KR20050019133A - Device and method for controlling the flow of a powder - Google Patents

Abstract

The apparatus 100 for filling a container with powder includes a hopper 105 having an outlet 120 and holding a powdered medicine 115. The vibrating member 135 is located in, on, or near the hopper and is spaced apart from the powder in the hopper and can fluidize the powder in the hopper. Powder flowing through the outlet under the control of the vibrating member enters the vessel 175 or enters the transfer chamber 125 for delivery to the vessel.

Description

Powder flow control device and its control method {DEVICE AND METHOD FOR CONTROLLING THE FLOW OF A POWDER}

The need for effective patient care has led to the development of various techniques for administering medications to patients. The prior art has been to administer the drug in the form of pills, capsules and the like. It has also been proven that inhaled medications in which the patient inhales aerosol-type medications into the mouth or nose for administration to the patient's respiratory system are effective. In one inhalation technique, the medicament is delivered deep into the patient's lungs for absorption into the blood. In another inhalation technique, a medicament is delivered to a target area of the respiratory system to treat that area. There are various types of inhalation devices, including devices for aerosolizing dry powder medications.

The medication is often packaged and readily available to the user. For example, a single dose or part thereof may be stored between layers of a multilayer package, commonly referred to as blisters or blister packs. In general, a cavity is formed in the lower layer such that the drug accumulates in the cavity and the drug is held in the cavity by heating and / or pressing all the layers so that the upper layer is sealed to the lower layer. Alternatively, the single dose may be stored in a capsule capable of swallowing or aerosolizing the medicament. Packaging, such as bottles or vials, may also be used to store the drug.

It is often difficult to fill the package efficiently with medication. For example, during the powder filling process, it is difficult to fluidize the powder and / or to keep the flow characteristics of the powder constant. Incorrectly adjusted powder flow results in inconsistent filling of the package. For example, the fill mass may vary from package to package, resulting in either a dose impact on the patient to be administered in a single dose or too much or too little dose packed in a multi-dose package. In addition, the packaging properties of the powder in the package may vary, resulting in an inconsistent powder flow during the filling process.

Thus, it is desirable to be able to control the flow of powders, particularly powdered medicines. It is more desirable to be able to control the flow of the powdered medicament so that the packaging is effectively and consistently filled with the powdered medicament. It is more desirable to control the flow of the powdered drug in such a way as to reduce any adverse effects on the powdered drug.

The features, aspects, and advantages of the invention will be better understood from the following description, claims and drawings which illustrate exemplary embodiments of the invention. However, each of the forms of the invention may be used in general, and is not merely used within the scope of the specific drawings, the invention includes any combination of these forms.

1 is a schematic cross-sectional view of a powder filling apparatus according to the present invention.

2A-2C are schematic cross-sectional views of various containers to be filled using a powder filling apparatus according to the present invention.

3 is a schematic cross-sectional view of another type of powder filling device.

4A to 4B are cross-sectional views schematically showing the operation of another type of powder filling device.

5 is a schematic cross-sectional view of yet another form of powder filling apparatus.

6A-6B are schematic cross-sectional views of the powder filling apparatus of FIG. 5 during a powder filling process.

7 is a front sectional view schematically showing a multi-chamber powder filling apparatus.

8A to 8B are front cross-sectional views schematically showing different types of multi-chamber powder filling apparatus.

9 is a sectional view schematically showing the inside of the powder filling apparatus.

10 is a schematic cross-sectional view of a powder filling device with a bulk powder container.

11 shows a more detailed schematic cross section of a powder filling apparatus with a bulk powder container.

The present invention satisfies the above needs. In one aspect of the invention, the powder flow from the hopper is controlled in an improved manner.

In another aspect of the invention, an apparatus for filling a chamber comprises a hopper containing a powdered medicament, the hopper comprising an outlet. The apparatus also includes a disturbing member capable of disturbing the media in the hopper, the disturbing of the media being sufficient to regulate the flow of powder through the outlet. The chamber may be filled with powder entering the chamber through the outlet.

In another aspect of the invention, an apparatus for filling a chamber comprises a hopper containing a powdered medicament, the hopper comprising an outlet. The apparatus also includes a vibrating member located in, on, or near the hopper that is separated from the powder in the hopper, which may fluidize the powder in the hopper. The chamber may be filled with powder entering the chamber through the outlet.

In another aspect of the present invention, a method for filling a chamber includes supplying powder medicament to a hopper, disturbing the medium in the hopper to fluidize the powder, and sending the powder through the outlet into the chamber.

In another aspect of the invention, a method of filling a chamber includes supplying a powdered medicament, vibrating a member away from the powder to fluidize the powder, and sending the powder through the outlet into the chamber.

In another aspect of the invention, a pharmaceutical package includes preparing a container, filling the container with powdered drug fluidized by a fluidizing member away from the powdered drug, and sealing the container to secure the powdered drug in the container. Made by process.

The present invention relates to powder flow control which regulates the flow of powder during the packaging filling process. Although the process is described in terms of packaging powdered medicines, the present invention may be used in other processes and should not be limited to the examples described herein.

A powder filling apparatus 100 according to the invention is shown schematically in FIG. 1. The powder filling apparatus 100 consists of a hopper 105 having a reservoir 110 that can contain a powder layer 115, such as a powdered medicament. Hopper 105, of any suitable size and shape, includes an outlet 120 through which fluidized powder can flow. The chamber 125 is located near the outlet 120 such that powder flowing through the outlet 120 enters the chamber 125 and fills the chamber 125.

The powder flower 130 may be located in, above or near the hopper 105. The powder flower 130 includes a disturbing member 135 that causes disturbances in the hopper 105. In one form, the disturbing member 135 may be actuated by the actuator 140 to cause disturbances in the hopper 105 to regulate the flow of powder 115 in the hopper 105. For example, the disturbing member 135 may disturb the medium 145, such as air or other gas in the hopper 105, in such a way that the disturbed medium 145 causes fluidization of the powder 115. Thus, at least one portion 135 of the disturbing member can be positioned to be separated from the powder 115 by the medium 145.

