JP4976514B2 - Powder flow rate control device and control method - Google Patents

Description

  The present invention relates to controlling the flowability of a powder, for example, by controlling the flow rate of the powder in a package filling process.

BACKGROUND The need for effective treatments for patients has led to the development of various technologies for delivering pharmaceutical formulations to patients. One conventional technique is a technique for orally delivering a pharmaceutical preparation in the form of a pill or capsule. Inhalation drug delivery in which an aerosolized pharmaceutical formulation is orally or nasally inhaled to deliver the pharmaceutical formulation to the patient's respiratory tract has proven to be an effective method of delivery. In one inhalation technique, the pharmaceutical formulation is delivered deep into the patient's lungs where it is absorbed into the bloodstream. In another inhalation technique, the pharmaceutical formulation is delivered to a target area in the respiratory tract and provides local treatment to the target area. There are also many types of inhalation devices, including devices that aerosolize dry powder pharmaceutical formulations.

  Pharmaceutical formulations are often packaged for ease of use by the user. For example, a single dose of a pharmaceutical formulation or a single dose of a pharmaceutical formulation is typically stored between layers of a multi-layer package called a blister or blister pack. Typically, a recess is formed in the lower layer, the pharmaceutical formulation is disposed in the recess, and an upper layer is placed over the lower layer to retain the pharmaceutical formulation in the recess. These layers are sealed by heating and / or pressing. Alternatively, a single dose of the pharmaceutical formulation is stored in a capsule for swallowing or aerosolizing the pharmaceutical formulation. Other packages such as bottles and vials are also used to store pharmaceutical formulations.

  By the way, it is often difficult to efficiently fill a package with a pharmaceutical preparation. For example, it is difficult to fully fluidize the powder during the powder filling process and / or to maintain the fluidity of the powder consistently. If the powder is not well controlled, the package will not fill consistently. For example, the fill volume varies between packages, which can adversely affect the dose delivered to the patient as a unit dose package, or can be packaged in multiple dose packages. Too little or too little. Furthermore, the powder flow rate is inconsistent during the filling process, which can lead to various filling characteristics of the powder in the package.

  Therefore, it is desirable to be able to control the flow rate of powder, particularly the flow rate of powder pharmaceutical preparations. In particular, it is desirable to be able to control the flow rate of the powdered pharmaceutical formulation so that the package is effectively and consistently filled with the pharmaceutical formulation. It is also desired to control the flow rate of the pharmaceutical preparation so as to reduce the adverse effect on the pharmaceutical preparation.

Summary The present invention satisfies these needs. Also, in one aspect of the invention, the powder flow rate from the hopper is controlled in an improved manner.

  In yet another aspect of the invention, the chamber filling device comprises a hopper that contains the powdered pharmaceutical formulation and has an outlet. The apparatus also includes an agitating member capable of agitating the medium in the hopper and sufficiently stirring the medium to control the flow rate of the powder passing through the outlet. The chamber is filled with powder flowing into the chamber through the outlet.

  In yet another aspect of the invention, the chamber filling device comprises a hopper that contains the powdered pharmaceutical formulation and has an outlet. The apparatus also includes an oscillating member disposed in, on or near the hopper and spaced from the powder in the hopper and capable of fluidizing the powder in the hopper. The chamber is filled with powder that flows into the chamber through the outlet.

  In yet another aspect of the present invention, a method of filling a chamber comprises providing a powder of a pharmaceutical preparation in a hopper, stirring a medium in the hopper, fluidizing the powder, and the powder Feeding the gas through the outlet to the chamber.

  In still another aspect of the present invention, a method of filling a chamber includes providing a powder of a pharmaceutical preparation, vibrating a member disposed away from the powder, and fluidizing the powder. Feeding the powder through an outlet to a chamber.

  In still another aspect of the present invention, the pharmaceutical package comprises a step of providing a container, a step of filling the container with a powdered pharmaceutical preparation fluidized by a fluidizing member disposed away from the powder, Sealing the container and holding the powdered pharmaceutical preparation in the container.

Drawings described, the scope of the appended claims, and with reference to the following drawings illustrating an example of a feature of the present invention will feature of the present invention, aspects, and advantages can be better understood. However, in the present invention, each feature is used in a general form and not only in connection with a specific drawing, and the present invention includes a combination of these features.

FIG. 1 is a schematic cross-sectional side view of the powder filling apparatus of the present invention. 2A-2C are schematic side cross-sectional views of various containers filled using the powder filling apparatus of the present invention. FIG. 3 is a schematic cross-sectional side view of another embodiment of a powder filling apparatus. 4A and 4B are schematic side sectional views showing the movement of the powder filling device. FIG. 5 is a schematic cross-sectional side view of another embodiment of a powder filling apparatus. 6A and 6B are schematic side cross-sectional views of the powder filling apparatus of FIG. 5 during the powder filling process. FIG. 7 is a schematic front sectional view of a multi-chamber type powder filling apparatus. 8A and 8B are schematic front cross-sectional views of another embodiment of a multi-chamber powder filling apparatus. FIG. 9 is a schematic cut-away view showing the inside of the embodiment of the powder filling apparatus. FIG. 10 is a schematic side cross-sectional view of a powder filling apparatus provided with a mass powder container. FIG. 11 is a more detailed schematic cross-sectional side view of a powder filling apparatus with a bulk powder container.

Described the invention, for example, by controlling the flow rate of powder into the package filling process relates to controlling the flow rate of the powder. Although this process is described in the context of packaging a powder pharmaceutical formulation, the present invention can be used for other processes and is not limited to the examples described herein.

