Dry powder inhalers with dual piercing members and related devices and methods

[Cross-reference of related applications] This application is filed on April 20, 2009, US Provisional Patent Application No. 61 / 170,801, September 26, 2008, US Provisional Patent Application No. 61 / 100,482, and January 30, 2009. It claims the gains and priorities of US Provisional Patent Application No. 61 / 148,520 filed on the same day, the disclosures of which are hereby by reference, as if they were described in their entirety. It shall be included in.

[Field of invention] The present invention relates to an inhaler, particularly suitable for a dry powder inhaler.

The Dry Powder Inhaler (DPI) is an alternative to the pMDI (Pressurized Metering Spray Inhaler) device for delivering drug aerosols without the use of propellants. Typically, the DPI is configured to deliver a powdered drug or drug mixture containing excipients and / or other components. In general, well-known single / multiple dose dry powder DPI devices are (a) individual pre-weighed doses in blister containing a drug that can be inserted into the device prior to administration. ) Or (b) a bulk powder container configured to administer a continuous dose of the drug to the patient through a dosing chamber designed to administer the appropriate dose.

In terms of operation, the DPI device aims to administer a uniform aerosol dispersion of dry powder with the desired physical form (eg particle size) into the patient's respiratory tract and direct it to the desired internal retention site. ..

<p> However, there is still a need for alternative inhalers and / or dose containment devices that can be used to deliver the drug.</p>

<p> Embodiments of the present invention will provide a dry powder inhaler with reciprocating inner and outer puncture mechanisms that facilitates the use of doze rings or doze discs with concentric doze containers. According to some embodiments, the dry powder inhaler is sequentially with a doze container disc having a plurality of dry powder containers arranged in first and second concentric rows of different radii and separated from each other in the circumferential direction. It comprises a puncture mechanism configured to open the dry powder doze container in the first row and then open the dry powder doze container in the second row. The piercing mechanism includes first and second elongated piercing members that are adjacent to each other and separated from each other in the radial direction. Each puncture member is capable of reciprocating between a puncture position and a non-puncture position and includes a distal puncture portion and a proximal head portion. The first piercing member is configured to pierce the sealant of the dough container in the first row, and the second piercing member is configured to pierce the sealant of the dough container in the second row. There is.</p><p> According to some embodiments, the dry powder inhalers are circumferentially spaced in the first row and second radius of the dosing containers, which are spaced apart from each other by the top and bottom main surfaces facing each other and the first radius. It comprises a second row of doze containers separated from each other, and a doze container disc having. The first and second columns are concentric with respect to the center of the disc. The dose container contains dry powder. A first flexible sealant is placed over the opening on the top surface and a second flexible sealant is placed over the opening on the bottom surface to contain the powder in the dough container.</p><p> The puncture mechanism is operably associated with the dough container disc and is configured to pierce the first and second sealants that seal the doze container. The piercing mechanism comprises two reciprocating piercing tools that sequentially switch between two rows of dosing vessels in the dosing vessel disc. Each elongated piercing member is designed to be projected and retracted to pierce the first and second sealants of the dough container in each row. Each elongated puncture member comprises a distal puncture portion and a proximal puncture portion. In some embodiments, the distal puncture site can be a solid puncture tool configured to pierce the sealant. In some embodiments, the distal puncture site can be a corkscrew puncture tool configured to pierce the sealant by moving it straight in the vertical direction without rotation. In some embodiments, the distal puncture site can have, for example, a grooved puncture tool with three or four lobes configured to pierce the sealant.</p><p> Each elongated piercing member is capable of reciprocating between a piercing position and a non-piercing position. At the puncture position, the distal puncture portion of the puncture member penetrates the first and second sealants of the dose vessel. In the retracted position, the distal puncture site retracts above the dose vessel in order to rotate the dose vessel disc freely. The urging member is configured to urge each of the piercing members toward a retracted position.</p><p> The rotatable slope disc comprises a set of first slope elements and a set of second slope elements that are spaced apart from each other in a staggered concentric circumferential direction. The slope disc is designed to rotate in only one direction, driven by an actuator mechanism that is moved forward by the user, and returned in the opposite direction by the user's action to close the mouthpiece cover of the inhaler. .. When the slope disc rotates as a result of the user moving the actuator mechanism, the first set of slope elements is configured to move the first piercing member between the retracted position and the protruding position. The set of second slope elements is configured to move the second piercing member between the retracted position and the protruding position. The slope elements are staggered so that the piercings alternate between the dose vessels in the first and second rows. Each slope element in the first set of slope elements and the second set of slope elements comprises a first slope portion, a flat portion, a second slope portion, and a shelf portion.</p><p> The actuator mechanism can be moved between the first position and the second position by the user. Moving the actuator from the first position to the second position causes the slope disc to rotate, resulting in the slope elements in the first set of slope elements causing the first puncture member to doze the container in the first row. It will pierce the upper and lower sealants. Then (ie, after the inhaler has been used), moving the actuator from the first position to the second position causes the slope disc to rotate, resulting in the slope elements in the second set of slope elements. , The second piercing member will pierce the sealant above and below the dose container in the second row. This alternating piercing procedure will be repeated each time the inhaler is used. In some embodiments, the movement of the actuator from the first position to the second position causes the puncture member to pierce the sealant above and below the dose vessel and then partially retract. There is.</p><p> The inhaler according to the embodiment of the present invention has many advantages over the conventional inhaler. For example, the use of two piercing members eliminates the need for tight control over the position and operation of a single movable piercing tool. Further, by using the two piercing members, the wear of each piercing member is significantly reduced. Therefore, a material that is cheaper than the material required if only a single piercing member was used may be used for these piercing members. In addition, the structure of the two piercing members can increase the flexibility of the design of the spring used to urge the piercing member into the retracted position. For example, the spring does not need to be positioned below the piercing member. Therefore, it is possible to obtain an inhaler device in which the height requirement is relaxed as compared with the conventional inhaler device.</p><p> The use of separate slope discs and actuator mechanisms will provide other advantages of the suction device according to embodiments of the present invention. Since the indexing of the dose vessel assembly is driven by the slope disc, the indexing mechanism can be moved inside the inhaler with more space available, thereby reducing the overall size of the inhaler. Can be done. Since the slope disk and the actuator mechanism are separate components, each material selection can be optimized. For example, a material having good frictional properties for a slope disc can be selected, and a material having strength and decorative features for the actuator mechanism can be selected.</p><p> It should be noted that the aspects of the invention described for one embodiment may be included in another embodiment, even though they are not specifically described in this regard. That is, the features of all embodiments and / or any embodiment may be combined in any way and / or in any coordination. The applicant initially has the right to modify any claims originally filed, or to file any new claims accordingly, eg, any claims originally filed as such. It reserves the right to be subordinate to and / or amended to include any feature of any other claim, even if not stated. These and other aspects and / or aspects of the invention will be further clarified by the detailed description described below.</p>

<figref num="1A">FIG. 3 is a front perspective view of a covered inhaler according to some embodiments of the present invention, in which the cover is in the closed position.</figref><figref num="1B">FIG. 1A is a front perspective view of the inhaler of FIG. 1A with the cover moved to the open or operating position.</figref><figref num="1C">FIG. 1B is a front perspective view of the inhaler of FIG. 1B showing an actuator lever accessible to a user who has moved to a second position.</figref><figref num="2A">FIG. 3 is an upward perspective view of a dose container assembly according to some embodiments of the present invention.</figref><figref num="2B">It is an exploded perspective view of the assembly shown in FIG. 2A.</figref><figref num="2C">FIG. 3 is a partially cut perspective view of an airway passage lined up with two dose containers according to some embodiments of the present invention.</figref><figref num="2D">FIG. 3 is an upper perspective view of another exemplary dose container assembly according to some embodiments of the present invention.</figref><figref num="2E">It is an exploded perspective view of the dose container assembly shown in FIG. 2D according to the embodiment of the present invention.</figref><figref num="3A">FIG. 3 is an upward perspective view of a dose container ring according to some embodiments of the present invention.</figref><figref num="3B">FIG. 3 is an upward perspective view of a dose vessel ring according to some other embodiment of the present invention.</figref><figref num="3C">FIG. 6 is a partial cut-out view of a single dose container according to some embodiments of the present invention.</figref><figref num="3D">FIG. 6 is a partial cut-out view of a single dose container according to some embodiments of the present invention.</figref><figref num="4A">It is an enlarged upper perspective view of the lower airway disc according to some embodiments of the present invention.</figref><figref num="4B">It is a top view of the lower airway disc according to some embodiments of the present invention.</figref><figref num="4C">It is a bottom view of the lower airway disc shown in FIG. 4B.</figref><figref num="5A">It is an enlarged upper perspective view of the upper airway disc according to some embodiments of this invention.</figref><figref num="5B">FIG. 5 is an enlarged perspective view of an upper airway disc according to another embodiment of the present invention.</figref><figref num="6">FIG. 5 is an enlarged partial perspective view of a dose container assembly shown in FIG. 2A according to an embodiment of the present invention.</figref><figref num="7A-7C">FIG. 3 is a partially cut perspective view of a dose vessel assembly within an inhaler that works in concert with a puncture mechanism in a three-step operating procedure according to some embodiments of the present invention.</figref><figref num="8A">It is a top view of the dose container ring according to some embodiments of this invention.</figref><figref num="8B">It is an enlarged partial view of a part of the ring shown in FIG. 8A.</figref><figref num="9">It is a side view of the ring shown in FIG. 8A.</figref><figref num="10A">It is a perspective view which shows by cutting a part of the inhaler which has the double piercing mechanism which reciprocates according to some embodiments of this invention.</figref><figref num="10B">FIG. 5 is a perspective view showing a part of an inhaler having a reciprocating piercing mechanism according to some embodiments of the present invention.</figref><figref num="11A">FIG. 10A is an upward perspective view of the inhaler of FIG. 10A with the cover and upper and lower housings removed.</figref><figref num="11B">FIG. 10B is an upward perspective view of the inhaler of FIG. 10B, with the cover and upper and lower housings removed.</figref><figref num="11C">FIG. 10B is a top view of the inhaler of FIG. 10B showing a ratchet arm in a cover that works in concert with the teeth of a slope disc, with the cover 11 being seen through for clarity.</figref><figref num="12A">FIG. 10A is an upward perspective view of the inhaler of FIG. 10A with the slope disc removed, according to some embodiments of the present invention.</figref><figref num="12B">FIG. 10B is an upward perspective view of the inhaler of FIG. 10B with the slope disc removed, according to some embodiments of the present invention.</figref><figref num="13A">FIG. 10A is a downward perspective view of the slope disc of the inhaler of FIG. 10A according to some embodiments of the present invention.</figref><figref num="13B">FIG. 10B is a downward perspective view of the slope disc of the inhaler of FIG. 10B according to some embodiments of the present invention.</figref><figref num="13C">FIG. 3 is an upward perspective view of a slope disc of FIG. 13B according to some embodiments of the present invention.</figref><figref num="14A">The dose disc indexing mechanism according to some embodiments of the present invention is shown, and is a downward perspective view showing a part of the inhaler of FIG. 10A cut out.</figref><figref num="14B">It is a partial plan view of the lower disk of a dose container assembly, showing the dose markings according to some embodiments of the present invention.</figref><figref num="14C">The dose disc indexing mechanism according to some embodiments of the present invention is shown, and is a downward perspective view showing a part of the inhaler of FIG. 10B cut out.</figref><figref num="14D">It shows a window opening centered on a dose mark indicating that 60 doses remain, and is an enlarged plan view of a part of the suction device of FIG. 14C.</figref><figref num="14E">It shows a window opening centered on a dose mark indicating that no dose remains (0), and is an enlarged plan view of a part of the suction device of FIG. 14C.</figref><figref num="15A">It shows the dose disk indexing mechanism which concerns on the dose container assembly by some embodiments of this invention, and is the upper perspective view which shows the part of the inhaler of FIG. 10A cut out.</figref><figref num="15B">It shows the dose disk indexing mechanism which concerns on the dose container assembly by some embodiments of this invention, and is the upper perspective view which shows the part of the inhaler of FIG. 10B cut out.</figref><figref num="15C">FIG. 10B is an exploded side perspective view of the components of the indexing mechanism of the inhaler shown in FIG. 10B.</figref><figref num="16A">Demonstrates a dose disc urging post associated with an actuator accessible to the user for urging a dose disc towards a mouthpiece according to some embodiments of the present invention, the inhalation of FIG. 10A. It is a lower perspective view which shows by cutting a part of a vessel.</figref><figref num="16B">Demonstrates a dose disc urging post associated with an actuator accessible to the user for urging a dose disc towards a mouthpiece according to some embodiments of the present invention, the inhalation of FIG. 10B. It is a lower perspective view which shows by cutting a part of a vessel.</figref><figref num="17A-17E">In the upper cut view of the inhaler of FIG. 10A, which illustrates an exemplary operating procedure according to some embodiments of the present invention, in which a portion of a layer or member / disc is seen through for clarity. is there.</figref><figref num="18A-18C">In the upper cut view of the inhaler of FIG. 10B, which illustrates an exemplary operating procedure according to some embodiments of the present invention, in which a portion of a layer or member / disc is seen through for clarity. is there.</figref><figref num="19A">FIG. 5 is an enlarged cross-sectional view of a part of a piercing member according to some embodiments of the present invention.</figref><figref num="19B">FIG. 6 is an enlarged cross-sectional view of a portion of a piercing member similar to that shown in FIG. 19A according to some embodiments of the present invention.</figref><figref num="19C">It is a front view of a part of a piercing member having a grooved structure according to some embodiments of the present invention.</figref><figref num="19D">It is an end view of the apparatus shown in FIG. 19C.</figref><figref num="19E">FIG. 5 is a schematic front view of a portion of another grooved piercing tool structure according to some embodiments of the present invention.</figref><figref num="19F">FIG. 3 is an end view of a grooved piercing tool having four lobes exemplary according to some embodiments of the present invention.</figref><figref num="20">FIG. 5 is an enlarged cross-sectional view of a portion of an inhaler having a substantially U -shaped suction flow path for each dose according to some embodiments of the present invention.</figref>

