Patent Publication Number: US-9889953-B2

Title: Dosing heads for direct fill dry powder systems configured for on/off controlled flow

Description:
RELATED APPLICATIONS 
     This application is a second divisional application of U.S. patent application Ser. No. 13/029,356, filed Feb. 17, 2011, which claims the benefit of and priority to U.S. Provisional Patent Application Ser. No. 61/306,291, filed Feb. 19, 2010, through first divisional application, U.S. patent application Ser. No. 14/221,648, filed Mar. 21, 2014, the contents of which are hereby incorporated by reference as if recited in full herein. 
    
    
     FIELD OF THE INVENTION 
     The present invention relates to systems for filling containers with dry powder such as drugs, chemicals and toners and may be particularly suitable for filling multi-dose disks or other containers for dry powder inhalers. 
     BACKGROUND OF THE INVENTION 
     Known dry powder dose filling devices use injectors, pistons or sleeves, such as described in U.S. Pat. Nos. 3,847,191, 4,116,247, 4,850,259, and 6,886,612. Despite the above, there remains a need for alternate dose filling systems. 
     SUMMARY OF EMBODIMENTS OF THE INVENTION 
     Embodiments of the invention provide dosing heads with a plurality of spaced apart elongate channels that communicate with a dry powder bed to concurrently directly fill a plurality of aligned dose containers. 
     Embodiments of the invention provide a relatively high-speed filling process for concurrently filling all the dose containers held by a dose container member, such as a disk, in sub-second time. 
     In some embodiments, the dosing head has at least one row of circumferentially spaced apart elongate channels (e.g., 30) and can directly fill an underlying dose container disk with an aligned row of spaced apart concentric dose containers (typically in less than about 1 second). In particular embodiments, the dosing head has two radially spaced apart circular rows of elongate channels, e.g., two rows of 30 channels arranged in a circle. 
     The dosing head can include at least one plate that provides the elongate channels. The dosing head can be configured to interchangeably hold different plates with different elongate channel geometries for accommodating specific dose container form factors and/or for use with different dry powder formulations. The dosing head plate can be substantially circular. 
     The dosing systems can be configured to fill a dose container disk with 30, 60 or, in particular embodiments, even 120 dose containers in less than about 1 second. 
     Some embodiments are directed to an apparatus for dispensing a defined amount of dry powder concurrently to a plurality of spaced apart dose receiving containers. The apparatus includes: (a) a dosing head comprising a support body with a plurality of spaced apart elongate channels having a channel length with an upper end defining an entry orifice and a lower end defining an exit port; (b) a dry powder bed residing above and in communication with the dosing head; and (c) at least one vibration source in communication with the dosing head channels configured to controllably apply a vibration flow signal. The channels are sized and configured to prevent a free-flow of dry powder therefrom. When the vibration flow signal is applied to the dosing head channels, dry powder from the dry powder bed flows through the elongate channels and out of the exit port. When the vibration flow signal is removed, dry powder does not flow through the dosing head elongate channels. 
     The spaced apart channels can be arranged so that the respective entry orifices are substantially circumferentially spaced apart in at least one circle. In some particular embodiments, the channel entry orifices are arranged in two substantially concentric circles. 
     The vibration source can include a substantially cylindrical body actuator mechanism with a radially extending flange having an array of circumferentially extending apertures extending therethrough. The apparatus can further include a tube plate with an array of upwardly extending tubes having upper and lower ends. The tube plate can be positioned between the actuator body flange and the dose head body so that each tube extends through a respective flange aperture with upper ends of the tubes in communication with dry powder in a dry powder hopper and lower ends of the tubes residing proximate the dosing head channels. 
     The channels can have orifices that have a diameter of about 3 mm or less and a geometry that defines a miniature-hopper selected to provide an on/off flow pattern and mass flow rate to deliver a defined dose amount in the range of between about 0.5-15 mg. 
     The channels can be sloped along at least a major portion of the channel length. For example, the channels can slope downward at an angle that is between about 30 degrees to about 45 degrees for at least a major portion of the length of the channel. The channels may have a first portion that angles downwardly to merge into a second portion that is substantially vertical at the exit port. 
     In some embodiments, the dosing head includes a holder with upstanding sidewalls and a lower inwardly extending ledge. The dosing head can include a plate that mounts to the holder and resides on the ledge and the plate defines the channels. 
     In some embodiments, the dosing head includes at least one substantially circular plate that defines the channels, the plate having a center. The apparatus can include an upstanding rod that is aligned with the center of the plate. The rod is in communication with the plate and the vibration source to apply the vibration flow signal to the plate. 
     In some embodiments, the apparatus includes a substantially circular tube plate with an array of circumferentially spaced apart tubes. The dosing head body can be defined by a substantially circular orifice plate that includes at least one row of circumferentially spaced apart elongate channels. The vibration source can include an actuator mechanism with a substantially cylindrical body with a vertically extending centerline aligned with a vertical linear vibration axis of the orifice plate. The actuator mechanism can have a radially extending flange that is attached to the orifice plate and the tube plate. The actuator mechanism can include a plurality of linear actuators that cause the tubes to vibrate in a vertical direction to feed dry powder to the orifice plate and to apply the vibration signal to the orifice plate. 
     The dosing head can have a lower primary surface that is horizontally oriented. The vibration source can be substantially in-line with a vertical axis associated with the dosing head and is configured to apply energy so that the dosing head operates with a vertical displacement that is less than about 100 microns, and wherein the target dose container is a disk that is closely spaced apart from a lowermost surface of the dosing head. 
     The vibration source can include: (a) a plurality of actuators, one residing proximate each channel to individually apply the flow signal; (b) a single actuator that is configured to apply the flow signal to all the flow channels; or (c) a plurality of actuators, at least one for sub-groupings of the channels. 
     The dry powder bed can hold a dry powder having a pharmaceutically active agent including, but not limited to, bronchodilators and the bronchodilator may be used in the form of salts, esters or solvates to thereby optimize the activity and/or stability of the medicament. 
     The dosing head can include at least one plate that defines at least some of the channels, and wherein the dosing head is configured to releasably engage different plates having different channel geometries to thereby allow a user to dispense different dry powders. 
     The apparatus channels communicate with the dry powder bed to define miniature hoppers that each hold a plurality of bolus amounts of dry powder and controllably directly dispense a bolus amount to an aligned dose container in response to the on and off application of the vibration flow signal. 
     Other embodiments are directed to methods of filling a dose container disk assembly. The methods include: (a) providing a dose container disk having upper and lower primary surfaces with a plurality of circumferentially spaced apart apertures associated with dose containers; (b) placing the dose container disk under a dosing head that resides below a dry powder bed, the dosing head having a plurality of circumferentially spaced apart dose filling channels with respective exit ports over the dose container disk so that the exit ports are aligned with the dose disk apertures; (c) applying a vibration flow signal to the dosing head to cause the dry powder to concurrently flow out of the channels into the dose disk apertures; (d) directly filling the dose container disk with a defined amount of dry powder in response to the applying step; and (e) ceasing the applying step to stop the flow of dry powder thereby filling a dose container disk with a defined amount of dry powder in each of the dose containers. 
     The flow vibration signal can be in-line and can be a frequency modified (modulated) signal. The dose container disk can have at least 30 apertures and the dosing head has at least 30 dose filling channels, and the filling step is carried out to fill at least 30 dose containers on a disk or other substrate in less than 1 second, typically in less than 0.5 seconds. 
     The dosing head can be attached to a tube plate that includes an array of upwardly extending tubes that communicate with the dry powder bed. The applying step can be carried out to also cause the tubes to vibrate up and down to feed the dosing head channels (which may optionally reside in a lower orifice plate). 
     Yet other embodiments are directed to dosing heads for a powder filling system that include a plurality of circumferentially spaced apart filling channels with exit ports residing on inner and outer radially spaced apart rows. 
     The dosing head can include a circular orifice plate that holds the filling channels. 
     The dosing head can be in combination with a tube plate attached to the orifice plate and an actuator mechanism with a radially extending flange with an array of apertures attached to the tube plate and the orifice plate. 
     The tube plate can have upper and lower planar surfaces with the upper surface having at least one row of upwardly extending circumferentially spaced apart tubes positioned so that the upwardly extending tubes of the tube plate extend through the flange apertures and the tube plate resides between the orifice plate and the actuator flange. 
     It is noted that aspects of the invention described with respect to one embodiment, may be incorporated in a different embodiment although not specifically described relative thereto. That is, all embodiments and/or features of any embodiment can be combined in any way and/or combination. Applicant reserves the right to change any originally filed claim or file any new claim accordingly, including the right to be able to amend any originally filed claim to depend from and/or incorporate any feature of any other claim although not originally claimed in that manner. These and other objects and/or aspects of the present invention are explained in detail in the specification set forth below. 
    
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
         FIG. 1  is a side perspective view of a filling system according to embodiments of the present invention. 
         FIGS. 2A and 2B  are schematic cross-sectional views of a dose filling head and aligned dose containers for filling according to embodiments of the present invention. 
         FIG. 3A  is a top perspective view of a dose container disk according to some embodiments of the present invention. 