Powder flowr 130 may be used to control the powder filling process in hopper 105. In one form, powder flower 130 may be operated continuously or at short intervals to maintain powder 115 in a constant flow state. In such a case, the powder 115 may flow through the outlet 120 until the hopper 105 is empty or the chamber 125 is filled. In other cases, the powder flower 130 may adjust the flow timing of the powder 115 and / or control the amount of powder 115 flowing into the chamber 125 through the outlet 120 of the hopper 105. have. For example, the outlet 120 of the hopper 105 may be small enough so that undisturbed powder 115 does not flow through or exit constantly through the outlet 120. When powder 115 has to flow into chamber 125, actuator 140 causes disturbance member 135 to perturb medium 145 and thus fluidize powder 115 such that powder 115 exits 120. ) Into the chamber 125. When the chamber 125 is sufficiently filled, the actuator 140 stops or reduces disturbances, for example, to block the flow of powder exiting through the outlet 120, thereby allowing the powder 115 to flow out of the outlet 120. Decrease the amount of

In one form, powder flower 130 causes disturbances in hopper 105, which disturbances include vibrations 150. The disturbing member 135 may include a vibrating body such as the membrane 155 in, on, or near the hopper 105, which membrane 155 may vibrate by an actuator 140 causing vibration. have. The vibrating membrane 155 disturbs the medium 145. For example, when the membrane 155 moves downward, a portion of the medium immediately before 145 is compressed to increase the pressure slightly, and then the membrane decreases as it moves in the opposite direction past its original position. . This process continues with one or more wavelengths alternated from the high and low pressures emitted from the film 155. The wave contacts the powder 115 and the resulting impact is sufficient to at least instantiate the powder 115.

The frequency of vibration 150 may be selected to fluidize a particular powder 115 and / or best suit a particular filling process. In one particular form, vibration 150 may be within an audible range. In another form, the membrane 155 may vibrate at frequencies in the inaudible range to reduce discomfort for the practitioner. Vibration can be at any frequency or overlapping frequency as long as the powder 115 can be preferably fluidized or the flow of powder 115 can be 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, Most preferably, the vibration may be at one or more frequencies consisting of frequencies in the range of about 120 Hz. In one embodiment, the frequency can be selected. For example, a particular desired frequency for a particular shape and / or powder may be selected through experimentation or modeling, such as the frequency determined to cause resonance in the hopper 105 through experimentation or analysis.

The chamber 125 includes a hole 160 that can be positioned relative to the outlet 120 in the hopper 105 to receive powder flowing from the hopper 105 through the outlet 120. In one form, such as the form shown in FIG. 1, the apertures 160 of the chamber 125 are substantially the same shape and size as the outlet 120, so that an excessive amount of powder 115 is applied to the hopper 105 and the chamber ( 125 is prevented between the members 165 supporting or retaining 125. As shown in the form of FIG. 1, the hopper 105 includes a converging sidewall 170 that provides a converging flow path towards the outlet 120 for the powder 115. Converged flow passages increase the reservoir volume of the hopper 105. In other aspects, the chamber holes 160 and the outlet 120 may be different in size. For example, if it is desirable to fill a relatively large chamber with the amount of precisely controlled powder 115 or if it is not desirable to provide a mechanism for accurately positioning the chamber 125 below the outlet 120, the outlet ( 120 may be smaller than the aperture 160. Alternatively, if it is preferable to use the hopper 105 to fill the chamber 125 of various sizes or if the powder 115 is lost to the space between the hopper 105 and the member 165, it is not a big problem. The hole 160 may be smaller than the outlet 120.

Chamber 125 may be in a container 175 used to store powder 115. For example, the container 175 may be in the form of a primary or secondary packaging used to store powdered medicines. In one form, the container 175 includes a multilayer package, commonly referred to as a blister or a blister pack, and the chamber 125 is in this multilayer package. As shown in FIG. 2A, powder 115 flows from hopper 105 into cavity 180 in the lower layer 185 of the multilayer package. Then, an upper layer (not shown) to secure the powder in the cavity 180, as described in U.S. Patent 5,865,012 and U.S. Patent Application 10 / 301,820, filed November 20, 2002, which is incorporated herein by reference in its entirety. May be sealed to bottom layer 185 by heating and / or pressing. In one form, the multilayer packaging may include a bottom layer comprising a metal containing layer, such as a layer comprising aluminum, and / or a top layer comprising a metal containing layer. The metal-containing layer may be thick enough to substantially prevent passage of significant amounts of moisture. For example, the metal containing layer may be about 10 μm to about 100 μm, more preferably about 20 μm to about 80 μm. The bottom and top layers may be sealed together with a layer of sealing material such as a lacquer layer that is about 1 μm to about 20 μm. In another form, container 175 includes a capsule for swallowing or aerosolizing a medicament, and chamber 125 is in the capsule. As shown in FIG. 2B, the first portion 190 of the capsule is in a position to receive the powder flowing through the outlet 120 of the hopper. After filling, the second portion (as described in US Pat. No. 4,247,066, US Pat. No. 4,864,876, US Pat. No. 6,357,490, and PCT application WO 00/07572, published February 17, 2000, all incorporated herein by reference) (Not shown) is placed over the first portion 190 to form a capsule and retain the powder in the capsule. In another form, as shown in FIG. 2C, the chamber 125 is in a container 195, such as a bottle, vial, or the like. For example, in this form, the container 195 can be used to hold multiple doses of powdered medicament, such as the container introduced in US Pat. No. 4,524,769, which is incorporated herein by reference in its entirety.