  FIG. 1 schematically shows a powder filling apparatus 100 of the present invention. The powder filling device 100 has a hopper 105 with a reservoir 110 that can contain a powder 115 such as a powder pharmaceutical formulation. The hopper 105 is appropriately sized and shaped and has an outlet 120 through which the fluidized powder flows. A chamber 125 is disposed near the outlet 120 so that the powder flowing through the outlet 120 flows into the chamber 125 and fills the chamber 125.

  The powder fluidizer 130 is disposed in the hopper 105, on the hopper, or near the hopper. The powder fluidizer 130 includes a stirring member 135 that provides stirring in the hopper 105. In one embodiment, the agitation member 135 is actuated by the actuator 140 to provide agitation in the hopper 105 and control the flow rate of the powder 115 in the hopper 105. For example, the agitating member 135 agitates a medium 145 such as air or other gas in the hopper 105, and the agitated medium 145 fluidizes the powder 115. Accordingly, at least a part of the stirring member 135 is disposed away from the powder 115 by the medium 145.

  The powder fluidizer 130 is used to control the powder filling process in the hopper 105. In one embodiment, the powder fluidizer 130 operates continuously or at short intervals, to keep the powder 115 fluidized at all times. In this embodiment, the powder 115 flows through the outlet 120 until the hopper 105 is empty or until the chamber 125 is filled. In another embodiment, the powder fluidizer 130 controls the amount of powder 115 flowing into the chamber 125 through the outlet 120 of the hopper 105, or alternatively, controlling the timing of the powder 115 flow. To do. For example, the outlet 120 of the hopper 105 is small enough that unstirred powder 115 does not flow through the outlet 120 or does not flow continuously through the outlet 120. When the powder 115 is required to flow into the chamber 125, the actuator 140 causes the stirring member 135 to stir the medium 145, thereby fluidizing the powder 115, and the powder 115 passes through the outlet 120 into the chamber 125. To be able to flow into. When the chamber 125 is fully filled, the actuator 140 may stop agitation or reduce the degree of agitation, thereby reducing the amount of powder 115 flowing through the outlet 120, e.g. Stop the flow of powder through.

  In one embodiment, the powder fluidizer 130 provides agitation within the hopper 105, and the agitation includes vibration 150. The agitation member 135 has an object that can vibrate in, on or near the hopper 105, such as a membrane 155, which when driven by the actuator 140, vibrates to create vibration. be able to. The vibration film 155 stirs the medium 145. For example, as the membrane 155 moves downward, the portion of the media 145 immediately in front of it is compressed, the pressure increases slightly, and then the pressure decreases as the membrane returns beyond its rest position. As such processing continues, the membrane 155 emits one or more waves that alternately increase or decrease in pressure. The wave contacts the powder 115 and the resulting impact is sufficient to at least temporarily fluidize the powder 115.

  The frequency of vibration 150 is selected so that a particular powder 115 can be fluidized and / or best suited for a particular filling process. In certain embodiments, vibration 150 is in the audible range. In another embodiment, the membrane 155 is vibrated at a frequency in the non-audible range to alleviate operator discomfort. Such vibration may be any frequency or a plurality of frequencies as long as the powder 115 is fluidized in a desired form or the flow rate of the powder 115 is controlled. For example, in the embodiment shown in FIG. 1, the membrane 155 is about 10 Hz to about 1000 Hz, more preferably about 90 Hz to about 500 Hz, more preferably about 100 Hz to about 200 Hz, and most preferably about Vibrates at one or more frequencies including a frequency of 120 Hz. In some embodiments, the frequency is selectable. A particularly desirable frequency for a particular configuration and / or powder, for example, a frequency determined through experimentation and analysis as causing resonance in the hopper 105 is selected through experimentation and modeling.

  The chamber 125 has an opening 160 that can be positioned corresponding to the outlet 120 of the hopper 105 so that powder flowing from the hopper 105 through the outlet 120 can be received. For example, in an embodiment such as that shown in FIG. 1, to prevent excessive amounts of powder 115 from being trapped between the hopper 105 and the member 165 having or supporting the chamber 125. In addition, the opening 160 of the chamber 125 is substantially the same shape and the same size as the outlet 120. As shown in the embodiment of FIG. 1, the hopper 105 has side walls 170 that converge toward each other to provide the powder 115 with a flow path that converges toward the outlet 120. The converging flow paths can increase the capacity of the hopper 105 that can be accommodated. In another embodiment, the size of the chamber opening 160 and the size of the outlet 120 may be different. For example, if it is desired to fill a relatively large chamber with a precisely controlled amount of powder 115, or it would be desirable to provide a mechanism for accurately positioning the chamber 125 under the outlet 120. If not, the outlet 120 may be smaller than the opening 160. Alternatively, if it is desired to use a hopper 105 to fill various sized chambers 125, or the loss of powder 115 into the space between the hopper 105 and member 165 is not critical. In some cases, the opening 160 may be smaller than the outlet 120.

