 3B are circuit diagrams of an electrostatic chuck that has two electrodes. 3A shows the holding device without a lower conductive layer and 3B shows the holding device with a lower conductive layer.

4A is a top view of a schematic representation of the individual electrodes of FIG 4B ,

4B Figure 3 is a cross-sectional view of a schematic representation of an electrostatic chuck Device with a single electrode on the upper conductive layer, which protrudes from the dielectric layer according to the present invention.

4C Figure 3 is a cross-sectional view of a schematic representation of an electrostatic chuck according to the present invention with a single electrode on the top conductive layer recessed into the dielectric layer.

5 is a schematic cross-sectional view of an electrostatic chuck with floating electrodes on the top conductive layer for charge imaging.

6 is a top view of a floating electrode according to 5 ,

7 Figure 3 is a circuit diagram of an electrostatic chuck with a floating electrode on the top conductive layer.

8th is a schematic cross-sectional view of a sensor electrode.

9 is a schematic top view of a sensor electrode with the position of the sensor electrode outside the deposition area.

10A is a schematic top view of a sensor electrode, the position of the sensor electrode being within the range of the deposition.

10B is a top view of a schematic representation of a sensor electrode, the position of the sensor electrode in the form of a tablet being within the deposition area.

11 Fig. 10 is a circuit diagram of an electrostatic chuck with a sensor electrode.

12A Figure 12 is a top view photograph of a floating electrode after powder deposition in a holder without the lower conductive layer with the circuit board attached. The photograph was made at about 50 times magnification, so that the line next to the photograph corresponds to a length of about 0.5 mm.

12B is a top plan view photograph of a floating electrode after powder deposition with a holder having the lower conductive layer with the board attached. The photograph was taken at about 50 times magnification, so that the line next to the photograph corresponds to a length of about 0.5 mm.

13A Figure 12 is a top view photograph of a floating electrode after powder deposition with a holder without the bottom conductive layer with the board removed. The photograph was taken at about 50 times magnification, so that the line next to the photograph shows a length of about 0.5 m.

13B "is a photograph of a top view of a floating electrode after powder deposition, with a holder having the bottom electrically conductive layer with the circuit board (printed circuit board) removed. The photograph was taken at about 50x magnification; the line beside. ***" photography therefore corresponds to a length of approximately 0.5 mm.

14A-C are graphical representations of the detection of deposited powder using a sensor electrode with an electrostatic chuck of the present invention. The X axis represents the time in minutes and the Y axis represents the charge in microcoulombs. dq / dt corresponds to the deposition rate or rate.

15 Figure 3 is a schematic diagram of an electrostatic chuck according to the present invention for the generation of multiple dose units.

16A-C provide three photographs of an electrostatic chuck according to the present invention. 16A shows the circuit of the electrostatic chuck; 16B shows a window mask for the holding device and 16C shows the holding device structure with a tablet field or a tablet arrangement.

17A 12 is a schematic cross-sectional view of a modified quartz crystal monitor and 17B is a circuit diagram of the in 17A shown monitoring device.

PRECISE DESCRIPTION THE INVENTION

For The following terms are intended for the purpose of the present application have the meanings given.

• - Acoustic Dispenser: a device for dispensing particles, the device vibrating at a frequency in the acoustic (Audible) Area used.
• - Holding device: a bracket or holder for holding an object or objects.
• - holding device for the Positioning objects: a holding device that has a configuration that uses can be to the objects on the holding device essentially in a selected pattern to arrange.
• - Electrostatic holding device: a "clamp" or holder for holding an object or objects using electrostatic forces.
• - electrostatic Holding device with conduction paths: an electrostatic holding device for the Positioning objects, in which the holding device has a layer which the positioning of the objects defines, and wherein this layer has paths that a conductive Material included.
• - Mechanical Holding device: a tensioning device used for holding an object Pressure or compression used.
• - Non-mechanical Holding device: a holding device that does not apply pressure or compression used to hold an object, including but not limited on a holding device, the electrostatic devices or Vacuum devices (e.g. negative pressure) for one Keep used.
• - object or object: a material object.
• - particles: an object with a width or diameter of 1 mm or less than 1 mm.
• - Pitch: the repetitive distance between the edge or the edge a depression to the corresponding edge or the edge of the neighboring Well, for example in a microtiter plate.
• - receiving substrate: an object of a surface or has a layer coated with objects or a coating of objects absorbs, such as particles.
• - Upper conductive Layer: the conductive Layer of an electrostatic chuck, which objects to the Holding device attracts or holds on.

1. Using the electrostatic Holding devices of the invention.

"Holders" are defined above as brackets or brackets for holding an object or objects. Instead of using it conventional staples that use mechanical or compressive force, The present invention relates to the use of static electricity in a electrostatic chuck directed as the device which is used in connection with the holding device for holding objects becomes. Things can optionally positioned, transported and separated or deposited become. The holding devices preferably use a force for holding of objects, that differs from active pressure. The holding devices according to the present Invention can according to one Aspect for the positioning of objects can be used as in the US patent application with the serial no. 08 / 630,012 ("Holding devices and method for positioning multiple objects on a substrate " on April 9, 1996).

In one aspect, the present Invention electrostatic holding devices for electrostatic tightening of an object or a plurality of objects. Without hereby one restriction to be based on any theory, it is assumed that if an electrical potential to the electrostatic holding devices according to the invention is applied between the electrodes of the holding device capacitors are formed and that the Objects through electrostatic force can be maintained. One of the advantages of using it an electrostatic holding device in the chemical or pharmaceutical industry is that, unlike plasma loading, electrostatic charge (also known as friction charge) generally does not adversely affect chemical substances. Farther guaranteed the use of an electrostatic chuck the ability to for example, to hold a pharmaceutical substrate without a mechanical Force is required which tears or tears the substrate to destroy could.

The holding devices according to the present Invention can used to hold one or more items during one chemical or pharmaceutical processing or processing against gravitational forces to keep. additionally the present invention provides methods of chemical manufacture ready to use a holding device to hold an object or several objects attract to a substrate, the items being used in chemical manufacturing be used. According to one In another aspect, the present invention provides methods of manufacture a pharmaceutical composition prepared by a holding device is used to attach one or more items to one Substrate to be used, the items are used to pharmaceutical Manufacture composition. The holding device can be manufactured in this way be that they have enlarged dimensions to attract an object that has an enlarged area.

In one aspect, the present sees Invention the use of an electrostatic chuck before that has a bias potential for attracting one or more objects has a substrate. The bias potential is preferably greater than about 1000 volts. The use of the holding device according to the present Invention provides the opportunity a bias potential since a bias potential is not necessarily damage of a pharmaceutical substrate as opposed to one Wafer in the semiconductor industry, which is sensitive to voltage responding.

If an electrostatic chuck the temperature is preferably between about -50 ° C to about 200 ° C and preferably between about 22 ° C up to about 60 ° C. The humidity is preferably between 0 and 100%, the Moisture does not cause condensation; it is more preferred when the humidity is 30%.

The use of electrostatic Holding devices according to the invention can be larger than one huge Continuous manufacturing range, such as by using a sheet or a sheet or a sheet from an edible Substrate for use with tablets or, for example, a web of one Inhalation substrate, which, for example, can be used for individual bands for individual Inhaler devices can be perforated.

