ES2391174T3 - Device and method to control the flow of a powder - Google Patents

Abstract

A pharmaceutical powder filling apparatus for use in packaging a pharmaceutical powder formulation, elaparate (100) comprises: a hopper (105) adapted to contain a pharmaceutical powder formulation (115), the hopper (105) comprises an outlet (120) , a vibrating member and an actuator (140) adapted to cause the vibrating member to vibrate so that dust flows from the outlet such that a chamber (125) can be filled with dust (115) flowing through the outlet (120); and characterized in that the vibrating member comprises a membrane (155) positioned in, on, or near the latch (105) such that the vibrating member separates from the dust (115) in the hopper, the vibrating member, in use, is excited by the actuator to produce vibrations continuously, or periodically in short intervals, to alter a medium inside the hopper and therefore keep the powder in the hopper (105) in a constantly fluidized state such that it flows through the outlet (120) .

Description

Device and method to control the flow of a powder

Background

The need for effective therapeutic treatment of patients has resulted in the development of a variety of techniques to deliver a pharmaceutical formulation to a patient. A traditional technique involves the oral supply of a pharmaceutical formulation in the form of a pill, capsule, or the like. Inhalable drug delivery, when a patient inhales orally or nasally a pharmaceutical aerosol formulation to deliver the formulation to the patient's airways, has also proven to be an effective form of delivery. In an inhalation technique, a pharmaceutical formulation is deeply delivered into the patient's lungs where it can be absorbed into the bloodstream. In another inhalation technique, a pharmaceutical formulation is delivered to a target region in the airways to provide local treatment to the region. There are many types of inhalation devices that include devices that aerosolize a dry powder pharmaceutical formulation.

The pharmaceutical formulation is frequently packaged in such a way that it is readily available to a user. For example, a dose or part of a dose can be stored between the layers of a multilayer package, conventionally referred to as a blister or blister package. Normally, a cavity is formed in a lower layer, the pharmaceutical formulation is deposited inside the cavity, and an upper layer is sealed over the lower layer, such as when heating and / or compressing the layers, to ensure the pharmaceutical formulation within The cavity. Alternatively, the dose can be stored in a capsule to be swallowed or from which the pharmaceutical formulation can be aerosolized. Other packages, such as bottles, bottles, and the like, can also be used to store the pharmaceutical formulation.

It is often difficult to effectively fill packages with the pharmaceutical formulation. For example, during the powder filling process, it is difficult to sufficiently fluidize the powder and / or maintain the consistent flow properties of the powder. Poorly controlled dust flow can result in inconsistently full packaging. For example, the filling mass may vary from package to package, thereby affecting the dose to be delivered to a patient for a unit dose package or resulting in many or very few doses that are packaged in a multi-package. dose. Additionally, the packing characteristics of a powder in a package may vary as a result of the inconsistent flow of dust during the filling process.

Therefore, it is desirable to be able to control the flow of a powder, particularly a pharmaceutical powder formulation. It is further desirable to be able to control the flow of a pharmaceutical powder formulation such that a package can be filled effectively and consistently with the pharmaceutical formulation. It is still further desirable to control the flow of a pharmaceutical formulation in a manner that reduces any adverse effects on the pharmaceutical formulation.

WO 2004/002827 describes an apparatus for the measured transport of fine powders in the receptacles. The apparatus comprises a hopper that has an opening and an element. A bed of fine powder is disposed inside the hopper and the element vibrates inside the powder near the opening. US 3,259,272 describes a method and apparatus for delivering dust using sound energy pulses.

Summary

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

According to the invention a pharmaceutical powder filling apparatus is provided for use in the packaging of a pharmaceutical powder formulation, the apparatus comprises:

A hopper adapted to contain a pharmaceutical powder formulation, the hopper comprises an outlet, a vibrating member and an actuator adapted to cause the vibrating member to vibrate such that the powder flows from the outlet such that a chamber can be filled with the dust flowing through the outlet; and characterized in that the vibrating member comprises a membrane positioned in, on, or near the hopper such that the vibrating member separates from the dust in the hopper, the vibrating member, in use, is excited by the actuator to produce vibrations continuously , or periodically in short intervals, to alter a medium within the hopper and therefore keep the powder in the hopper in a constantly fluidized state such that it flows through the outlet.