Hereinafter, the present invention will be described in more detail with reference to the accompanying drawings showing embodiments of the present invention. However, the present invention may be implemented in many different embodiments and should not be construed as limited to the embodiments described herein. Throughout, similar numbers shall refer to similar elements. In the drawings, some layers, components, or features may be exaggerated for clarity, and dashed lines indicate optional features or operating processes, unless otherwise specified. ing. In addition, the sequence of operations (or strokes) is not limited to the order described in the drawings and / or claims, unless otherwise specified. Features described with respect to one drawing or embodiment may be associated with other embodiments or drawings without being specifically described or illustrated.

When a feature, such as a layer, region, or substrate, is said to be "on" the other feature or element, the feature is of the other feature or element. It should be understood that it may be located directly on top of it, or that intervening features and / or elements may be present. In contrast, when an element is said to be "directly on" to another feature or element, there are no intervening elements. When one feature or element is referred to as "connected," "attached," or "coupled" to another feature or element. It should also be understood that the feature or element may be directly connected, attached or connected to another element, or may have intervening elements. In contrast, one feature or element is "directly connected", "directly attached", or "directly attached" to another element. When referred to as "coupled)", there are no intervening elements. Even if it is described or illustrated with respect to one embodiment, the features described or illustrated as such may be applied to other embodiments.

The terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the invention. The singular forms "a," "an," and "the" as used herein are also intended to include the plural, unless the context clearly indicates otherwise. The terms "comprises" and / or "comprising" as used herein of the features, strokes, operations, elements, and / or components described. It will identify its existence, but it should be further understood that it does not preclude the existence or addition of one or more other features, processes, operations, elements, components, and / or groups thereof. As used in the present invention, the term "and / or" includes any combination and all combinations of one or more of the items listed in association with each other.

"Under", "below", "lower", "over", "upper", etc. Space-related terminology is used herein to facilitate description of the relationship between one element or feature shown in a drawing and one or more other elements or features. May be used in writing. It should be understood that these terms related to space are also intended to include different orientations of the device during use or operation, in addition to the orientations depicted in the drawings. For example, if the device in the drawing is inverted, an element that is described as being located "under" or "beneath" of another element or feature is another element or feature. It will be oriented "over" of the part. Therefore, the exemplary term "under" includes both upward and downward orientations. The device may be otherwise oriented (ie, rotated 90 ° or in any other direction), in which case the space-related descriptive term used herein. However, it should be interpreted accordingly. Similarly, in the present specification, terms such as "upwardly", "downwardly", "vertical", and "horizontal" are used unless otherwise specified. Used for explanatory purposes only.

Although the terms "first" and "second" are used herein to describe the various areas, layers, and / or areas, these areas, layers, and / or areas. Please understand that should not be limited to these terms. These terms are used only to distinguish one area, layer, or area from another area, layer, or area. Thus, without departing from the suggestions of the present invention, the first region, layer, or zone described below may be referred to as a second region, layer, or zone, as well as the second region, described below. Area, layer, or area of may be referred to as a first area, layer, or area. Throughout, similar part numbers shall refer to similar elements.

Unless otherwise defined, all terms used herein (including technical and scientific terms) have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention belongs. Have. Terms such as those defined in commonly used dictionaries should be construed to have meaning consistent with their meaning in the context of this specification and related arts and are expressly herein. It should be further understood that unless otherwise specified, it should not be interpreted in an idealized or overly formal sense. Well-known functions or structures may not be described in detail for brevity and / or clarity.

In the description of the present invention described below, some terms are used to refer to the positional relationship between one structure and another. As used herein, "front" or "forward" and its derivatives refer to the general or main direction in which the dry powder travels to be administered to the patient from the dry powder inhaler. pointing. This term is intended to be synonymous with the term "downstream". The term "downstream" is often used in a manufacturing or logistics environment to indicate that a material that is moving or reacting is farther along the process than another material. .. Conversely, "rearward" or "upstream and its derivatives refer in the opposite direction to the anterior or downstream direction. The term" deagglomeration "and its derivatives. Refers to treating the dry powder in the airway pathway of the inhaler so that the dry powder remains agglomerated or sticky during inhalation or is prevented from agglomerating or sticking. ..

The inhalers and methods of the present invention are particularly suitable for retaining a single or multiple doses of a single or multiple doses of a single or multiple granular dry powder material. It should be noted that the dry powder material is formulated for in vivo inhalation dispersion (using an inhaler) to a subject, eg, but not limited to, an animal, typically a human patient. This inhaler has come to be used for inhalation delivery by nasal and / or oral (mouth) breathing, but is typically an oral inhaler.

The terms "sealant", "sealant layer" and / or "sealant material" include forms having at least one layer of at least one type of material. It may be provided as a continuous layer covering the entire top and / or bottom, or it may cover part of the device, eg, above at least one or more targeted dose container openings. It may be provided as a strip or fragment. The terms "sealing material" and "sealing layer" include single-layer and multi-layer materials, typically including at least one foil layer. The sealing material or sealing layer can be a thin multilayer sealing material having a laminated structure including an elastomer material and a foil material. The sealing layer may be selected to provide drug stability upon contact with the dry powder in each dose container.

The term "reciprocating" means that the piercing member moves up and down to open each dose container.

The sealed doze container may be configured to block the ingress of oxygen and moisture in order to provide a sufficient shelf life.

The term "primary surface" refers to a surface that has a larger area than other surfaces and can be substantially planar, but may be configured non-planar. For example, the main surface will include protrusions or recesses, for example, when a blister configuration is used. Specifically, the disc can have a top and bottom main surface and a secondary surface (eg, a thick wall) that extends between the two main surfaces and connects them.

Dry powder materials include one or more active pharmaceutical ingredients and biocompatible additives for producing the desired formulation or mixture. As used herein, the term "dry powder" is synonymous with the term "dry powder formulation" and is composed of one or more components within one or more (average) particle size ranges. It means that it can contain substances or ingredients. The term "low density" dry powder is about 0.8 g / cm.³It means a dry powder having the following densities. In certain embodiments, the low density powder is about 0.5 g / cm.³It has the following densities. The dry powder may be a dry powder that tends to be sticky or cohesive.

The term "filling" means supplying a weighed dry powder for bolus or sub-bolus administration. Therefore, each dose container does not necessarily have to be sufficient in volume.

In any case, the individually dispersible amount of the dry powder formulation can contain a single component or multiple components, whether active or inactive. Inactive ingredients include additives added to promote fluidity or to promote aerosolization delivery to the desired subject. The dry powder drug formulation can have a non-uniform active particle size. The device is particularly suitable for dry powder formulations with fine particles in the range of about 0.5 μm to 50 μm, typically about 0.5 μm to 20.0 μm, and more typically about 0.5 μm to 8.0 μm. There is. The dry powder drug formulation may also contain flow-promoting ingredients, typically having a particle size larger than the particle size of the active ingredient. In some embodiments, the flow-promoting component may comprise an excipient having a particle size in the range of about 50 μm to 100 μm. Examples of excipients include lactose and trehalose. Other types of excipients, such as, but not limited to, by the U.S. Food and Drug Administration (FDA), as antifreeze agents (eg, mannitol), as solubility promoters (eg, cyclodextrins), or " Sugars approved as other excipients that are generally recognized as safe (GRAS) may be used.

The "active agent" or "active ingredient" described herein includes a composition of an ingredient, substance, agent, compound, and substance or mixture that provides a beneficial pharmacological effect. I'm out. Examples of this include foods, dietary supplements, nutrients, drugs, vaccines, vitamins, and other beneficial substances. As used herein, these terms further include any physiologically or pharmacologically active substance that has local and / or systemic effects within the patient's body.

The active ingredient or agent delivered can include antibiotics, antivirals, antiepileptic agents, analgesics, anti-inflammatory agents, and bronchodilators, and may be inorganic and / or organic compounds. Inorganic and / or organic compounds are, but are not limited to, peripheral nerves, adrenergic receptors, choline receptors, skeletal muscle, cardiovascular system, smooth muscle, vasculature, synoptic sites, neuroeffector junctions, It contains drugs that act on the endocrine / hormonal system, immune system, genital system, skeletal system, autologous drug system, digestive and excretory system, histamine system, and central nervous system. Suitable activators are, for example, but not limited to polysaccharides, hormones, hypnotics and sedatives, psychostimulants, tranquilizers, anticonvulsants, muscle relaxants, anti-Parkinsons, analgesics, anti-inflammatory agents. , Muscle contractants, antibacterial agents, anti-malaria agents, hormonal agents including contraceptives, sympathomimetics, polypeptides and / or proteins (which can elicit physiological effects), diuretics, hyperlipidemia Selected from therapeutic agents, anti-androgen agents, anthelmintic agents, tissue renewal agents, antitumor agents, hypoglycemic agents, nutritional supplements and nutritional supplements, growth supplements, lipids, anti-enteritis agents, electrolytes, vaccines and diagnostic agents It is good.

The activator may be a natural molecule, may be the result of genetic recombination, or may be a natural or recombinant activator with the addition or removal of one or more amino acids. It may be an analog consisting of. In addition, the activator may contain an attenuated or inactivated virus suitable for use as a vaccine. When the activator is insulin, the term "insulin" refers to naturally extracted human insulin, recombinant human insulin, insulin extracted from bovine and / or porcine and / or other sources, recombinant porcine, bovine. Alternatively, it contains insulin extracted from other suitable donors, and a mixture of any of these. Insulin may be pure (ie, in its substantially purified form), but may also contain commercially formulated excipients. The term "insulin" also includes insulin analogues in which one or more amino acids have been removed or added to natural or recombinant insulin.

Two or more active ingredients or active agents may be included in the aerosolization activator formulation, and the use of the term "agent" or "ingredient" is such that two or more such. It should be understood that the use of aerosols is by no means excluded. In fact, in some embodiments of the invention, it is intended to administer a combination drug that will be mixed in the field.

Examples of diseases, health conditions, or diseases treatable by embodiments of the invention are, but are not limited to, diabetes and other insulin resistant diseases, as well as asthma, COPD (chronic obstructive pulmonary disease). , Viral or bacterial infections, influenza, allergic reactions, cystic fibrosis, and other respiratory illnesses. Dry powder inhalation delivers systemic drugs such as peptides and proteins such as insulin, as well as topical agents such as antibacterial agents, proteolytic enzyme inhibitors, and nucleic acids / origionucleotides. May be used for. For example, antibacterial agents such as anti-tuberculous compounds, proteins such as insulin for diabetes therapy or other insulin resistance related diseases, leuprolide acetate for the treatment of prostate cancer and / or endometriosis. Peptides and nucleic acids or ogligonucleotides for cystic fibrosis gene therapy may be delivered by inhaler. See, for example, Wolff et al .: "Generation of Aerosolation Agents", J. Aerosol. Med.pp. 89-106 (1994). Also, US Patent Application Publication No. 2001/0053761 entitled "ASPB28-Methods for Administering Human Insulin" and US Patent Application Publication No. 2001/0007853 entitled "Methods for Administering Monomer Insulin Similarities". Please refer to the specification. By reference, the contents of these patents shall be included here as if they were completely described.