The present invention provides also procedures for depositing a selected one Number of items ready with: (a) providing an electrostatic chuck, an area or area which is X- or Y-addressable, (b) bringing the holding device into contact with objects, whereby things adhere to the holding device essentially in the areas which are X or Y addressable, and (c) releasing the items a receiving substrate which is aligned with the surfaces of the holding device is on which the objects be liable. The present invention also provides methods of making a dosage form, with:

• (a) providing an electrostatic chuck, the one area which is X or Y addressable, (b) contacting the holding device with particles that have a contain pharmaceutically active ingredient, the particles adhere to the holding device essentially in the areas which are X or Y addressable, and
• (c) Release or release of the particles on a pharmaceutical carrier that matches the surfaces of the Holding device is aligned, on which the particles adhere.

Advantages of the present invention conclude the ability a, a pharmaceutical substrate without the use of mechanical Hold facilities. The present invention thus provides an electrostatic mechanism for holding a tablet ready, which is only slightly compressed and which would be very brittle or crumbly if by mechanical means or by a vacuum holder would be held. additionally stands without being bound by any particular theory that the pharmaceutical acceptable or suitable carrier for example in the form of tablets are often electrically conductive and their charge in less than about a millisecond distribute or deliver. An electrostatic holding device ensures an advantage by maintaining their charge while a pharmaceutical substrate otherwise would lose its charge, for example.

The present invention provides also electrostatic holding devices that are used order one or more items during processing in the chemical and pharmaceutical industries. Such Processing includes the deposition of particles on objects, such as the Deposition of a pharmaceutically active powder on tablets. This is particularly useful, for example, when the active ingredient with the rest Part of the tablet is incompatible or is incompatible.

Furthermore, more than one type of active ingredient or ingredient, such as two active ingredients, stacked on an object, such as a tablet become. The tablet can also continue to be processed after the particles are deposited on it have been, for example, the tablet after deposition again coated. Preferably the particles are under Dispensed using an acoustic delivery device that is in of the US patent application with the serial no. 08 / 630,049 is.

Without being limited to a certain theory is to be made, it is assumed that this of the electrostatic chucks according to the present invention generated electrical potential should both serve a conductive object, such as a tablet, to hold in place; as also attract a charged object, such as particles within a powder, on a receiving substrate. additionally can the electrostatic holding devices according to the invention for inhalation substrates be used. See for example the pending registration entitled "Inhaler with an electronic device for the increased levy dry powder ", which coexists with the present application is submitted. See also the following sections on charge imaging Holding devices.

2. Objects that are held by electrostatic holding devices according to the invention.

A. Dimensions and types of items

Preferably, the thickness of an object held by an electrostatic chuck according to the present invention is less than about 300 mm, and more preferably less than about 100 mm and, more preferably, less than about 50 mm, more preferably less than 25 mm, more preferably less than about 10 mm, more preferably less than 5 mm and most preferably less than 3 mm. Thus, in certain preferred embodiments, the article is a small article, such as a particle, that has an average width or diameter less than about 1 mm. In certain preferred embodiments, the holding devices according to the invention are used with a multiplicity of small objects, which preferably have a size of approximately 5 micrometers to approximately 500 micrometers, and preferably for use in the chemical or pharmaceutical industry. The use of an electrostatic chuck in the chemical and pharmaceutical industries is one of the novelties of the present invention.

In certain preferred embodiments are the objects which are held by a holding device, pharmaceutical Substrates and the objects are round, such as tablets. Alternatively, the items are for example elongated and you can for example capsules or sleeves. If the item is a tablet, it preferably has one Thickness that is not more than about 3 mm. The present invention sees also the use of a holding device to hold an object or objects to keep that in some embodiments coated with particles while being held. In preferred embodiments the particles are in a powder, which is a pharmaceutical has effective composition.

The powder is preferably in a dry, downsized form, for example using of an air jet milling process and the particles have at least a micrometer in diameter and preferably between about 1 to about 10 microns, and more preferably between about 4 to about 8 microns. The powder is preferably charged electrostatically, before it is applied to the holding device, for example by mixing with pearls, for example by mechanical shaking.

Other pharmaceutical substrates conclude for example a suppository or an edible substrate such as a pharmaceutical tablet, capsule or sleeve or a water-soluble film, such as hydroxypropylmethyl cellulose resin. Other substrates conclude Additive or preparation agent, bandages and pads, as well such as a substrate for an inhalant. For example the inhalation device can be a flat, ceramic disc on which a plurality of drug dosages are arranged are. See for example US serial no. 08 / 471,889 on June 6, 1995.

The holding devices according to the present Invention can for numerous other types of items used, including (Without being limited to this to be) a thin one conductive substrate, like an edible one Polymer substrate which is used as a substrate for the deposition of a pharmaceutical effective powder can be used, and the substrate can then be used , for example to produce or coat a tablet. Excess items are preferred do not adhere electrostatically to the holding device before transferring the objects removed on a substrate. To solve these objects, you can put on a Tension can be ended or the tension can be reversed for greater release force.

In addition to pharmaceutical objects or particles can the electrostatic chucks of the present invention used to attract any other particles, that can adhere to an electrostatic chuck. For example can the holding devices additionally used to attract liposomes and in capsules for cosmetic To separate purposes.

B composition of items which are held by the holding devices.

The tablets preferably have by the electrostatic holding devices according to the invention should be kept, a significant proportion of cellulose on, preferably more than about 50% cellulose, and more preferably more than 60% cellulose, with more than 75% cellulose being even more preferred and most preferably more than 90% cellulose, most preferably about 95% cellulose. In other embodiments, the tablets about 65% lactose and about 34% cellulose. In certain embodiments the tablets contain about 80% lactose. Preferably they have Tablets not an ingredient that would cause them to lose their properties, to be either a good conductor or a good dielectric. For example includes a conductive Tablet, such as one that is essentially cellulose is manufactured, no dielectric metal oxides, such as 2- or 3-valent iron oxide or titanium oxide. The amount is preferably iron oxide, if present, less than about 1%. Also includes the tablet preferably does not contain moisture and preferably also contains not a sizeable one Amount of salt, such as sodium bicarbonate, which is high Moisture conductive is, which makes the particularly effective operation of the electrostatic Holding device would be affected by moisture. The Tablets can optionally also additional Have components, including sodium and magnesium stearate, but not limited to.

If an edible substrate, for example has a pharmaceutically active powder deposited on it, with a tablet is melted, so there is the edible substrate preferably from essentially the same ingredient as the tablet, such as cellulose. For example, hydroxypropylmethyl cellulose such as Edisol M Film M-900 or EM 1100, available from Polymer Films Inc. (Rockville, CT).

Preferably the density of the tablet is such that if it is about 5.6 mm in diameter, the tablet will not weighs more than about 100 mg. If the diameter of the tablet is twice is so big so the weight can be proportional to the square of the diameter.