The invention also provides a method for filling a chamber, the method comprises:

provide a chamber to be filled; provide a pharmaceutical powder formulation; providing a filling apparatus comprising a hopper having an outlet and a vibrating member that

it comprises a membrane; The pharmaceutical powder formulation is located in the hopper and the apparatus arranged in such a way that the member

The vibrating position is positioned in, on, or near the hopper so that the vibrating member separates from the dust in the hopper; arrange the chamber in such a way that the powder flows from the outlet so that it flows in the chamber; vibrate the vibrating member continuously, or periodically in short intervals, to alter a medium

inside the hopper and therefore keep the powder in the hopper in a constantly fluidized state such that it flows through the outlet; and allow dust to flow through the outlet in the chamber.

Drawings These features, aspects, and advantages of the present invention will be better understood with respect to the following description, appended claims, and accompanying drawings illustrating the exemplary features of the invention. However, it is understood that each of the features can be used in the invention in general, not only in the context of the particular drawings, and the invention includes any combination of these features, wherein:

Figure 1 is a schematic sectional side view of a powder filling apparatus of the invention;

Figures 2A to 2C are schematic sectional side views of various receptacles that can be filled using the powder filling apparatus of the invention; Figure 3 is a schematic sectional side view of another version of a powder filling apparatus; Figures 4A and 4B are schematic sectional side views of the operation of another version of an apparatus

for powder filling; Figure 5 is a schematic sectional side view of another version of a powder filling apparatus; Figures 6A and 6B are schematic sectional side views of the powder filling apparatus of Figure 5

during dust filling processes; Figure 7 is a schematic sectional front view of a multi-chamber apparatus for powder filling; Figures 8A and 8B are schematic sectional front views of other versions of the camera apparatus

powder filling manifold;

Figure 9 is a schematic cross-sectional view showing the inside of a version of an apparatus for powder filling; Figure 10 is a schematic sectional side view of a powder filling apparatus together with a container

volume powder; Y

Figure 11 is a more detailed schematic sectional side view of a version of an apparatus for filling powder with a dust container by volume. Description The present invention relates to the control of the flow of a powder, such as controlling the flow of dust during

A packing filling process. Although the process is illustrated in the context of packaging a pharmaceutical powder formulation, the present invention can be used in other processes and should not be limited to the examples provided herein.

A powder filling apparatus 100 according to the present invention is schematically shown in Figure 1. The powder filling apparatus 100 comprises a hopper 105 having a reservoir 110 capable of containing a bed of dust 115, such as a formulation Pharmaceutical powder. Hopper 105, which can be of any suitable size and shape, comprises an outlet 120 through which the fluidized powder can flow. A chamber 125 can be positioned in proximity to the outlet 120 such that the dust flowing through the outlet 120 will flow into the chamber 125 to fill the chamber 125.

A powder fluidizer 130 may be positioned in, on, or near the hopper 105. The powder fluidizer 130 comprises an alteration member 135 that provides an alteration within the hopper 105. In one version, the alteration member 135 is it can be operated by means of an actuator 140 to cause an alteration within the hopper 105 to control the flow of dust 115 in the hopper 105. The alteration member 135 alters a means 145, such as air or other gas, that is in the hopper 105 such that the altered medium 145 causes fluid fluidization

115. According to the foregoing, the alteration member 135 is positioned such that it is separated from the dust 115 by means 145.

The powder fluidizer 130 can be used to control a powder filling process within the hopper 105. The powder fluidizer 130 is capable of operating continuously or periodically at short intervals to keep the powder 115 in a constantly fluidized state. In this version, the powder 115 can flow through the outlet 120 until the hopper 105 is empty or until the chamber 125 is filled. In another version, the powder fluidizer 130 can control the time of the powder flow 115 and / or can control the amount of dust 115 flowing through the outlet 120 of the hopper 105 and into the chamber 125. For example, the outlet 120 in the hopper 105 can be small enough such that the unaltered powder 115 does not flow through outlet 120 or does not flow consistently through outlet 120. When it is desired that dust 115 flow into chamber 125, actuator 140 causes alteration member 135 to alter medium 145 and by therefore the fluid 115 fluidizes to allow the powder 115 to flow through the outlet 120 and into the chamber 125. When the chamber 125 is sufficiently filled, the actuator 140 can cause the alteration to stop or be reduced, reducing by so much the cant Powder unit 115 flowing through outlet 120, for example at the end of the flow of dust through outlet 120.