In another form, the chamber 125 may be a transfer chamber 200 that transfers powder from the hopper 115 into the transfer chamber 200 to another chamber, such as a chamber in the package 175. For example, as shown in FIG. 3, the transfer chamber 200 may be provided within the movable member 205. When the transfer chamber 200 is in the filling position shown in FIG. 3, it receives powder from the hopper 115. The movable member 205 then moves the transfer chamber 200 to a position near the package 175, at which at least a portion of the contents of the transfer chamber 200 are emptied and delivered into the package 175. The transfer chamber 200 can be sized to hold a predetermined amount of powder. For example, the transfer chamber 200 can be sized to contain a single dose of powdered medicament and the correct dose can be delivered to the package 175. A doctor blade 210 may be provided to scrape excess powder into the transfer chamber 200.

As shown in Figures 4A and 4B, a powder transfer aid 215 is provided. In one form, the powder transfer aid 215 comprises a channel 220 leading to the transfer chamber 200. The channel 200 may be connected to a suction source when the transfer chamber 200 is in the powder receiving position shown in FIG. 4A. In this way, a suction source 225 may be provided in the transfer chamber 200 to help collect the powder 115 in the transfer chamber 200. A filter 230 may be provided in the transfer chamber 200 to prevent the powder 115 from being sucked into the channel 200. For example, the filter may comprise holes having a diameter of about 0.10 μm to about 0.65 μm, most preferably 0.65 μm. When the transfer chamber 200 moves to the powder discharge position shown in FIG. 4B, the channel 220 generates pressure 235 in the channel 220 such that the powder in the transfer chamber 200 is discharged into the container 175. It can be connected to a source of compressed gas. Examples of powder transfer aids are described in US Pat. No. 5,826,633, incorporated herein by reference.

The powder filling apparatus 100 provides an advantageous powder filling process. One advantage is that the amount of physical contact between the powder in the hopper 105 and other objects is reduced. This reduction in contact can be useful for preventing undesirable conditions in powdered pharmaceuticals. For example, if there are excessive physical contacts under certain conditions, one or more of the following conditions may occur: formation of lumps, increased electrostatic interaction, denaturation, reduced aerosol formation. These negative effects can be prevented or compensated for in a costly and rugged way, but the reduction of direct physical contact is a particularly simple and useful alternative.

In another form, the powder filling apparatus 100 further includes a powder flowr 130 of the type described above that is coupled with the powder fluidizing member. For example, as shown in FIG. 5, the powder filling apparatus may include a second powder flowr 240. The second powder fluidizer 240 includes an actuator 255 for driving the powder fluidizing member 250 in a manner to fluidize the powder 115 in the powder fluidizing member 250 and the hopper 105. For example, the powder fluidization member 250 may be a member in direct contact with the powder 115, and the motion of the fluidization member 250 fluidizes the powder 115. In the form shown, the powder fluidizing member 250 includes a rod 260 extending under the powder layer 115. Holding arm 265 secures the rod 260 in the hopper 105. An actuator 255 is connected to the rod 260 in a manner that is connected to drive the holding arm 265 to drive the rod 260 or is connected between the rod 260 and the holding arm 265. Can be connected directly. Powder fluidization in this manner is introduced in US Pat. No. 6,182,712, incorporated herein by reference. The rod 260 may vibrate by an actuator 240. For example, as shown in FIG. 5, the rod may have a distal end positioned near the outlet 120, and the actuator 240 may cause the rod to move up and down 270 to fluidize the powder to form an outlet ( Flows into chamber 125 through 120. In a particular form, the rod 260 may be connected to a motor, such as a piezoelectric motor, with about 1000 Hz to about 180,000 Hz, more preferably 10,000 Hz to 40,000 Hz, most preferably about 15,000 Hz to about 25,000 Hz Oscillate with frequency. Additionally or instead, the rod 260 may vibrate or move in other directions, such as in the lateral or rotational direction. In another form, the added powder fluidizing member may comprise an agitator or other flow device.

The powder flower 130 and the second powder flower 240 may operate in a tandem manner or alone to fluidize the powder 115 in the hopper 105. For example, as shown in FIG. 5, the powder flower 130 simultaneously generates a vibration 150 in the medium 145 and causes the second powder flower (270) to vibrate directly 270 the powder 115. 240 may be operated at the same time. For some powders, this combined operation gives the best fluidization capacity. In another form, the powder fluidizer 130 and the second powder fluidizer 240 may be operated at different times or in a complementary manner. For example, as shown in FIGS. 6A and 6B, the powder flower 130 may serve to supplement the operation of the second powder flowr 240. As shown in FIG. 6A, for some powders, vibration of rod 260 is sufficient to fill chamber 125, but results in the formation of one or more empty spaces 275 in the region near rod 260. It can also be generated. After the void 275 is formed, the vibration of the rod 260 has little fluidization capacity. To fill this void 275, the powder flower 130 can be operated, as shown in FIG. 6B. The disturbance of the medium 145 is sufficient to bring the powder 115 back into contact with the rod 260 so that the rod 260 vibrates again to fluidize the powder 115. The powder flower 130 and / or the second powder flower 240 continue to operate to continuously maintain the fluidized state while the powder 115 fills the multiple chambers 125 through the outlet 120. Can work. Alternatively, the powder flower 130 and / or the second powder flowr 240 may only operate when the powder 115 is to be fluidized, and the outlet 120 may allow the powder to exit without operation of the powder flowr. It may be sized so as not to flow through the real fabric through 120.

In one form, as shown in FIG. 7, the powder filling apparatus 100 may be in the form of simultaneously filling a plurality of chambers 125. In this form, the hopper 105 includes two, three, four, or more multiple outlets 120. The powder flower 130 is in a position to fluidize the powder 115 in the hopper 105 for all outlets 120. In the form shown in FIG. 7, the powder flowing through the outlet 120 enters the transfer chamber 200 in the movable member 205, which in this form is a rotatable member. When the transfer chamber 200 is filled, the movable member 205 rotates from the filling position shown in the figure to the discharge position where the transfer chamber 200 is located above each container 175. The container 175 is supported by the platform 300. The platform 300 can move relative to the movable member 205 to bring the container 175 to the position shown in FIG. 7 and take it when the container 175 is filled, at which time the transfer chamber 200 Goes back to the charging position. This process continues until the required number of containers is filled. In one form, the platform 300 may be a movable and indexable plate with holes for receiving a container. In another form, the platform 300 can be a belt of a roller system.