The conductivity of a tablet can be determined by measuring the DC impedance by placing the tablet between a voltage source and a picoammeter in an electrical circuit. The capacity of the tablet can be measured by placing the tablet sample in parallel with a Hewlett Packard 4192A low frequency impedance analyzer set to 1 kHz. The tablets are preferably coated on both sides with a thin layer of conductive silver paint to ensure good electrical contact. Different compositions were tested and conductivities between 2.4 × 10 ⁹ Ω and 6.3 × 10 ⁹ Ω were found. The impedance range was between about 2 × 10 ⁹ Ω and 23 × 10 ¹⁰ Ω. The capacitance was determined to be 0.3 pF to 0.5 pF, which means a charge holding time of 100 μsec to 1 msec. equivalent.

3. Loading the objects

In certain preferred embodiments the objects to be attached to the holding device their attachment loaded. For example, the cargo can either a plasma charge or an electrostatic charge, depending on the type of object attached to the holding device shall be. For example, if pearls or beads are used, either a plasma charge or an electrostatic charge is used as neither causes damage to the beads. For others objects the possibly damaged by plasma charge electrostatic charge is preferably used. In preferred embodiments include the process of electrostatically charging the item before applying the same to the holding device. Regarding the For details on using carrier beads for loading, see the hereby simultaneously submitted continuation-in-part application with the US serial no. 08 / 630,049, filed April 4, 1996.

4. Design the holding devices

The size of the holding device depends on the number and size of the objects to be tightened using the holding device. For example, a 2 inch x 2 inch (5.082 cm ² ) holder can hold approximately 100 tablets, each tablet approximately 5.6 mm in diameter. The holding device is preferably reusable and can be washed or cleaned between uses.

If a holding device according to the present Invention used to during the separation of particles, such as a powder, which contains a pharmaceutically active ingredient, a receiving substrate, such as For example, to hold a tablet, the tablets are preferred densely packed on the holding device, so that only the Tablets absorb the powder and the holder itself does not is coated with the powder. For example, the electrostatic holding devices are used according to the invention, by about 81 tablets in rows of 9 tablets and columns of 9 tablets to keep.

According to one aspect, the present invention provides an electrostatic holding device which has a conductive layer which has at least one electrode for electrostatically attracting a plurality of objects. In other preferred embodiments, the holding device has an electrically conductive layer which forms two electrodes which, in certain embodiments, are interdigitated in a serpentine or finger-like manner and ensure a higher probability that the area of the two electrodes which is covered by the same object is the same, so that objects are therefore kept at the same potential at different locations on the holding device. In addition, the surface area is conveniently inversely proportional to the object that must be held by the holding device. For example, in preferred embodiments, the electrode has a larger surface area to hold a smaller object electrostatically. The conductive layer which attracts objects to or through which they adhere to the holder is called the "upper conductive layer" and this layer is not necessarily the outermost layer of the holder. For example, the top conductive layer may have a thin dielectric layer thereon that lies between the conductive layer and the objects. Furthermore, the holding device can have more than one electrically conductive layer which forms an electrode, even if only the conductive layer which objects are attached to the holder direction attracts or sticks to it, is referred to as the "upper conductive layer".

In certain preferred embodiments are the electrostatic holding devices made of solid materials, such as glass or silicon dioxide or other ceramics manufactured which have good dielectric strength and thus inherent in a better attraction of objects. The better one dielectric strength guaranteed also a thinner one Layer and a lower voltage, which increases safety. Farther the materials are well characterized, durable, mechanically strong and readily available.

A. Electrostatic Holding device with two electrodes in the upper conductive layer

According to 1 is the lower electrically conductive layer 610 the holding device 620 with a dielectric layer 630 coated. On top of the dielectric layer is an upper, conductive layer 640 , which forms interdigitated electrodes, with a first electrode 650 and a second electrode 660 , A second dielectric layer 670 is on top of the top electrically conductive layer 640 arranged. 2 shows a view from above of the two interdigitated electrodes 650 and 660 , This holding device 620 can be used to make an item as shown 680 to attract.

During use of an electrostatic chuck that has an upper electrically conductive layer with two interdigitated electrodes, a voltage is applied to the two electrodes of the chuck, preferably from about 200 to about 2000 volts. See for example the example 4 which follows below. The voltage applied to an electrostatic chuck can be a direct voltage (DG) or an alternating voltage (AC), provided that the same amount of voltage is applied.

B. Mathematical calculation the holding force of the holding device

Without being limited to any particular theory want to make, it is assumed that a contact surface for the tablet of 1 mm2 is present.

Therefore, assuming that X is the thickness of the dielectric layer and for a 60 mg tablet, gravity = 60 × 10 ^-5 kg × 9.8 N / kg ≅ 600 μN, the electrostatic force is about 70 times larger than that gravity.

Without intending to be bound by any particular theory, it is believed that the article need not necessarily be in direct body contact with an electrode in the upper conductive layer in order to be held electrostatically by the holder. When the retainer, which has an upper conductive layer with interdigitated electrodes, is used to deposit a charged powder on, for example, a tablet, the electrostatic force holding the tablet increases as the charged powder is deposited on the tablet , and thereby provides an additional advantage in the form of a stronger holding force. There is a limited amount of charged powder that can be deposited using the interdigitated holding device that is biased to a bias potential. This holding device therefore provides the advantage that it is able to determine the amount of powder which is deposited on a substrate by the men of the remaining charge is measured. The charge can be measured, for example, using an electrometer or picoammeter. The value of the charge can be used to determine the mass of the powder deposited. The design of this holding device ensures its ability, in principle, to hold any object which is conductive in comparison to the strong dielectric layer on the upper side of the holding device.

Without intending to be bound by any particular theory, the following mathematical formulas can be used to determine the holding force for those shown in the circuit diagram 3 to calculate the holding device shown. 3A shows a circuit diagram of an electrostatic chuck having an upper conductive layer which has two electrodes, each electrode having an object that has been attracted to it, and the lower conductive layer missing. 3B shows a circuit diagram of a holding device with an upper conductive layer having two electrodes, each electrode attracting the same object and with the lower conductive layer present. Cp ₁ is the capacitance of the capacitor formed between an object such as a tablet and the first electrode. Cp ₂ is the capacitance of the capacitor formed between an object, such as a tablet, and the second electrode; Rp is the resistance due to the object and V represents the holding potential which is related to the force holding the object on the holding device. According to 3B Ce _{1 is} the capacitance of the capacitor formed between the lower conductive layer and the first electrode. Ce ₂ is the capacitance of the capacitor formed between the lower electrically conductive layer and the first electrode, and V represents the bias potential.

ist, wobei ε₀ die Dielektrizitätskonstante im Vakuum ist und ε_r die relative dielektrische Konstante der dielektrischen Schicht auf der Oberseite der Elektroden in der oberen elektrisch leitfähigen Schicht ist. A ist die Kontaktfläche und d ist die Dicke der dielektrischen Schicht. Die Kraft, welche den leitfähigen Gegenstand und die Elektrode in der oberen, elektrisch leitfähigen Schicht hält, ist gegeben durch:

wobei V die Spannung ist, die über der dielektrischen Schicht anliegt. Unter der Annahme, daß ε_r = 3 für ein Polymer ist, V = 350 Volt, d = 10 μm und A = 15 mm², ist die elektrostatische Kraft 0,24 N. Wenn das Material eine Masse von 60 mg hat, so ist die Schwerkraft 0,59 mN. Die elektrostatische Kraft ist über 400 mal stärker als die Schwerkraft.A conductive article and the electrode in the upper conductive layer form a capacitor with a capacitance that is approximately equal

is, where ε _{0 is} the dielectric constant in vacuum and ε _{r is} the relative dielectric constant of the dielectric layer on the top of the electrodes in the upper electrically conductive layer. A is the contact area and d is the thickness of the dielectric layer. The force that holds the conductive object and the electrode in the upper, electrically conductive layer is given by:

where V is the voltage across the dielectric layer. Assuming that ε _r = 3 for a polymer, V = 350 volts, d = 10 μm and A = 15 mm ² , the electrostatic force is 0.24 N , If the material has a mass of 60 mg, gravity is 0.59 mN. The electrostatic force is over 400 times stronger than gravity.