         FIG. 3B  is a top perspective view of a dose container disk according to some other embodiments of the present invention. 
         FIG. 3C  is a partial section view of an exemplary disk container configuration for dose containers associated with the dose container disk of  FIG. 3A or 3B  according to embodiments of the present invention. 
         FIG. 3D  is a partial section view of another exemplary dose container configuration for dose containers associated with the dose container disk of  FIG. 3A or 3B  according to embodiments of the present invention. 
         FIG. 4  is a sectional view taken along line  4 - 4  of  FIG. 1 . 
         FIG. 5A  is a perspective view of a filling system according to embodiments of the present invention. 
         FIG. 5B  is a partial cutaway view of the filling system shown in  FIG. 5A . 
         FIG. 5C  is a partial cutaway side perspective view the dosing head shown in  FIG. 5A  according to embodiments of the present invention. 
         FIG. 5D  is a side partial sectional view of the dosing head shown in  FIG. 5C . 
         FIG. 5E  is a perspective partial cutaway view of the dosing head shown in  FIG. 5C . 
         FIG. 6  is an enlarged side perspective view of a plate with dosing channels according to embodiments of the present invention. 
         FIG. 7  is an enlarged side perspective view of another example of a plate with dosing channels according to embodiments of the present invention. 
         FIG. 8A  is a side sectional view of the plate shown in  FIG. 7  according to some embodiments of the present invention. 
         FIG. 8B  is a side sectional view of the plate shown in  FIG. 6  according to some embodiments of the present invention. 
         FIG. 8C  is an alternate side sectional view of the plate shown in  FIG. 7  according to yet other embodiments of the present invention. 
         FIG. 9A  is a schematic fragmented sectional view of a dosing channel with a sloping geometry and aligned dose container member according to embodiments of the present invention. 
         FIG. 9B  is a schematic fragmented sectional view of a dosing channel with an alternate sloping geometry and aligned dose container member according to embodiments of the present invention. 
         FIG. 10  is a schematic sectional view of different exemplary channel geometries according to embodiments of the present invention. 
         FIG. 11  is a schematic illustration of a filling system with interchangeable dosing heads or portions thereof (e.g., plates) with different channel geometries according to embodiments of the present invention. 
         FIGS. 12A and 12B  are schematic illustrations of exemplary dose filling systems with multiple filling stations according to embodiments of the present invention. 
         FIG. 12C  is an enlarged section view of an exemplary holder for aligning a dose container member with a dosing head and/or dosing channels according to embodiments of the present invention. 
         FIG. 13  is a control circuit diagram of a filling system according to embodiments of the present invention. 
         FIG. 14  is a flow chart of operations that can be used to fill at least one dose container member with multiple dose containers according to some embodiments of the present invention. 
         FIG. 15  is a schematic illustration of a data processing system according to embodiments of the present invention. 
         FIG. 16  is a graph showing data for flow channels with different geometries and “no flow”, “flow with vibration” and “free flow” limits with respect to channel outer diameter sizes (mm) and minimum displacement. 
         FIG. 17A  is a top perspective view of a plate with about 41 degree funnel shaped channels. 
         FIG. 17B  is a top perspective view of a plate with about 30 degree funnel shaped channels. 
         FIG. 17C  is a top perspective view of a plate with substantially cylindrical (vertical) channels. 
         FIG. 17D  is a graph of flow of Inh230 dry powder with “hand tapping”, “no flow” and “free flow” with respect to channel size (OD) for different geometry dosing flow channels. 
         FIG. 18  is a graph of flow (mg/second) versus displacement (microns) for a 0.9 mm, 41 degree inverted funnel channel geometry. 
         FIG. 19  is graph illustrating a minimum threshold displacement (microns/micrometers) to induce flow (at 300 Hz for Inh230) versus channel nominal outer diameter size (mm) for three different channel geometries, cylindrical, 30 and 41 degree funnels. 
         FIG. 20A  is a graph of flow (mg/s) versus channel OD (nominal OD in mm at minimum displacement for flow using a 300 Hz vibratory signal for Inh230. 
         FIG. 20B  is a graph of flow rate (mg/s) versus channel area (mm 2 ) for a 41 degree funnel. 
         FIG. 21A  is a top perspective cutaway view of a dosing head with alternating inward and outward sloping channels according to embodiments of the present invention. 
         FIG. 21B  is a bottom perspective cutaway view of the device shown in  FIG. 21A . 
         FIG. 21C  is a top view of the device shown in  FIG. 21A . 
         FIG. 21D  is a bottom view of the device shown in  FIG. 21A . 
         FIG. 22A  is a top view of another embodiment of a dosing head with alternating inward and outward sloping channels according to embodiments of the present invention. 
         FIG. 22B  is a side perspective cutaway view of the device shown in  FIG. 22A . 
         FIG. 22C  is a bottom perspective view of the device shown in  FIG. 22A . 
         FIG. 23A  is a cutaway view of yet another embodiment of a dosing head with alternating inward and outward sloping channels according to embodiments of the present invention. 
         FIG. 23B  is a top perspective view of the device shown in  FIG. 23A . 
         FIG. 24A  is a top perspective view of a dosing head with alternating inward and outward sloping channels similar to that shown in  FIG. 23A  but with larger exit ports according to embodiments of the present invention. 
         FIG. 24B  is a top view of the device shown in  FIG. 24A . 
         FIG. 24C  is a bottom view of the device shown in  FIG. 24A . 
         FIG. 24D  is a cutaway view of the device shown in  FIG. 24A . 
         FIG. 24E  is another cutaway view of the device shown in  FIG. 24A . 
         FIG. 25A  is a partial cutaway top view of a dose filling system according to embodiments of the present invention. 
         FIG. 25B  is a partial cutaway bottom view of the dose filling system shown in  FIG. 25A . 
         FIG. 26  is an exploded view of the system shown in  FIG. 25A . 
         FIG. 27  is a schematic illustration of an example filling tube to orifice channel alignment according to some particular embodiments of the present invention. 
     
    
    
     DESCRIPTION OF EMBODIMENTS OF THE INVENTION 
     The present invention will now be described more fully hereinafter with reference to the accompanying figures, in which embodiments of the invention are shown. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Like numbers refer to like elements throughout. In the figures, certain layers, components or features may be exaggerated for clarity, and broken lines illustrate optional features or operations unless specified otherwise. In addition, the sequence of operations (or steps) is not limited to the order presented in the figures and/or claims unless specifically indicated otherwise. In the drawings, the thickness of lines, layers, features, components and/or regions may be exaggerated for clarity and broken lines illustrate optional features or operations, unless specified otherwise. Features described with respect to one figure or embodiment can be associated with another embodiment of figure although not specifically described or shown as such. 
     It will be understood that when a feature, such as a layer, region or substrate, is referred to as being “on” another feature or element, it can be directly on the other feature or element or intervening features and/or elements may also be present. In contrast, when an element is referred to as being “directly on” another feature or element, there are no intervening elements present. It will also be understood that, when a feature or element is referred to as being “connected”, “attached” or “coupled” to another feature or element, it can be directly connected, attached or coupled to the other element or intervening elements may be present. In contrast, when a feature or element is referred to as being “directly connected”, “directly attached” or “directly coupled” to another element, there are no intervening elements present. Although described or shown with respect to one embodiment, the features so described or shown can apply to other embodiments. 
     The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention. As used herein, the singular forms “a”, “an” and “the” are intended to include the plural forms as well, unless the context clearly indicates otherwise. It will be further understood that the terms “comprises” and/or “comprising,” when used in this specification, specify the presence of stated features, steps, operations, elements, and/or components, but do not preclude the presence or addition of one or more other features, steps, operations, elements, components, and/or groups thereof. As used herein, the term “and/or” includes any and all combinations of one or more of the associated listed items. 
     Spatially relative terms, such as “under”, “below”, “lower”, “over”, “upper” and the like, may be used herein for ease of description to describe one element or feature&#39;s relationship to another element(s) or feature(s) as illustrated in the figures. It will be understood that the spatially relative terms are intended to encompass different orientations of the device in use or operation in addition to the orientation depicted in the figures. For example, if a device in the figures is inverted, elements described as “under” or “beneath” other elements or features would then be oriented “over” the other elements or features. Thus, the exemplary term “under” can encompass both an orientation of over and under. The device may be otherwise oriented (rotated 90 degrees or at other orientations) and the spatially relative descriptors used herein interpreted accordingly. Similarly, the terms “upwardly”, “downwardly”, “vertical”, “horizontal” and the like are used herein for the purpose of explanation or relative descriptor only unless specifically indicated otherwise. 
     It will be understood that although the terms “first” and “second” are used herein to describe various components, regions, layers and/or sections, these regions, layers and/or sections should not be limited by these terms. These terms are only used to distinguish one component, region, layer or section from another component, region, layer or section. Thus, a first component, region, layer or section discussed below could be termed a second component, region, layer or section, and vice versa, without departing from the teachings of the present invention. Like numbers refer to like elements throughout. 
     Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the specification and relevant art and should not be interpreted in an idealized or overly formal sense unless expressly so defined herein. Well-known functions or constructions may not be described in detail for brevity and/or clarity. 