  Chamber 125 is within container 175, which is used to store powder 115. For example, the container 175 is in the form of a primary package or auxiliary package used to store powdered pharmaceutical formulations. In some embodiments, the container 175 has a multi-layer package, commonly referred to as a blister or blister pack, and the chamber 125 is within the multi-layer package. As shown in FIG. 2A, the powder 115 flows from the hopper 105 to the recess 180 of the lower layer 185 of the multilayer package. As described in US Pat. No. 5,865,012, which is incorporated herein in its entirety, and US Patent Application No. 10 / 301,820, filed Nov. 20, 2002, for example, both layers are heated and By applying pressure, an upper layer (not shown) is sealed on the lower layer 185, and the powder is held in the recess 180. In some embodiments, the multilayer package has a lower layer made of a metal-containing layer, such as a layer containing aluminum, and / or an upper layer made of a metal-containing layer. These metal-containing layers are sufficiently thick to prevent a substantial amount of moisture from passing therethrough. For example, the metal-containing layer is about 10 μm to about 100 μm, more preferably about 20 μm to about 80 μm. The lower layer and the upper layer are adhered to each other by a layer of a sealing agent such as a lacquer layer of about 1 μm to about 20 μm. In another embodiment, the container 175 includes a capsule, for example, a capsule for swallowing or an aerosolization of a pharmaceutical formulation, and the chamber 125 is in the capsule. As shown in FIG. 2B, the capsule first portion 190 is arranged to receive the powder flowing through the hopper outlet 120. After filling, a second part (not shown) is placed on the first part 190 to form a capsule and contain the powder in the capsule. This is described in U.S. Pat. No. 4,247,066, U.S. Pat. No. 4,864,876, U.S. Pat.No. 6,357,490, and PCT application WO00 / 07572, disclosed on Feb. 17, 2000, which is incorporated herein in its entirety. . In another embodiment, there is a chamber 125 in a container 195, such as a bottle or vial, as shown in FIG. 2C. For example, in this embodiment, container 195 is used to contain multiple doses of a powdered pharmaceutical formulation, such as the container described in US Pat. No. 4,524,769, which is incorporated herein in its entirety. The

  In another embodiment, the chamber 125 is a transport chamber 200 that transports powder, which transports the powder flowing from the hopper 115 to the transport chamber 200 to another chamber, such as a chamber in the package 175. And transport. For example, as shown in FIG. 3, the transport chamber 200 is provided in the movable member 205. As shown in FIG. 3, the transport chamber 200 receives powder from the hopper 115 in the filling position. The movable member 205 then transports the transport chamber 200 closer to the package 175. Here, at least a portion of the contents of the transport chamber 200 is transferred to the package 175. The transport chamber 200 is sized to accommodate a predetermined amount of powder. For example, the transport chamber 200 is sized to collect a prescribed dose of powdered pharmaceutical formulation and the exact prescribed dose is transported into the package 175. A doctor blade 210 may be provided to scrape off excess powder in the transport chamber 200.

  In the embodiment shown in FIGS. 4A and 4B, a powder transport assist mechanism 215 is provided. In one embodiment, the powder transport assist mechanism 215 has a passage 220 that communicates with the transport chamber 200. The passage 220 can be connected to a suction source when the transport chamber 200 is in the powder collection position shown in FIG. 4A. Thus, suction 225 is provided to the transport chamber 200 to assist in collecting the powder 115 into the transport chamber 200. A filter 230 is provided in the transport chamber 200 that prevents the powder 115 from being drawn into the passage 220. The filter has a plurality of pores having a diameter of, for example, about 0.10 μm to about 0.65 μm, and most preferably about 0.65 μm. The passage 220 is added to generate a pressure 235 in the passage 220 to discharge the powder in the transportation chamber 200 to the container 175 when the transportation chamber 200 is moved to the powder discharge position shown in FIG. 4B. It can be connected to a pressurized gas source. An example of a powder transport aid mechanism is described in US Pat. No. 5,826,633, which is incorporated herein in its entirety.

  The powder filling apparatus 100 provides an advantageous powder filling process. One advantage is that it reduces the amount of physical contact between the powder in the hopper 105 and other objects. Such a reduction in contact is useful to prevent the powdered pharmaceutical formulation from becoming undesirable. For example, excessive physical contact causes, under some circumstances, one or more of the following situations: aggregate formation, increased electrostatic interaction, denaturation, and reduced aerosol performance. there is a possibility. These undesirable effects have been prevented or supplemented in an expensive and cumbersome manner, but reducing the amount of direct physical contact provides a particularly simplified and useful alternative. Become.

  In another embodiment, the powder filling device 100 has a powder fluidizing device 130 of the type described above in combination with an additional powder fluidizing member. For example, as shown in FIG. 5, the powder filling apparatus includes a second powder fluidizing apparatus 240. The second powder fluidizing device 240 has a powder fluidizing member 250 and an actuating device 255, which actuates the powder fluidizing member 250 to fluidize the powder 115 in the hopper 105. For example, the powder fluidizing member 250 is a member in direct contact with the powder 115, and the powder 115 is fluidized by the movement of the fluidizing member 250. In the illustrated embodiment, the powder fluidizing member 250 has a rod 260 that extends down to the powder 115 being spread. The holding arm 265 holds the rod 260 in the hopper 105. Actuator 255 is connected to drive rod 260 by driving arm 265, or is connected directly to rod 260, eg, connected between rod 260 and arm 265. . Such fluidization of powders is described in US Pat. No. 6,182,723, which is incorporated herein in its entirety. Actuator 240 causes rod 260 to vibrate. For example, as shown in FIG. 5, the rod has a distal end that can be positioned near the outlet 120, and the actuator 240 moves the rod up and down 270 to fluidize the powder and cause the powder to flow through the outlet 120. Flow into chamber 125. In certain embodiments, the rod 260 is attached to a motor, such as a piezoelectric motor, and is about 1000 Hz to about 180,000 Hz, preferably about 10,000 Hz to 40,000 Hz, and most preferably about 15,000 Hz to about It can be vibrated at a frequency of 25,000 Hz. In addition or alternatively, the rod 260 may be vibrated or moved in another direction, eg, lateral or rotational. In another embodiment, the additional powder fluidizing member may have a stirrer or other fluidizing mechanism.