In the circuit diagram, which in 3 is shown, V _ad = V. Provided that enough charge time has passed after the voltage V is applied, V _bc = 0. When the charged powders land on Rp, the voltage across the two capacitors is regenerated. However, the current or voltage supply keeps the total voltage drop V _ad constant. In a practical interpretation, C _{p1 is} approximately the same as C _p2 and V _ab ~ V _cd ~ V / 2. The total attractive force is proportional to (V _ab ² + V _cb ² ) ~ V ^Z / 2. When the voltage at the point b (or c) to V 'is changed due to the impact of the charge powder, then the new attractive force is proportional to V ^2/2 + 2V' ² = V ^2/4 + V '. ² As a result of the addition of the charged powder, the attractive force increases. In addition, the normal leakage current through the two capacitors, which have a limited resistance, is also supplied through the power supply.

The applied potential V can be kept at a separate voltage difference V _f with respect to ground. The potential on the conductive material (in this application the conductive material is a tablet) is V _f + V / 2. When the tablet is exposed to a cloud of charged powder, the powder experiences the field due to the potential V _f + V / 2 and is attracted or repelled according to the sign of the charge on the powder. If the resulting force is attractive, the powder is deposited on the tablet. Since both V _f and V can be controlled in terms of their size as well as their sign, the resulting force can be controlled so that they are used for the divorce is attractive.

Without limitation to any particular theory, it is believed that before any conductive material is applied to the in 1 and in the circuit diagram in 3 Holding device shown is attached, the charges concentrate on the edges or corners of the electrodes. There is a relatively weak electrical fringe field on the top of the electrostatic chuck. This field may not be strong enough to redistribute the load in the tablet to attach the tablet to the cradle. This limitation is eliminated by adding a lower conductive layer under the retainer, also known as the back or support level. This conductive layer causes the charges on the electrodes to redistribute themselves more evenly across the electrodes. As a result, a higher electric fringe field is formed on the top of the holder and a better initial attraction between the tablet and the holder. The new equivalent circuit is in 3B shown.

C. Electrostatic chuck with single electrode in the upper conductive layer

In other preferred embodiments, the holding device has an upper conductive layer that has a single electrode. The holding device preferably comprises three layers. The lower layer is preferably a lower electrically conductive layer made of metal, such as aluminum. Alternatively, the lower layer can also be semiconducting, for example, such as a silicon wafer. The middle layer is a dielectric layer that preferably has high dielectric strength, such as thermally grown silicon dioxide. The upper layer is an upper conductive layer which forms the electrode and which may extend outwardly or may be recessed from the top of the dielectric layer, extending inwardly into the dielectric layer. The upper conductive layer is made of a conductive material, such as metal, for example copper wires, or a semiconductor, for example polycrystalline silicon. The upper conductive layer preferably has no appreciable negative effect on a pharmaceutically active composition. In preferred embodiments, the thickness of the top conductive layer is between about 100 nm and about 500 nm. Preferably, the top electrically conductive layer has conductive strips, and when used to attract multiple items, the width of the area between the strips is preferably approximately equal to the average diameter of the articles, thereby providing full coverage of the electrode when the maximum number of articles is held by the holder. Thus, if the holding device is used to hold objects while particles are being deposited on the objects, this configuration essentially ensures removal or avoidance of deposition on the holding device itself. See, for example 16 ,

According to 4B has the electrostatic chuck 910 for example a lower electrically conductive layer 920 with a dielectric layer 930 thereon. The top conductive layer 940 stands either outward from the dielectric layer 930 before how it in 4B is shown, or it is recessed or pressed into the dielectric layer 930 as it is in 4C is shown. A top view of the stripes or striations in the upper electrically conductive layer 940 is in 4A shown. During use of the electrostatic chuck, there is a bias potential between the upper conductive layer 940 and the lower conductive layer 920 created.

With no intention of limiting any certain theory it is believed that if the above described Holding device with a single electrode in the upper electrical conductive Layer is used, for example, around tablets electrostatically to hold while a charged powder is applied to the tablets, no charge redistribution is in the tablet, but instead the tablet is charged directly through contact with the electrode. Therefore an unlimited amount of loaded powder is deposited on the tablets become.

5. X-Y addressability the holding devices and their use

One of the conductive layers, such as the lower conductive layer of the electrostatic chuck, can be x-addressable or xy-addressable so that the position of objects that are attracted to the chuck can be selected. For example, in an x-addressable holding device, the lower electrically conductive layer has rows, of which a single row can be activated at a time. It is therefore possible to select the placement of objects only on a certain row of the electrostatic holding device, instead of on each row of the holding device. In the case of an xy-addressable holding device, the area of the lower electrically conductive layer corresponds in each case to a row and a column and it can therefore preferably be independent of the remaining area of the lower conductive layer which corresponds to any other rows and columns for each object be made. For example, the arrangement of objects can only be selected on certain surfaces of the electrostatic holding device instead of on the entire holding device.

Furthermore, the present Invention an electrostatic chuck ready a Design for depositing a selected one Number of items has only on a receiving substrate. Preferably they have objects a thickness of less than about 3 mm and the design of the holding device preferably has an electrically conductive layer that a x or y addressable area for the Deposit a selected one Number of items has on the receiving substrate. The holding device preferably has several areas, the x or y addressable are, each face preferably a separate substrate, such as a pharmaceutical Carrier, equivalent. In preferred embodiments become the objects deposited essentially simultaneously on several substrates and in certain embodiments the substrates are connected to each other. For example, the Substrates are a pharmaceutical carrier and the articles can be, for example, particles in a powder, microsphere or liposomes, which are a pharmaceutically active ingredient included, and they can together produce a pharmaceutical dosage form or form. If the substrates are bonded together, then a multiple dose pack is formed on which the Dosage for example decreases from one unit to the next, such as a multiple dose pack for birth control. The dosage can be determined by the number of items that can be arranged in or on each pharmaceutical carrier Use an electrostatic chuck. The present The invention thus provides a multiple dosage or multiple dosage form ready which units has, of which each unit has a dosage has at least two units of different doses, and the dosages determined by the number of microspheres in the unit become. In certain preferred embodiments, the average is Diameter of the microspheres between about 1 and about 500 microns, preferably in some cases between 100 and 500 microns, and in other cases preferably up to about 50 microns.