     In the description of the present invention that follows, certain terms are employed to refer to the positional relationship of certain structures relative to other structures. As used herein, the term “front” or “forward” and derivatives thereof refer to the general or primary direction that the dry powder travels from a powder bed to a receiving container such as a dose disk; this term is intended to be synonymous with the term “downstream,” which is often used in manufacturing or material flow environments to indicate that certain material traveling or being acted upon is farther along in that process than other material. Conversely, the terms “rearward” and “upstream” and derivatives thereof refer to the direction opposite, respectively, the forward or downstream direction. 
     The term “deagglomeration” and its derivatives refer to flowing or processing dry powder to inhibit the dry powder from remaining or becoming agglomerated or cohesive. 
     The term “free-flow” refers to the ability of a channel to allow dry powder to flow therethrough when in an operative position and in the absence of any vibratory flow signal. 
     The filling systems can be particularly suitable for filling a partial or bolus dose or doses of one or more types of particulate dry powder substances that are formulated for in vivo inhalant dispersion (using an inhaler) to subjects, including, but not limited to, animal and, typically, human subjects. The inhalers can be used for nasal and/or oral (mouth) respiratory inhalation delivery, but are typically oral inhalers. 
     The terms “sealant”, “sealant layer” and/or “sealant material” includes configurations that have at least one layer of at least one material and can be provided as a continuous layer that covers the entire upper surface and/or lower surface or may be provided as strips or pieces to cover portions of the device, e.g., to reside over at least one or more of the dose container apertures. Thus, terms “sealant” and “sealant layer” include single and multiple layer materials, typically comprising at least one foil layer. The sealant or sealant layer can be a thin multi-layer laminated sealant material with elastomeric and foil materials. The sealant layer can be selected to provide drug stability as they may contact the dry powder in the respective dose containers. 
     The sealed dose containers can be configured to inhibit oxygen and moisture penetration to provide a sufficient shelf life. 
     The term “primary surface” refers to a surface that has a greater area than another surface and the primary surface can be substantially planar or may be otherwise configured. For example, a primary surface can include protrusions or recesses, such as where some blister configurations are used. Thus, a component such as a disk and/or plate can have upper and lower primary surfaces and a minor surface (e.g., a wall with a thickness) that extends between and connects the two. 
     The dry powder substance may include one or more active pharmaceutical constituents as well as biocompatible additives that form the desired formulation or blend. As used herein, the term “dry powder” is used interchangeably with “dry powder formulation” and means that the dry powder can comprise one or a plurality of constituents, agents or ingredients with one or a plurality of (average) particulate size ranges. The term “low-density” dry powder means dry powders having a density of about 0.8 g/cm 3  or less. In particular embodiments, the low-density powder may have a density of about 0.5 g/cm 3  or less. The dry powder may be a dry powder with cohesive or agglomeration tendencies. 
     The term “filling” means providing a bolus or sub-bolus metered or defined amount of dry powder. Thus, the respective dose container is not required to be volumetrically full. 
     The term “direct” with respect to filling means that no additional components are required to carry out the operation, e.g., the dry powder is directly deposited from the dosing head channel into a blister or other dose container. 
     As will be appreciated by one of skill in the art, embodiments or aspects of the invention may be embodied as a method, system, data processing system, or computer program product. Accordingly, the present invention may take the form of an entirely software embodiment or an embodiment combining software and hardware aspects, all generally referred to herein as a “circuit” or “module.” 
     In any event, individual dispensable quantities of dry powder formulations can comprise a single ingredient or a plurality of ingredients, whether active or inactive. The inactive ingredients can include additives added to enhance flowability or to facilitate aerosolization delivery to the desired target. The dry powder drug formulations can include active particulate sizes that vary. The systems may be particularly suitable for filling dry powder formulations having particulates which are in the range of between about 0.5-50 μm, typically in the range of between about 0.5 μm-20.0 μm, and more typically in the range of between about 0.5 μm-8.0 μm. The dry powder formulation can also include flow-enhancing ingredients, which typically have particulate sizes that may be larger than the active ingredient particulate sizes. In certain embodiments, the flow-enhancing ingredients can include excipients having particulate sizes on the order of about 50-100 μm. Examples of excipients include lactose and trehalose. Other types of excipients can also be employed, such as, but not limited to, sugars which are approved by the United States Food and Drug Administration (“FDA”) as cryoprotectants (e.g., mannitol) or as solubility enhancers (e.g., cyclodextrine) or other generally recognized as safe (“GRAS”) excipients. 
     “Active agent” or “active ingredient” as described herein includes an ingredient, agent, drug, compound, or composition of matter or mixture, which provides some pharmacologic, often beneficial, effect. This includes foods, food supplements, nutrients, drugs, vaccines, vitamins, and other beneficial agents. As used herein, the terms further include any physiologically or pharmacologically active substance that produces a localized and/or systemic effect in a patient. 
     The active ingredient or agent that can be delivered includes antibiotics, antiviral agents, anepileptics, analgesics, anti-inflammatory agents and bronchodilators, and may be inorganic and/or organic compounds, including, without limitation, drugs which act on the peripheral nerves, adrenergic receptors, cholinergic receptors, the skeletal muscles, the cardiovascular system, smooth muscles, the blood circulatory system, synoptic sites, neuroeffector junctional sites, endocrine and hormone systems, the immunological system, the reproductive system, the skeletal system, autacoid systems, the alimentary and excretory systems, the histamine system, and the central nervous system. Suitable agents may be selected from, for example and without limitation, polysaccharides, steroids, hypnotics and sedatives, psychic energizers, tranquilizers, anticonvulsants, muscle relaxants, anti-Parkinson agents, analgesics, anti-inflammatories, muscle contractants, antimicrobials, antimalarials, hormonal agents including contraceptives, sympathomimetics, polypeptides and/or proteins (capable of eliciting physiological effects), diuretics, lipid regulating agents, antiandrogenic agents, antiparasitics, neoplastics, antineoplastics, hypoglycemics, nutritional agents and supplements, growth supplements, fats, antienteritis agents, electrolytes, vaccines and diagnostic agents. 
     The active agents may be naturally occurring molecules or they may be recombinantly produced, or they may be analogs of the naturally occurring or recombinantly produced active agents with one or more amino acids added or deleted. Further, the active agent may comprise live attenuated or killed viruses suitable for use as vaccines. Where the active agent is insulin, the term “insulin” includes natural extracted human insulin, recombinantly produced human insulin, insulin extracted from bovine and/or porcine and/or other sources, recombinantly produced porcine, bovine or other suitable donor/extraction insulin and mixtures of any of the above. The insulin may be neat (that is, in its substantially purified form), but may also include excipients as commercially formulated. Also included in the term “insulin” are insulin analogs where one or more of the amino acids of the naturally occurring or recombinantly produced insulin has been deleted or added. 
     It is to be understood that more than one active ingredient or agent may be incorporated into the aerosolized active agent formulation and that the use of the term “agent” or “ingredient” in no way excludes the use of two or more such agents. Indeed, some embodiments of the present invention contemplate filling a single dose container or a single disk with combination drugs that may be mixed in situ. 
     Examples of diseases, conditions or disorders that may be treated using dry powder filled with the filling systems of embodiments of the invention include, but are not limited to, asthma, COPD (chronic obstructive pulmonary disease), viral or bacterial infections, influenza, allergies, cystic fibrosis, and other respiratory ailments as well as diabetes and other insulin resistance disorders. The dry powder may be used to deliver locally-acting agents such as antimicrobials, protease inhibitors, and nucleic acids/oligionucleotides as well as systemic agents such as peptides like leuprolide and proteins such as insulin. For example, inhaler-based delivery of antimicrobial agents such as antitubercular compounds, proteins such as insulin for diabetes therapy or other insulin-resistance related disorders, peptides such as leuprolide acetate for treatment of prostate cancer and/or endometriosis and nucleic acids or ogligonucleotides for cystic fibrosis gene therapy may be performed. See e.g. Wolff et al.,  Generation of Aerosolized Drugs , J. Aerosol. Med. pp. 89-106 (1994). See also U.S. Patent Application Publication No. 20010053761, entitled  Method for Administering ASPB 28- Human Insulin  and U.S. Patent Application Publication No. 20010007853, entitled  Method for Administering Monomeric Insulin Analogs , the contents of which are hereby incorporated by reference as if recited in full herein. 
     Typical dose amounts of the unitized dry powder mixture dispersed by inhalers may vary depending on the patient size, the systemic target, and the particular drug(s). The dose amounts and type of drug held by a dose container (also known as a “dose container system”) may vary per dose container or may be the same on a platform such as a disk. In some embodiments, the dry powder dose amounts can be about 100 mg or less, typically less than 50 mg, and more typically between about 0.1 mg to about 30 mg. 
     In some embodiments, such as for pulmonary conditions (i.e., asthma or COPD), the dry powder can be provided as about 5 mg total weight (the dose amount may be blended to provide this weight). A conventional exemplary dry powder dose amount for an average adult is less than about 50 mg, typically between about 10-30 mg and for an average adolescent pediatric subject is typically from about 5-10 mg. A typical dose concentration may be between about 1-5%. Exemplary dry powder drugs include, but are not limited to, albuterol, fluticasone, beclamethasone, cromolyn, terbutaline, fenoterol, β-agonists (including long-acting β-agonists), salmeterol, formoterol, cortico-steroids and glucocorticoids. 