In one version, the powder fluidizer 130 provides an alteration within the hopper 105, and the alteration comprises vibrations 150. The alteration member 135 may comprise a vibrating object, such as a membrane 155, inside, in or near the hopper. 105, membrane 155 is capable of vibrating when excited by actuator 140 to produce vibrations. The vibrating membrane 155 alters the medium 145. For example, when the membrane 155 moves in a downward direction, the portion of the medium 145 immediately in front is compressed causing a slight increase in pressure, then moves back beyond from its resting position and causes a reduction in pressure. The process can continue in such a way that one or more alternating high and low pressure waves radiate away from the membrane 155. The waves contact the dust 115 and the resulting impact is sufficient to at least momentarily fluidize the dust 115.

The frequency of the vibrations 150 can be selected to fluidize a particular powder 115 and / or to be suitable for a particular filling process. In a particular version, the vibrations 150 may be in the audible range. In yet another version, membrane 155 may vibrate at a frequency in a non-audible range to decrease operator discomfort. The vibration may be at any frequency, or multiple frequencies, that desirably fluidizes or otherwise controls the flow of the dust 115. For example, in the version shown in Figure 1, the membrane 155 may vibrate at one or more frequencies comprising a frequency of about 10 Hz to about 1000 Hz, more preferably from about 90 Hz to about 500 Hz, more preferably from about 100 Hz to about 200 Hz, and more preferably at about 120 Hz. In one version, the frequency can be selected . For example, through experimentation or modeling, a particularly desirable frequency can be selected for a particular configuration and / or powder, such as a frequency that is determined through experimentation or analysis to cause resonance within hopper 105.

The chamber 125 comprises a positionable opening 160 in relation to the outlet 120 in the hopper 105 to receive the powder flow from the hopper 105 through the outlet 120. In one version, such as the version shown in Figure 1, the opening 160 in chamber 125 has substantially the same shape and size as outlet 120 to prevent excessive amounts of dust 115 from being trapped between hopper 105 and a member 165 that contains or supports the chamber

125. As also shown in the version of Figure 1, the hopper 105 may comprise convergent side walls 170 that provide a convergent flow path to the outlet 120 for the dust 115. The convergent flow path allows the volume of the reservoir to be increased. in hopper 105. In another version, chamber opening 160 and outlet 120 may have different sizes. For example, the outlet 120 may be smaller than the opening 160 when it is desirable to fill a relatively large chamber with a precisely controlled amount of dust 115 or when it is not desirable to provide a mechanism to precisely position the chamber 125 below the outlet 120 Alternatively, the opening 160 may be smaller than the outlet 120 when it is desirable to use hopper 105 to fill chambers of various sizes 125 or in situations where loss of dust 115 in spaces between hopper 105 and is not of fundamental interest. member 165.