8A and 8B show a powder filling apparatus 100 capable of filling multiple chambers 120 simultaneously and including a powder flower 130 and a second powder flowr 240. In the form shown in FIG. 8A, the second powder flower 240 includes a rod 260 capable of vibrating in the up and down direction 270. This structure also allows the rod 260 to move laterally 310 through each hole. Typical examples of transmission structures are described in US Pat. No. 6,182,712, mentioned above and incorporated herein by reference. In the form shown in FIG. 8B, a plurality of vibration rods 260 are provided. For example, rods 260 are coupled in pairs to each outlet 120.

A detailed view of an embodiment of the powder filling device according to FIG. 8A is shown in FIG. 9. In this form, the powder flower 130 and the second powder flower 240 are used to regulate the flow of powder in the hopper through the plurality of outlets 120. The rod 260 of the second powder flower is connected to the piezoelectric actuator or the motor 320 so that the rod 260 can vibrate up and down. A structure such as a screw drive is provided inside the arm 265 so that the rod 260 can translate 310 across the hopper 105. The first seal 325 and the second seal 330 may be provided to maintain the requirements in the powder filling device 100. For example, for some powders, such as powdered medicines, it may be desirable to maintain a clean and sterile environment for the powder. It may also be required to maintain some relative humidity inside the closure, especially when the powder experiences a significant amount of humidity change. For example, the one or more seals include such as medical stainless steel, engineering polymers, PVC, and the like. In one form, multiple powder flowers 130 may be provided in the second seal. This may be useful when using a very large hopper 105. An inlet 335 leading to the closure 325 allows powder to be introduced into the hopper 105.

At least one portion of the powder flower 130 is housed in the second seal 330. In one form, the membrane 155 may be part of the speaker cone of a conventional audio speaker. The speaker is connected to a functional generator that supplies power and frequency range to the speaker through an amplifier. Every time the speaker cone vibrates, fluidized sound is generated. The speaker cones may include, for example, 3 inch woofers, 4 inch woofers, 6.5 inch woofers, and the like. In another embodiment, the powder flower includes a membrane away from the speaker such that when the speaker cone vibrates, the membrane also vibrates. This configuration is useful for maintaining a controlled environment in the hopper 105 in that the speaker is fully housed in the second seal 330 and is not directly exposed to the hopper 105.

Additionally or instead, bulk powder flower 350 may be provided to fluidize bulk powder 355 contained within bulk powder container 360. Bulk powder container 360 may be used to supply powder to hopper 105 as shown in FIG. 10. In this form, the bulk powder container 360 includes an outlet 365 that communicates with the inlet 335 of the hopper 105. A bulk powder flowr 350 including an actuator 375 and a membrane 370 similar to that described above is operated when required to fluidize the bulk powder 355 and send it through the outlet 365 to the hopper 105. This operation continues and a small amount of powder is continuously supplied to the hopper 105 at a rate at which the powder flows to one or more outlets 120 of the hopper 105. Alternatively, the operation may be periodic. In one form, bulk powder flower 350 can be operated when the height of the powder in hopper 105 is lower than a predetermined height. This may include manual operation or level sensors such as capacitive sensors may be used for automated recharging. A gate or valve may also be provided near the inlet 335.

A powder filling apparatus 100 incorporating the embodiments of FIGS. 9 and 10 is shown in FIG. 11. In this embodiment, a valve 380 may be provided to selectively introduce the powder in the bulk powder container 360 into the hopper 115. In this form, the valve 380 opens when the height of the powder layer 115 in the hopper 105 falls below a predetermined height. The height of the powder layer is sensed by the capacitive sensor 385 in a position that is activated to generate a signal when its height falls below a predetermined height. The signal is transmitted to a controller that controls opening and closing valve 380. Additionally or instead, a laser sensor can be used. In the form shown, a second seal 390 may also be provided in at least one portion of the bulk powder flowr 350.

The powder filling device 100 has been developed for filling powder into containers in an improved manner. The powder filling device 100 is particularly efficient at filling fine dry powder in a unit dose container. For example, Table 1 shows a comparison between filling a fine dry powder medicine, ie, powder A, using a powder filling machine 100 according to the present invention and a powder filling machine of the prior art. Prior art powder chargers are shown in US Pat. No. 6,182,712. The powder filling apparatus 100 of FIG. 11 with the transfer chamber shown in FIGS. 4A and 4B was used as a comparative example. In the table, N is the number of filled containers, SD is the standard error, and RSD is the relative standard error. As shown, in each of the five separate tests, the prior art system could not meet the filling consistency of the powder filling apparatus 100. In fact, even in the best experiments using the prior art apparatus, the filling range was more than twice the range using the powder filling apparatus 100 according to the invention.

Table 1

The powder filling apparatus 100 according to the invention also shows a universal adaptability for filling various powders. The powder filling apparatus 100 of FIG. 11 with the transfer chamber shown in FIGS. 4A and 4B was used to compare different powders and the results are shown in FIG. 2. Six different powders were filled in unit dose containers. Each powder varies in size, composition, active agent, excipients and properties. However, as can be seen from the data, a very consistent filling is made for each powder. Very low RSD was obtained for each powder. In addition, the powder filling apparatus 100 exhibits the ability to consistently fill containers with both small and large doses.

TABLE 2

A computer controller may be provided to control the operation of the bulk powder flowr 350 and / or to control the operation of the powder flowr 130 and / or the second powder flowr 240. The controller may control the operation of the entire powder filling device 100. The controller may be a single control device, a plurality of control devices connected to each other, or a plurality of control devices that may be connected to other components of the package device 100.