     In certain embodiments, the bolus or dose can be formulated with an increase in concentration (an increased percentage of active constituents) over conventional blends. Further, the dry powder formulations may be configured as a smaller administrable dose compared to the conventional 10-25 mg doses. For example, each administrable dry powder dose may be on the order of less than about 60-70% of that of conventional doses. In certain particular embodiments, using the dispersal systems provided by certain embodiments of the DPI configurations of the instant invention, the adult dose may be reduced to under about 15 mg, such as between about 10 μg-10 mg, and more typically between about 50 μg-10 mg. The active constituent(s) concentration may be between about 5-10%. In other embodiments, active constituent concentrations can be in the range of between about 10-20%, 20-25%, or even larger. In particular embodiments, such as for nasal inhalation, target dose amounts may be between about 12-100 μg. 
     In certain particular embodiments, the dry powder in the filling system for a particular dose container, drug compartment or blister may be formulated in high concentrations of an active pharmaceutical constituent(s) substantially without additives (such as excipients). As used herein, “substantially without additives” means that the dry powder is in a substantially pure active formulation with only minimal amounts of other non-biopharmacological active ingredients. The term “minimal amounts” means that the non-active ingredients may be present, but are present in greatly reduced amounts, relative to the active ingredient(s), such that they comprise less than about 10%, and preferably less than about 5%, of the dispensed dry powder formulation, and, in certain embodiments, the non-active ingredients are present in only trace amounts. 
     In some embodiments, the target unit dose amount of dry powder for a respective drug compartment or dose container is between about 5-15 mg, typically less than about 10 mg, such as about 5 mg of blended drug and lactose or other additive (e.g., 5 mg LAC), for treating pulmonary conditions such as asthma. Insulin may be provided in quantities of about 4 mg or less, typically about 3.6 mg of pure insulin. The dry powder may be inserted into a dose container/drug compartment in a “compressed” or partially compressed manner or may be provided as free flowing particulates. 
     The filling can be carried out to fill dose containers in any suitable number of doses, typically between about 30-120 doses, and more typically between about 30-60 doses. 
     Certain embodiments may be particularly suitable for dispensing medication to respiratory patients, diabetic patients, cystic fibrosis patients, or for treating pain. The inhalers may also be used to dispense narcotics, hormones and/or infertility treatments. 
     The dose filling systems may be particularly suitable for dispensing medicament for the treatment of respiratory disorders. Appropriate medicaments may be selected from, for example, analgesics, e.g., codeine, dihydromorphine, ergotamine, fentanyl or morphine; anginal preparations, e.g., diltiazem; antiallergics, e.g., cromoglycate, ketotifen or nedocromil; antiinfectives e.g., cephalosporins, penicillins, streptomycin, sulphonamides, tetracyclines and pentamidine; antihistamines, e.g., methapyrilene; anti-inflammatories, e.g., beclomethasone dipropionate, fluticasone propionate, flunisolide, budesonide, rofleponide, mometasone furoate or triamcinolone acetonide; antitussives, e.g., noscapine; bronchodilators, e.g., albuterol, salmeterol, ephedrine, adrenaline, fenoterol, formoterol, isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine, pirbuterol, reproterol, rimiterol, terbutaline, isoetharine, tulobuterol, or (−)-4-amino-3,5-dichloro-α-[[6-[2-(2-pyridinyl)ethoxy]hexyl]methyl]benzenemethanol; diuretics, e.g., amiloride; anticholinergics, e.g., ipratropium, tiotropium, atropine or oxitropium; hormones, e.g., cortisone, hydrocortisone or prednisolone; xanthines, e.g., aminophylline, choline theophyllinate, lysine theophyllinate or theophylline; therapeutic proteins and peptides, e.g., insulin or glucagon. It will be clear to a person of skill in the art that, where appropriate, the medicaments may be used in the form of salts, (e.g., as alkali metal or amine salts or as acid addition salts) or as esters (e.g., lower alkyl esters) or as solvates (e.g., hydrates) to optimize the activity and/or stability of the medicament. 
     Some particular embodiments of the filling system can be used to dispense meted quantities of medicaments that are selected from the group consisting of: albuterol, salmeterol, fluticasone propionate and beclometasone dipropionate and salts or solvates thereof, e.g., the sulphate of albuterol and the xinafoate of salmeterol. Medicaments can also be delivered in combinations. Examples of particular formulations containing combinations of active ingredients include those that contain salbutamol (e.g., as the free base or the sulphate salt) or salmeterol (e.g., as the xinafoate salt) in combination with an anti-inflammatory steroid such as a beclomethasone ester (e.g., the dipropionate) or a fluticasone ester (e.g., the propionate). 
     Turning now to the figures,  FIG. 1  illustrates an example of a filling system  10 . The filling system  10  includes a dosing head  20  with a plurality of spaced apart dosing channels  20   ch . A dry powder bed  23  with dry powder  23   p  ( FIG. 2A ) resides above the channels  20   ch . The channels  20   ch  all include inlet orifices  20   a  and opposing exit ports  20   e  and sidewalls  20   w  ( FIG. 2A ). The filling system  10  includes a vibration source  25  that is in communication with the channels  20   ch . The vibration source  25  communicates with a vibratory control circuit  28  to generate a defined vibration flow signal  28   s  which is transmitted to the dry powder channels  20   ch  for a defined time to cause dry powder  23   p  to flow out of the dosing channels  20   ch  and into aligned dose containers  30   c  to dispense a metered amount of the dry powder therein. The flow signal  28   s  can generate a small stimulation motion  28 M, typically in-line (e.g., substantially vertical) with a suitable displacement profile as will be discussed further below. 
     The geometry of the channel  20   ch , including one or more of the size of the orifice  20   a , size (volume and cross-sectional area) of the channel between entry orifice  20   a  and the exit port  20   e , shape and length of the channel and the size and shape of the exit port can be selected so that there is no “free flow” of powder out of the exit port  20   e  when dispensing is not desired (e.g., when the vibratory flow signal is “off” or not transmitted to the flow channels). 
     The channel geometry and the flow signal  28   s  can be selected to define a reliable flow rate with the “on” and “off” flow control corresponding to when the flow signal is applied or withheld without requiring any physical barrier or valving of the exit ports  20   e . The flow rates can be within a range of between about 5 mg/second to about 100 mg/second, typically between about 10 mg/second to about 30 mg/second. It may be desired to have the channel geometry and the vibration provide a sub-second filling rate, e.g., a suitable flow rate for an “on” time for the vibratory flow signal of less than about 1 second, typically about 0.5 seconds or less to fill all 30 or 60 doses (or other numbers of dose containers). 
     As shown in  FIGS. 2A and 2B , during filling, the dosing head  20  can reside closely spaced apart from (but not contacting) an underlying dose container member  30  with a plurality of spaced apart dose containers  30   c . The spacing can be at distance “d”, typically between about 0.1 mm to about 2.0 mm, and may, in some particular embodiments be between about 0.5 mm to about 1.0 mm. 
       FIGS. 5A and 5B  illustrate another example of a filling system  10 . As shown in  FIG. 5B , the dosing head  20  resides closely spaced to the dose container  30 .  FIG. 5B  also illustrates that the channels  20   ch  are held aligned with/registered to a corresponding dose container aperture  30   a.    
     The dry powder bed  23  with the dry powder  23   p  can be enclosed in a housing or open to atmosphere but is not required to be sealed in a pressurized chamber. That is, as the geometry of the channel and the vibratory flow signal directly dispense the dry powder into aligned dose containers  30   c . The system  10  does not require either pressure or vacuum to dispense the dry powder and the dry powder bed can be environmentally protected from exposure but is not sealed in a pressure-tight manner. 
     Referring to  FIG. 2A , as shown, before or after active dispensing ( FIG. 2B ), at least one bolus quantity of the dry powder can reside in the dose channel  20   ch . In this way, the channels  20   ch  act as miniature hoppers of one or a few dose quantities of the dry powder  23 . In other embodiments, the dry powder  23   p  remains in the powder bed  23  above the channels  20   ch  and the dry powder only enters and flows through the channels when the flow signal  28   s  is applied to the dosing head  20  and/or channels  20   ch . The latter operational configuration may be particularly true for some channel geometries, such as those with very small entry orifices or those having inverted funnel shapes (where the smallest orifice of the channel is at the top of the device in contact with the powder bed), for example. 
     The dry powder  23   p  in the channel can be replenished via a powder bed residing directly above the channels  20   ch  (contacting the upper primary surface the dosing head  20  and the entry orifices  20   a ). The powder  23   p  in the powder bed  23  can be maintained at a desired level or may be allowed to fluctuate in levels, typically between defined upper and lower limits, such as between a 3 mm to a 150 mm bed height above the entry orifices  20   a , typically between 3 mm and 15 mm. The powder  23   p  in the powder bed  23  can be continuously replenished or may be replenished based on a level sensor and/or after a defined number of dose container members  20  have been filled. 