The typical dose amount of the dry powder mixture, which is the unit dispersed in the inhaler, can be varied depending on the patient's profile, systemic target site, and specific one or more agents. The dose amount and type of drug retained by the dose container system may vary from dose container to dose container or may be the same. In some embodiments, the dose amount of the dry powder can be no more than about 100 mg, typically less than 50 mg, and more typically between about 0.1 mg and about 30 mg.

In some embodiments, for example, in the case of lung disease (ie, asthma or COPD), a total weight of about 5 mmg of dry powder may be supplied (dose amount adjusted to supply this weight). Good). The dose amount of a conventional exemplary dry powder is less than about 50 mg for the average adult, typically between about 10 mg and 30 mg, and typically about 5 mm for the average adolescent patient. Between -10 mg. A typical dose concentration should be between about 1% -5%. Examples of exemplary dry powder agents include, but are not limited to, albuterol, fluticasone, bechrometazone, chromolin, terbutaline, fenoterol, beta stimulants (including long-acting beta stimulants), salmeterol, formoterol, cortical steroids. , And glucocorticoids.

In some embodiments, the amount of bolus or dose administered can be formulated to be higher in concentration than the conventional mixture (so that it contains a higher concentration of active ingredient). In addition, the dry powder formulation can be configured as a lower dose dose as compared to conventional 10-25 mg doses. For example, the amount of each dose of dry powder that can be administered can be less than about 60-70% of the conventional dose. By using the dispersion system provided by some embodiments of the DPI configuration of the present invention, the dose amount for adults is less than about 15 mg, eg, between about 10 μg and 10 mg, and more typically about 50 μg and up. It has been reduced to 10 mg. The concentration of one or more active ingredients is preferably about 5-10%. In other embodiments, the concentration of the active ingredient can be in the range of about 10-20%, in the range of 20-25%, or higher. In certain embodiments, for nasal inhalation, the target dose amount can be from about 12 μg to 100 μg.

In some specific embodiments, during inhalation, the dry powder in a particular drug compartment or blister is a high concentration of one or more active agents that is substantially free of additives (such as excipients). It may be blended as an ingredient. As used herein, the term "substantially without salts" refers to a substantially pure activity in which the dry powder contains only a minimum amount of other non-biopharmaceutical active ingredients. It means that it is a compound. The term "minimum amount" is free of non-active ingredients or very small relative to one or more active ingredients, specifically less than about 10% of the dry powder formulation administered. , Preferably, it is contained in an amount of less than about 5%, and in some embodiments, it means that the inactive component is contained in a trace amount below a certain reference value.

In some embodiments, the unit dose amount of dry powder retained in each drug compartment or dose container is less than 10 mg, typically about 5 mg, when treating lung diseases such as asthma. A mixture of less than a drug and lactose or other additives (eg, 5 mg LAC). Less than about 4 mg of pure insulin equivalent, typically about 3.6 mg of insulin may be given. The dry powder may be "compressed" or partially compressed and inserted into the dose container / drug compartment, or may be contained as freely flowing particles.

Some embodiments of the present invention are intended for inhalers capable of delivering a large number of agents that differ from each other for combinatorial delivery. Thus, for example, in some embodiments, some or all of the dose containers may contain two different agents, or different dose containers containing different agents may be administered substantially simultaneously. It may be configured to do so.

In some embodiments, the doze container discs for the inhaler are the first row of doze containers that are circumferentially separated from each other in the first radius and the doze containers that are circumferentially separated from each other in the second radius. It is good to have two columns, with the first and second columns being substantially concentric. In some embodiments, the same drug may be included in all of the dose containers. In another embodiment, the first drug is contained in the dough container in the first row, and a second drug different from the first drug is contained in the dough container in the second row. You may be.

The inhaler may be configured to contain any suitable number of doses, typically about 30-120 doses, and more typically about 30-60 doses. .. The inhaler can deliver one type of drug or combination drug. In some embodiments, the inhaler has approximately 30-60 doses of two different agents (which may have the same or different unit amounts), and thus in total. It may contain about 60-120 unit doses. The inhaler can supply the drug over a period of 30 to 60 days (or more). In some embodiments, the inhaler is configured to contain approximately 60 doses of the same drug or combination drug (which may have the same or different unit amounts). It may have been done. This allows the drug to be supplied for 30 days (when administered twice daily) and the drug for 60 days when treated once daily.

Some embodiments are particularly suitable for administering the drug to a respiratory patient, a diabetic patient, a cystic fibrosis patient, or a patient treating distress. This inhaler may be used to administer anesthetics, hormones, and / or fertility drugs.

This dose container assembly and inhaler are particularly suitable for administering drugs for the treatment of respiratory diseases. Suitable agents are, for example, analgesics, such as codeine, dihydromorphine, ergotamine, fentanyl, or morphine; angina preparations, such as zirchiazem; antiallergic substances, such as chromoglycate, ketotiphen, or nedocromyl; anti-infection. Drugs such as cephalosporin, penicillin, streptomycin, sulfonamide, tetracycline, and pentamidine; antihistamines such as metapyrrylene; antiinflammatory agents such as dipropionate bechrometazone, propionate fluticazone, flunisolide, budesonide, lofreponide, furoate mometazone , Or triamsinolone acetonide; antitussives, such as noscapine; bronchial dilators, such as albuterol, salmeterol, ephedrine, adrenaline, phenotelol, formoterol, isoprenaline, metaproterenol, phenilefurin, phenylpropanolamine, pyrubuterol, reproterol, limiterol , Isoetaline, salmeterol, or (-)-4-amino-3,5-dichloro-α-[[6- [2- (2-pyridinyl) ethoxy "hexyl] methyl] benzenemethanol; diuretics, such as amylolide; Anticholinergic agents such as ipratropium, thiotropium, atropine, or oxytropium; hormones such as cortisone, hydrocortisone, or prednisolone; xanthin, such as aminophylline, cholineteophilinate, lysineteophylline, or theophylline; It may be selected from therapeutic proteins and peptides, such as insulin or glucagon. If appropriate, these agents may be used in the form of salts (eg, as alkali metal or amine salts or acid addition salts) to optimize the activity and / or stability of the agents. It will be apparent to those skilled in the art that they may be used as esters (eg, low alkyl esters) or as solvates (eg, hydrates).

Some suitable embodiments of the dose vessel assembly and / or inhaler include albuterol, salmeterol, fluticasone propionate, and beclomethasone dipropionate, and salts and solvent products thereof such as salmeterol sulfate and salmeterol xinaho. Contains agents selected from the group consisting of acid salts. The agents may be delivered in combination. As an example of a particular formulation containing a combination of active ingredients, in combination with an anti-inflammatory agent such as beclomethasone ester (eg dipropionate) or fluticasone ester (eg propionate) (eg free group or sulfate). Examples include those containing salbutamol (as a salt) or salmeterol (eg, as a xinafoate).

Some properties of the DPI device according to embodiments of the present invention are 1) the ability to protect the dry powder from moisture ingress, 2) the number of doses contained within the inhaler, and 3) the overall size of the inhaler. is there. In addition, it is advantageous to load the largest number of doses in practical use into the smallest inhaler. However, the individual doses need to be spaced apart from each other to allow sufficient sealing area and material thickness for moisture protection of the powder. One solution is to use a dose ring where the dose vessels are located equidistant from each other at two different radii. This is sometimes referred to as the doze arrangement of "staggered concentric structures".

Unfortunately, however, the challenge of staggered concentric dozelings is how to access each doze container for opening and inhalation. If all of the outer dough containers are opened first, then all of the inner dough containers are opened, then a "half step" to transition from the outer doze container ring to the inner doze container ring. ) , While a full step indexing device is required for all other dose containers. It is difficult to bring this indexing function to the inhaler. As an alternative, it is conceivable to make a doze ring with a special arrangement of doze containers on the doze ring. However, unfortunately, this complicates automatic processing and filling of the powder into the doze ring.

The drawings will be described below. 1A-1C show an example of a multi-dose inhaler 10 having a cover 11, a suction port 10p, and upper and lower housing portions 12, 13. However, the configuration of this inhaler is shown solely for the purpose of integrity, and embodiments of the present invention are not limited to the configuration of this inhaler, but other morphological factors, other Covers, and other inlet configurations may be used. In FIG. 1A, the cover 11 is in the closed position. In FIG. 1B, the cover 11 has been moved to the open or operating position. FIG. 1C shows the user lever 320 of the actuator mechanism 306 that has moved from the first position (FIG. 1B) to the second position, as described below.

FIG. 2A shows the dose vessel assembly 20 used within the multi-dose vessel 10. The doze container assembly 20 comprises a doze ring or doze disc 30 having a plurality of doze containers 30c. As shown in FIGS. 2B and 2E, in some embodiments, the dose ring or dose disc 30 may include a plurality of through openings 30a that are spaced apart from each other in the circumferential direction. These openings 30a form part of the dose container 30c. As shown in FIG. 2E, the dose vessel 30c is defined by a dose vessel opening 30a and an upper sealant 36 and a lower sealant 37.

As shown, the dose vessel assembly 20 comprises a lower airway disc 40 and an upper airway disc 50. In other embodiments, the dose vessel assembly 20 may include only one dose vessel disc 30, a lower airway disc 40 or an upper airway disc 50. In such a configuration, on the other side of the disk 30, there are other types of airways, such as other, unrestricted, fixed or "global" upper or lower airways. , May be used with the individual airways provided by either the upper airway disc 50 or the lower airway disc 40. It is also expected that the upper airway disc 50 and the lower airway disc 40 described herein will be used upside down (ie, carelessly, unusually) as in normal operation. It has been. Specifically, it is also considered that the lower airway disc becomes the upper airway disc and the upper airway disc becomes the lower airway disc.

As shown in FIGS. 2A and 2B, the lower airway disc 40 and the upper airway disc 50 each include a plurality of airway passages 41, 51 that are spaced apart from each other in the circumferential direction. Typically, the discs 40,50 have one aisle 41,51 for one dose container 30c. However, in other embodiments, each airway passage 51,41 from one or both of the discs 50', 40' communicates with two different dose vessels 30c, for example, as shown in FIG. 2C. You may be doing it. This configuration allows (simultaneously) combined delivery of dry powder from two containers in each airway aisle pair (or single airway aisle), or one dose container 30c.₁Discharges dry powder into airway passages 41 and / or 51, then another dose container 30c₂Allows the dry powder to be released again into the airway passages 41 and / or 51. Thus, in embodiments of the present invention, some or all of the airway passages 41,51 can be used once or twice. Also, embodiments of the present invention have been shown to release only the dose from a single dose container 30c during a single delivery, whereas in other embodiments there are two inhalers. By delivering the above dose container 30c using the respective airway passages 41 and 51, it is possible to administer the combination drug.

In some embodiments, airway passages 41,51 are present in the airway passages once the inhaler has been repositioned elsewhere and as a result the airway passages no longer communicate with the suction port 10p. It defines an airway that prevents the dry powder from being released to the user. These passages (unless, as mentioned above, a two-use configuration is used and the airway passage may be used to release another dose only once) to prevent overdose. For this purpose, it may be configured to have a "sink trap" that prevents leakage according to some embodiments of the present invention.

When two airway discs, eg, both the upper airway disc 50 and the lower disc 40, are used, the inhaler 10 can be operated even when the disc is inverted and has the same overdose prevention function. It can be configured to have. Leakage of dry powder from the doze container 30c when the doze container 30c is opened may be affected by gravity. For example, in the case of a normal left-right semicircular quadrilateral or elliptical mouthpiece shape, there are two main device orientations (front side up and surface side down). The inhaler can be operated in any of these orientations. For example, in the embodiment shown in FIG. 2A, this is a target dose vessel 30c corresponding to an individual airway area for each dose vessel 30c (or multiple dose vessels if delivery of a combination drug is desired). It will be achieved by placing it both above and below.

2A, 2D and 3A show that the doze container disc 30 can include 60 doze containers 30c, and FIG. 3B shows that the doze container disk 30 includes 30 doze containers 30c. It shows that it can be done. More or fewer dose containers may be used. FIG. 2E shows that the sealing layers 36,37 are preferably configured as an annular flat ring, as shown, and may be used to seal the top and bottom surfaces of the dose disc 30. Shown. The sealing layers 36 and 37 may be made of the same material or different materials. Examples of sealing layers 36,37 include foils, one or more polymers and / or one or more elastomers or other suitable materials, or combinations of these materials, such as laminates. Typically, the sealing layers 36,37 are thin flexible sealing layers made of foil. Sealing layers 36,37 (if used) may be provided as substantially continuous rings, as shown in FIG. 2E, or may be placed above and below the opening 30a. It may be attached to the dose container disc 30 as individual sealant strips or spot pieces. In other embodiments, the sealing layer may be provided on only one main surface of the dose disc 30. In this case, the opening 30a is not a through hole but is closed on one side (not shown). In yet another embodiment, the dose disc 30 may have a blister structure.