  The powder fluidizer 130 and the second powder fluidizer 240 work together or work alone to fluidize the powder 115 in the hopper 105. In the example shown in FIG. 5, the powder fluidizer 130 is operated simultaneously with the second powder fluidizer 240 to generate vibration 150 in the medium 145 and simultaneously cause the powder 115 to vibrate 270 directly. For some powders, this combined action provides excellent fluidization possibilities. Further, as another embodiment, the powder fluidizer 130 and the second powder fluidizer 240 may be operated at different timings or may be operated in a form supplementing each other. In the example shown in FIGS. 6A and 6B, the powder fluidizer 130 serves to supplement the operation of the second powder fluidizer 240. As shown in FIG. 6A, for some powders, the vibration of the rod 260 is sufficient to fill the chamber 125, but forms one or more voids 275 in the region close to the rod 260. End up. After the gap 275 is formed, the vibration of the rod 260 has almost no possibility of fluidization. There, the powder fluidizer 130 is activated as shown in FIG. 6B to fill the gap 275. The agitation of the medium 145 here is sufficient to allow the powder 115 to fluidize when the powder 115 is again brought into contact with the rod 260 so that the rod 260 is vibrated again. The powder fluidizer 130 and / or the second powder fluidizer 240 operate continuously to maintain the powder 115 in a continuous fluidized state while filling the plurality of chambers 125 through the outlet 120. Alternatively, the powder fluidizer 130 and / or the second powder fluidizer 240 are only operated when it is desired that the powder 115 be fluidized, and the size of the outlet 120 is set so that such fluidizer operates. It may be sized so that substantially no powder flows through the outlet 120 when not being done.

  As shown in FIG. 7, in some embodiments, the powder filling apparatus 100 is configured to fill a plurality of chambers 125 simultaneously. In this embodiment, the hopper 105 has a plurality, for example 2, 3, 4, or more outlets 120. The powder fluidizer 130 is arranged to fluidize the powder 115 in the hopper 105 across all of the outlets 120. In the embodiment shown in FIG. 7, the powder flowing through the outlet 120 flows into the transport chamber 200 in the movable member 205, which in this embodiment is a rotatable member. When the transport chamber 200 is filled, the movable member 205 is rotated from the illustrated fill position to a discharge position where the transport chamber 200 is disposed on each container 175. The container 175 is supported by the platform 300. The container 175 is transported to the position shown in FIG. 7, and the platform 300 is movable relative to the movable member 205 to move the container to the position shown in FIG. After filling the container, the container 175 can be removed when the transport chamber 200 is returned to its filling position. This process continues until the desired number of containers is filled. In another embodiment, the platform 300 may be an indexable movable plate with an opening for receiving a container. As yet another embodiment, the platform 300 may be a belt on a roller system.

  8A and 8B show an embodiment of a powder filling device 100 that can fill multiple chambers 120 at the same time and has a fluidizer 130 and a second fluidizer 240. In the embodiment of FIG. 8A, the second powder fluidizer 240 has a rod 260 that is vibrated in the up-down direction 270. Further, a mechanism is provided that can translate the rod 260 in the horizontal direction 310 across each opening. A typical translation mechanism is described in the aforementioned US Pat. No. 6,182,712, incorporated herein by reference as described above. In the embodiment of FIG. 8B, a plurality of vibrating rods 260 are provided. For example, each rod 260 is made to correspond to the outlet 120.

  A diagram showing details of an embodiment of the powder filling apparatus according to the embodiment shown in FIG. 8A is shown in FIG. In this embodiment, the powder fluidizer 130 and the second powder fluidizer 240 are used to control the flow rate of powder in the hopper through multiple outlets. The rod 260 of the second powder fluidizer is connected to a piezoelectric actuator or motor 320 that vibrates the rod 260 up and down. In the arm 265, a mechanism such as a screw-type driving device that translates 310 the rod 260 across the hopper 105 is provided. In order to maintain a desired state in the powder filling apparatus 100, a first enclosure 325 and a second enclosure 330 are provided. For example, for certain powders, such as powdered pharmaceutical formulations, it is desirable to maintain a clean and sterilized environment. It is also desirable to maintain a certain relative humidity within the enclosure, particularly when filling powders that undergo changes when exposed to substantial amounts of moisture. One or more of the enclosures are made of, for example, medical quality stainless steel, industrial polymers, PVC, and the like. As an embodiment, a plurality of powder fluidizers 130 may be provided in the second enclosure. This is advantageous when a very large hopper 105 is used. An inlet 335 that passes through the enclosure 325 also allows a large amount of powder to be introduced into the hopper 105.

  At least a part of the powder fluidizer 130 is accommodated in the second enclosure 330. In some embodiments, the membrane 155 is part of a speaker cone from a conventional audio speaker. This speaker is connected via an amplifier to a function generator that can provide a range of power and frequency to the speaker. When the speaker cone vibrates, fluidized sound is generated. The speaker cone includes, for example, a 3 inch woofer, a 4 inch woofer, a 6.5 inch woofer, and the like. In another embodiment, the powder fluidizer may have a membrane disposed away from the speaker cone so that the membrane can be vibrated when the speaker cone vibrates. This structure is useful in maintaining a controlled environment within the hopper 105, i.e., an environment in which the speakers are fully contained within the second enclosure 330 and are not directly exposed to the hopper 105.

  In addition or alternatively, a mass powder fluidizer 350 may be provided to fluidize the bulk powder 355 contained in the bulk powder container 360. As shown in FIG. 10, a bulk powder container 360 is used to supply powder to the hopper 105. In this embodiment, the bulk powder container 360 has an outlet 365 that communicates with the inlet 335 and leads to the hopper 105. The bulk powder fluidizer 350 includes the membrane 370 and the actuator 375 as described above, and is activated when a large amount of powder 355 is required to fluidize and flow into the hopper 105 via the outlet 365. The This operation is generally continuous so that small amounts of powder are continuously fed to the hopper 105 at a flow rate of powder flowing through one or more outlets 120 of the hopper 105. However, this operation may be intermittent. In some embodiments, the bulk powder fluidizer 350 is activated when the powder level in the hopper 105 falls below a predetermined level. Note that this operation may include a manual operation, or a level sensor such as a capacitive sensor may be provided so that it can be automatically refilled. Further, a gate or a valve may be provided near the inlet 335.