     In particular embodiments, the channels  20   ch  can be sloped and/or angled to inhibit “rat-holing” or undesired trapping of the dry powder. Rat-holing refers to circumstances in which powder is retained against the walls of a length of the channel. Bridging and rat-holing can both be caused by a reduction in the channel width or cross sectional area. This may lead to the powder becoming compacted and forming stresses within the body of the powder. These stresses can lead to stable structures that are difficult to break up. This problem is usually amplified by high wall friction and a head of powder above the blockage. Although vibration can be used to break a bridge or to cause a rat hole to collapse, it can also have the adverse effect of compacting the powder. 
     To facilitate controlled flow, in some embodiments, as shown in  FIG. 9A  (and  FIGS. 17A and 17B ), the channels  20   ch  can have an angle (e.g., slope) for a least a major portion of the length of the channel. The angle “a” can be defined with the slope of the wall defining the channel flow floor for the powder and/or with respect to the longitudinally extending centerline of the channel. The angle “a” can be between about 30 degrees to about 75 degrees from horizontal, and more typically is between about 30 degrees to about 45 degrees, such as about 40 or 41 degrees from horizontal. 
       FIGS. 21A-21D  show about a 40 degree funnel angle with overlapping entry ports  20   a  and alternating inward and outward sloping channels  20   ch .  FIGS. 22A-22C  show a 60 degree funnel angle with overlapping entry ports  20   a  and alternating inward and outward sloping channels  20   ch .  FIGS. 5D and 5E  show a 60 degree channel with all of the channels  20   ch  angled inward (and with an oval top entry port  20   a  with the long sides of the oval circumferentially oriented about the plate  20   p .  FIGS. 23A-23B and 24A-24E  show a 30 degree funnel (with overlapping entry ports  20   a  and alternating inward and outward sloping channels  20   ch ). 
     In some embodiments, the channels  20   ch  can have an offset geometry that can help prevent the undesired plugging or rat-holing of powder flow. That is, as shown in  FIG. 9B , in some embodiments, the channels  20   ch  can have sidewalls with one portion  21   u  with a longitudinally extending centerline  21   c  which angles or slopes downward at a first defined angle “α 1 ” that merges into a lower portion  21   l  with sidewalls  20   w  that are oriented at a second different angle “α 2 ”, such as a lower channel portion with a vertically extending centerline  21   v  at the exit port  20   e . Typically, the first angle α 1  is between about 30 degrees to about 75 degrees from horizontal, and more typically is between about 30 degrees to about 45 degrees, such as about 40 or 41 degrees from horizontal. 
     It is also noted that although shown as angling down in the right hand direction in several figures, the channels  20   ch  can slope the opposite way. Indeed, different channels in a dosing head or plate can be oriented to angle in the opposite directions, e.g., the channels  20   ch  associated with exit ports  20   e  on the outer row can angle down and outward while the channels associated with exit ports  20   e  on the inner row can angle down and inward (where two rows of concentric/circular channels are used) or vice versa. See, for example,  FIGS. 21A, 22A, 23A, and 24A  which illustrate alternating inward and outward sloping channels  20   ch  with 60 channels  20   ch ,  30  exit ports  20   e  on each of the inner and outer circular rows (and offset from each other). 
     The vibration signal  28   s  can be generated by any suitable vibratory source, including electrical means, mechanical means, electromagnetic means and/or electro-mechanical means. As shown, the vibration source  25  includes at least one actuator  25  in communication with the dosing head  20  and a vibration control circuit  28 . It is contemplated that more than one actuator may be used for each set of dosing channels or for each plate  20   p  (the dosing plate is shown in various figures, e.g.,  FIGS. 5A, 8A-8C, 17A-17C ). 
     The actuator(s)  25  can be configured to be substantially in-line with the dosing head  20  and one-directional. The actuator  25  can apply the flow signal (e.g., flow energy) in a substantially vertical (only) direction. As shown in  FIGS. 1 and 5A , the actuator  25  can be mounted to a rod  29  that is attached to a center of the dosing head  20 . The flow signal/energy  28   s  can be applied so that the displacement is substantially all vertical but typically so that there is limited physical vertical displacement during the dispensing step. The actuator  25  can be an in-line magnetostrictive actuator or any other suitable actuator or controllable vibrating member. For example, Model CU18 magnetostrictive actuator from Etrema Products, Ames, Iowa. The stimulation or vibration motion can have a defined displacement profile, such as a non-harmonic displacement profile. The stimulation/vibration flow signal  28   s  can be generated in-line with a vertical axis associated with the dosing head (“A”) so as to apply the flow energy so that the dosing head with a vertical displacement that is less than about 25 microns. As noted above, the target dose container member  30  can be closely spaced apart from a lowermost surface of the dosing head  20 , such as between about 20-100 microns, during filling. 
     In other embodiments, a piezoelectric material (e.g., crystal or ceramic) with an opening that aligns to the entry orifice  20   a  can be attached to each dosing channel. This can provide an individual actuator for each channel (not shown). 
     The vibration signal  28   s  is selected to dispense dry powder at a defined flow rate (with acceptable variation, typically +/−5-10%) for a particular channel geometry. As noted above, the channel geometry can be selected so that the flow is controllable, e.g., there is no free-flow of powder out or through the channels  20   ch  without the flow signal  28   s . In operation, a continual vibration signal or signals can be applied to the dosing head (or individually to the channels  20   ch ), and a “burst” of energy can be applied as the flow signal  28   s  for a short duration to carry out the filling process. For example, a vibratory signal can be applied to the dosing head/powder bed to help avoid powder segregation. A high frequency can be modulated “on” and “off” as impulses for providing the vibratory flow signal. In other embodiments, no “background” vibration is used and the vibration can be applied only to generate the flow signal. The vibration signal  28   s  can include, for example, a saw tooth, square or sine wave associated with a waveform generator. The signal  28   s  can be configured to generate less than about an 80 micron vertical displacement of the head  20  and/or plate  20   p . The frequency or frequencies of the flow signal  28   s  can be between about 100 Hz to about 5000 Hz, but other frequencies may be used. The vibration signal can be frequency modified, e.g., a frequency modulated sinusoidal signal. Powder-specific signals may be used. See, e.g., U.S. Pat. No. 6,985,798, the content of which is hereby incorporated by reference as if recited in full herein. 
     The dosing head  20  can have integrated dosing channels  20   ch  or the dosing channels  20   ch  can be provided in a plate  20   p  ( FIGS. 6, 7, 21  et seq.) or other member that is attached to a portion of the dosing head. The plate  20   p  can be releasably attached to a frame or sidewalls of the dosing head  20  under the dry powder of the powder bed  23 . In other embodiments, one dosing head can hold a plurality of the plates in spaced apart arrangements ( FIG. 12B ) and/or can include a plurality of integrated spaced apart circular dosing channels to allow for filling a plurality of disks with a single dosing head  20  and powder bed  23 . 
     In some embodiments, as shown in  FIGS. 1, 3A-3D and 5A-5C , for example, the dose container member  30  is a dose disk with at least one row of dose containers  30   c  that are circumferentially spaced apart. Thus, the dosing head  20  can include a corresponding arrangement of dosing channels  20   ch . In some embodiments, such as shown in  FIGS. 6 and 8B , there is one entry orifice  20   a  and associated dosing channel  20   ch  for each dose container  30   c . In other embodiments, such as shown in  FIGS. 7, and 8A , for each dose container  30   c , the dosing head  20  has a plurality of closely spaced entry orifices  20   a  and corresponding dosing channels  20   ch . In other embodiments, as shown in  FIG. 8C , there can be a plurality of orifices  20   a  that open into a common dosing channel  20   ch  for a respective dose container  30   c.    
       FIG. 3A  illustrates a dose container assembly  20  with a dose ring or disk  30  having a plurality of dose containers  30   c . The dose containers  30   c  can have a volume (prior to filling and sealing) that is less than about 24 mm 3 , typically between 5-15 mm 3 . The powder bulk density can be about 1 g/cm 3  while the power nominal density when filled (for reference) can be about 0.5 g/cm 3 . The maximum compression of a drug after filling and sealing in the dose container  30   c  can be less than about 5%, typically less than about 2%. 
     In some embodiments, the dosing channel exit ports  20   e  (e.g., orifice) can have a cross-sectional length or width (e.g., diameter) that is about 3.2 mm or less. 
     As shown in  FIGS. 3A and 3B , in some embodiments, the dose ring or disk  30  can include a plurality of circumferentially spaced apart through apertures  30   a  that form a portion of the dose containers  30   c . As shown in  FIGS. 3C and 3D , the dose containers  30   c  can be defined by the dose container apertures  30   a  and upper and lower sealants  36 ,  37  (after filling with the dry powder  23  therein).  FIG. 3A  illustrates that the dose container disk  30  can include 60 dose containers  30   c  while  FIG. 3B  illustrates that the dose container disk  30  can include 30 dose containers  30   c . Greater or lesser numbers of dose containers may be used. As noted above, the dosing head  20  can include a like number of or at least the same number of dosing channels  20   ch  (or more if more than one dosing channel  20   ch  is used to fill a corresponding container  30   c  such as shown in  FIG. 7 ). The sealant layers  36 ,  37  can have the same or different material(s) and may include foil, polymer(s) and/or elastomer(s), or other suitable material or combinations of materials, including laminates. Typically, the sealant layers  36 ,  37  are thin flexible sealant layers comprising foil. 