2B, 3A and 3B show that the dose container disc 30 may have at least one indexing notch 34. These indexing notches are illustrated as a plurality of indexing notches 34 that are spaced apart from each other in the circumferential direction. To assemble the assembly 20, one of the airway discs 40, 50, typically a tab on the lower disc 40, has a tab 45 extending radially (FIG. 4A). The tabs 45 are aligned with one of the notches 34 and engage with the notches 34 in order to position the passages 41, 51 in a straight line with the dose vessel 30c. Other alignment means may be used, eg, a configuration opposite to the notch / tab configuration described herein (eg, the airway disc has a notch and the dose container disc has a tab).

As shown in FIGS. 2B, 3A and 3B, the doze containers 30c may be arranged so as to be circumferentially separated from each other along one or more rows. As shown in Figure 3A, the dose vessels 30c are in alternating concentric rows, specifically the front row 31 at the first radius from the center of the disc and a second radius different from the first radius. It is located in the back row 32. As shown in FIG. 3A, the dose vessels 30c in each row are separated from each other with a distance "D". The misalignment of the centerline of the doze container in the back row with respect to the centerline of the doze container in the front row is "D / 2". The dose container disc 30 may be a molded polymer, copolymer or mixture, and a derivative thereof, a metal or a combination thereof, or a material capable of providing sufficient moisture resistance. You may.

The dose vessel disc 30 has an outer diameter of about 50 mm to 100 mm, typically about 65 mm, and a thickness of about 2 mm to 5 mm, typically about 3 mm (FIG. 9). It is good. The disc 30 may be made of a cyclic olefin (COC) copolymer. The opening 30a can have a diameter between about 2 mm and 5 mm, typically about 3 mm. Also (when the molding process is used to form the disc 30), to facilitate mold release, the side walls 30w of the dose container 30c are each about 1 °, as shown in FIG. 3D. Between -3 °, it is typically good to have an angle or tilt of about 1.5 °. The dose container 30 is configured to provide the desired number of doses for the overall size of the small inhaler and to protect the powder from moisture ingress. The individual dose containers 30c are separated from each other to obtain sufficient sealing area and sufficient material thickness for moisture protection of the powder.

Similar to the embodiment shown in FIG. 2E, FIG. 3C shows that the dose vessel 30c is defined by an opening 30a sealed by sealing layers 36, 37 above and below the opening 30a. Examples of sealants include foils, polymers and / or elastomers, or suitable materials or combinations of materials, such as laminates. In the dry powder drug inhaler 10, the drug powder is stored in the enclosed moisture resistant space provided by the dose container 30c.

Embodiments of the present invention can provide a suitable seal for the dose ring or dose disc 30, and can facilitate the attachment of the airway discs 40, 50 to the dose ring or dose disc 30. Assembly 20 is provided. In some embodiments, the dose container disc 30 contains sealants 36,37 that form a continuous layer on the upper and lower surfaces (main surfaces) of the dose disc 30, with the upper and lower airway discs 50, 40, respectively. It comes in contact with the sealing material of the above and also in contact with the dose disc, and can be tightened and fitted. The exemplary mounting feature shown in FIG. 2E allows airway discs 40, 50 to be tightly fitted to the dose disc 30 to reduce air leakage. The discs 40, 50 sandwich the dose disc 30, and the dose ring can function as a "stop" that determines the depth of engagement of the assembly features of the airway discs 40, 50. In the embodiment of the present invention, a feature portion for indexing the airway discs 40 and 50 with respect to the dose disc 30 and some simple friction engaging members are provided. Examples of frictional engaging members, for example, but not limited to, are provided on one or both of the airway discs 40, 50 to secure the fixtures to each other, as described in more detail below. "Crush rib" is mentioned.

FIG. 4A shows an example of the lower airway disc 40. As shown, the disc 40 defines a plurality of passages 41 that are spaced apart from each other in the circumferential direction. For staggered concentric doze vessel configurations, the disc 40 may include alternating long airway passages 42 and short airway passages 43. Each aisle 41 has an end portion 41a, 41b facing each other, specifically one (substantially or completely) closed end portion 41a, which is generally positioned adjacent to the dose vessel 30c, and one. It has an open end 41b. The open end portion 41b is integrated with the outlet 10p and / or the mouthpiece 10m (FIGS. 7A-7C) and / or is arranged adjacent to it. The flow of intake air may be in either direction, and the open end 41b may be configured to face either the inner or outer circumference of the disc 40 (eg, the innermost or radial end of the disc 40). It should be positioned on the outermost side in the radial direction). The passage 41 comprises an upwardly extending side wall 41w, and a pair of long and short passages adjacent to each other share one of these side walls 41w. Optionally, the passage 41 may include a small air vent 48, as shown by the dashed line with respect to the feature 48 in FIG. 4A. The air vents 48 are sized to allow air to enter while preventing dry powder from flowing out of the air vents (how many air vents 48 are for ease of explanation). Shown only for that passage 41).

FIGS. 4A and 4B show that the disc 40 has tabs 47 extending upwardly spaced apart from each other in the circumferential direction. One of the tabs 47 has a tab 45 extending radially as described above. The disk 40 can also include recesses 49 extending in the circumferential direction. The recess 49 is arranged so that it is aligned with the tab of the upper airway disc 50, and is for sandwiching the dose disc between them. The tab 47 may include a crushing rib 47r. The rib 47r should be fitted to tab 57 (FIG. 5A) of the upper airway disc 50 to hold the three-part assembly 30 with sufficient force without the need for any additional mounting means. It has become.

FIG. 4C shows that the disc 40 can also be equipped with a dose mark 44 so that the user can visually see which dose is being administered or how much dose remains in the inhaler. ing. The dose mark 44 may be arranged in line with the dose reading opening of the inhaler housing. This allows the user to visually check the doze marks / information that are visible to the naked eye when each dose is indexed to the dosing position or next to the dosing position. The dose mark 44 may, additionally or alternatively (not shown), be placed on the upper disk 50 and aligned with the dose read opening, or (also not shown). However, it may be located on both disks. FIG. 14C shows that the dose markings may be placed along the outer periphery of the underside of the lower disk 40. In this case, the dose markings are numbered 1-60, but other patterns may be used depending on the arrangement of openings (and the number of doses on the disc). In some embodiments, the doze marking numbers may be numbered so that when the doze containers are sequentially opened in alternating rows, they are moved back and forth between the rows of doze containers 30 to increase in sequence. .. For example, the outer row doze containers can be numbered 1, the inner row doze containers can be numbered 2, the outer row doze containers can be numbered 3, and so on. On the contrary, it may be numbered). However, other dose numbering patterns may be used, depending on the arrangement of openings (and the number of doses on the disc). That is, this numbering is such that if two rows of doze containers are used, the inhaler opens one row of doze containers and then the adjacent doze containers in the other row (eg, on the inner ring). When the doze container is opened alternately from the doze container to the outer ring doze container or from the outer ring doze container to the inner ring doze container), and this opening order is repeated.Suitable for. However, in other embodiments, the inner or outer dose container may be opened entirely and then the other row of dose containers may be opened, or the inner and outer row doze containers may alternate differently. It may be opened according to the pattern. Therefore, in this case, it is preferable that the mark of the dose number is affixed on the disc 40 and / or the disc 50 according to the order of such opening.

FIG. 5A shows an example of the upper airway disc 50. In this embodiment, the upper airway disc 50 is shown inverted (inverted with respect to the orientation shown in FIG. 2A) from its normal use position. As shown, the disc 50 defines a plurality of passages 51 that are spaced apart from each other in the circumferential direction. For staggered concentric doze vessel configurations, the disc 50 can include alternating long and short airway passages 52, respectively. Each passage 51 includes end portions 51a, 51b facing each other. The closed or substantially closed portion 51a is usually located adjacent to the doze vessel 30c. The flow of intake air may be in either direction, and the open end 51b may be configured to face either the inner or outer circumference of the disk 50 (eg, the innermost or most radial direction). It should be positioned somewhere outside). The other (open) end portion 51b is integrated with the outlet 10p and / or the mouthpiece 10m (Figures 7A-7C) and / or the supply air port or passage and / or positioned adjacent to it. There is. The passage 51 has an outwardly extending side wall 51w, and a pair of long and short passages adjacent to each other share one of these side walls 51w. Optionally, the passage 51 may include a small air vent 48 (shown in the figure only for some passages for ease of explanation). The air vent 48 is sized to allow air to enter while preventing dry powder from flowing out of the air vent.

As shown in FIG. 5A, each passage 51 can include an opening 55. The opening 55 is configured to be located above each dose container 30c. The upper sealing layer 36 of the dose container 30c is located below the opening 55. The opening 55 allows a puncture (eg, sliced or punctured) member (eg, members 220a, 220b of FIG. 10A) to open the sealing layers 36, 37 (FIG. 3C) through the opening 55. To do. As shown in FIG. 5A, the upper disc 50 may also include one or more indexing ribs 58 and / or inner peripheral gear teeth 60 or other features. These features allow the disc to be rotated and indexed in the inhaler. Indexing will be performed to feed a different dose vessel 30c to the dosing position and / or to position the puncture mechanism on the target dosing vessel for administration in order to open the dose vessel 30c. .. In other embodiments, one or both (or different features) of these rotation / positioning mechanisms may be provided on the lower disk 40 or dose disk 30.

FIG. 5B shows that disk 50 may have three tabs 57 instead of four tabs as shown in FIG. 5A (in this embodiment, the lower disk 40 may also be provided). , May have 3 tabs instead of 4 tabs, see Figures 4B and 4C). One of the tabs 57 may have a vertically extending oriented rib 56 shown on the inner peripheral surface of the tab 57. In some embodiments, the oriented rib 56 of the upper disc 50 is adapted to work with a puncture frame associated with a puncture mechanism fixed within the inhaler housing. Specifically, the alignment tab 56 is placed straight with the frame, sets the first exact position with a dose number (eg, 1), and the indexing is for the dose in the disk assembly 20. It is designed to prevent the number from being exceeded. In other words, the alignment rib 56 works with the inhaler housing to set the initial position of the disc assembly 20 and stop the disc assembly 20 from rotating more than once.

FIG. 5B shows that the opening 55 may be configured to have a geometry that corresponds to the shape of the piercing tool 220. The opening 55 may be configured to tightly surround the piercing tool 220. The piercing tool 220 can be a grooved piercing tool. As shown, the opening 55 has three lobes 55l to tightly fit and accept the corresponding three lobeed (grooved) piercing tools 220 (FIG. 19D). The grooved piercing tool may have a number of other lobes, eg, four lobes separated in the circumferential direction, as shown in FIG. 19F, with the opening 55 having the corresponding four lobe shapes. May have. These lobes 55l can have different orientations in the inner and outer rows, eg, 180 ° rotated orientation.

2A and 6 show the integrally mounted dose container assembly 20. 2B, 4A and 5A show exemplary disk components 30, 40, 50. The tab 57 of the disc 50 is fitted into the space 49 of the disc 40, the tab 47 of the disc 40 is fitted into the space 59 of the disc 50, and the crushing rib 47r is firmly in contact with the outer edge of the tab 57. This allows the discs 40, 50 to sandwich the dose disc 30 and frictionally engage these parts with each other for a flush fit by a relatively easy "press-fit" method. The doze container disc 30 is located on the upper side via a tab 45 (extending radially outward) that engages with one of the alignment notches 34 of the doze container ring 30 as described above. And will be placed straight side by side with the lower airway discs 50, 40, but other mounting configurations may be used, along with other alignment features or other markings.

Upper and lower airway discs 50, 40 (if both are used) will be attached to the dose vessel disc 30 so as to reduce the gap in the airway pathway defined by the disc. The disc 30 can serve as a stopper for the mounting features of the airway discs 40 and 50. The disc 30 with the sealants 36,37 can have substantially flat upper and lower main surfaces without the need for any mounting features. The lower portion of the upper airway disc 50 and the upper portion of the lower airway disc 40 can be closely aligned with respect to the respective opposing main surfaces of the dose vessel disc 30. Therefore, the mounting features / components are provided only on the upper disk 50 and the lower disk 40, which allows between the disks 30, 40, 50 without the gaps created by the tolerances in other assembly structures. It is possible to provide a sufficiently airtight interface that is in close contact with the. This press-fitting installation, which provides a substantially airtight interface without the use of adhesives, is advantageous and cost effective. However, as mentioned above, other mounting configurations, such as ultrasonic welding, bonding, laser welding, other friction fitting and / or fitting configurations, and combinations thereof may be used. Also, there is a seal (O-ring, gasket, etc.) between the contiguous zone of the airway passage wall facing the dose vessel 30c and the sealing layers 36,37 above and / or below the dose vessel 30c on the disc. It may be used.