The chamber 125 may be inside a receptacle 175 used to store the powder 115. For example, the receptacle 175 may be in the form of primary or secondary packaging used to store a pharmaceutical powder formulation. In one version, the receptacle 175 comprises a multilayer package, conventionally referred to as a blister or blister package, and the chamber 125 is within the multilayer package. As shown in Figure 2A, the powder 115 flows from the hopper 105 to a cavity 180 in a lower layer 185 of the multi-layer gasket. Then an upper layer (not shown) can be sealed in the lower layer 185, such as when heating and / or compressing the layers, to secure the dust inside the cavity 180, as described for example in US Patent 5,865,012 and in U.S. Patent Application 10 / 301,820, filed on November 20, 2002, which are incorporated herein by reference in their entirety. In one version, the multilayer packaging may comprise a bottom layer comprising a metal containing layer, such as a layer comprising aluminum, and / or an upper layer comprising a metal containing layer. The metal-containing layers can be thick enough to substantially prevent a significant amount of moisture from passing through them. For example, the metal-containing layers may be from about 10 µm to about 100 µm, and more preferably from about 20 µm to about 80 µm. The bottom layer and the top layer can be sealed by a layer of sealing material, such as a lacquer layer that can be from about 1 µm to about 20 µm. In another version, the receptacle 175 comprises a capsule, such as a capsule to be swallowed or from which the pharmaceutical formulation can be aerosolized, and the chamber 125 is within the capsule. As shown in Figure 2B, a first portion 190 of a capsule is positioned to receive powder flowing through the outlet 120 of the hopper. After filling, a second portion (not shown) may be placed on the first portion 190 to form the capsule and to contain the powder within the capsule, as described in US Patent 4,247,066, US Patent 4,864,876, US Patent 6,357,490 , and in PCT application WO 00/07572 published on February 17, 2000, all of which are incorporated herein by reference in their entirety. In another version, as shown in Figure 2C, the chamber 125 may be inside a container 195, such as a bottle, bottle or the like. For example, in this version, container 195 can be used to contain multiple doses of a pharmaceutical powder formulation, such as a container described in US Patent 4,524,769 which is incorporated herein by reference in its entirety.

In another version, the chamber 125 may be a transfer chamber 200 that transfers dust flowing from the hopper 115 within the transfer chamber 200 to another chamber, such as a chamber within a package 175. For example, as shown in Fig. 3, the transfer chamber 200 can be provided in a movable member 205. The transfer chamber 200 receives dust from the hopper 115 when it is in a filling position as shown in Fig. 3. The movable member 205 then transports the transfer chamber 200 to a position in proximity to the gasket 175 when at least a portion of the contents of the transfer chamber 200 can be emptied into the gasket 175. The transport chamber 200 can be sized in such a way that Contains a predetermined amount of powder. For example, the transport chamber 200 can be sized to collect a dose of a pharmaceutical powder formulation, and the exact dose can be supplied to the package 175. A cleaning blade 210 can be provided to scrape off any excess dust in the chamber. of transport 200.

In the version shown in Figures 4A and 4B, a dust transfer assist mechanism is provided

215. In one version, the dust transfer assist mechanism 215 comprises a channel 220 in communication with the transfer chamber 200. The channel 200 can be connected to a suction source when the transfer chamber 200 is in the position that collect dust shown in figure 4A. In this way, suction 225 can be provided to the transfer chamber 200 to assist in collecting dust 115 inside the transfer chamber 200. A filter 230 can be provided in the transfer chamber 200 to prevent dust 115 from getting suction into channel 200. For example, the filter may comprise openings having a diameter of about 0.10 micrometers to about 0.65 micrometers, more preferably about 0.65 micrometers. When transfer chamber 200 is moved to a dust ejection position as shown in Figure 4B, channel 220 can be connected to a pressurized gas source to create pressure 235 within channel 220 to cause dust to be ejected in transfer chamber 200 in receptacle 175. An example of a dust transfer assist mechanism is described in US Patent 5,826,633, which is incorporated herein by reference in its entirety.

The powder filling apparatus 100 provides an advantageous powder filling process. Said advantage is that there is a reduction in the amount of physical contact between the powder in the hopper 105 and other objects. This reduced contact may be useful in avoiding undesirable conditions in the pharmaceutical powder formulation. For example, excessive physical contact may in some situations cause one or more of the following situations: aggregate formation, increased electrostatic interactions, denaturation, and reduced aerosol performance. Although these adverse reactions have been avoided or compensated in a complicated way and with high costs, reducing the amount of direct physical contact provides a useful and particularly simplified alternative.