     In other embodiments, the bottom of the dose container  30   c  may be provided by a closed floor of the substrate rather than a sealant layer. In yet other embodiments, the dose disk  30  can have a blister configuration which is filled by the dose head  20 . 
       FIGS. 3A and 3B  also illustrate that the dose container disk  30  can include at least one indexing notch  34 , shown as a plurality of circumferentially spaced apart indexing notches  34 . 
     As shown in  FIGS. 5A-5E , the system  10  can include a mounting member  22  that has a threaded member  22   t  with a collar  22   c  that holds the stem  29  to the dosing head  20  to releasably engage the dosing head  20  and align the dose container  30  with the dosing head  20  using one or more of the notches  34 . For example, the holder  40  can include a spring-loaded, radially outwardly extending finger or tab that releasably engages one or more of the notches  34  to position the dose containers  30   c  so that they are aligned with channels  20   ch .  FIG. 12C  illustrates an alternate holder  40  configuration with a center post  44  with a channel  41  and upstanding outer indexing tabs  40   p . Other holders and alignment means may be used. 
     As shown in  FIGS. 3A and 3B , the dose containers  30   c  may be arranged so that they are circumferentially spaced apart in one or more rows. As shown in  FIG. 3A , the dose containers  30   c  are arranged in staggered concentric rows, a front row  31  at a first radius from a center of the disk and a back row  32  at a second different radius. Thus, the dosing channels  20   ch  and the corresponding dose containers  30   c  can be arranged so that centerlines of the dosing channels  20   ch  and dose containers  30   c  of the back row are circumferentially offset from the centerlines of the dosing channels and dose containers  30   c  in the front row by a distance. As shown in  FIG. 3A , the dose containers  30   c  on each respective row are spaced apart a distance “D” and the offset of the centerlines of those on the back row to those on the front row is “D/2”. The dosing channels  20   ch  can have a corresponding layout or arrangement. The dose container disk  30  can be a molded polymer, copolymer or blends and derivatives thereof, or may comprise metal, or combinations thereof, or other materials that are capable of providing sufficient moisture resistance. The dosing head can comprise stainless steel or other suitable non-reactive material or materials that can be cleaned to meet regulatory cleanliness standards. 
     The dose container disk  30  can have an outer diameter of between about 50-100 mm, typically about 65 mm and a thickness of between about 2-5 mm, typically about 3 mm. The disk  30  can comprise a cyclic olefin (COC) copolymer. The apertures  30   a  can have a diameter of between about 2-5 mm, typically about 3 mm and the sidewalls  30   w  of the dose containers  30   c  may have an angle or draft of about 1-3 degrees per side, typically about 1.5 degrees, as shown in  FIG. 3D , to facilitate removal from a mold (where a molding process is used to form the disk  30 ). The dose container  30  is configured to be able to protect the powder from moisture ingress, while providing a desired number of doses in a compact overall inhaler size. The individual dose container apertures  30   a  are spaced apart from each other to allow sufficient seal area and material thickness for moisture protection of the powder. 
       FIG. 4  illustrates an exemplary configuration of a dosing head  20  attached to the rod  29  and having a bracket  22  with a support  22   s  that engages a lower portion of the bed  23  in a manner that does not occlude any of the flow channels. The bracket  22  can include outwardly extending arms  22   a  that attach to an upper portion of the powder bed  23 . The channels  20   ch  can be integral to the bed  23  or may be provided in a plate, disk or other component that attaches to the dosing head. 
       FIGS. 5A-5E  illustrates the dosing head  20  with a lower plate  20   p  defining the channels  20   ch . As shown in  FIGS. 5B and 5C , for example, the plate can include an inwardly extending ledge or lip  22   l . The plate  20   p  can reside on the ledge  22   l  and can be releasably attached to the head  20  and/or bed  23 . 
     Referring to  FIG. 5A , the filling system  10  can include a dose container holder  40  that registers the dose container apertures  30   a  to the filling channel exit ports  20   e  using the indexing notches  34  on the container  30  ( FIGS. 3A / 3 B). However, the system can use other components, geometry or indexing configurations to carry out the registration. For example, in other embodiments, the dosing head  20  can be configured to rotate to align with the dose containers  30   a  using optical or proximity sensors, lasers or other automated position controlled devices. 
     As shown in  FIGS. 5C-5E, 8A-8C, and 21-24 , the dosing head plate  20   p  can have an open center space  20   o  that receives the support bracket or member  22  which is substantially in-line with the rod  29 . In some embodiments, the dosing head  20 , plate  20   p  and/or support frame  22  can be configured so that the vibration transferred by the rod  29  is substantially evenly distributed from the center to a location that is at least co-extensive with the outer row of dosing channels. 
       FIGS. 25A, 25B and 26  illustrate an alternate mounting of the actuator  25 ′ and dosing head  20  (which typically includes a dosing plate  20   p , also referred to as an “orifice plate”). In this embodiment, the actuator  25 ′ is positioned closely spaced to the dosing head  20  so as to not require an overhead actuator and connecting rod to improve coupling of the vibration to the orifice plate/dosing head  20   p / 20 . As before, although the dosing head  20  is shown comprising a (releasable) dosing plate  20   p , the dosing head may be an integral body device with the channels  20   ch . Where an orifice plate  20   p  is used, the plate  20   p  can be provided in two or more matable pieces (not shown) and may include inner or outer sidewalls that form part or all of the powder bed (also not shown). In this embodiment, the (lowermost) orifice plate  20   p  is mounted to a tube plate  325  with an array of tubes  326  that penetrate through aligned apertures  123   a  in the floor  123   f  of a (small) powder bed  23 . The combined orifice plate  20   p  and tube plate  325  can attach directly to an integrated central actuator  25 ′ that vibrates them. The vibrating tubes  326  help flow powder to the orifice plate  20   p  while the orifices  20   ch  still provide on/off flow control for controlled dispensing. 
       FIGS. 25A, 25B and 26  illustrate that the dry powder bed  23  can be provided by a rigid powder hopper  123  having a rigid bottom floor  1231 . The floor  123   f  can include apertures  123   a  ( FIG. 26 ) that receive the array of upwardly extending tubes  326 . The floor apertures  123   a  can have geometries that funnel powder downward. 
     The actuator  25 ′ can include a radially extending planar flange  225  with a plurality of circumferentially spaced apart apertures  226 . The vibrating tubes  326  extend through these apertures  226  to communicate with the power bed  23 . The tubes  326  are free to vibrate up and down in response to the vibration input from the actuator  25 ′ during operation as there is a non-contact clearance around each vibrating tube  326 , actuator flange  225  and hopper bottom  123   f . As before, the actuator  25 ′ can be configured to be substantially in-line with the dosing head  20  and one-directional. The actuator  25 ′ can apply the flow signal (e.g., flow energy) in a substantially vertical (only) direction. The flow signal/energy  28   s  can be applied so that the displacement is substantially all vertical but typically so that there is limited physical vertical displacement during the dispensing step. The actuator  25 ′ can be an in-line magnetostrictive actuator or any other suitable actuator or controllable vibrating member. In some embodiments, the actuator  25 ′ includes a plurality of, typically three, spaced-apart precision linear actuators that vibrate at least 3 points on a plane concurrently. For example, Model PI P/N S-900C002 actuator from PI (Physik Instrumente) L.P., Auburn, Mass. The stimulation or vibration motion can have a defined displacement profile, such as a non-harmonic displacement profile. The stimulation/vibration flow signal  28   s  can be generated in-line with a vertical axis associated with the dosing head (“A”) so as to apply the flow energy so that the dosing head with a vertical displacement that is less than about 25 microns. As noted above, the target dose container member  30  can be closely spaced apart from a lowermost surface of the dosing head  20 , such as between about 20-100 microns, during filling. 
     The actuator  25 ′ can be configured to have a pre-load tensioning/compression to achieve a desired bipolar action in a dynamic mode. Actuator power wiring  25   p  can be provided via the top of the cylindrical body  25 ′ as shown in  FIG. 25A  (but side or even bottom wiring (or wireless) may also be used). 
     As shown in  FIG. 26 , an elastomeric gasket  140  can reside under the floor  123   f  and above the flange of the actuator  25 ′. The gasket  140  can include an array of apertures  140   a  that align with the actuator flange apertures  226 . The gasket  140  is not a compression spring. An O-ring  142  can also be placed against the outer wall of the actuator cylinder and the hopper floor  123   f  to form a seal. 
     As shown in  FIGS. 25A, 25B and 26 , the tube plate  325  has a planar upper surface  325   u  that holds the array of upwardly extending tubes  326  and this surface can be positioned to abut the flange actuator lower surface  225   b . The tube plate  325  can also have a planar lower surface  325   b  that can be positioned to abut the top of the orifice plate  20   p . The tubes  326  can be bonded, brazed, ultrasonically or metallurgically welded to the plate  325  or may be molded as a single-piece body or otherwise suitably formed.  FIG. 25B  shows that the tube plate  325  can be aligned with flange apertures and the tubes  326  slidably advanced to attach the tube plate  325  to the actuator flange  225  (the gap space shown between the actuator flange lower surface  225   b  and the upper surface of the tube plate  325   u  is not the typical operative position). It is also noted that, in lieu of flange apertures, slots or other passages or flange shapes may be used to allow the tubes  326  to extend above the flange to communicate with the hopper bed  23 . 