As shown in FIGS. 7A-7C, during operation, pairs of upper and lower aisles 51 aligned with each other are located above and below each dose container 30c. The passages 41 and 51 will communicate with each other through the opened dose container 30c and the opening 30a. That is, as shown in FIG. 7A, the piercing member 220 advances and pierces the upper sealing layer 36 and the lower sealing layer 37 (FIG. 3). The puncture member 220 may be configured to project into the lower airway passage and be retained in the passage, or after opening the lower sealant and prior to administration (partially or completely). ) It may be designed to retreat. Further, although the state of projecting downward to pierce the sealing layer is shown, the piercing member 220 may be configured to project upward from the bottom side. In any case, the piercing member 220 may be configured to close the opening 55 of the upper disc (or lower disc).

As shown in FIG. 7B, the puncture member 220 is then retained, either partially or completely retracted or protruding into the lower (or upper) airway passage, depending on the structure of the puncture mechanism. It will be. However, typically, the piercing member 220 works with a member capable of closing and / or closing the opening 55 of the upper disk 50 (or the lower disk 40 if pierced from the bottom). This passage by acting or by the piercing member 220 and / or the collaborative member substantially blocking, ie, blocking (and / or sealing) the hole / opening 55 (FIGS. 2A, 5A and 5B). It is configured to block 55. In this way, if the inhaler is inverted, the powder will be prevented from leaking out of the passage 51 due to the blockage created by the puncture member 220. The airflow path 10f may be in the direction from top to bottom of the dose container 30c or vice versa, or in the direction from the inner circumference to the outer circumference or vice versa. For example, only in FIG. 7B, an arrow indicates an airflow path 10f in which air flows upward from the lower passage, through the opening 30a, and from the upper passage 51 to the mouthpiece 10m. It should also be noted that the exit or open end of passages 41b, 51b may face the inner circumference of the disc assembly 20 rather than the outer circumference.

After administration, the puncture member 220 is fully retracted, the dose vessel assembly 20 is rotated to the dosing position, and / or the puncture member 220 opens a different dose vessel 30c, as shown in FIG. 7C. Will be operated to do. During operation, the dose vessel assembly 20 is to be pushed radially outward to seal the airway passage 41 and / or the airway passage 51 to the mouthpiece 10 m or to provide an exit path in close contact with them. It may be. Seals such as O-rings may be used to provide a sufficiently airtight path between the airflow outlet path and the disc assembly 20. Other airflow path closure or blockage configurations may be used.

8A, 8B and 9 show an example of a doze container disc or ring 30 with two rows of openings 30a used for the doze container 30c. The dose container disc 30 can be relatively thin, for example, having a thickness of about 2 mm to 4 mm. The opening 30a of the dose vessel is configured such that the inner row 32 is at least about 2 mm away from the outer row 31 and the inner and outer rows of the dose vessel are separated inward by about 2 mm from their respective perimeters. It is good. This interval will provide sufficient moisture permeability and / or oxygen resistance.

FIG. 10A is a perspective view showing a part of the inhaler 10 according to some embodiments of the present invention. A dose container assembly 20 with a dose container disc 30 and upper and lower airway discs 50, 40 is rotatably secured within the inhaler housing portions 12, 13. As described above with respect to FIGS. 3A and 3C, in some embodiments, the dose container disc 30 is a first of the doze containers 30c that are spaced apart from each other in the circumferential direction with the upper and lower main surfaces facing each other and the first radius. It has a row and a second row of doze containers 30c that are circumferentially separated from each other at a second radius. The first and second columns are concentric with respect to the center of disk 30. The dose container 30c contains dry powder and is defined by an opening 30a. The opening 30a may be sealed by sealants 36,37 disposed above and below the opening 30a. However, in some embodiments, the dough container disc 30 may have a solid bottom, as will be appreciated by those skilled in the art, in which case one sealant will open the doze container opening. It is better to cover it.

As shown in FIG. 10A, in some embodiments, the inhaler 10 comprises a reciprocating dual puncture mechanism 200. The double piercing mechanism 200 is attached to the piercing frame 300 and is controlled by a rotatable slope disc 400. The inhaler 10 also includes an indexing mechanism 500 for rotating the disc container assembly 20. The puncture mechanism 200 is operably associated with the doze container assembly 20 and is configured to pierce the first and second sealants 36, 37 that seal the doze container 30c. The piercing mechanism 200 includes two piercing members 220a and 220b. The piercing members 220a and 220b are configured to pierce the sealants 36, 37 above and below the dosing container 30c in the two rows of the dosing container 30c, respectively. For example, the first piercing member 220a is configured to pierce the sealants 36, 37 above and below the dosing container 30c in the first row of the dosing container opening 30a. The second piercing member 220b is configured to pierce the sealants 36, 37 above and below the dosing vessel 30c in the second row of the dosing vessel opening 30a. Each puncture member 220a, 220b includes a distal puncture end 221 and a proximal end 222.

FIG. 10B is a perspective view showing a part of the inhaler 10 according to another embodiment of the present invention. The inhaler 10 shown in FIG. 10B includes the slope disc 400 of FIGS. 11B, 13B and 13C and the piercing frame 300 of FIG. 16B, which are described below.

With reference to FIGS. 11A-11C, 12A, 12B and 13A-13C, the piercing mechanism 200 according to various embodiments of the present invention and the components operably associated with the piercing mechanism are shown. .. FIG. 11A is an upward perspective view of the inhaler of FIG. 10A with the cover 11 and the upper and lower housing portions 12, 13 removed. In the orientation shown, the slope disc 400 covers the piercing frame 300, and the piercing frame 300 covers the dose container assembly 20. The actuator mechanism 306 is rotatably fixed to the piercing frame 300 and operably associated with the slope disc 400, rotating the slope disc 400 and piercing each of the piercing members 220a, 220b of the piercing mechanism 200. It is designed to be selectively moved between and the retracted position, more specifically between the puncture position, the partially retracted position, and the fully retracted position.

11B is an upward perspective view of the inhaler of FIG. 10B, showing the slope disc 400 of FIGS. 13B and 13C. In this figure, the cover 11 and the upper and lower housings 12, 13 are removed. FIG. 11C is a top view of the inhaler of FIG. 10B, showing the ratchet arm 12a of the upper housing portion 12 cooperating with the teeth 400t on the first side 402 of the slope disc 400. In this figure, for clarity, cover 11 is seen through and some parts are shown by dashed lines. The collaborative action between the ratchet arm 12a and the teeth 400t will serve to prevent retreat. This setback prevention function is similar to the function of preventing the reverse rotation of the slope disc 400, which will be described later, with respect to the setback prevention post 350 and the fastener 420 shown in FIGS. 12A and 13A.

FIG. 12A is an upward perspective view of the piercing frame 300 for the inhaler 10 of FIG. 10A. In this figure, the slope disc 400 has been removed for ease of explanation and clarity. As shown, the piercing frame 300 has a substantially flat surface 302, the flat surface 302 having a post 304 whose center extends upward. A user-accessible actuator mechanism 306 is rotatably fixed to the piercing frame 300. The actuator mechanism 306 is configured to rotate the slope disc 400, as described below. The illustrated actuator mechanism 306 includes first and second ring members 308,310. These ring members 308, 310 are connected to each other by members 312 extending in the radial direction so as to be substantially concentric. In the first ring member 308, the actuator mechanism 306 is the axis A as described below.₁It is rotatably connected to the post 304 so that it rotates between a first position (FIG. 1B) and a second position (FIG. 1C) about.

Actuator mechanism 306 includes a plurality of spaced arc arms 314 disposed between the first and second ring members 308, 310, as shown in FIG. 12A. Each arc arm 314 has a proximal end 314a and a distal free end 314b fixed to a first ring 308. The distal free end 314b of each arc arm 314 comprises a claw 316. The claw 316 is configured to engage the spaced step members 414 (FIG. 13A) on the slope disc 400 and rotate the slope disc 400 in one direction, as described below.

The illustrated actuator mechanism 306 also includes an arcuate body 318 extending radially outward from the second ring member 310. The arcuate main body 318 includes a user lever 320. The user lever 320 extends outward from the inhaler so that it can be grasped by the user of the inhaler 10. The user moves the actuator mechanism 306 from the first position to the second position by the lever 320 as described below, thereby rotating the slope disc 400 and piercing the dose container 30c. .. This structure of the actuator mechanism 306 allows the stroke of the lever 320 from the first position (FIG. 1B) to the second position (FIG. 1C) to be relatively short (eg, 60 °).

The main body 318 of the actuator mechanism is configured to slide along the piercing frame surface 302 as the actuator mechanism 306 moves between the first and second positions. The piercing frame 300 includes first and second blocking members 322,324. These blocking members 322 and 324 extend upward from the piercing frame surface 302 and are configured to limit the rotational movement of the actuator mechanism 306. For example, when the actuator mechanism 306 is in the first position, the end 318a of the arcuate main body 318 comes into contact with the blocking member 322. When the actuator mechanism 306 moves to the second position, the end 318b of the arcuate main body 318 comes into contact with the blocking member 324.

In the illustrated embodiment, the illustrated body 318 comprises a U-shaped guide 326 that slides along a rail 328 associated with the piercing frame 300. The guide 326 and rail 328 are designed to facilitate the smooth sliding operation of the actuator mechanism 306 between the first and second positions. In addition, the U-shaped guide 326 and rail 328 may be configured to prevent foreign matter from entering the inhaler 10 as well as to block the visibility of the internal components of the inhaler 10.

Actuator mechanism 306 can also include a post 360 that urges the dose vessel assembly, as shown in FIG. 16A. The post 360 extends downward from the second ring member 310 of the actuator mechanism 306 through the arcuate elongated hole 362 formed in the piercing frame 300. The urging post 360 is configured to contact the tab 530 of the indexing arm 510 of the indexing frame 508 (FIG. 10A) as the actuator mechanism 306 moves to the second position. The urging post 360 flexes the tab 530 against the inner circumference of the dose vessel assembly 20 during inhalation, urging the dose vessel assembly 20 toward the mouthpiece 10 m, between the mouthpiece 10 m and the dose vessel assembly. It is designed to bring a close interface to the assembly.

15B and 16B show alternative embodiments of the urging mechanism. This urging mechanism urges the disc assembly 20 towards the mouthpiece 10 m of the inhaler 10 of FIG. 10B during inhalation and then releases to allow rotation for indexing of the disc assembly 20. Or it is designed to be withdrawn. As mentioned above, in some embodiments, the inhaler 10 rotates the disc assembly 20 by a specified angular rotation, eg, about 6 °, continuously from doze containers arranged alternately in the inner and outer rows. It may be configured to be dosed to or to have continuous access to the dose container. The urging mechanism may be configured to be operated by a lever 320 similar to that described above, but may be actuated using other components or features.

As shown in FIG. 16B, the urging mechanism can include a post 360 located near the inner circumference of the dose vessel disc 20. The post 360 may be located within the elongated hole 362 extending in the circumferential direction. The elongated hole 362 has an end portion that is united with the elongated hole portion 363. The elongated hole portion 363 extends radially outward toward the inner circumference of the dose container disc assembly 20. During and / or shortly before the release of the drug to the user for inhalation (eg, "dosing"), the post 360 moves within the long hole 362 until it reaches the long hole portion 363 and the disc. The inner circumference of the assembly 20 is pushed (typically indirectly) to urge the disc assembly 20 toward the mouthpiece 10 m.

In some embodiments, the post 360 may be interlocked with the stationary post 360a on the indexing frame 508 (FIG. 15B). In the illustrated embodiment, the urging post 360 contacts the post 360a and presses against the post 360a, thereby bending the post 360a radially outward with respect to the dose vessel assembly 20. It is configured. The two posts 360, 360a may be configured to project relative to each other. Specifically, one post may be configured to project upward and the other post may project downward. The post 360a is typically located near the inner circumference of the dose disc assembly 20.