  A powder filling apparatus 100 with features of the embodiment of FIGS. 9 and 10 is shown in FIG. In this embodiment, a valve 380 is provided to selectively introduce the powder in the bulk powder container 360 into the hopper 105. In this embodiment, the valve 380 is opened when the level of the powder 115 spread in the hopper 105 falls below a predetermined level. Also, the level of the spread powder is detected by a capacitive sensor 385 operably arranged to generate a signal when the level of the spread powder falls below the predetermined level. This signal is provided to a controller that controls the opening and closing of the valve 380. Alternatively or in addition, a laser sensor may be used. Also in the illustrated embodiment, a second enclosure 390 is provided for at least a portion of the bulk powder fluidizer 350.

  The powder filling apparatus 100 is manufactured to fill a container with powder in an improved form. This powder filling apparatus 100 is particularly effective for filling a fine dose powder into a unit dose container. For example, Table 1 shows a comparison of filling of powder A, which is a fine dry powder pharmaceutical formulation, when using a conventional powder filling machine and when using the powder filling apparatus 100 of the present invention. A conventional powder filling machine is that described in US Pat. No. 6,182,712. For this comparison, the powder filling apparatus 100 shown in FIG. 11 equipped with the transport chamber shown in FIGS. 4A and 4B was used. In the table, N represents the number of filled containers, SD represents standard deviation, and RSD represents relative standard deviation. As shown, in each of the five independent trials, the conventional system cannot match the filling consistency of the powder filling device 100. In fact, even in the best trials when using conventional systems, the filling range was more than double that when using the powder filling device 100 of the present invention.

  The powder filling apparatus 100 of the present invention has shown a general adaptability for filling various powders. The powder filling apparatus 100 shown in FIG. 11 with the transport chamber shown in FIGS. 4A and 4B was used for comparison with different powders and the results are shown in Table 2. Six different powders were filled into unit dose containers. These powders varied in size, composition, active agent, excipients and properties. However, as can be seen from the data, a very consistent filling was achieved for each powder. Also, very low RSD was achieved for each powder. Furthermore, the powder filling device 100 has shown that containers can be consistently filled with small doses and can be consistently filled with large doses.

  A computer controller is provided to control the operation of the bulk powder fluidizer 350 and / or to control the operation of the powder fluidizer 130 and / or the second powder fluidizer 240. This controller controls the driving of the powder filling apparatus 100 as a whole. The controller may be a single control device, a plurality of control devices connected to each other, or a plurality of control devices connected to various elements of the package device 100.

  In some embodiments, the controller has electronic hardware with electrical circuitry including integrated circuits that is suitable for operation or control of the powder filling apparatus 100. Generally, the controller is adapted to receive data input, execute algorithms, and generate useful output signals, detect data signals from one or more sensors and other device elements, and powder filling Used to monitor or control processing in apparatus 100. However, the controller may simply be adapted to perform one of these tasks. In one embodiment, the controller operates or identifies (i) a computer having a central processing unit (CPU) and peripheral controllers connected to the memory system, and (ii) certain elements of the powder filling device 100. One or more of application specific integrated circuits (ASICs) that perform the process of (iii) and (iii) one or more controller interface boards with appropriate support circuitry. Typical CPUs include PowerPC ™, Pentium ™, and other similar processors. ASICs are designed and pre-programmed for retrieval of specific tasks, such as data from powder filling apparatus 100 and other information, and / or operation of specific device elements, for example. Typical support circuits include, for example, coprocessors, clock circuits, caches, power supplies, and other known components connected to the CPU. For example, the CPU often operates in conjunction with a random access memory (RAM), a read only memory (ROM), and other storage devices known in the art. The RAM can be used to store the software execution of the present invention during execution of the process. The programs and subroutines of the present invention are typically stored in a mass storage device and recalled for temporary storage in RAM when executed by the CPU.

  The software execution computer program code product of the present invention is stored, for example, in a memory device, such as EPROM, and is referred to as RAM during execution by the controller. The computer program code is created in a conventional computer readable programming language such as assembly language, C, C ″, Pascal, or native assembly. The appropriate program code is written to a single file or multiple files using a conventional text editor, and stored or embodied in a computer-usable medium, such as, for example, a computer system memory. Is done. If the written code text is in a high-level language, the code is compiled against compiler code that is combined with pre-compiled Windows library routine object code. To execute the combined and compiled object code, the system user calls the object code and causes the computer system to read the code in memory and perform the tasks identified by the computer program.

  In one embodiment, the controller may comprise a sufficiently small and low power consumption microprocessor or ASIC housed on or in the powder filling device 100. For example, suitable microprocessors used as local microprocessors include the MC68HC711E9 from Motorola, the PIC16C74 from Microchip, and the 82930AX from Intel. The microprocessor may have one microprocessor chip, multiple processors, and / or coprocessor chips, and / or digital signal processor (DSP) capabilities.