Preferably, the microspheres have a pharmaceutically acceptable or compatible polyalkylene, such as polyethylene glycol, which is preferably present in a concentration of at least about 90% and more preferably with about 95% polyethylene glycol. The holding devices described here, such as for attracting tablets and for generating charge images with another dielectric layer, can be used to produce the multiple dosage forms described above. See for example 15 ,

6. Charge imaging electrostatic holding devices with floating electrodes

In further preferred embodiments are electrostatic chucks according to the invention for use used in charge imaging or charge imaging. In particular points such an electrostatic holding device is a floating electrode for the Charge mapping on. An electrostatic chuck for charge imaging has three layers, preferably with an optional one fourth layer. The lower layer is the lower electrical conductive Layer that also acts as a back electrode or collecting electrode is known. The second layer, which is on the lower conductive Layer is a dielectric layer. The third layer is an upper conductive Layer on top of the dielectric layer and this top conductive layer has two types of electrodes, namely floating electrodes and shielding electrodes. In preferred embodiments the floating electrodes are electrical from the other conductors isolated and there is a gap between the floating and the Shielding. The fourth (optional) layer above on the top conductive Layer is a dielectric layer, which is preferably that Layer that is in contact with the drug powder. Without intent to limit on a certain theory it is assumed that if a potential between the shielding and the rear or Collecting or support electrodes charge redistribution is applied to the floating electrodes or charge redistribution occurs. This charge redistribution causes that electrostatic loaded items to the surfaces the holding device, which are the floating electrodes correspond, resulting in deposition in these areas leads. There is preferably a high marginal field in the gap between floating and shielding electrodes, however this field is preferred not big enough, to cause an electrical discharge.

The lower electrically conductive layer may, for example, be made of metal, such as silver, copper or aluminized polypropylene, and it preferably has a thickness of about 500 nm. The dielectric layer may, for example, be made of polyimide, polypropylene or a semiconducting layer, such as for example a ceramic, for example SiO ₂ , such as a thermally grown silicon dioxide, and is preferably about 0.5 to 2 mils (thousandths of an inch) thick. The upper electrically conductive layer is preferably made of metal, such as silver. Preferably, the upper conductive layer is made of a material that is not negative for pharmaceutically active materials affected.

The upper conductive layer can, for example from a thin Gold film coating can be made and preferably have the floating and the shield electrodes the same thickness, which is preferred is about 500 nm. In preferred embodiments has the gap between the floating electrode and the shielding electrode a measure of about 25 microns to about 500 microns. The shape of the floating Electrode can be varied and it can be irregular as long as the gap between the floating electrode and the shielding electrode remains essentially constant. In certain preferred embodiments the floating electrode is round and forms a point that uses can be a selected one Generating patterns. In certain preferred embodiments the shielding electrode is grounded. The shielding electrode is related to the lower conductive Prestressed layer. The polarity the bias is preferably opposite to the tension of the powder to be deposited on the substrate.

The fourth layer on top of the top conductive Layer is an optional thin dielectric layer, which are preferably made of polyimide or another higher material dielectric strength is made and preferably a thickness of about 10 microns to about 50 microns.

The floating electrodes of the charge-imaging holding device determine the pattern of the deposition of the medicament powder on the substrate and they hold the powder thereon. During the deposition of powder, the charge-imaging holding device is electrically connected to a current or voltage source, which is then separated off after the deposition. The floating electrodes can be configured, for example so that they spatially _n individual Dosierunge set on a substrate. Such substrates include, for example, a tablet and an inhalation substrate.

In preferred embodiments for the Charge mapping is used to target the floating electrodes Particles on a substrate in contact with the floating electrodes to attract. The substrate preferably has physical contact with the floating electrodes. Without intending to limit a particular one Theory is believed to be Use of floating electrodes for the electrostatic holding device creates an image of charges by capacitive coupling. each floating electrode has a charge that is shifted when charged Particles come into contact with the electrode. The process of deposition the charged particles on the floating electrode continues until the floating electrode can no longer shift potential, namely at the point where it has the same potential as the shield electrode.

According to 5 has the holding device 1110 a lower conductive layer 1120 with a dielectric layer 1130 thereon. The dielectric layer has an upper conductive layer 1140 thereon. The top conductive layer 1140 is electrically connected, but with a gap 1150 between a shielding electrode 1160 and a floating electrode 1170 , A top view of the top conductive layer 1140 is in 6 shown, the floating electrode 1170 located in the center, with a gap 1150 between the floating electrode and the surrounding shield electrode 1160 , The area of the lower conductive layer 1120 that corresponds to each floating electrode can be made addressable in rows, such as the x-addressable holding system described above, and can be individually addressable, such as the xy-addressable holding system described above.

While of use is between the shielding electrode and the lower one conductive Layer applied a bias potential. If the ones to be deposited Particles are positively charged, the bias potential is negative, and if the particles to be separated are negatively charged, then the bias potential is positive. The shielding electrode is preferably connected to ground. While the deposition of particles becomes the duration of the deposition preferably continued until actually every single floating electrode has reached its limit in which the potential of the floating Electrode matches the potential of the shielding electrode.

When using an electrostatic Holding device with floating electrodes for the separation of powder on a substrate, the amount of deposited on the substrate Powder determined by the charge or the bias potential of the Holding device and it can only have a limited amount of powder be deposited. Without intent to limit with regard to a particular theory, it is believed that the deposition of powder then stops when the charges on the floating electrode are no longer redistributed can be which occurs when the shield electrode and the floating electrode have essentially the same potential. Preferably located both the floating and the shielding electrodes are at ground potential, when the deposition is complete or is completed. The amount of powder to be separated can therefore be controlled or set by checking the bias potential and it is unrelated to the duration of the deposition once the limit has been reached. Furthermore, the pattern of Deposition determined by the pattern of the floating electrodes, whereby a charge image is generated.

For example, a holding device can be used for charge imaging on a substrate in order to fix the deposition of particles in a specific pattern on the substrate. In be preferred embodiments, particles of a powder containing a pharmaceutically active ingredient are deposited in a selected pattern on a receiving pharmaceutical substrate. In certain preferred embodiments, the receiving substrate is a thin dielectric material such as polypropylene or other thin edible substrate such as hydroxypropylmethyl cellulose, which is preferably about 25 microns thick.

Alternatively, for example electrostatic, charge-imaging holding device with an ungrounded Electrode can be used to form an inhalation substrate and the electrostatic deposition of, for example, dry Determine powder on the substrate. The holding device with charge mapping can be used for example to make the spatial positioning more individual Determine dosages on a substrate. In addition, the conductive layer the electrostatic chuck in the inhalation substrate be used for the electronically supported supersede of the powder as it is entitled in the pending application "Inhalation device with an electronic device for enhanced release dry powder "which is described simultaneously with the present Application has been submitted.

Furthermore, the charge imaging Holding device outside used in the pharmaceutical industry, such as for the Determining the deposition pattern of a sugar coating a food item. The electrostatic, charge-imaging Holding devices according to the invention can used to items for example for the application of a design pattern, such as one Sugar coating on an edible Substrate. Alternatively, for example, the electrostatic Holding devices with charge mapping are used to hold items for application dry powder painting or powder coating or varnishing, to obtain.