     Bolts  27 ,  227 ,  327  can be used to releasably attach the tube plate  325 , the actuator flange  225 , the orifice plate  20  and/or the floor  123   f  together. However, in other embodiments, two or more of the components may be bonded, brazed, welded or otherwise be integrally attached together. It is contemplated that the assembly configuration used should be allow the tubes  326  to be free moving so as to not disrupt the vibration of the orifice plate/dosing head  20   p ,  20  and allow for uniformity of vibration over the ring of orifices in the dosing head/plate. 
     In some embodiments particularly suited for filling a dose disk with 60 dose containers in two concentric rows with the dose containers in each row having circumferentially offset centers, the tubular plate  325  can include 20 equally circumferentially spaced apart tubes  326  positioned at a common defined radial distance. The underlying orifice plate  20   p  can include 60 channels  20   ch  that align with 60 dose container apertures  30   c  for one dose disk  30  as described above ( FIG. 1 ). As shown in  FIG. 27 , each tube  326  can define a feed path  326   f  that can be equally spaced apart over a set of three closely spaced channels  20   ch  of the orifice plate  20   p  to feed dry powder concurrently to each of those three channels  20   ch . The center of a respective feed tube  326  can reside above a triangle drawn by lines connecting the centers of each of the respective three channels  20   ch.    
     In other embodiments, a single tube  326  can feed a single orifice plate channel  20   ch  or more than one tube  326  can feed a respective one channel  20   ch . As noted above, the dose filling system  10 ′ may be configured to concurrently fill all dose containers  30   c  on a disk  30  or other configuration and the disk can include different numbers of dose containers  30   c , such as 30 dose containers. The orifice dispensing channels  20   ch  can feed one or more underlying dose containers  30   c  or more than one channel  20   ch  can be used to fill an underlying dose container  30   c  as discussed above. 
       FIG. 10  illustrates different exemplary geometries for flow channels  20   ch . The geometries include “straight” vertical flow channel geometries (with a suitable, very small size, orifice to avoid “free-flow” of the dry powder), funnel, inverse funnel, funnel to straight, funnel to angled and multiple angle changes over the length of the flow channel. 
       FIGS. 21-24  show examples of channels  20   ch  with different geometries. To be clear, although the channels  20   ch  are shown with respect to a dosing plate  20   p  with respect to different figures including  FIGS. 21-24, 5A-5E, and 25A-25B , the channel geometries are not required to be implemented using a plate  20   p  but instead can be included into other structures, members or components, including an integral dosing head. The plate  20   p , where used, may, in some embodiments, have a diameter or cross-sectional length of about 70 mm and may include a lip  22   l  ( FIG. 5C ). However, other shape and size plates may be used. 
       FIGS. 21A-21D  show about a 40 degree funnel angle with overlapping entry ports  20   a  and alternating inward and outward sloping channels  20   ch .  FIGS. 22A-22C  show a 60 degree funnel angle with overlapping entry ports  20   a  and alternating inward and outward sloping channels  20   ch .  FIGS. 5D and 5E  show a 60 degree channel with all of the channels  20   ch  angled inward (and with an oval top entry port  20   a  with the long sides of the oval circumferentially oriented about the plate  20   p .  FIGS. 23A-23B and 24A-24E  show a 30 degree funnel (with overlapping entry ports  20   a  and alternating inward and outward sloping channels  20   ch ). These figures also illustrate that the channels  20   ch  can define miniature hoppers which may help uniformly distribute powder  23  from the powder bed  23   b  into the channels  20   ch  and into the target receiving containers  30   a.    
       FIGS. 21-24  also illustrate alternating inward and outward sloping channels  20   ch  with the upper portion of the channels having geometries configured to define overlapping entry ports  20   a  for at least two exit ports  20   e , the upper portions of the channels  20   ch  a distance under the entry ports  20   a  merge into two respective exit ports  20   e  on front and back rows. The “crisscross” of downwardly sloping and narrowing funnels creates a shared upper collector bed that merges into lower isolated channel segments a distance down below the open top ports  20   a  toward (or even below) the middle portion. That is, the overlapping entry funnel shapes (shown as having semicircular outer perimeters) bifurcate into separate sloping lower channels  20   ch  at a location between about 30-80% of the channel length, typically between about 40-60% of the overall channel length (associated with the plate thickness) to angle in or out to feed adjacent pairs of inner and outer exit ports  20   e . This creates a “mid-stage” powder bed that with vibration can provide a desired flow control and uniform powder distribution. 
     As shown in  FIGS. 22A-C , the channels  20   ch  have geometries and exit port sizes configured so as to have minimal or no direct powder path from the top  20   a  to the exit port  20   e . That is, when looking down from the top as shown in  FIG. 22A , the exit port  20   p  is mostly, if not substantially entirely occluded from view. The exit port/orifice size can vary, but is typically less than about 1.8 mm, and more typically between about 1.2 mm-1.6 mm, for the limited or no “light” view path configuration. 
       FIG. 11  illustrates that the filling system  10  can be configured to accept interchangeable dosing plates  20   p  with different configurations of dosing channels  20   ch . The control circuit  28  can be configured with a controller that has a library of “recipes” for selecting the corresponding operational parameters for generating the desired dose amounts of different dry powder formulations using the different dosing plates  20   p . The dosing plates  20   p  can have an RFD or other electronic or optically readable data that identifies the plate type automatically. 
       FIGS. 12A and 12B  illustrate examples of a filling system  100  with multiple sub-systems  10 . The sub-systems  10  can be in a row as shown in  FIG. 12A  with the underlying dose container support members  30  provided in-line on a conveyor or other moving floor. A proximity sensor can be used to indicate when the dose containers  30   c  are in alignment with respective dosing channels  20   ch  and the vibratory flow signal  28   s  can be applied to fill the dose containers  30   c . Each sub-system  10  can include its own powder bed  23  or, as shown, one line of the sub-systems includes a shared powder bed  23  and the other line includes another powder bed  23 . Other dose bed arrangements can be used, such as two dosing heads in one line sharing one bed, four dosing heads can share a single bed  23  (two from each line or four from one line) and the like. 
       FIG. 12B  shows that the sub-systems  10  can be closely spaced apart to overlie a circular holder with the containers  30 . The system  100  can include a single powder bed or multiple powder beds (not shown). The holder  40  can be mounted to a carousel that rotates to present different holders  40  with collections of empty members  30  to the dosing station for filling. A proximity sensor can be used to indicate when the dose containers  30   c  are in alignment with respective dosing channels  20   ch  and the vibratory flow signal  28   s  can be applied to fill the dose containers  30   c.    
     The holder  40  can be configured to hold a plurality of dose container members  30  in alignment with each other and with the dose containers  30   c  in position for alignment with the corresponding dose channels  20   ch . As shown in  FIG. 12C , the floor of each holder  40   f  can include a receiving channel  41  that matably engages the disk  30 . The holder  40  can also include tabs  40   p  that engage the alignments slots  34  for circumferential alignment. 
       FIG. 13  is an exemplary schematic of a filling system  100  that includes multiple dosing heads  20  and multiple transducers  25 . As shown, the system  100  includes a vibration flow signal circuit  28  that includes or communicates with a controller  128 . The controller  128  typically includes a digital signal processor and can include an HMI (Human Machine Interface) to allow a user to enter certain inputs. The controller  128  can include or communicate with a recipe module (computer program)  130 . The recipe module  130  can be programmed with an electronic library of defined operating parameters correlated to a particular dry powder or product (e.g., a product name, powder formulation and/or desired dose amount). The recipe module can provide the system  100  with data regarding the proper setting of various components and allow the controller to implement these settings, e.g., vibration flow signal configuration, on/off time of the flow signal and, where used, the recipe can take into account a configuration of the dosing head for systems that allow for interchangeability of the dosing head  20  and/or dosing plate  20   p.    
     The system  100  can also include proximity sensors  125  or other sensors that provide feedback on the position of the dose containers which can be electronically monitored to facilitate the timing of the on-off flow signal for automated filling. 
       FIG. 14  is an exemplary flow chart of a method that can be used to carryout embodiments of the invention. The method includes providing a dose container disk having upper and lower primary surfaces with a plurality of circumferentially spaced apart apertures associated with dose containers (block  200 ). The dose container disk can be placed under a dosing head that resides below a dry powder bed, the dosing head having a plurality of circumferentially spaced apart dose filling channels with respective exit ports over the dose container disk so that the exit ports are aligned with the dose disk apertures (block  210 ). A vibration flow signal is applied to the dosing head to cause the dry powder to concurrently flow out of the channels into the dose disk apertures (block  220 ). The dose container disk is directly filled with a defined amount of dry powder in response to the applying step (block  230 ). The applying step is ceased (abruptly or via a ramp down of the signal) to stop the flow of dry powder thereby filling a dose container disk with a defined amount of dry powder in each of the dose containers (block  240 ). The ramp down of the signal may allow for a more controlled powder flow stoppage. 