In one form, the controller includes electronic hardware that includes an electrical circuit with an integrated circuit suitable for controlling or operating the powder filling device 100. In general, the controller is adapted to accept data inputs, perform calculations, produce useful output signals, and also sense signals from one or more sensors and other device components and oversee the process of powder filling apparatus 100. And can be used to control. However, the controller may perform only one of these functions. In one embodiment, the controller operates (i) a computer comprising a central processing unit (CPU) interconnected to a memory system with a peripheral control unit, (ii) operating or specifying a particular component of the powder filling unit 100. One or more of one or more controller interface boards with application specific integrated circuits (ASICs) to operate the process, and (i) suitable support circuitry. Typical CPUs include PowerPC ^™ , Pentium ^™ , and other processors. ASICs are designed and programmed for specific tasks, such as retrieval of data and other information from the powder filling device 100 and / or operation of a particular device. Typical support circuitry includes, for example, coprocessors, clock circuits, caches, power supplies, and other well known components in communication with the CPU. For example, a CPU often works in conjunction with random access memory (RAM), read-only memory (ROM), and other known storage devices. RAM can be used to store software implementations of the present invention during process execution. Programs and subroutines of the present invention are generally stored in mass storage and recalled for temporary storage in RAM when executed by the CPU.

The software execution and computer program code products of the present invention may be stored in a storage device such as an EPROM and recalled into RAM during execution by a controller. The computer program code is written in a conventional computer readable programming language such as, for example, assembly language, C, C ", Pascal, or native assembly. Appropriate program code can be written in a computer system using a conventional text editor. A computer, such as a memory, enters a single file or a plurality of files stored or contained on an available medium, and if the input code text is a high level language, the code links with the object code of the precompiled Windows library routines. To execute linked and compiled object code, the system user invokes the object code, causing the computer system to load the code into memory to perform the tasks identified in the computer program. do.

In one form, the controller may include a microprocessor or ASIC having a sufficiently small size and power consumption accommodated on or in the powder filling device 100. For example, suitable microprocessors for use as local microprocessors include the MC68HC711E9 from Motorola, the PIC16C74 from Microchip, and the 82930AX from Intel. The microprocessor includes one microprocessor chip, a plurality of processor and / or coprocessor chips, and / or a digital signal processor (DSP) capability.

In one particularly useful implementation, powder filling apparatus 100 may be used to fill pharmaceutical containers, such as blisters, capsules, vials, bottles, and the like with powdered medicine. For example, the powder filling device 100 has been proved particularly useful for filling dry powder inhalable medicaments into containers capable of aerosolizing the powdered medicament for the user to inhale. 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 can be initially stored in a sealed package, before the powder is aerosolized. The packaging opens. Or as disclosed in US Pat. No. 4,995,385, US Pat. No. 3,991,761, US Pat. No. 6,230,707, PCT Publication WO 97/27892, the powder may be stored in a capsule, which capsule may be inserted before, during or after insertion into an aerosolization device. Can be opened. Compressed air introduced in US Pat. No. 5,458,135, US Pat. No. 5,785,049, US Pat. No. 6,257,233 or US Patent Application Nos. 09 / 556,262 and PCT, filed Apr. 24, 2000, entitled "Aerosolization Apparatus and Method thereof" WO 00/72904 By means of an active element, such as the propellant introduced in, in either bulk, blister, capsule, or the like, the powder may be aerosolized. Alternatively, as illustrated in US Patent Application 09 / 583,312 and US Patent 4,995,385, the powder may be aerosolized in response to inhalation of the user. All of the above references are hereby incorporated by reference in their entirety.

The powdered medicament may comprise an active agent. Active agents described herein include agents, drugs, compounds, compositions or mixtures thereof that provide a pharmacological, often beneficial effect. This includes foods, supplements, nutrients, drugs, vaccines, vitamins, and other beneficial actives. As used herein, the term includes any physiological or pharmacologically active substance that produces a local or systemic effect on a patient. Active agents that are bound to the agents described herein include, without limitation, peripheral nerves, adrenergic receptors, cholinergic receptors, skeletal muscle, circulatory system, smooth muscle, blood circulation system, synoptic sites, nerve effector junctions, endocrine system and hormone system, Inorganic or organic compounds, including agents acting on the immune system, genital system, skeletal system, pulmonary circulation system, otacoid system, digestive system and embryo design, histamine system, and central nervous system. Suitable active agents include, for example, sleeping pills and sedatives, psychoactive agents, neurostabilizers, respiratory drugs, anticonvulsants, muscle relaxants, antiparkinson drugs (dopamine antagonists), analgesics, anti-inflammatory drugs, anti-anxiety drugs, appetite suppressants, antimigraine drugs, Muscle contractors, anti-infectives (antibiotics, antiviral agents, antifungal drugs, vaccines), anti-arthritis agents, antimalarial drugs, anti-emetic drugs, antiepileptic drugs, bronchodilators, cytokines, growth factors, anticancer drugs, antithrombin drugs, hypertension drugs, heart drugs Hormonal drugs, including antiarrhythmics, antioxidants, asthma and contraceptives, sympathomimetics, diuretics, fat control drugs, anti-male hormones, repellents, anticoagulants, tumors, anti-tumor drugs, hypoglycemic drugs, nutritional supplements and supplements, Growth supplements, anti-inflammatory agents, vaccines, antibodies, diagnostics, and contrast agents. Active agents administered by respiration may act locally or systemically.