Without intending to be bound by any particular theory, the following mathematical formulas can be used to determine the amount of powder that can be held by the floating electrode electrostatic chuck shown in the circuit diagram shown in FIG 7 is provided. According to 7 C is the capacitance of the capacitor formed between the lower conductive layer e _l and the floating electrode e _f . Cs is the stray capacitance of the capacitor formed between the floating electrode e _l and the lower conductive layer e _l . C 'is the capacitance of the capacitor between the floating electrode o _f and the virtual electrode e _v , which in turn is formed by the deposited charged powder. The potential of the floating electrode can only assume any value between that of the shielding electrode es and the lower conductive layer e ₁ , the shielding electrode in the in 7 shown diagram is grounded.

wobei A der Oberflächenbereich der erdfreien Elektrode und d die Dicke der dielektrischen Schicht zwischen der erdfreien Elektrode und der Abschirmelektrode ist.The maximum charge that the floating electrode can hold depends on the bias potential and the capacitor C, according to the equation Q _max = CV. If the boundary field is neglected to calculate the maximum charge, the following equation applies:

where A is the surface area of the floating electrode and d is the thickness of the dielectric layer between the floating electrode and the shielding electrode.

wobei μ das Ladung-zu-Masse-Verhältnis des geladenen Pulvers ist. Beispielsweise ist, wenn ε_r = 2, d = 50 μm, der Durchmesser der erdfreien Elektrode = 4 mm, μ = 50 μC/g und V = 8 kV ist, M gleich 1,2 mg. Die maximale Masse an Pulver, die man unter diesen Bedingungen für die Abscheidung erwarten kann, beträgt also 1,2 mg. DaCs ≪ C, ist Q' = C'V' ≈ Q. Since C _{s is} very small compared to C, the deposited charge Q 'is approximately equal to Q. The mass M of the deposited powder is then as follows:

where μ is the charge to mass ratio of the charged powder. For example, if ε _r = 2, d = 50 μm, the diameter of the floating electrode = 4 mm, μ = 50 μC / g and V = 8 kV, M is 1.2 mg. The maximum mass of powder that can be expected for the deposition under these conditions is therefore 1.2 mg. DaC s ≪ C, Q '= C'V' ≈ Q.

Therefore, the maximum amount of powder loaded is given by the following equation:

In addition to providing electrostatic chucks, the present invention provides also propose methods for charge imaging or deposition of particles on selected areas of a substrate, the method including the use of an electrostatic chuck with floating electrodes in the areas of the chuck that correspond to the selected areas on the substrate. Furthermore, the present invention also provides an object with selected areas on which particles are applied to the object via electrostatic devices. In preferred embodiments, the particles have a pharmaceutically active ingredient. The object is preferably suitable for human consumption. In certain embodiments, the article comprises a pharmaceutical substrate, such as an inhalation substrate, a tablet, a suppository, a treatment agent, a bandage or a pad. Preferably, the amount of particles applied to the article is determined using a sensor electrode in an electrostatic chuck.

Advantages of using an electrostatic Holding device for the deposition of particles and for charge mapping include the ability a to coat a substrate more precisely and evenly, which is special is important when the dosage of the active ingredient is low such as in the range of 1 μg to 1 mg. Other low dose ranges conclude for example the range from 1 μg to about 500 μg and of about 10 μg up to about 250 μg and of about 20 μg up to about 100 μg such as about 25 μg. Furthermore, the use of an electrostatic chuck provides for the Separation of particles and for charge mapping, for example, the advantage of a mechanism for the Application of an active ingredient to a pharmaceutical Carrier, which may be not miscible or otherwise incompatible or incompatible with this effective ingredient.

7. Sensor electrode for determining the amount of objects, which are deposited on a receiving substrate

In addition to the deployment electrostatic holding devices with floating electrodes for charge imaging the present invention also sees holding devices with sensor electrodes for the sensing the amount of charge deposited on a substrate. Farther can a single holding device both floating and sensor electrodes to have. According to certain Aspects of the present invention is the amount of charge applied the holding device can be deposited on a finite Limited number or size and this limitation provides a mechanism for the exact determination of the amount of powder on the by the holding device held substrate is deposited.

Looks at another aspect the present invention provides an electrostatic holding device, which is a sensor electrode for feeling the number of particles attracted to the holder have been, especially if the holding device with respect to the Amount of charged particles on one of the holding device held substrate can not be deposited automatically self limited. The electrostatic chucks or others surfaces, on which a receiving substrate is arranged, optionally close Sensor electrodes around the deposited on the receiving substrate Detect or sense the amount of charge. According to certain aspects of the present Invention is the amount of charge, for example, on an electrostatic Holding device can be deposited on a finite number limited and this limitation provides a mechanism for the exact determination of the amount of powder on one of the holding device held substrate is deposited. Alternatively, the amount of deposition not be self-limiting or automatically limited. A sensor electrode can be used with an acoustic delivery device, for example to determine the amount of powder deposited on a tablet the powder containing a pharmaceutically active ingredient. The The sensor electrode thus provides a more precise and uniform Way for delivering a selected one Lot of items ready. For example, the invention sees the exact deposition a selected one Amount of a pharmaceutically active ingredient based on is deposited on a substrate, especially if the effective one Component is only available in small doses.

The sensor electrode preferably has two layers. The bottom layer is a lower conductive layer, the one electrode made of metal such as aluminum forms. The top layer that is exposed to the particles which is a dielectric layer and it is made of a material that has a high dielectric Has strength, such as alumina. In addition can the sensor electrode, for example, from a thin, aluminized polypropylene sheet or a thin one Polyimide sheet with a copper backing be made. Without one restriction to be made on a particular theory, it is assumed that the charged particles land on the dielectric layer and one same and opposite charge on the conductive layer induce. Because of the presence of the dielectric layer is the possibility charge neutralization is considerably reduced.

According to 8th is the sensor electrode 1310 for example from a lower conductive layer 1320 and an upper dielectric layer 1330 built up. As in 9 shown, the sensor electrode 1310 for example in an area outside the substrate 1410 can be arranged, which receives the separation of the particles. In this figure the sensor electrode 1310 the shape of a ring and other shapes can be used. The sensor electrode 1310 can for example also within the area of the substrate 1410 can be arranged, which takes up the separation of the particles, as in 10A is shown when there is a single deposit picked up by the substrate. Alternatively, for example, if there are multiple substrates 1410 there, the sensor electrode 1310 be arranged within the deposition area, preferably in the form of one of the substrates 1410 which absorb a deposit, such as a tablet. According to 10B mimics the shape of the sensor electrode, for example 1310 the shape of one of the substrates 1410 to.

The sensor electrode is preferred arranged in an area that has a lot of on the sensor electrode particles to be deposited in direct proportion to the amount of deposition guaranteed on the substrate. For a single substrate can more than one sensor electrode can be used. For example the presence of two sensor electrodes during the deposition on a single substrate used to build the relationship between the amount of deposition on the substrate and in the Areas outside of the substrate occurs. The mass of the on the substrate (the substrates) deposited particles is determined as soon as the Charge of the sensor electrode is measured.

To measure the amount of charge deposited, the sensor electrode is connected in series with a capacitor of known value. For example, a 1 nF capacitor will induce a 1 volt voltage when a 1 nC charge has been collected. The other pole of the known capacitor is connected to ground and the potential at the capacitor is measured. An illustrative circuit diagram is shown in FIG 11 played. According to 11 V _{m is} a voltmeter or a high impedance electrometer, C is the capacitance of a capacitor of known size, such as 1 μF, C 'is the capacitance of between the sensor electrode es and the deposited charge e _p resulting from the separation of charged particles results, formed capacitor.