       FIG. 15  is a block diagram of exemplary embodiments of data processing systems that illustrates systems, methods, and computer program products in accordance with embodiments of the present invention. The processor  410  communicates with the memory  414  via an address/data bus  448 . The processor  410  can be any commercially available or custom microprocessor. The memory  414  is representative of the overall hierarchy of memory devices containing the software and data used to implement the functionality of the data processing system  405 . The memory  414  can include, but is not limited to, the following types of devices: cache, ROM, PROM, EPROM, EEPROM, flash memory, SRAM, DRAM and magnetic hard drives. 
     As shown in  FIG. 15 , the memory  414  may include several categories of software and data used in the data processing system  405 : the operating system  452 ; the application programs  454 ; the input/output (I/O) device drivers  458 ; the vibratory signal generator module  450 ; and the data  456 . The data  456  may include a plurality of dry powder data  451  corresponding to particular recipes with operating parameters for each dry powder or product, which may be obtained from an operator or stored by the dispensing system  420  and/or timing data that defines the meted dose amounts, flow rates, and flow signal “on” time for the dispensing port (allowing automatic control of the dispensing operation). As will be appreciated by those of skill in the art, the operating system  452  may be any operating system suitable for use with a data processing system, such as OS/2, AIX, OS/390 or System390 from International Business Machines Corporation, Armonk, N.Y., Windows CE, Windows NT, Windows95, Windows98, Windows2000, WindowsXP and WindowsVista, from Microsoft Corporation, Redmond, Wash., Unix or Linux or FreeBSD, Palm OS from Palm, Inc., Mac OS from Apple Computer, LabView, or proprietary operating systems. The I/O device drivers  458  typically include software routines accessed through the operating system  452  by the application programs  454  to communicate with devices such as I/O data port(s), data storage  456  and certain memory  414  components and/or the dispensing system  420 . 
     The application programs  454  are illustrative of the programs that implement the various features of the data processing system  405  and preferably include at least one application which supports operations according to embodiments of the present invention. Finally, the data  456  represents the static and dynamic data used by the application programs  454 , the operating system  452 , the I/O device drivers  458 , and other software programs that may reside in the memory  414 . 
     While the present invention is illustrated, for example, with reference to the signal generator module  450  being an application program in  FIG. 15 , as will be appreciated by those of skill in the art, other configurations may also be utilized while still benefiting from the teachings of the present invention. For example, the module  450  may also be incorporated into the operating system  452 , the I/O device drivers  458  or other such logical division of the data processing system  405 . Thus, the present invention should not be construed as limited to the configuration of  FIG. 15 , which is intended to encompass any configuration capable of carrying out the operations described herein. 
     The I/O data port can be used to transfer information between the data processing system  405  and the dispensing system  420  or another computer system or a network (e.g., an intranet and/or the Internet) or to other devices controlled by the processor. These components may be conventional components such as those used in many conventional data processing systems which may be configured in accordance with the present invention to operate as described herein. 
     While the present invention is illustrated, for example, with reference to particular divisions of programs, functions and memories, the present invention should not be construed as limited to such logical divisions. Thus, the present invention should not be construed as limited to the configuration of  FIG. 15  but is intended to encompass any configuration capable of carrying out the operations described herein. 
     The flowcharts and block diagrams of certain of the figures herein illustrate the architecture, functionality, and operation of possible implementations of dry powder-specific dispensing and/or vibratory energy excitation means according to the present invention. In this regard, each block in the flow charts or block diagrams represents a module, segment, or portion of code, which comprises one or more executable instructions for implementing the specified logical function(s). It should also be noted that in some alternative implementations, the functions noted in the blocks may occur out of the order noted in the figures. For example, two blocks shown in succession may in fact be executed substantially concurrently or the blocks may sometimes be executed in the reverse order, depending upon the functionality involved. 
     In certain embodiments, the present invention can provide computer program products for operating a flowing dry powder dispensing system having channels  20   ch  and a vibration energy source associated therewith to facilitate controlled flow. The computer program product can include a computer readable storage medium having computer readable program code embodied in the medium. The computer-readable program code can include: (a) computer readable program code that a plurality of different vibration energy signals associated with a “recipe” that correlates the formulation to the dosing head/dosing plate geometry and/or dose container geometry; and (b) computer readable program code that directs the dispensing system to operate using the vibration energy signal for defined “on” and “off” times to dispense the desired dose amount (at the desired flow rate). 
     The invention will now be described in more detail in the following non-limiting example. 
     EXAMPLE 
     “On/off” flow control evaluation data was obtained using a laboratory system. To deliver the vibratory signal, the laboratory system included a harmonic signal drive configuration with a HP33120A function generator that can provide a carrier signal source connected to a timer (such as a Panasonic LT4H timer) to gate the drive signal, connected to a power amplifier connected to an electromagnetic (linear) actuator from Ling Dynamic Systems, model number V203. Preliminary results indicate relatively limited powder bed depth sensitivity, at least between about 3 mm to about 6 mm of initial bed depth. Powder bed depth for most trials was set to 6 mm and replenished if dropped below about 3 mm for a particular trial. 
       FIG. 16  is a graph showing flow channels with different geometries and no flow, flow with vibration and free flow limits with respect to channel outer diameter sizes (mm) and minimum displacement to cause flow for inh230 dry powder. The flow start/stop control with the plate vibration was observed for a range of about 0.4 mm displacement for 1.5 mm deep cylindrical channels. Flow start/stop with the plate vibration was observed at about 1.0 mm displacement for funnel shaped channels. It is noted that even at the minimum displacement threshold to induce flow through a channel, sporadic stopping of the flow sets the upper size limit of the channel. The OD (outer diameter) measurement was taken at the bottom of the plate, e.g., at the exit port/opening. 
       FIG. 17A  is a top perspective view of a plate  20   p  with about 41 degree funnel shaped channels  20   ch .  FIG. 17B  is a top perspective view of a plate  20   p  with about 30 degree funnel shaped channels  20   ch .  FIG. 17C  is a top perspective view of a plate  20   p  with substantially cylindrical (vertical) channels.  FIG. 17D  illustrates flow of inh230 dry powder with hand tapping, no flow and free flow with respect to channel size (OD) measured at the exit port and geometry. 
       FIG. 18  is a graph of flow (mg/second) versus displacement (microns) for a 0.9 mm, 41 degree inverted funnel. The 0.9 mm measurement with respect to the funnel refers to the exit port (the smaller orifice of the funnel shape) and with respect to the inverted funnel refers to the entry port or orifice (also the smaller orifice of the “funnel” shape). As the displacement of the plate increased beyond the minimum threshold to induce flow, flow increases rapidly with displacement, then begins to decrease with further increases in displacement. Thus, smaller displacements can be more optimal for flow control and rate. This behavior may aid in selecting a vibration displacement operating point with reduced sensitivity of flow to displacement. It may be desirable to configure the vibration to cause displacement that is just under or approaching the peak flow. 
       FIG. 19  illustrates a minimum threshold displacement (microns/micrometers) to induce flow (at 300 Hz for Inh230) versus channel nominal outer diameter size (mm) (at the exit port) for three different channel geometries (cylindrical, taken at two different small sizes), and 30 and 41 degree funnels. Over the exit port diameter of interest, the displacement threshold has little variation. 
       FIG. 20A  is a graph of flow (mg/s) versus channel OD (nominal OD in mm at exit port) at minimum displacement for flow using a 300 Hz vibratory signal for Inh230. 
       FIG. 20B  is a graph of flow rate (mg/s) versus channel area (mm2) taken at the exit port for a 41 degree funnel. The target flow rate for sub-second filling operations of a dose ring or disk for Inh230 is shown as greater than 5 mg/s, typically between about 10-25 mg/s, which correlates to an opening size of about 2 mm 2  with about a 41 degree funnel channel geometry using the minimum displacement for flow and a flow signal of about 300 Hz. At the minimum displacement threshold, the 41 degree funnel geometry flow rate increase proportional to the area of the exit port. 
     The following exemplary claims are presented in the specification to support one or more devices, features, and methods of embodiments of the present invention. While not particularly listed below, Applicant preserves the right to claim other features shown or described in the application. 
     The foregoing is illustrative of the present invention and is not to be construed as limiting thereof. Although a few exemplary embodiments of this invention have been described, those skilled in the art will readily appreciate that many modifications are possible in the exemplary embodiments without materially departing from the novel teachings and advantages of this invention. Accordingly, all such modifications are intended to be included within the scope of this invention as defined in the claims. In the claims, means-plus-function clauses, where used, are intended to cover the structures described herein as performing the recited function and not only structural equivalents but also equivalent structures. Therefore, it is to be understood that the foregoing is illustrative of the present invention and is not to be construed as limited to the specific embodiments disclosed, and that modifications to the disclosed embodiments, as well as other embodiments, are intended to be included within the scope of the appended claims. The invention is defined by the following claims, with equivalents of the claims to be included therein.