Active agents flow into one of a number of structural lines, including but not limited to small molecules, peptides, polypeptides, proteins, polysaccharides, steroids, proteins that induce physiological effects, nucleotides, oligonucleotides, polyoligonucleotides, fats, electrolytes, and the like. Enter

Examples of active agents suitable for use in the present invention include calcitonin, amphotericin B, erythropoietin (EPO), factor VII, factor VII, seredase, serezime, cyclosporine, granulocyte colony stimulating factor (GCSF), thrombopoie Ethine (TPO), alpha-1 proteinase inhibitor, elkatonin, granulocyte leukocyte macrophage colony stimulating factor (GMCSF), growth hormone, human growth hormone (HGH), growth hormone stimulating 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, Progesterone Promoting Hormone (LHRH) , Factor VII, insulin, proinsulin, insulin analogues (eg, monoacylated insulins as disclosed in US Pat. No. 5,922,675, incorporated herein by reference), amylin, C-peptide, somatostatin, octreo Tied Somatostatin analogues, vasopressin, follicle stimulating hormone (FSH), insulin type growth factor (IGF), insulin tropin, macrophage colony stimulating factor (M-CSF), nerve growth factor (NGF), tissue growth factor Latino growth factor (KGF), glycal growth factor (GGF), tumor necrosis factor (TNF), endothelial growth factor, parathyroid hormone (PTH), glucagon-type peptide thymosin alpha1, IIb / IIIa inhibitors, alpha-1 anti Trypsin, phosphodiesterase (PDE) compounds, VLA-4 inhibitors, bisphosphonates, respiratory conjugated virus antibodies, cystic fibrosis membrane control (CFTR) genes, deoxyribonuclease (Dnase), bactericidal / permeability promoting proteins (BPI), Anti-CMV antibody, 13-cis retinoic acid; Erythromycin, oleandomycin, troledomycin, roxithromycin, clarithromycin, daversin, azithromycin, flurithromycin, dirisromycin, probemycin, spiromycin, midecamycin, leucomycin Macrolides, such as myokamycin, locamycin, andaziromycin, and swinolide A; Cyprofloxacin, Ofloxacin, Levofloxacin, Trobafloxacin, Alatrofloxacin, Moxifloxacin, Norfloxacin, Enoxacin, Grepafloxacin, Gatifloxacin, Lomefloxacin, Spafloxacin, Theme Fluoroquinolones, gentamicins, such as phloxacin, pefloxacin, amifloxacin, flefloxacin, tolufloxacin, frulifloxacin, irroxacin, pajufloxacin, clinafloxacin, and citafloxacin, Aminoglycosides, vancomycin, teicoplanin, lampolanin, mideplanin, colistin, daptomycin, graphene, such as netylmycin, paramesin, tobramycin, amikacin, kanamycin, neomycin, and streptomycin Micidine, colistimetate, polymyxins such as polymyxin B, capreomycin, bacitracin, penems; Penicillin including penicillin-sensitive agents such as penicillin G, penicillin V, penicillinase-resistant agents such as methicillin, oxacillin, clocksacillin, dicloxacillin, floxacillin, naphcillin; Gram negative microbial active agents such as ampicillin, amocillin, and hetacillin, silin, and galampicillin; Antisudomonal penicillins such as carbenicillin, ticarcillin, azolocillin, mezlocillin, and piperacillin; Seppodoxim, Sepprozil, Sepbuten, Septizomim, Septriaxone, Cephalotin, Sephapirine, Cephalexin, Cepradrin, Sepoxycitin, Sephamandol, Sephazoline, Cephaloridine, Sephaclo, Sephadroxil, Cephaloglycine, Cefuroximine, Celandide, Cytotaxime, Sephatrizin, Cephacetyl, Cefepime, Sepicsim, Cenysid, Ceferrazone, Cetethetan, Cefmethazole, Ceftazidim Monobactams such as cephalosporins, aztreonam, such as loracarbef, and oxalactam; And carbapenems such as imipenem, meropenem, pentamidine isethioate, albuterol sulfate, lidocaine sulfate, metaproterenol sulfate, beclomethasone di prepionate, triamcinolone acetamide, budesonide acetonide, flutica One or more of hand, ifpratropium bromide, flunisolid, chromoline sodium, ergotamine tartrate and analogs applicable thereto, promoters, antagonists, inhibitors, and pharmaceutically acceptable salts of the medicament It is not limited. With respect to peptides and proteins, the present invention includes synthetic forms, natural forms, glycosylated forms, unglycosylated forms, pegylated forms, and biologically active fragments and analogs thereof.

The active agent used in the present invention is suitable for transfection or modification of a bare nucleic acid molecule, a vector, a related viral particle, a plasmid DNA or RNA, or other cell for example, ie antisense. It further comprises a nucleic acid structure of a type suitable for gene therapy, including. Active agents may also include live, weak or dead viruses suitable for use as vaccines. Other available drugs include those listed in Physician's Desk Reference (latest version).

The amount of active agent in the medicament will be the amount necessary to release an effective amount of the active agent per unit dose to achieve the desired result. In fact, this varies widely depending on the particular agent, activity, difficulty of the treatment condition, patient demand, dose conditions, and the desired therapeutic effect. The composition generally comprises any of about 1% to about 99% by weight of the active agent, generally about 2% to about 95% by weight of the active agent, more generally 5% to about 85% by weight of the active agent It also depends on the relative amounts of the additives included in the composition. The compositions of the present invention are particularly useful for active agents which come in dosages of 0.001 mg / day to 100 mg / day, preferably 0.01 mg / day to 75 mg / day, more preferably 0.10 mg / day to 50 mg / day. . One or more active agents are incorporated into the compositions described herein and the use of the term “medicament” never excludes the use of two or more such agents.