Without being limited to any particular theory want to can The following mathematical formulas are used to measure corresponding to the deposited charges by the sensor electrode evaluate the circuit diagram above.

C 'refers to the capacitor, that is formed by the sensor electrode and the charged particles becomes. C is a capacitor of known value, C has an initial charge from zero. If charged particles land on the sensor electrode, so they cause one same size Amount of opposite charge is induced on the electrode which subsequently results in a corresponding amount of opposite charge induced on C. The overall effect leads to the same Amount of charge of the same sign is induced on C by an electrometer can be measured. Furthermore, the dominant electrical noise associated with an active power source is eliminated. The accumulated charge Q 'is equal to C times V.

With this monitoring method using the sensor electrode, two parameters must be determined in order to monitor the amount of actual deposition. These two parameters are the q / m (charge-to-mass) ratio of the charged powder and the ratio factor k between the monitored charge Q 'and the deposited charge Q on the deposition area of interest (ie k = Q / Q'). Accordingly, the separated mass M is determined by the equation:

The reliability of the sensor electrode requires the Variable k during the total deposition is essentially constant.

The use of the sensor electrode is preferred with the use of an ammeter or voltmeter inside the circuit because the sensor electrode for example the advantages that a collection provides charges from the surrounding atmosphere and other leak paths, which are induced by the holding device is corrected.

Preferably, the charge to mass ratio is the items to be delivered while of the deposition process is measured to provide feedback control for termination to provide the deposition when the desired number of items are deposited has been. For example, feedback control can be used to monitor the deposition of a pharmaceutical powder, until the appropriate dose has been reached.

For example, the average charge to mass ratio can be measured using a velocimeter and a modified quartz crystal monitor. According to 17A has the quartz crystal monitor 1305 an upper sensing layer 1307 and a bottom layer 1309 for connection to a measuring device. The quartz crystal monitor is made by adding a charge sensing layer 1308 modified, wel che is a second conductive layer, and by a dielectric layer 1312 as it is in 17A is shown. This modification causes the monitor to sense and sense both charge and mass at the same time. See, for example, the circuit diagram of the monitor, which is in 17B in which Cs is the capacitor due to the dielectric layer which measures the accumulated charge. Preferably, at least two charge-to-mass monitors are used, one with the acoustic delivery device and the other with the holding device or other devices that hold the receiving substrate or the receiving substrates.

According to another aspect the present invention thus a method for attracting a selected number multiple particles on a substrate, with (a) providing an electrostatic holding device with a sensor electrode, (b) applying a plurality of electrostatically charged particles onto the holder, and (c) sensing the number of particles, which are attracted by the holding device. Are preferred the particles particles of a dry powder and the process is used to place on a substrate attached to the holding device is attracted to determine the amount of powder deposited. The invention therefore provides a method of dosing in a pharmaceutical To determine tablet exactly.

In addition, the invention provides a method of making a pharmaceutical composition ready with (a) providing a pharmaceutical substrate, and (b) electrostatically depositing particles on the substrate, the deposition preferably using an electrostatic chuck having. The electrostatic holding device preferably has a floating electrode and the particles become essentially on an area deposited the substrate which corresponds to the floating electrode, and the electrostatic chuck preferably continues to have a sensor electrode for determining the amount of particles deposited on the substrate.

8. Items that using the electrostatic chucks according to the invention be generated

The invention additionally provides objects the selected one Have areas on or in which particles on objects by means of electrostatic holding devices are applied as by Charge imaging. The use of an electrostatic device creates a more precise separation of particles after a selected area or pattern and thus provides a kind of identification for one Item ready. The deposition also takes place with greater uniformity and guaranteed less particle waste.

In preferred embodiments the particles have a pharmaceutically active ingredient and the item is for suitable for human consumption and preferably has a pharmaceutical Substrate, such as a tablet, capsule or sleeve. In other preferred embodiments the item is a suppository or it becomes part of the group selected, which consists of an inhalation substrate, a processing agent, one Bandage and a pad exists. Preferably the amount of particles applied to the object using a Predetermined sensor electrode in the electrostatic device. Moreover are in preferred embodiments the particles using an acoustic delivery device, which is described below, applied to the object.

The invention is further illustrated by the following non-limiting examples.

EXAMPLE 1. Electrostatic Holding device with an upper conductive layer, the two finger-like interlocking electrodes.

An electrostatic chuck with an upper conductive Layer that has two interdigitated electrodes, was as follows manufactured. A glass substrate was used, which is an ITO (Indium tin oxide) has an electrode that interlocks like a finger and the one upper conductive layer less than about 25 microns thick. On top of the top conductive Layer was a thin one Polystyrene layer about 1 thousandth of an inch (25 μm) thick, using a Scotch brand tape.

In a test, 1000 volts were turned on the electrodes and a tablet weighing about 65 mg and a diameter of approximately 5.6 mm was on the holding device held. After 1400 volts were applied, the tablet became repelled by the holding device, possibly due to a sudden Voltage rise, resulting in discharge due to a repulsive force led.

In a second test, the tablet placed on top of the belt and there was a DC voltage of 500 volts applied to the electrodes. The holding device was turned upside down and the tablet was on the holding device held in place.

In a third test, three tablets were attached to the holder using 500 volts and the voltage was lowered until all three fell off the holder. The first tablet dropped at 300 volts, the second tablet dropped at 200 volts, and the third tablet dropped at 100 volts. The test results showed that the holding force is proportional to V ² .

In another test, 600 Volt on one of the two interdigitated electrodes the holder and the other electrode was grounded. A tablet was placed on the polystyrene side of the holder arranged and the tablet remained on the holding device after she was turned upside down and the tablet of gravity has been suspended.

The holding device was also tested for the Deposit powder on a tablet while it is held by the holder was held. Using an air drive for separation a positively charged steroid in a 3% suspension Perlen found that at least about 47 μg had been deposited.

EXAMPLE 2. Electrostatic Holding device with a single electrode in the upper conductive layer.

An electrostatic chuck with a single electrode in the top conductive layer as follows designed. The bottom of the holding device consisted of a lower conductive Layer that was made of aluminum on a dielectric Layer of polyimide was layered, which was laminated to copper was (Good Fellows, Berwyn, PA). The thickness of the polyimide layer was approximately 2 thousandths of an inch. Three copper wires on top of the polyimide layer formed the top conductive layer and served as an electrode. The thickness of the copper layer was approximately 4 thousandths of an inch (0.1 mm). The distance between the copper wires was about 5.6 mm. 68 tablets were used, each one in diameter of about 5.6 mm and each weighed about 65 mg and which ones 95% cellulose and about 3% lactose were made, each with a thickness of about 2 mm. The tablets were left for about 5 Minutes stick to the holding device, with 1500 volts between the upper and lower conductive Layers were created.

A medical steroid powder was made applied to the tablets and as follows from that described above Holding device held. A mixture of 3% medicinal active ingredient with steel beads or spheres coated with Kynar (Vertex Image Products, Yukom, PA), which were about 100 microns in diameter, were taken up in a Teflon bottle. 585.0 mg of a medical Powders were made in a combination of a medical ingredient and balls, which weighed 20.6354 g, for about 6 minutes deposited on the tablets, the acoustic Dispenser was used as described in Example 8 below was at a frequency of 87 Hz, which is the optimal frequency for the dispenser was determined. The screen of the acoustic delivery device for the separation of the medical powder from the beads or pearls was in a distance of 0.5 to 1 inch (1.25 to 2.5 cm) from the tablets arranged that took up the powder.