In another version, the powder filling apparatus 100 comprises a powder fluidizer 130 of the type discussed above in combination with an additional powder fluidizing member. For example, as shown in Figure 5, the powder filling apparatus may comprise a second powder fluidizer 240. The second powder fluidizer 240 comprises a powder fluidizing member 250 and an actuator 255 which directs the powder fluidizing member 250 in a form that fluidizes the powder 115 in the hopper 105. For example, the fluidizing fluid member 250 may be a member that directly contacts the powder 115, and the movement of the fluidizing member 250 causes the powder 115 to fluidize. In the version shown, the fluidizing fluid member 250 comprises a bar 260 extending downward in the bed of dust 115. A support arm 265 holds the bar 260 in the hopper 105. The actuator 255 can be connected to drive the arm 265 to drive the bar 260 or can be connected directly to the bar 260, such as being connected between the bar 260 and the arm 265. Powder fluidization in this way is described in Patent E US 6,182,712 which is incorporated herein by reference in its entirety. The bar 260 can be caused to vibrate by the actuator 240. For example, as shown in Figure 5, the bar can have a distal end that can be positioned close to the outlet 120, and the actuator 240 can propel the bar in an up and down movement 270 to fluidize the powder to cause it to flow through the outlet 120 and into the chamber 125. In a particular version, the bar 260 can be attached to a motor, such as a piezoelectric motor, and vibrates at a frequency of about 1000 Hz to about 180,000 Hz, more preferably from about 10,000 Hz to about 40,000 Hz, and more preferably from about 15,000 Hz to about 25,000 Hz. Additionally or alternatively, bar 260 may vibrate or move in another direction , such as laterally or rotationally. In another version, the additional powder fluidizing member may comprise a stirrer or other fluidizing mechanism.

The powder fluidizer 130 and the second powder fluidizer 240 can work in tandem or only to fluidize the powder 115 in the hopper 105. For example, as shown in Figure 5, the powder fluidizer 130 can act concurrently with the second Powder fluidizer 240 to simultaneously generate vibrations 150 in medium 145 and to directly vibrate powder 115. For some powders this combined action provides superior fluidization capabilities. In another version, the powder fluidizer 130 and the second powder fluidizer 240 may act at different times or act in a manner to complement each other. For example, as shown in Figures 6A and 6B, the powder fluidizer 130 may serve to complement the action of the second powder fluidizer 240. As shown in Figure 6A, for some powders, the vibration of the bar 260 may be sufficient for a chamber 125 to be filled but it can also result in the formation of one or more gaps 275 in the area in proximity to the bar 260. After the vacuum 275 has been created, the vibration of the bar 260 would have little capacity of fluidization. To fill the vacuum 275, the powder fluidizer 130 can act, as shown in Figure 6B. The alteration in the medium 145 is sufficient to cause the powder 115 to come back into contact with the bar 260 such that the bar 260 can vibrate again to fluidize the powder 115. The powder fluidizer 130 and / or the second Powder fluidizer 240 may operate continuously to maintain powder 115 in a continuously fluidized condition during filling of multiple chambers 125 through outlet 120. Alternatively, powder fluidizer 130 and / or the second powder fluidizer 240 may operate alone when it is desired to have the fluidized powder 115, and the outlet 120 may have a size such that the powder does not flow substantially through the outlet 120 in the absence of such operation of the fluidizers.

In one version, as shown in Figure 7, the powder filling apparatus 100 is configured to simultaneously fill a plurality of chambers 125. In this version the hopper 105 comprises a plurality of outputs 120, such as two, three, four , or more. The powder fluidizer 130 is positioned to fluidize the powder 115 in the hopper 105 through all the outlets 120. In the version shown in Figure 7, the powder flowing through an outlet 120 passes in a transfer chamber 200 in a movable member 205, which in this version is a rotating member. When the transfer chamber 200 is filled, the movable member 205 is rotated from the filler position shown in the figure to an ejection position when the transfer chambers 200 are positioned above the respective receptacles 175. The receptacles 175 are they support by a platform 300. The platform 300 can be moved relative to the movable member 205 in order to allow the receptacles 175 to be brought in the position shown in Figure 7 and to place the receptacles 175 far after they are filled, at which time which transfer chambers 200 move to their fill positions. This process can continue to a desired number of receptacles that have been filled. In one version, platform 300 may be a movable and indexable plate that has openings for receiving receptacles. In another version, platform 300 may be a belt on roller system.