The medicament may also comprise a pharmaceutically acceptable excipient or carrier which acts on the lungs, in particular on the lung in question, without the significant reverse toxin effect in question. In addition to the active agent, the medicament may further comprise one or more excipients suitable for lung disease management. Such excipients, if any, are generally present in amounts ranging from about 0.01% to about 95% by weight, preferably from about 0.5% to about 80% by weight, more preferably from about 1% to about 60% by weight. Present in the composition. Preferably, the excipient is, in part, to provide a more efficient and reproducible dosage of the active agent, to improve the handling properties of the powder, such as flowability and consistency, and / or to manufacture and fill unit dosage forms. It further serves to further improve the characteristics of the active factor composition. In particular, excipient materials may further improve the physical and chemical stability of the active agent, minimize residual moisture content and retard moisture absorption, particle surface features such as particle size, cohesion, wrinkles, ease of inhalation, and May function to enhance drug targeting. One or more excipients may also serve as bulking agents when the concentration of active agent in the medicament is to be reduced.

Pharmaceutical excipients and additives for use in the medicaments of the present invention may be present in single or combined states, such as amino acids, peptides, proteins, non-biological polymers, biological polymers, carbohydrates such as sugars, alditols, aldonic acids acid), sugar derivatives such as esterified sugars, and sugar polymers. Suitable excipients are introduced in WO 96/32096 which is incorporated by reference in its entirety. The excipient may have a glass transition temperature (Tg) of about 35 ° C, preferably about 40 ° C, more preferably 45 ° C, most preferably 55 ° C.

Exemplary protein excipients include albumin, such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, hemoglobin and the like. Suitable amino acids (dillusyl-peptides of the invention) that can also act as buffering capacity are: alanine, glycine, arginine, betadine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, Aspartame, tyrosine, tryptophan and the like. Preferred are amino acids and polypeptides that function as dispersants. Amino acids belonging to this category include hydrophobic amino acids such as leucine, valine, isoleucine, tryptophan, alanine, methionine, phenylalanine, tyrosine, histidine, and proline. Dispersion enhancing peptide excipients include dimers, trimers, tetramers, and pentamers comprising one or more hydrophobic amino acid components as described above.

Carbohydrate excipients suitable for use in the present invention include, for example, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; Disaccharides such as lactose, sucrose, trihalose, cellobiose and the like; Polysaccharides such as raffinose, melezitose, maltodextrin, dextran, starch and the like; And alditol, such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol), pyranosyl sorbitol, myoinositol and the like.

The medicament may also include salts obtained from buffers or pH adjusting agents, generally organic acids or bases. Representative buffering agents include organic acid salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, phthalic acid, tris, tromethamine hydrochloride or phosphate buffer.

The medicaments also include polymeric excipients / additives such as cellulose derivatives such as polyvinylpyrrolidone, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylmethylcellulose, picol (sugar polymers), hydroxyethyl starch , Dexrate (eg, cyclodextrin, such as 2-hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin), polyethylene glycol, and pectin.

Such agents include flavors, taste-masking substances, inorganic salts (eg sodium chloride), antibacterial agents (eg benzalkonium chloride), sweeteners, antioxidants, antistatic agents, surfactants (eg "TWEEN 20" and " Polysorbates such as TWEEN 80 "), sorbitan esters, lipids (e.g., phospholipids such as lecithin and other phosphatidylcholines, phosphatidylethanolamines), fatty acids and fatty esters, steroids (e.g. cholesterol), and chelating agents (Eg, EDTA, zinc and other suitable cations). "Remington: Science and Pharmacy Practice", 19 ^th ed., Williams & Williams, (1995), and all other pharmaceutical excipients and / or excipients suitable for use in the compositions according to the invention are hereby incorporated by reference in their entirety. Physician's Desk Reference, 52 ^nd de., Medical Economics, Montvale, NJ (1998).

Since the powders of the present invention are generally scattered (ie, particle sizes range), "mass median diameter" or "MMD" is to measure the average particle size. Many commonly used techniques can be used to determine the average particle size, but here the MMD value is determined by centrifugal sedimentation test. "Mass median aerodynamic diameter" or "MMAD" is to measure the aerodynamic diameter of dispersed particles. Aerodynamic diameter is used to describe the aerosolized powder in terms of its settling motion, and generally refers to the diameter of unit density spheres having the same settling rate as the particles in air. Aerodynamic diameters include the shape, density and physical size of the particles. As used herein, MMAD refers to the midpoint of the aerodynamic particle size of aerosolized powders determined in tight contact in series.

In one form, the powder formulations used in the present invention have a particle size selected to penetrate into the alveoli of the lung, ie preferably 10 μm, preferably 7.5 μm or less, most preferably 5 μm or less. Dry powders having MMD and usually in the range of 0.1 μm to 5 μm. The dosed dose efficiency (DDE) of these particles is at least 30%, more preferably at least 40%, more preferably at least 50%, most preferably at least 60%, and aerosol particle size The distribution is about 1.0-5.0 μm MMAD, usually 1.5-4.5 μm MMAD, preferably 1.5-4.0 μm MMAD. Such dry powders contain up to about 10 weight percent, usually up to about 5 weight percent, and preferably up to about 3 weight percent moisture. The powders are introduced in WO 95/24183, WO 96/32149, WO 99/16419, WO 99/16422, all of which are incorporated herein by reference.

While the invention has been described in considerable detail with respect to certain preferred embodiments, other embodiments are possible, and modifications, substitutions, and equivalents of the illustrated embodiments will become apparent to those skilled in the art through the description and drawings in the specification. For example, the relative position of the elements may be changed as a countermeasure for relative movement. In addition, various features of the embodiments herein may be combined in various ways to provide further embodiments of the invention. In addition, certain terms are used for the purpose of clarity of explanation and do not limit the scope of the present invention. For example, the use of terms such as "up" and "down" and "first" and "second" may be reversed in the specification. Accordingly, the appended claims should not be limited to the details of the preferred embodiments contained herein, but should include all changes, substitutions, and equivalents within the true spirit and scope of the invention.