EXAMPLE 3. Electrostatic Holding device with floating electrodes

An electrostatic chuck was tested with floating electrodes of the following design. The lower conductive Layer was made from a copper tape and had a thickness approximately 4 mils (0.1 mm). The next shift was a dielectric layer on a polystyrene tape Scotch brand was manufactured and a thickness of 1 thousandth Had customs. An upper layer was located on this dielectric layer conductive Layer made from a standard multi-purpose board with through holes and winding contacts (radioshack) and about 0.0625 Inches thick (about 1.6 mm), and which formed an electrode with a gap between a shielding electrode and a floating electrode, that were electrically connected. The floating electrode was round and was about 2.5 mm in diameter. The shield electrode was round and was about 2.5 mm in diameter. The gap between the shielding and the floating Electrode was about 200 microns. A substrate was on the top conductive Layer arranged, wherein the substrate is a dielectric layer which was made from a Scotch brand polystyrene tape and was about 1 thousandth of an inch thick (0.025 mm).

To use the holder, about -1800 volts were applied to the top conductive layer. Next, steroid drug particles were made using the ones in the example 8th Dispensing device described applied to the holding device.

The 12 - 13 show the deposition of the powder on a floating electrode using a bias potential of -1800 volts in the holding device described above. The lower conductive layer, which is a printed circuit board, shows control over the orientation of the powder during the deposition. In the 12A and 13A the lower conductive layer was omitted while it was in the 12B and 13B was present. 12A shows that in the absence of the lower conductive layer, the charged particles accumulate on the edges of the floating electrode. In contrast, they show 12B and 13B that in the presence of the lower conductive layer, the charged particles are evenly distributed over the floating electrode. The largest amount of powder deposited was used for the 13B existing conditions found in the presence of the lower conductive layer.

EXAMPLE 4. Electrostatic Holding device with sensor electrode

An electrostatic chuck with a sensor electrode is constructed as follows. The sensor electrode consists of a lower conductive Layer that is made of aluminum and that on its top has a dielectric layer made of alumina. A Sensor electrode is on the electrostatic chuck arranged so that they outside of the receiving substrate, which is exposed to the deposition shall be. The sensor electrode is used to indirectly measure the Determine the amount of deposition of the charged particles by the charge change is measured before and after the deposition.

Another electrostatic chuck is built with a sensor electrode on the holding device is arranged in the area within the receiving substrate and causes both the sensor electrode as well as the receiving substrate of the deposition are exposed. In this case the sensor electrode is used the amount of deposition of the charged particles by measuring the change to determine the charge before and after deposition.

A third electrostatic chuck is constructed with two sensor electrodes, one of which is inside of the receiving substrate and the other outside of the receiving substrate is arranged. In this case the sensor electrode is inside of the receiving substrate used to determine the amount of deposition of the charged Particles by measuring the change determine the charge directly before and after deposition, and it is also used to measure the deposition by the Sensor electrode outside of the deposition area to be calibrated.

A sensor electrode in a ring structure was made using anodized alumina (with aluminum as conductive Layer formed the electrode and the oxide layer formed the dielectric). 15 g pearls or beads were used and were scaled down to a micrometer size Steroid medicine powder (cortisone, Aldrich Chemical Co., Milwaukee, WI) for shaken for about 30 minutes. Two Powder concentrations were used, being a 450 mg powder per 15 g pearls (3% mixture) and the other 900 mg powder for 15 g pearls (6% mixture). There were on the electrostatic chuck 1800 volts applied. Acoustic energy was used to make the powder according to example 8 to accelerate, with either 1400 (corresponding to 12 watts) 1600 or 1800 were used. The one that occurs during the deposition charge change was done by recording the voltage on the electrometer every 30 Seconds during the first 2 minutes and then every minute thereafter until a total of 30 minutes had passed. The on a previously weighed Amount of powder of aluminum deposited was also measured.

Multiple tests have been performed by depositing on aluminum foil, with the time required for complete deposition to take about 5 minutes. The tests showed that when deposited in the steady state, k varies by up to 4% in each direction. k is the ratio between the observed charge Q 'and the deposited charge Q and is actually a function of all the operating parameters of the holding device and the acoustic delivery device; therefore k is determined experimentally. An inconsistency of k over 10% is accompanied by a change in the properties of the dispenser. The data for the sensor electrode obtained in the tests are in the 14A - C shown, which provide a graphical representation of experimental data using a sensor electrode in the monitoring ring design.

Claims (14)

A method for producing a pharmaceutical composition comprising: (a) providing a pharmaceutical substrate, characterized by (b) holding the substrate on a holding device ( 620 ), the holding device ( 620 ) a flat dielectric layer ( 630 ) and a flat conductive layer ( 640 ) disposed directly on the dielectric layer, the conductive layer being adapted (650, 660) to electrostatically attract particles, and (c) electrostatically adhering pharmaceutically active particles to the substrate held by the holder the particles are held on the substrate by electrostatic forces. A method according to claim 1, characterized in that the electrostatic holding device has a floating electrode ( 1170 ) and that the particles have essentially on an area of the substrate which corresponds to the floating electrode. A method according to claim 2, characterized by comprising the selection of a bias potential, which is based on the electrostatic Holding device is applied to the amount of particles attached determine which has been attached to the pharmaceutical substrate are, and to apply the bias potential to the holding device. The method of claim 1 or 2, characterized in that it further comprises measuring the amount of particles deposited on the substrate by measuring ion currents generated by those on an interrogation electrode ( 1310 ) particles induced on the pharmaceutical substrate during the application of the particles. A method according to claim 1, characterized in that the pharmaceutical Substrate selected from the group which consists of an inhalation substrate and an edible polymer Substrate exists. A method according to claim 4, characterized in that it further shows that the Application of particles is stopped when the measured amount is deposited Particle has reached a target value. A method according to claim 1, characterized in that the substrate is selected from the group which consists of a tablet, a capsule, a caplet, a suppository, a preparation, a bandage and a pad exists. Particle separation device, characterized in that it comprises: an electrostatic holding device ( 620 ) which is a flat dielectric layer ( 630 ) and a flat conductive layer ( 640 ) which is arranged on the dielectric layer and with at least one electrode ( 650 . 660 ) to electrostatically attract particles with pharmaceutically active ingredients to a substrate, and devices for attaching the substrate to the holding device. Device according to claim 8, characterized in that the electrostatic holding device comprises a floating electrode ( 1170 ) having. Device according to claim 8 or 9, characterized in that it further comprises an interrogation electrode ( 1310 ) to measure the amount of particles deposited on the substrate. Particle separation device according to claim 8, characterized in that she Facilities for that Controlling the amount of particles attracted to the substrate. Particle separation device according to claim 11, characterized in that that she means for separating the controlled amount of particles at a plurality of separate locations. Device according to one of claims 8 to 12, characterized in that that she furthermore a pharmaceutical held on the holding device Includes substrate. Device according to claim 13, characterized in that the substrate is a pharmaceutical inhalation substrate.