Figures 8A and 8B show versions of a powder filling apparatus 100 capable of simultaneously filling a plurality of chambers 120 and comprising a powder fluidizer 130 and a second powder fluidizer 240. In the version of Figure 8A, the second Powder fluidizer 240 comprises a bar 260 that can be vibrated in an upward and downward direction 270. Additionally, a mechanism is provided that allows the bar 260 to be translated laterally 310 through each of the openings. An example translation mechanism is described in US Patent 6,182,712 mentioned above which is incorporated herein by reference, as discussed above. In the version of Figure 8B, a plurality of vibration bars 260 are provided. For example, a bar 260 can be associated with a respective output 120.

A detailed view of an embodiment of a powder filling apparatus according to the version of Figure 8A is shown in Figure 9. In this version, a powder fluidizer 130 and a second powder fluidizer 240 are used to control the dust flow into the hopper through a plurality of outlets 120. The bar 260 of the second powder fluidizer is connected to an actuator or piezoelectric motor 320 to cause the bar 260 to vibrate up and down. Within the arm 265 a mechanism is provided, such as a screw unit, which causes the bar 260 to move 310 through the hopper 105. A first closure 325 and a second closure 330 are provided to maintain desirable conditions within the apparatus for powder filling 100. For example, for some powders, such as pharmaceutical powder formulations, it may be desirable to maintain a clean or sterile environment for the powder. It may also be desirable to maintain a certain humidity to maintain a certain relative humidity within the enclosures, particularly the filler powders undergo a change when subjected to significant amounts of moisture. One or more of the enclosures may comprise, for example, an engineered polymer, of medical grade stainless steel, PVC, or the like. In one version, multiple powder fluidizers 130 can be provided within the second enclosure. This can be advantageous when very large hoppers 105 are used. An inlet 335 through closure 325 allows the introduction of bulk powder into hopper 105.

At least a part of the powder fluidizer 130 can be accommodated within the second closure 330. In one version, the membrane 155 may have a part of a speaker cone of a conventional audio speaker. The speaker is connected to a function generator that can provide frequency and power ranges to the speaker through an amplifier. When the speaker cone vibrates, fluidizing sound is created. The speaker cone may comprise, for example, a speaker for 3-inch bass sounds, a speaker for 4-inch bass sounds, a speaker for 6.5-inch bass sounds, or the like. In another version, the powder fluidizer may comprise a membrane that separates from the speaker cone such that when the speaker cone vibrates, the membrane is caused to vibrate. This configuration can be useful in maintaining a controlled environment within the hopper 105 in which the speaker can be housed completely within the second closure 330 and is not directly exposed to the hopper 105.

Additionally or alternatively, a bulk powder fluidizer 350 can be provided to fluidize bulk powder 355 contained in a bulk powder container 360. The bulk powder container 360 can be used to deliver powder to hopper 105, as shown in Figure 10. In this version, the bulk powder container 360 comprises an outlet 365 that is in communication with the inlet 335 in the hopper 105. The bulk powder fluidizer 350, which may comprise a membrane 370 and actuator 375 similar to those described above, it acts when it is desired to fluidize the bulk powder 355 to cause it to flow through outlet 365 and into hopper 105. This performance can be continuous such that a small amount of powder is continuously supplied. to hopper 105 at about the rate at which dust flows through one or more outlets 120 in hopper 105. Alternatively, the performance may be periodic. In one version, bulk powder fluidizer 350 can act when the level of dust in hopper 105 falls below a predetermined level. This may involve manual actuation or a level sensor, such as a capacity sensor, that can be provided to allow automatic filling. A door or valve can be provided near inlet 335.

A powder filling apparatus 100 is shown in Figure 11 incorporating the features of the version of Figures 9 and 10. In this version, a valve 380 is provided, to selectively introduce powder to the bulk powder container 360 in the hopper 115. In this version, valve 380 opens when the level of the powder bed 115 in hopper 105 falls below a predetermined level. The bed level is detected by a capacitive sensor 385 operatively positioned to generate a signal when the bed level falls below the predetermined height. The signal is provided to a controller that controls the opening and closing of the valve 380. Alternatively or additionally, a laser sensor can be used. In the version shown, a second closure 390 is also provided for at least a portion of the bulk powder fluidizer 350.