Claims (58)

A hopper having an outlet and containing a powdered medicament, A disturbance member capable of disturbing the medium in the hopper sufficient to regulate the powder flow through the outlet, And the chamber may be filled by powder flow entering the chamber through the outlet. The chamber filling apparatus of claim 1, wherein the medium comprises a gas. The chamber filling apparatus of claim 1, wherein the medium comprises air. The chamber filling apparatus according to claim 1, wherein the disturbing member is a vibration member capable of causing vibration in the hopper. 5. The chamber filling apparatus of claim 4, wherein the vibrating member comprises a membrane. 6. The chamber filling apparatus of claim 5, wherein the membrane vibrates at a selected frequency to fluidize the powder. 6. The chamber filling apparatus of claim 5, wherein the membrane vibrates at a frequency selected to cause resonance in the vessel. The chamber filling apparatus of claim 1, wherein the vibrating member vibrates at a frequency of about 10 Hz to about 1000 Hz. The chamber filling apparatus of claim 1, further comprising a powder vibrating member. 10. The chamber filling apparatus according to claim 9, wherein the powder vibrating member includes a member vibrating in contact with the powder. 10. The chamber filling apparatus according to claim 9, wherein the powder vibrating member has a longitudinal axis and vibrates in a direction parallel to the longitudinal axis. 2. The chamber filling apparatus of claim 1, wherein the chamber is a chamber in a container. 13. The chamber filling apparatus of claim 12, wherein the container is a blister pack. 13. The chamber filling apparatus of claim 12, wherein the container is a capsule. The chamber filling apparatus of claim 1, further comprising a chamber for delivering the powder to the container. The chamber filling apparatus of claim 15, wherein the chamber is a metering chamber. 16. The chamber filling apparatus according to claim 15, wherein the chamber is in a rotating member. 18. The chamber filling apparatus according to claim 17, wherein the rotating member is rotatable between the powder accommodating position and the powder discharging position. The chamber filling apparatus of claim 1, wherein the hopper includes a seal having sidewalls. 20. The chamber filling apparatus according to claim 19, wherein the hopper includes a cover and the vibrating member includes a membrane near the cover. 20. The chamber filling apparatus of claim 19, wherein the hopper comprises a cover, the cover comprising a vibrating member. A hopper having an outlet and containing a powdered medicament, A vibrating member positioned in, on, or near the hopper and capable of fluidizing the powder in the hopper while being separated from the powder in the hopper, And the chamber may be filled by powder flow entering the chamber through the outlet. 23. The chamber filling apparatus according to claim 22, wherein the vibrating member includes a membrane. 24. The chamber filling apparatus of claim 23, wherein the membrane vibrates at a selected frequency to fluidize the powder. 23. The chamber filling apparatus according to claim 22, further comprising a second vibrating member. 27. The chamber filling apparatus of claim 25, wherein the second vibrating member includes a member in contact with the powder. 26. The chamber filling apparatus according to claim 25, wherein the second vibrating member has a longitudinal axis and vibrates in a direction parallel to the longitudinal axis. 23. The chamber filling apparatus of claim 22, wherein the chamber comprises a container. 23. The chamber filling apparatus according to claim 22, further comprising a chamber for delivering said powder to a container. 30. The chamber filling apparatus of claim 29, wherein the chamber is a metering chamber. Providing a powdered medicament in the hopper, Disturbing the medium in the hopper to fluidize the powder, and Moving the powder into the chamber through the outlet. 32. The method of claim 31 wherein the medium comprises a gas. 32. The method of claim 31 wherein the medium comprises air. 32. The method of claim 31, comprising disturbing the medium by causing vibrations in the medium. 35. The method of claim 34, wherein the vibration is generated by vibrating the membrane. 36. The method of claim 35 wherein the membrane vibrates at a selected frequency to fluidize the powder such that the powder passes through an outlet. 37. The method of claim 36, wherein the membrane vibrates at a frequency of about 10 Hz to about 1000 Hz. 32. The method of claim 31, further comprising oscillating the member in contact with the powder. 32. The method of claim 31 wherein the chamber comprises a container and the method further comprises sealing the container. 32. The method of claim 31, further comprising moving the powder from the chamber to the vessel. 32. The method of claim 31 including rotating the chamber from a powder receiving position to a powder discharge position. Providing a powdered medicament, Vibrating a member away from the powder to fluidize the powder, and Moving the powder into the chamber through the outlet. 43. The method of claim 42 wherein the member is a membrane. 44. The method of claim 43, wherein the membrane vibrates at a selected frequency to fluidize the powder so that the powder passes through the outlet. 43. The method of claim 42, wherein the powder vibrates at a frequency of about 10 Hz to about 1000 Hz. 43. The method of claim 42, further comprising oscillating the second member in contact with the powder. Providing a container, Filling the container with powdered medicine fluidized by a fluidizing member away from the powdered medicine, and A pharmaceutical package produced by the process comprising the step of sealing the container to secure the powdered medicine. 48. The pharmaceutical package of claim 47, wherein the container comprises a blister package. 49. The pharmaceutical package of claim 48, wherein the blister package comprises a bottom layer having a cavity. 50. A pharmaceutical package as claimed in claim 49 wherein the blister package includes an upper layer that can be sealed over the lower layer. 51. A pharmaceutical package as defined in claim 50 wherein at least one of the layers comprises a metal. 51. A pharmaceutical package as defined in claim 50 wherein both layers comprise a metal. 48. The pharmaceutical package of claim 47, wherein the container is at least part of a capsule. 48. The pharmaceutical package of claim 47, wherein the container is at least part of a vial. 48. A pharmaceutical package according to claim 47 wherein the container is a bottle. 48. A pharmaceutical package as recited in claim 47 wherein the package is further prepared by a step of weighing the powder in a metering chamber prior to filling the container with powder. 59. A pharmaceutical package as claimed in claim 56 wherein the package is manufactured by a process further comprising rotating the metering chamber. 48. A pharmaceutical package according to claim 47, wherein the package is produced by a process in which the powdered drug is also fluidized by a vibrating member in contact with the powdered drug.