The post 360 is typically attached to or interlocked with a lever 320 that is accessible to the user. However, the post 360 may be adapted to move the post 360 within the elongated hole 362 and interlock with other mechanisms that urge the disc assembly 20 to the mouthpiece 10 m. As shown in FIG. 15B, the indexing frame 508 may be located below the gear 514 associated with the indexing mechanism 500. The rotary gear 514 may be held by mount 515 on the piercing frame member 300, as shown in FIG. 15C. Generally, the gear 514 is interlocked with the teeth 411 on the indexing post 410 (which can be part of the slope disc 400) and the gear teeth 504 on the disc assembly 20 (eg, the lower disc 40). .. When the indexing post 410 is rotated, the gear 514 is rotated so that the disc assembly 20 is indexed. The other gear teeth 502 (located near the bottom of the inhaler housing) can be interlocked with the indexing control arm 510 of the indexing frame 508, as shown in FIG. 14C. , It is possible to promote the rotation of the dose container assembly more accurately by a desired rotation amount.

With reference to FIG. 12A again, the arm 330 extends outward from the second ring member 310, as shown. The arm 330 comprises a proximal end 330a and a distal free end 330b attached to a second ring member 310. The distal free end 330b comprises a claw 331 extending from it. The claw 331 is adapted to engage the teeth 332 of the rack 334 attached to the piercing frame 300. The claw 331 allows the actuator mechanism 306 to be moved by the user only in one direction from the first position to the second position. The claw 331 prevents the actuator mechanism from moving in the opposite direction (that is, toward the first position) until the actuator mechanism 306 reaches the second position. When the actuator mechanism 306 reaches the second position, the claw 331 is disengaged from the teeth 332 of the rack 334, and the actuator mechanism 306 is free to return to the first position while the arm 330 moves on the rack 334. Is possible. The actuator mechanism 306 will return to its first position as a result of the user closing the cover 11 of the inhaler 10.

In some embodiments, when the claw 331 engages the teeth 332 of the rack 334 as the actuator mechanism 306 moves from the first position to the second position, the distal free end 330b of the arm 330 is thed. It will be urged inward toward the ring member 310 of 2. When the claw 331 is detached from the tooth 332, the distal free end 330b is offset outward. The distal free end 330b of the arm 330 has a tapered structure. As a result, when the free end 330b is offset outward, the tapered structure causes the free end 330b to slide along the outer wall 336 of the rack 334, thereby returning the actuator mechanism 306 to its first position. , The claw 331 cannot engage with any of the teeth 332. When the actuator mechanism 306 is in the first position, the tapered structure of the distal free end 330b of the arm 330 causes the claw 331 to re-engage with the teeth 332 of the rack 334, thereby causing the claw 331 to be the third of the actuator mechanism 306. It will prevent the opposite movement between the 1st position and the 2nd position.

Further referring to FIG. 12A, the reciprocating dual piercing mechanism 200 comprises an inner piercing member or a first piercing member 220a that is adjacent to and separated from each other and an outer piercing member or a second piercing member 220b. ing. The piercing members 220a and 220b are configured to reciprocate between the retracted position and the protruding piercing position independently of each other. The piercing members 220a, 220b are movably attached to a support structure 224 extending upward from the piercing frame 300, as shown. As shown, a pair of openings 340a, 340b are formed through the piercing frame surface 302. The openings 340a, 340b are arranged in line with the respective rows of the dough container 30c of the dough container assembly 20. During use, when the dose vessel assembly 20 is indexed, each dose vessel 30c in at least one row is positioned below the respective openings 340a, 340b, thereby causing the respective puncture members 220a, 220b. It is possible to pierce the upper and lower sealing layers 36, 37 of the dose container 30c.

An urging element 230, such as a torsion spring, is fixed to the piercing frame 300 and is in contact with the piercing members 220a, 220b, urging the piercing members 220a, 220b to the retracted position during operation. It is configured as follows. Although shown as a single urging element 230, two or more urging elements, such as two or more individual urging elements for each piercing member 220a, 220b, may be utilized. This structure of the piercing mechanism 200 can increase the flexibility of the design of the spring 230. For example, the spring 230 does not need to be arranged below the piercing members 220a, 220b, and may be arranged laterally or radially apart from the piercing members 220a, 220b. Therefore, it is possible to obtain a device in which the height requirement is relaxed as compared with the conventional inhaler device.

Each elongated puncture member 220a, 220b includes a distal puncture portion 221 (FIG. 10A) and a proximal puncture portion 222. In some embodiments, the distal puncture site 221 can be a corkscrew puncture tool. This corkscrew piercing tool is configured to pierce the sealants 36,37 of the dose vessel 30c by moving it vertically straight without rotating, as described with respect to FIGS. 19A and 19B below. There is. In some embodiments, the distal puncture site 221 can also be a grooved puncture tool configured to pierce the sealants 36, 37, as described with respect to FIGS. 18C-18F. According to embodiments of the present invention, various types of piercing tools and various piercing tool structures may be utilized without limitation.

As described below, in some embodiments, each puncture member 220a, 220b is used to occlude the opening 55 of the upper disk 50 of the inhaler 10 during and / or after drug release / inhalation. During the operation of the inhaler 10, it is partially retracted from the dose container 30c.

As shown in FIG. 12A, in some embodiments, the piercing frame 300 comprises a pair of anti-retract posts 350 that are facing each other. Each setback prevention post 350 in the figure comprises a tooth 350a extending inward in the radial direction at the free end of the post, as shown. The teeth 350a of each anti-retract post 350 are configured to engage the fastener 420 (FIG. 13A) of the slope disc 400 to prevent reverse rotation of the slope disc 400, as described below.

FIG. 12B is an upward perspective view of the piercing frame 300 for the inhaler 10 of FIG. 10B according to another embodiment of the present invention. In this figure, the slope disc 400 has been removed for ease of explanation and clarity. The piercing frame 300 shown in FIG. 12B does not include the pair of anti-retract posts 350 shown in FIG. 12A. Apart from that, the piercing frame 300 of FIG. 12B is substantially similar in structure and function to the piercing frame 300 of FIG. 12A.

With reference to FIG. 13A, a downward perspective view of the slope disc 400 for the inhaler 10 of FIG. 10A is shown. The slope disc 400 comprises a first face or side 402 (FIG. 11A) facing each other and a second face or side 404. The slope disc 400 also includes a set of first slope elements 406 and a set of second slope elements 408 extending outward from the second side 404. These slope elements 406,408 are staggered and concentric. The slope disc 400 also includes an indexing post 410 that extends outward from the center of the second side 404. In addition, the ring member 412 extends outward from the second side 404 between the set of second slope elements 408 and the indexing post 410.

The slope elements 406,408 typically have substantially the same structure, and each has a substantially curvilinear structure, as shown. The first slope element (outer slope element) 406 includes a first slope portion 406a, a flat portion 406b, a second slope portion 406c, and a shelf portion 406d, respectively. Similarly, the second slope element (inner slope element) 408 comprises a first slope 408a, a flat 408b, a second slope 408c, and a shelf 408d, respectively. In the set of the first slope element 406, the slope disc 400 is indicated by arrow A.₂Engage with the proximal end 222 of the outer puncture member 220b and move (push) the outer piercing member 220b between the retracted and protruding (piercing) positions when rotated in the direction indicated by. It is configured. In the set of the second slope element 408, the slope disc 400 is arrow A.₂Engage with the proximal end 222 of the medial puncture member 220a and move (push) the medial puncture member 220a between the retracted and protruding (piercing) positions when rotated in the direction indicated by. It is configured. The inner slope elements 408 are separated from each other with a distance of about 120 °. Similarly, the outer slope elements 406 are spaced apart from each other with a spacing of approximately 120 °.

The set of the first slope element 406 and the set of the second slope element 408 are A.₃They are angularly separated from each other by the angle indicated by. In some embodiments, angle A₃Should be between about 5 ° and 15 ° (5 ° to 15 °). In some embodiments, angle A₃Should be about 8 °. The indexing of the dose container assembly 20 (ie, the rotation of the dose container assembly 20 to position the dough container 30c containing the drug below the puncture members 220a, 220b) is A.₃Will be done within this angle of increase indicated by. That is, the indexing of the dose container assembly 20 is performed when none of the slope elements 406 and 408 are in contact with the respective piercing members 220a and 220b. Typically, if the puncture member is in the dough container 30c, the dough container assembly 20 cannot be properly indexed (rotated).

The ring member 412 extending outward from the side 404 of the slope disc comprises an outer surface 412a and an inner surface 412b, and an end portion 412c. The diameter of the ring member 412 and the diameter of the second ring member 310 (FIG. 12A) of the actuator mechanism 306 are substantially the same. Therefore, in some embodiments, within the inhaler 10, the end portion 412c of the ring member 412 of the slope disc is in contact with the outer ring member 310 of the actuator mechanism 306.

As shown in FIG. 13A, a plurality of step members 414 separated from each other extend inward in the radial direction from the inner surface 412b of the ring member. Each step member 414 includes an end 414a and a tapered portion 414b extending from the end 414a. Each end 414a of the step member 414 is configured to engage the claw 316 (FIG. 12A) of the free end 314b of the arc arm 314 of the actuator mechanism 306. The tapered portion 414b of each step member 414 allows the claw 316 to slide along the step member 414 and engage the end 414a. When the user moves the actuator mechanism 306 from the first position to the second position, the slope disc 400 is indicated by arrow A.₂Will rotate along the direction indicated by.

Hereinafter, the respective movements of the piercing members 220a and 220b by the slope elements 408 and 406 will be described based on the first slope element 406 and the outer piercing member 220b. Each of the first slope element 408 and the second slope element 406 is adapted to bring about the same motion with respect to the piercing members 220a, 220b. The actuator mechanism 306 is in the first position when the user opens the cover 11 of the inhaler 10 to the position shown in FIG. 1B. When the actuator mechanism 306 is in the first position, the proximal end 222 of the piercing member 220a is in contact with the shelf 408d of the slope element 408. The user moves the actuator mechanism 306 to move the slope disc 400 to arrow A.₂When rotated in the direction indicated by (ie, from the first position to the second position), the proximal end 222 of the piercing member 220a is no longer in contact with the shelf 408d, and the piercing member 220a , Will be completely retreated. Angle A₃During the rotation indicated by, the doze container assembly 20 will be indexed into the new doze container 30c by the rotation of the indexing post 410. Next, the first inclined portion 406a of the slope element 406 comes into contact with the proximal end 222 of the piercing member 220b, causing the piercing member 220b to protrude into the dose container 30c. When the actuator mechanism 306 is continuously moved, the flat portion 406b comes into contact with the proximal end 222 of the piercing member, and the piercing member 220b reaches the maximum depth in the dose container 30c. The continuous movement of the slope disc 400 causes the proximal end 222 of the piercing member to follow the second sloping portion 406c by the force of the spring 230, which causes the piercing member 220b to retract from the dose vessel 30c. ..

When the actuator mechanism reaches the second position, the proximal end 222 of the piercing member 220b contacts the shelf 406d, which partially holds the piercing member 220b within the opening 55 of the upper airway disc 50. As described above with respect to FIGS. 7A-7C, the drug will be prevented from falling out of the opened dose container 30c prior to inhalation by the user. The proximal end 222 of the puncture member is held in contact with the shelf 406d of the first slope element 406 even when the cover 11 of the inhaler 10 is returned to the closed position.

The indexing post 410 includes a plurality of spaced ribs 411 extending radially outward from the indexing post, as shown in FIG. 13A. As described with respect to FIGS. 14A, 15A, the ribs 411 of these indexing posts engage the idle gear 514 (FIG. 14A) operably associated with the indexing mechanism 500 to rotate the idle gear 514. Is configured in. The slope disc 400 is particularly advantageous because the slope elements 406,408 that provide piercing and the indexing post 410 that provides indexing of the dose vessel assembly are located on the same component of the inhaler. That is, the timing of piercing the dose container and indexing the dose container assembly will always be maintained appropriately.

The ring member 412 of the slope disc shown is provided with a plurality of anti-retract fasteners 420 extending circumferentially apart from its outer surface 412a. Each fastener 420 comprises a recess 420a configured to engage the teeth 350a of the anti-retract post 350 on the puncture frame. This engagement of the teeth 350a of the anti-retract post into the recess 420a of the fastener causes the slope disc 400 to point to arrow A.₂Rotation in the direction opposite to the direction indicated by will be prevented (ie, the slope disc may rotate in the wrong direction, especially when the claw 316 is flexing over the taper 414b. Will be blocked).