  In certain useful implementations, the powder filling device 100 is used to fill pharmaceutical containers, such as blisters, capsules, vials, bottles, etc., with powdered pharmaceutical formulations. For example, the powder filling device 100 has proven to be particularly advantageous for filling a dry powder inhalable pharmaceutical formulation into a container that aerosolizes the pharmaceutical formulation for inhalation by a user. For example, as described in U.S. Patent 5,785,049, U.S. Patent 5,415,162, U.S. Patent Application 09 / 583,312, when in powder form, the powder is first opened before aerosolization of the powder. Stored in a sealed package. Alternatively, as described in U.S. Pat.No. 4,995,385, U.S. Pat.No. 3,991,761, U.S. Pat.No. 6,230,707, and PCT Publication WO 97/27892, the powder is inserted prior to insertion into the aerosolization device. Or in a capsule that can be opened after insertion. Also, in the form of bulk, blisters, capsules, etc., the powder comprises an active element such as pressurized air as described in U.S. Patent 5,458,135, U.S. Patent 5,785,049, and U.S. Patent 6,257,233, Or high pressure as described in US patent application Ser. No. 09 / 556,262, filed Apr. 24, 2000, entitled “Aerosolization Apparatus and Method” and PCT Publication WO 00/72904. It is aerosolized by an active element such as a gas. Alternatively, the powder is aerosolized in response to a user's inhalation, as described in the aforementioned US patent application Ser. No. 09 / 583,312 and US Pat. No. 4,995,385. All documents cited above are incorporated herein in their entirety.

  The pharmaceutical formulation can include an active agent. The active agents described herein include compositions of drugs, drugs, compounds, substances or mixtures thereof and provide pharmacological effects, often beneficial effects. The active agents include foods, dietary supplements, nutrients, drugs, vaccines, vitamins, and other beneficial reagents. As used herein, these terms include any physiologically or pharmaceutically active substance that produces a localized or systemic effect in a patient. The active agents incorporated into the pharmaceutical formulations described herein may be inorganic or organic compounds, including but not limited to peripheral nerves, adrenergic receptors, cholinergic receptors, skeletal muscle , Cardiovascular system, smooth muscle, blood circulatory system, synaptic site, nerve effector junction site, endocrine and hormone system, immune system, reproductive system, skeletal system, lung system, local hormone system, digestive system and excretory system, histamine Contains drugs that affect the system and the central nervous system. Suitable active agents include, for example, hypnotics and sedatives, psychostimulants, tranquilizers, respiratory drugs, anticonvulsants, muscle relaxants, antiparkinsonians (dopamine antagonists), analgesics, anti-inflammatory drugs, anti-inflammatory drugs Anxiety drugs (anti-anxiety drugs), appetite suppressants, anti-migraine drugs, muscle contractants, anti-infectives (antibiotics, antiviral drugs, antifungal drugs, vaccines), anti-arthritic drugs, anti-malaria Agents, antiemetics, antiepileptics, bronchodilators, cytokines, growth factors, anticancer agents, antithrombotic agents, antihypertensive agents, cardiovascular agents, antiarrhythmic agents, antioxicants, antiasthma agents, hormones Drugs such as contraceptives, sympathomimetics, diuretics, lipid regulators, antiandrogens, anthelmintics, anticoagulants, tumor agents, antineoplastic agents, hypoglycemic drugs, nutritional drugs and nutritional supplements, Growth nutritional supplement, anti-enteritis agent, vaccine, antibody, diagnosis Includes drugs, and contrasting agents. The active agent may act locally or systemically when administered by inhalation.

  Active agents can be classified into one of many structural classes. Non-limiting examples include small molecules, peptides, polypeptides, proteins, polysaccharides, steroids, proteins that can induce physiological effects, nucleotides, oligonucleotides, polynucleotides, fats, electrolytes, and the like.

  Examples of active agents suitable for use in the present invention include, but are not limited to, one or more of calcitonin, amphotericin B, erythropoietin (EPO), factor VIII, factor IX, ceredase, cerezyme, cyclosporine, granulocyte colony stimulating factor (GCSF) ), Thrombopoietin (TPO), alpha-1 protease inhibitor, elcatonin, granulocyte macrophage colony stimulating factor (GMCSF), growth hormone, human growth hormone (HGH), growth hormone releasing hormone (GHRH), heparin, low molecular weight Heparin (LMWH), interferon alpha, interferon beta, interferon gamma, interleukin 1 receptor, interleukin 2, interleukin 1 receptor antagonist, interleukin 3, interleukin 4, interleukin 6, luteinizing hormone releasing hormone ( LH RH), Factor IX, insulin, proinsulin, insulin analogs (eg, mono-acylated insulin described in US Pat. No. 5,922,675, which is incorporated herein in its entirety), amylin, C -Peptides, somatostatin, somatostatin analogs such as octreotide, vasopressin, follicle stimulating hormone (FSH), insulin-like growth factor (IGF), insulintropin, macrophage colony stimulating factor (M-CSF), nerve growth factor ( NGF), tissue growth factor, keratinocyte growth factor (KGF), glial growth factor (GGF), tumor necrosis factor (TNF), endothelial growth factor, parathyroid hormone (PTH), glucagon-like peptide thymosin α1, IIb / IIIa inhibition Agent, α-1 antitrypsin, phosphodiesterase (PDE) , VLA-4 inhibitor, bisphosphonate, respiratory syncytial virus antibody, cystic fibrosis transmembrane regulator (CFTR) gene, deoxyribonuclease (Dnase), bactericidal / permeability increasing protein (BPI), anti-CMV Antibodies, 13-cis retinoic acid, macrolides such as erythromycin, oleandomycin, troleandomycin, roxithromycin, clarithromycin, daversin, azithromycin, flurithromycin, dirithromycin, josamycin Spiromycin, midecamycin, leucomycin, myomycin, rokitamycin, and azithromycin, and swinolide A; fluoroquinolones such as ciprofloxacin, ofloxacin, levofloxacin, toro Floxacin, alatrofloxacin, moxifloxacin, norfloxacin, enoxacin, grepafloxacin, gatifloxacin, lomefloxacin, sparfloxacin, temafloxacin, pefloxacin, amifloxacin, Fleroxacin, tosufloxacin, pullrifloxacin, irloxacin, pazufloxacin, clinafloxacin, and sitafloxacin, aminoglycosides such as gentamicin, netilmycin, paramesin, tobramycin, amikacin, kanamycin, neomycin, streptomycin, nincompramine, vancomycin, Rampolanin, mideplanin, colistin, daptomycin, gramicidin, Colistimethate, polymyxins such as polymyxin B, capreomycin, bacitracin, penem antibiotics; penicillin antibiotics such as penicillinase sensitive drugs such as penicillin G, penicillin V, penicillinase-resistant drugs such as methicillin, Oxacillin, cloxacillin, dicloxacillin, floxacillin, nafcillin; Gram-negative microbial active agents such as ampicillin, amoxicillin, and hetacillin, cillin, and galampicillin; , Mezulocillin, and piperacillin; cephalosporins such as cefpodoxime, cefprozil, ceftibutene, ceftizoxime, cef Riaxon, cephalothin, cephapillin, cephalexin, cephradrine, cefoxitin, cefamandol, cephazoline, cephaloridine, cefaclor, cephadroxyl, cephaloglycin, cefuroxime, ceforanide, cefatrice, cephalidine Cefepime, cefixime, cefonide, cefoperazone, cefotetan, cefmetazole, ceftazidime, loracarbef, and moxalactam, monobactams such as aztreonam; and carbapenems such as imipenem, meropenem, pentamidine isothiouate, Renol, beclomethasone diprepionate, tria Sinolone acetamide, budesonide acetonide, fluticasone, ipratropium bromide, flunisolide, cromolyn sodium, ergotamine tartrate, and their applicable analogs, agonists, antagonists, inhibitors, and pharmaceutically acceptable salt forms thereof May be included. With respect to peptides and proteins, the invention is intended to encompass synthetic, native, glycosylated, non-glycosylated, pegylated forms, and biologically active fragments and analogs thereof.