With reference to FIG. 13B, a downward perspective view of the slope disc 400 for the inhaler 10 of FIG. 10B is shown. The slope disc 400 is substantially similar in structure and function to the slope disc 400 of inhaler 10 of FIG. 10A. The slope disc 400 comprises a first face or side 402 (FIG. 13C) and a second face or side 404 facing each other, as well as a set of first slope elements 406 and a set of second slope elements 408. It has. These slope elements 406,408 are in a staggered concentric relationship, as described above with respect to FIG. 13A, and extend outward from the second side 404. However, the set of the first slope element 406 and the set of the second slope element 408 of FIG. 13B have a structure somewhat different from the set of the first slope element 406 and the set of the second slope element 408 of FIG. 13A. Have. The first slope element (outer slope element) 406 includes a first slope element 406a, a flat portion 406b, and a shelf portion 406d, respectively, similar to the slope element 406 of FIG. 13A. However, the second inclined portion 406c in FIG. 13B is inclined considerably sharper than the second inclined portion 406c in FIG. 13A. This sharp slope will facilitate a faster movement of the piercing member 220b from the protruding (piercing) position to the partially retracted position. In addition, the slope element 406 of FIG. 13B includes a ridge 406e configured to prevent the puncture member 220b from falling off the shelf 406d.

Similarly, the second slope element (inner slope element) 408 of FIG. 13B comprises a first slope element 408a, a flat portion 408b, and a shelf portion 408d, respectively, similar to the slope element 408 of FIG. 13A. ing. However, the second inclined portion 408c in FIG. 13B is inclined considerably sharper than the second inclined portion 408c in FIG. 13A. This sharper slope will facilitate a faster movement of the piercing member 220a from the protruding (piercing) position to the partially retracted position. In addition, the slope element 408 of FIG. 13B includes a ridge 408e configured to prevent the puncture member 220a from falling off the shelf 408d.

The indexing post 410 includes a plurality of spaced ribs 411 extending radially outward from the indexing post, as shown in FIG. 13B. These ribs 411 of the indexing post are configured to engage a pair of idle gears 514 (FIG. 14C) operably associated with the indexing mechanism 500 to rotate the idle gears 514. ..

The slope disc 400 shown in FIG. 13B includes an alignment opening 430. The alignment opening 430 penetrates the slope disc 400 from the first side 402 to the second side 404. These openings 430 can facilitate the automatic assembly and alignment of the slope disc 400 within the inhaler 10. In addition, since the inhaler 10 of FIG. 10B does not have a setback prevention post 350 as shown in FIG. 12A, the lamp disk 400 of FIG. 13B has a plurality of extending from the outer surface 412a of the ring member 412. Not equipped with anti-retract fasteners.

FIG. 13C is an upward perspective view of the slope disc 400 of FIG. 13B, showing the teeth 400t on the first side 402 of the slope disc 400. The ratchet arm 12a of the upper housing portion 12 of the inhaler 10 of FIG. 10B engages the teeth 400t and engages with the slope disc 400 in the same manner as the functions of the anti-retract post 350 and the fastener 420 of FIGS. 12A and 13A. It is configured to prevent reverse rotation.

FIG. 14A is a downward perspective view showing a dose disc indexing mechanism 500, in which a part of the inhaler of FIG. 10A is cut off. The lower disc 40 of the dose vessel assembly 20 comprises a set of first inner peripheral gear teeth 502 and a set of second inner peripheral gear teeth 504 that are vertically stepped, as shown. There is. The lower disc 40 also includes a spiral groove 506 extending circumferentially around the disc 40, as shown. As shown in FIG. 14A, the indexing frame 508 includes a plurality of arcuate indexing arms 510 that are separated from each other in the circumferential direction. Each indexing arm 510 comprises a free end 512 having teeth 512a. The indexing frame 508 is positioned relative to the lower disk 40 such that the teeth 512a of the free ends 512 of each indexing arm 510 engage the set of first inner peripheral teeth 502. The indexing arm 510 functions as a positioning member that ensures accurate positioning of the dose container 30c with respect to the openings 340a and 340b of the piercing frame from which the piercing members 220a and 220b will be projected.

FIG. 14C is a downward perspective view showing a dose disk indexing mechanism 500, in which a part of the inhaler of FIG. 10B is cut off. The indexing mechanism 500 is substantially similar in structure and function to the indexing mechanism 500 of the inhaler 10 of FIG. 10A, except that a pair of idle gears 514 are used. These idle gears 514 are engaged with the ribs 411 of the indexing post and are rotated by the ribs 411.

FIG. 14D is an enlarged plan view of a portion of the inhaler of FIG. 14C showing a dose window 520 centered on a dose mark indicating that 60 doses remain. FIG. 14E is an enlarged plan view of a portion of the inhaler of FIG. 14C showing a dose window 520 centered on a dose mark indicating that no dose remains. The dose window 520 comprises a post extending from it, which engages the spiral groove 506 of the lower disc 40. Grooves 506 and posts are configured to hold the dose window 520 directly above the dose mark on the lower disc surface 40a when the dose vessel assembly is indexed, as described below.

Referring to FIG. 15A, the indexing frame 508 of the inhaler 10 of FIG. 10A is fixed to the lower housing portion 13. The idle gear 514 is rotatably attached to the indexing frame 508 and is positioned so that the teeth 516 of the idle gear 514 engage the pair of second inner peripheral teeth 504 of the lower disc 40. .. A centrally located post 518 extends upward from the lower housing portion 13 and is configured to accommodate the indexing post 410 of the slope disc 400. The post 518 functions as the axis of rotation for the slope disc 400. The indexing post rib 411 is configured to engage the teeth 516 of the idle gear 514 when the post 518 is inserted into the indexing post 410.

When the user moves the actuator mechanism 306 from the first position to the second position by the user lever 320 in order to index the dose container assembly 20 by a predetermined amount, the slope disk 400 rotates. The rotation of the slope disc 400 causes the indexing post 410 to rotate, which in turn causes the idle gear 514 to rotate. This rotation of the idle gear 514 causes the dose vessel assembly to rotate by a predetermined amount through the set of second inner peripheral teeth 504 of the lower disc 40. According to some embodiments of the present invention, the actuator mechanism 306 is configured to rotate by 60 °. This corresponds to a 6 ° rotation of the dose vessel assembly 20 (ie, 6 ° between the dose vessel in one row and the adjacent dose vessel in the other row).

The indexing mechanism 500 according to the embodiment of the present invention does not require a dose container assembly having outer gear teeth. Therefore, the dose container assembly utilized can be made smaller.

Referring again to FIG. 14A, the inhaler 10 includes a dose window 520 located above the bottom surface 40a of the lower disk 40. The dose window 520 is a component independent of the lower housing portion 13 and is configured to move with respect to the lower housing portion 13. In some embodiments, the dose window 520 may be slidably attached to the lower housing portion 13. The dose window 520 comprises an opening 522 through which the user of the inhaler can see the dose mark 524 (FIG. 14B) on the lower disc surface 40a. The dose mark 524 indicates the number of doses remaining in the inhaler 10. Alternatively, in some embodiments, the dose mark 524 may be adapted to indicate the number of doses already used by the user of the inhaler 10. In some embodiments, the opening 522 is provided with a transparent cover or lens to prevent the entry of foreign matter and / or to facilitate observation of the dose mark 524. In some embodiments, a magnifying lens may be utilized to facilitate the user's observation of the dose mark 524.

The dose window 520 also has a post 526 extending from it. The post 526 engages the spiral groove 506 of the lower disc 40. Grooves 506 and posts 526 are configured to maintain the opening 522 directly above the dose mark on the lower disc surface 40a when the dose vessel assembly is indexed. As shown in FIG. 14B, the dose container assembly comprises 60 doses, with the dose mark 524 containing a number from 0 to 60 (0-60). Due to the geometry of the dose vessel assembly, the dose vessel 30c is placed every 6 ° around the dose vessel assembly. Therefore, the numbers "0" and "60" overlap each other. Appropriately indicate the 60 doses remaining when the inhaler is first used, and properly indicate the zero (0) doses remaining when all of the doses in the inhaler are used. To indicate, the dose mark 524 is spirally displayed on the lower disk surface 40a. The spiral groove 506 on the lower disc surface 40a corresponds to the spiral shape of the dose mark 524. In this way, when the dose container assembly 20 is indexed, the post 526 engaged in the spiral groove 506 will always maintain the window opening 522 centered on the dose mark 524.

Post 526 also has other important features. When all of the doses in the inhaler 10 have been used, the posts are adapted to abut the spiral groove 506 so that the dose container assembly 20 is not further indexed. Therefore, the post 526 will function as a "end of life" stopper for the inhaler 10.

Referring to FIGS. 15B and 15C, the indexing frame 508 of the inhaler 10 of FIG. 10B is fixed to the puncture frame 300. A pair of idle gears 514 are rotatably attached to the piercing frame and are positioned so that the teeth 516 of the idle gear 514 engage the pair of second inner peripheral teeth 504 of the lower disc 40. There is. These idle gears 514 engage with the ribs 411 of the indexing post and are rotated by the ribs 411. When the user moves the actuator mechanism 306 from the first position to the second position by the user lever 320 in order to index the dose container assembly 20 by a predetermined amount, the slope disk 400 rotates. The rotation of the slope disc 400 causes the indexing post 410 to rotate, which in turn causes the idle gear 514 to rotate. This rotation of the idle gear 514 causes the dose vessel assembly to rotate by a predetermined amount through the set of second inner peripheral teeth 504 of the lower disc 40. FIG. 15C is an exploded side perspective view of the components of the indexing mechanism of the inhaler of FIG. 10B.

With reference to FIGS. 17A to 17C, the operation of the puncture mechanism 200 of the inhaler 10 of FIG. 10A is shown. In FIG. 17A, the user has the cover 11 open and the actuator mechanism is in the first position. The proximal end 222 of the medial puncture member 220a is located on the shelf 408d of the slope element 408. Therefore, the inner piercing member 220a is partially retracted from the dose container 30c. In FIGS. 17A-17E, the slope disc 400 is shown as a dashed line for ease and clarity of description.

In FIG. 17B, the user points the lever 320 of the actuator mechanism 306 in the second position orientation (A).₂Moving in the direction indicated by). The claw 316 of each arc arm 314 of the actuator mechanism 306 is engaged with the end 414a of each step member 414 of the slope disc 400. Therefore, due to the movement of the actuator mechanism 306 (due to the lever 320), the slope disc 400 becomes arrow A.₂Will rotate along the direction indicated by. At the operational stage shown in FIG. 17B, the inner puncture member 220a is fully retracted and the first tilt portion 406a of the slope element 406 begins to engage the proximal end 222 of the outer puncture member 220b. There is. The rotation of the slope disc 400 causes the indexing post to rotate, rotating the idle gear 514, which causes the dose vessel assembly to index into the next dose vessel 30c. Further, at the operation stage shown in FIG. 17B, the claw 331 of the arm 330 is engaged with the teeth 332 of the rack 334, and the reverse movement of the actuator mechanism 306 is prevented.

In FIG. 17C, the user continuously moves the lever 320 of the actuator mechanism 306 toward the second position, thereby continuously rotating the slope disc 400. The proximal end 222 of the outer puncture member 220b engages the flat portion 406b of the slope element 406, which causes the outer puncture member 220b to project completely into the doze vessel 30c.

In FIG. 17D, the user has completely moved the lever 320 of the actuator mechanism 306 to the second position. As shown, the end 318b of the arcuate body 318 of the actuator mechanism 306 is in contact with the blocking member 324. In addition, the teeth 350a of each retract prevention post 350 are engaged with the respective fasteners 420 of the ring member 412 of the slope disc 400 to prevent reverse rotation of the slope disc 400. FIG. 17D shows the dosing position. At this point, the user will inhale the dose from the pierced dose container 30c. The proximal end 222 of the outer puncture member 220b engages the shelf 406d of the slope element 405.

Also, in FIG. 17D, the claw 331 is detached from the tooth 332 and the distal free end 330b of the arm is offset outward towards the relaxation position. When the actuator mechanism 306 returns to its first position (FIG. 17E), the claw 331 engages with any of the teeth 332 because the arm free end 330b is configured to slide along the outer wall 336 of the rack 334. It will not fit.

In FIG. 17E, the user closes the cover 11, resulting in the actuator mechanism 306 returning to its first position. The slope disc 400 does not move while the actuator mechanism 306 is returning to its first position. The tapered structure of the distal free end 330b of the arm 330 prepares the claw 331 to engage the teeth 332 of the rack 334 again when the actuator mechanism 306 reaches the first position.

The piercing frame 300, the actuator mechanism 306, the slope disc 400, the piercing mechanism 200, and the various components associated with them are said to be made of various materials, such as, but not limited to, polymeric materials. Good. Since the two piercing members 220a, 220b are utilized, the wear of each piercing member 220a, 220b (eg, caused by lactose in the drug powder in the dose container 30c) will be significantly reduced. Therefore, for the piercing members 220a and 220b, it is possible to use a material that is cheaper than the material required when only a single piercing member is used.