  The active agent used in the present invention is a nucleic acid, such as a naked nucleic acid molecule, a vector, a virus particle associated, plasmid DNA or RNA, or another nucleic acid construct, for transfecting or transducing cells. Further included are nucleic acid constructs of a type that are suitable, ie, suitable for gene therapy including antisense. Furthermore, the active agent may comprise a live attenuated vaccine or a killed virus suitable for use as a vaccine. Another useful drug is one listed in the Physician's Desk Reference (latest edition).

  The amount of active agent in a pharmaceutical formulation is that amount necessary to deliver a therapeutically effective amount of active agent per unit dose aimed at achieving the desired result. Indeed, the amount will vary widely depending on the particular drug, its activity, the severity of the illness being treated, the race of the patient, the dosage required and the desired therapeutic effect. The composition will generally be about 1% to about 99% active agent by weight anyway, typically about 2% to about 95% active agent by weight, and more typically by weight. Will contain from about 5% to 85% active agent and will depend on the relative amount of additives included in the composition. The compositions of the invention are delivered in particular at a dosage of 0.001 mg / day to 100 mg / day, preferably 0.01 mg / day to 75 mg / day, and more preferably 0.10 mg / day to 50 mg / day. It is particularly useful for active agents. It should be noted that one or more active agents may be incorporated into the formulations described herein, and the use of the term “agent” does not exclude the use of two or more such agents.

  Pharmaceutical formulations may include pharmaceutically acceptable excipients or carriers that can be taken into the lungs without causing significant adverse toxic effects to the patient, and particularly to the patient's lungs. In addition to the active agent, the pharmaceutical formulation optionally includes one or more pharmaceutical excipients suitable for pulmonary administration. The excipient, when present, ranges from about 0.01% to about 95% by weight, preferably from about 0.5% to about 80%, more preferably from about 1% to about 60%. Generally present in the composition in an amount. Preferably, such excipients are used in part to improve the characteristics of the active agent composition, for example by providing more efficient and reproducible active agent delivery properties of the powder. For example, by improving flowability and consistency and / or by facilitating filling or manufacturing of unit doses. In particular, the excipient material further improves the physical and chemical stability of the active agent, minimizes residual moisture content and prevents moisture uptake, and particle size, degree of aggregation, Often functions to enhance particle surface properties, such as wrinkles, ease of inhalation, and targeting particles to the lungs. One or more excipients can be provided to serve as a filler when it is desired to reduce the concentration of the active agent in the formulation.

  Pharmaceutical excipients and additives useful in the present pharmaceutical formulation include, but are not limited to, amino acids, peptides, proteins, non-biopolymers, biopolymers, carbohydrates such as sugars, sugar derivatives such as alditols, aldonic acids, esterified sugars And sugar polymers. These may be present alone or in combination. Suitable excipients are those provided in WO 96/32096. This document is hereby incorporated by reference in its entirety. The excipient has a glass transition temperature (Tg) of about 35 ° C or higher, preferably about 40 ° C or higher, more preferably 45 ° C or higher, and most preferably about 55 ° C or higher.

  Typical protein excipients include albumin such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, hemoglobin, and the like. Suitable amino acids that function in buffering capacity (except dileucil-peptides of the present invention) are alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame , Tyrosine, tryptophan, and the like. Amino acids and polypeptides that function as dispersants are preferred. Amino acids that fall into this category include hydrophobic amino acids such as leucine, valine, isoleucine, tryptophan, alanine, methionine, phenylalanine, tyrosine, histidine, and proline. Peptide excipients that enhance dispersibility include dimers, trimers, tetramers, and pentamers containing one or more hydrophobic amino acid elements, eg, the hydrophobic amino acids described above.

  Suitable carbohydrate excipients for use in the present invention include, for example, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, etc .; disaccharides such as lactose, sucrose, trehalose, cellobiose, etc .; polysaccharides For example, raffinose, melezitose, maltodextrin, dextran, starch and the like; and alditols such as mannitol, xylitol, maltitol, lactitol, xylitol, sorbitol (glucitol), pyranosyl sorbitol, myo-inositol and the like.

  The pharmaceutical formulation also includes a buffer or pH adjusting agent. Typically, it is a salt prepared from an organic acid or base. Exemplary buffers include organic acid salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid, tris, tromethamine hydrochloride, or phosphate buffer.

  Pharmaceutical formulations also include polymeric excipients / additives such as polyvinylpyrrolidone, derivatized cellulose such as hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylmethylcellulose, ficoll (polymeric sugar), hydroxyethyl starch, dextrates (e.g. Cyclodextrins such as 2-hydroxypropyl-β-cyclodextrin and sulfobutyl ether-β-cyclodextrin), polyethylene glycol, and pectin.

  Pharmaceutical preparations further include flavoring agents, taste masking agents, inorganic salts (e.g. sodium chloride), antibacterial agents (e.g. benzalkonium chloride), sweeteners, antioxidants, antistatic agents, surfactants (e.g. polysorbates). E.g. "TWEEN 20" and "TWEEN 80"), sorbitan esters, lipids (e.g. phospholipids such as lecithin and another phosphatidyl choline, phosphatidylethanolamine), fatty acids and fatty esters, steroids (e.g. cholesterol), and chelates Agents (eg, EDTA, zinc, and other such suitable cations) may be included. Another pharmaceutical excipient and / or additive suitable for use in the composition according to the invention is "Remington: The Science & Practice of Pharmacy", l9th ed., Williams & Williams, (1995), and in the "Physician's Desk Reference", 52nd ed., Medical Economics, Montvale, NJ (1998). Both documents are incorporated herein in their entirety.

  Since the powders of the present invention are generally polydisperse (ie, there is a range of particle sizes), the “mass median diameter”, ie, “MMD”, is a measure of the average particle size. Although several commonly employed techniques are used to measure average particle size, the MMD values reported herein were determined by centrifugal sedimentation. “Aerodynamic median diameter” or “MMAD” is a measure of the aerodynamic size of the dispersed particles. This aerodynamic mass median diameter is used to represent an aerosolized powder in terms of its settling behavior, and is generally a unit density sphere having the same settling velocity as particles in air. Is the diameter. Also, the aerodynamic mass median diameter includes particle shape, density, and physical particle size. As used herein, MMAD refers to the midpoint or midpoint of the aerodynamic particle size distribution of an aerosolized powder as determined by a cascade impactor.

  In one embodiment, the powder formulation used in the present invention is a dry powder having a particle size selected to be able to penetrate the alveoli, ie preferably 10 μm in diameter, preferably 7 A dry powder having a mass median diameter (MMD) in the range of less than 5 μm, most preferably less than 5 μm, usually in the range of 0.1 μm to 5 μm. The delivery dose efficiency (DDE) of these powders is greater than 30%, more preferably greater than 40%, more preferably greater than 50%, most preferably greater than 60%, and the aerosol particle size distribution is Aerodynamic mass median diameter (MMAD) of about 1.0-5.0 μm, usually 1.5-4.5 μm MMAD, preferably 1.5 μm-4.0 μm MMAD. These dry powders have a moisture content of less than about 10% by weight, usually less than about 5% by weight, and preferably less than 3% by weight. Such powders are described in WO95 / 24183, WO96 / 32149, WO99 / 16419, and WO99 / 16422, which are incorporated herein in their entirety.

  Although the present invention has been described in great detail with reference to certain preferred embodiments, other embodiments are possible and have been shown to those skilled in the art upon reading this specification and viewing the drawings. Alternatives, substitutions, and equivalents of the embodiments will be apparent. For example, in order to perform relative movement, the relative positions between elements can be varied to suit the purpose. Also, various features of the various embodiments described herein can be combined in various ways to provide other embodiments of the invention. Furthermore, certain terminology is used for the sake of clarity and is not intended to limit the invention. For example, in this specification, terms such as “upper”, “lower”, “first”, and “second” may be used in reverse. In other words, the appended claims should not be limited to the preferred embodiments contained herein, but all alternatives, substitutions, which fall within the true spirit and scope of the present invention, And equivalents.

Claims (12)

below:
Container;
Powder pharmaceutical made agents of the vessel that is fluidized by fluidizing member including a vibrating membrane which is disposed away from the powder; and seal to retain the powder pharmaceutical formulation to the container
A pharmaceutical package comprising:   The pharmaceutical package according to claim 1, wherein the container comprises a blister package.   The pharmaceutical package of claim 2, wherein the blister package comprises a lower layer with a recess.   4. The pharmaceutical package of claim 3, wherein the blister package comprises a sealable upper layer on the lower layer.   The pharmaceutical package of claim 4, wherein at least one of the layers comprises a metal.   The pharmaceutical package of claim 4, wherein both of the layers comprise a metal.   The pharmaceutical package according to claim 1, wherein the container is at least part of a capsule.   2. A pharmaceutical package according to claim 1, wherein the container is at least part of a vial.   The pharmaceutical package according to claim 1, wherein the container is a bottle.   2. The pharmaceutical package of claim 1 made by a step further comprising weighing the powder in a metering chamber prior to filling the container.   11. A pharmaceutical package according to claim 10 made by a process further comprising rotating the metering chamber.   The pharmaceutical package according to claim 1, wherein the powder pharmaceutical preparation is produced by a process of fluidizing with a vibrating member in contact with the powder.

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