In addition, since the actuator mechanism 306 and the slope disc 400 are separate parts, different materials can be used for each of these parts. For example, a decorative material may be used for the user lever 320 of the actuator mechanism 306, and a non-decorative material may be used for the slope disc 400 which is invisible to the user of the inhaler 10. Good.

18A-18C are upper cut views of the inhaler 10 of FIG. 10B, showing exemplary operating procedures for the inhaler according to some embodiments of the present invention. In this figure, a layer or part of a member / disc is seen through for clarity. In FIG. 18A, as described above, the user moves the lever 320 of the actuator mechanism 306 from the first position to the second position (A).₂Moving in the direction indicated by). The claw 316 of each arc arm 314 of the actuator mechanism 306 is engaged with the end 414a of each step member 414 of the slope disc 400. Therefore, due to the movement of the actuator mechanism 306 (via the lever 320), the slope disc 400 is directed by arrow A.₂Will rotate along the direction indicated by. At the operational stage shown in FIG. 18A, the medial puncture member 220a is retracted and the first tilt portion 408a of the slope element 408 begins to engage the proximal end 222 of the medial puncture member 220a. The rotation of the slope disc 400 causes the indexing post 410 to rotate, resulting in a pair of idle gears 514 (FIG. 14C), which causes the dose vessel assembly to index into the next dose vessel 30c.

In FIG. 18B, the user continuously moves the lever 320 of the actuator mechanism 306 toward the second position, thereby continuously rotating the slope disc 400. The proximal end 222 of the medial puncture member 220a engages the flat portion 408b of the slope element 408, which causes the medial puncture member 220a to project completely into the dose vessel 30c. In FIG. 18C, the user has moved the lever 320 of the actuator mechanism 306 completely to the second position. The proximal end 222 of the medial puncture member 220a engages the shelf 408d of the slope element 408. Also, during the operating phase shown in FIG. 18A, the ratchet arm 12a of the upper housing 12 cooperates with the teeth 400t on the first side 402 of the slope disc 400 to prevent the slope disc 400 from moving in the opposite direction. ing.

FIG. 19A shows an embodiment of the piercing mechanism 200 having a corkscrew piercing member 220. During operation, the corkscrew piercing member 220 typically does not rotate and moves straight up and down in the vertical direction, giving the sealing layers 36,37 the desired opening shape (eg, circular shape). There is. In other embodiments, the corkscrew puncture member 220 may be adapted to project and / or rotate during administration. In the illustrated embodiment, the corkscrew piercing member 220 is retained in the lower passage 41 and attached to the corkscrew piercing member 220 together while the dry powder is being fed into the airflow passage. The opening 30a is closed by the elastic member 120 that moves up and down. The piercing member 220 is designed to perform two operating stages, namely a sufficient ascending stage (for indexing) and a sufficient descending stage. The foremost portion of the corkscrew piercing member 220 can have a shaped tip that provides the sealant (eg, foil) with the desired cutting shape. In some embodiments, the corkscrew piercing member 220 cuts out a shape having ears on the sealants 36, 37 and then bends the ears downward to release dry powder. Retaining the corkscrew piercing member 220 in passage 41 during administration allows improved aerodynamic turbulence, shear turbulence, or impact turbulence to be introduced into the dry powder. The elastic member 120 is said to be composed of a foam block or other elastic member 120 (eg, a hard or rigid member urged by a spring) that can be used to seal or close the opening 30a of the disc 30. Good.

FIG. 19B shows a similar corkscrew piercing member 220 used with a disc assembly 20 having both an upper airway disc 50 and a lower airway disc 40. Elastic and / or flexible members 200p, such as polymer plugs and / or elastomer plugs or foam plugs, can be used to occlude or seal the opening 55 of the airway disc. The member 200p having such elasticity and / or flexibility may be used together with other types of piercing members (eg, solid piercing members, grooved members, etc.).

19C and 19D show a piercing mechanism 200 with a grooved solid piercing member 220. The groove may have a straight groove shape, or may have a twisted or partially twisted portion along its length. In the latter case, for example, the maximum and minimum values of the lobe may change axially along the length of the groove. Grooves have multiple lobes, typically 3 or 4 lobes, eg, 3 lobes as shown in Figures 19C, 19D, or 4 lobes as shown in Figure 19F. Can have a cross section to include. The grooved structure is such that only a partial anterior length is projected, as shown in FIG. 19E, with this partial anterior length located within the opening 55. It may be integrated into a constant diameter area to facilitate closure or sealing of the opening. In other embodiments, the structure of the solid or grooved piercing tool may be integrated with a cap or plug 200p that covers and / or is located within the opening 55. In some embodiments, a twisted grooved puncture member 220 is retained in the inferior disc 40 during administration, which allows it to promote turbulence and / or impact in the airways. There is.

FIG. 19D shows that the grooved piercing member 220 can form a round hole by rotating when piercing a foil or other sealing material, or may be projected straight without rotation. There is. In other embodiments, the grooved piercing tool 220 may be adapted to pierce one or more sealing layers 36,37 by projecting or advancing without rotation. In Figure 19E, the grooved piercing tool 220'has a length of "L".₁It has a grooved front part 220f with "", and this grooved front part 220f has a length of "L".₂It is shown that it is integrated with the solid portion 112 having a substantially circular cross section having a. L₁Is typically L₂Is longer than. Length L₁With the solid portion engaged to the airway disc opening 55, the grooved anterior portion 220f is held in the opening 30a of the dose vessel and / or at the same time in the lower sealant 37. It can be long enough (typically long enough to be held just below the lower sealant or directly or slightly above or below the underside of the disc 30).

The inhaler 10 can have a body with a relatively small "pocket-sized" structure that is portable. In some embodiments, the inhaler body is less than about 115 mm (about 4.5 inches), typically less than about 89 mm (about 3.5 inches) wide / length, and less than about 51 mm (about 2 inches), Typically, it is possible to have a thickness / depth of less than about 38 mm (about 1.5 inches). The inhaler body can also be configured so that the main surfaces facing each other are substantially flat so that they can be easily held in the pocket.

The inhaler may include circuits that can control some operations of the inhaler 10. The inhaler 10 may include a computer port (not shown). This port may be, for example, an RS232 port, infrared data communication (IrDA), or universal serial bus (USB). These are used to download or upload selected data between a computer application such as a clinician or other site or a remote computer and an inhaler. The inhaler 10 is configured to be able to communicate with the clinician or pharmacy and / or patient compliance for reordering the drug via a wired or wireless (one-way or two-way) communication link. You may. The inhaler 10 may include a communication port (not shown) for a second peripheral device. The inhaler 10 may be capable of communicating via the internet, telephone, mobile phone, or other electronic communication putrocol.

In some embodiments, the circuit may include computer program code and / or computer applications. These, as mentioned above, communicate additional data to the user (optionally the display) and / or to other remote devices (the term "remote" is used. During normal inhalation use, it refers to communication with devices that are present in the area but are usually not connected).

In some embodiments, the circuit may be adapted to communicate with a vibrating device (not shown). The vibrating device may be any suitable vibrating mechanism. The vibrating device may be configured to vibrate the dry powder in the airflow path. In some embodiments, the vibrating device can include a transducer configured to vibrate one or more open cartridges holding dry powder. Examples of vibrating devices are, but are not limited to, (a) super-with an audible wavelength or higher or less that can be used to momentarily apply a non-linear pressure signal to the dry powder. Sound waves or other acoustic or sound sources, (b) electrical or mechanical vibrations of the walls (side walls, ceilings, and / or floors) of the suction channel, such as magnetically induced vibrations (using electromagnets or permanent magnets) and / Or deflection, (c) solenoids, piezoelectrically actuated parts, etc., (d) one or more of oscillating or pulsating gases (airflows) that change one or more of the volumetric flow, linear velocity, and / or pressure. Be done. Examples of mechanical and / or electromechanical vibrating devices are described in US Pat. Nos. 5,727,607, 5,909,829, and 5,947,169. These contents shall be included here by reference, as if all were cited. A combination of various vibration mechanisms may be used.

In some embodiments, an example of a vibrating device is a small transducer with part number QMB-105PX commercially available from Star Micronics (Shizuoka). This transducer has a resonance frequency in the range of about 400-600 Hz.

In some embodiments, the inhaler 10 may include a visible sign (blinking light, "error" indication, or visible warning) and / or the dose is properly (and / or inappropriate) from the inhaler. It may be configured to provide an audible warning to the user that it has been inhaled or released. For example, some dry powder doses may have their dimensions adjusted to make it difficult for the user to know the inhalation of the drug (usually the doses are aerosolized, almost or completely tasteless and / Or it will enter the body without touching it). Therefore, a sensor (not shown) may be configured to communicate with the flow path of the inhaler and communicate with a digital signal processor or microcomputer located inside or outside the inhaler. .. During operation, the sensor is configured to detect selected parameters, such as weight differences, density of outlet aerosol components, etc., thereby confirming that the dose has been released. Good.

The sealed doze container 30c has a water vapor transfer coefficient of about 1.0 g / 100 inches.²Less than 24 hours, typically about 0.6g / 100inch²It is less than 24 hours and can be configured such that the oxygen transfer coefficient is suitable for the dry powder held in the dose vessel. Doze vessel assemblies 20,20'can be configured to have a stable shelf life of about 1-5 years, typically about 4 years.

Doze container 30c is about 24mm³Less than, typically 5mm ~ 15mm³It is possible to have a volume (before filling and sealing) between. The bulk density of the powder is about 1 g / cm³And the nominal density of the powder when filled (as a reference) is about 0.5 g / cm³It is possible to The maximum compression of the drug by filling and sealing the dose container 30c can be less than about 5%, typically less than about 2%. Maximum heating of the drug during filling and sealing should be maintained at the desired level so as not to adversely affect the effectiveness of the drug or formulation.

FIG. 20 shows a substantially U-shaped air path provided by the disk assembly 20 (eg, an upper disk passage 51 and a lower disk passage 41 extending radially across the disk body. Both long sides of the "U-shape" are defined). As shown, in this embodiment, the outer circumference of the disk assembly 20 has both an outlet and an inlet for the airflow path 10f. The "U-shaped" flow path (or, in some embodiments, a partial "U-shaped" flow path if one of the airflow discs 40,50 is used) is the deagglomeration of the powder. It can function as a vessel. As the dry powder particles 10d exit the dose vessel 30c, they collide with the opposing walls of the airway disc passage 51, resulting in sufficient force to deagglomerate the drug powder.

FIG. 20 also shows an example of the orbital 10d of dry powder particles associated with the airflow associated with the intake airflow path 10f. After the dry powder exits the doze vessel 30c into the airflow path 10f, the airflow and small powder particles in the air (10f) can rotate about 90 °, while the heavy dry powder (10d) is in the upper airflow disc passage. It will bounce off the inner wall 51w of 51. The angle of this bounce gradually decreases, and the heavy dry powder eventually straightens out of the mouthpiece 10m. The collision of heavy dry powder with the wall 51w will promote the deagglomeration of the dry powder. Referring again to FIG. 5A, in an embodiment in which the dough containers 30 are arranged in two rows, the aisle 51 is located in the aisle 51 depending on whether the doze containers 30 are arranged in the inner row or the outer row. The lengths are different.

In some specific embodiments, the airway passages 41,51 include alternating short and long passages (see, eg, FIG. 5A). Long passages (in these passages, the dose container is located on the inner circumference if the outlet is located on the outer circumference, and the dose container is located on the outer circumference if the outlet is located on the inner circumference. The length can be between about 5 mm and about 15 mm, typically about 10 mm. The length of the short passage can be between about 3-10 mm, typically about 5 mm (eg, about 40-70% of the length of the long passage). The depth (vertical height) of each passage 41,51 can be the same and may be different in some embodiments. An exemplary depth of passages 41,51 is between about 1 mm and about 3 mm, typically about 2 mm, but other depths may be used.

Some embodiments are particularly suitable for administering the drug to a respiratory patient, a diabetic patient, a cystic fibrosis patient, or a patient treating distress. This inhaler may be used to administer anesthetics, hormones, and / or fertility drugs.

The above description is merely an example of the present invention and should not be construed as limiting the present invention. Although some exemplary embodiments of the invention have been described, those skilled in the art can make many modifications in the exemplary embodiments without substantially departing from the suggestions and advantages of the invention. You will easily understand that there is. Therefore, all such modifications are intended to be included within the scope of the invention described in the claims. The present invention is defined by the following claims, and the equivalents of the claims should also be included in the claims.