It has been found that the powder filling apparatus 100 fills the powder in receptacles in an improved manner. The powder filling apparatus 100 is particularly effective in fine dry filler powders in unit dose receptacles. For example, Table 1 shows a comparison to fill a pharmaceutical formulation of fine, dry powder, powder A, using a prior art powder filling and using a powder filling apparatus 100 according to the present invention. The prior art powder filling is described in US Patent 6,182,712. The powder filling apparatus 100 shown in Figure 11 with a transfer chamber as shown in Figures 4A and 4B is used for comparison. In the Table, N represents the number of filling receptacles; DE represents the standard deviation; and DER represents the relative standard deviation. As can be seen, in each of five separate series, the prior art system is unable to match the filling consistency of the powder filling apparatus 100. In fact, even in the best series using the system of the prior art, the filling range was more than twice the range using the powder filling apparatus 100 of the present invention.

Table 1

Stuffing used

N SD (mg) DER (%) Medium filling mass (mg) Range (mg)

Powder Filling of the Prior Art, Series 1

404  0.11 1.5 7.52 1.2

Powder Filler of the Prior Art, Series 2

264  0.18 2.5 7.55 1.94

Prior Art Powder Filler, Series 3

491  0.16 2.1 7.52 1.11

Powder Filler of the Prior Art, Series 4

488  0.15 2.0 7.51 1.39

Prior Art Powder Filler, Series 5

356  0.32 4.3 7.50 1.99

Powder Filling Present 100

288  0.08 1.1 7.50 0.55

The powder filling apparatus 100 of the present invention has also shown universal adaptability to

5 fill various powders. The powder filling apparatus 100 shown in current Figure 11 with a transfer chamber as shown in Figures 4A and 4B is used for a comparison of different powders, and the results are shown in Table 2. Six powders are filled different in unit dose receptacles. The powders are of various sizes, compositions, active agents, excipients, and properties. However, as you can see from the data, very consistent filling is achieved with each of the powders. Very low DER are achieved for each

10 one of the powders. Additionally, the powder filling apparatus 100 demonstrates the ability to consistently fill large and small doses in a receptacle.

Table 2

Powder Filler Using Powder Filler Present 100

N SD (mg) DER (%) Medium Fill Mass (mg) Range (mg)

Powder A

288 0.08 1.1 7.50 0.59

B powder

120 0.03 0.9 4.06 0.16

Dust C

60 0.06 1.2 4.90 0.28

D powder

270 0.91 1.8 50.09 4.90

Powder E Powder F

89 30 0.55 0.18 1.1 1.8 51.32 10.09 3.04 0.82

A computer controller can be provided to control the performance of the bulk powder fluidizer 350

15 and / or to control the performance of the powder fluidizer 130 and / or the second powder fluidizer 240. The controller can control the operation of the complete powder filling apparatus 100. The controller may be a single controller device or it may be a plurality of controlling devices that can be connected to each other or a plurality of controlling devices that can be connected to different components of the packaging apparatus 100.

In one embodiment, the controller comprises electronic hardware that includes electrical circuit comprising integrated circuits that are suitable for operating or controlling the apparatus for dust filling 100. In general, the controller is adapted to accept data input, execute algorithms, produce useful output signals, and can also be used to detect data signals from one or more sensors and other device components, and to monitor or control the process in the powder filling apparatus 100. However, the controller can only perform One of these tasks. In one version, the controller may comprise one or more of (i) a computer comprising a central processing unit (CPU) that is interconnected to a memory system with peripheral control components, (ii) application-specific integrated circuits (ASIC) operating the particular components of the powder filling apparatus 100 or operating a particular process, and (iii) one or more controller interface boards together with the appropriate support circuit. Normal CPUs include PowerPC ™, Pentium ™, and others. The ASICs are designed and preprogrammed for particular tasks, such as data recovery and other information of the device for dust filling 100 and / or operation of particular device components. The typical support circuit includes, for example, coprocessors, clock circuits, cache, power supplies and other well-known components that are in communication with the CPU. For example, the CPU frequently operates in conjunction with a random access memory (RAM), a read-only memory (ROM) and other storage devices well known in the art. RAM can be used to store the software implementation of the present invention during the implementation process. The programs and subroutines of the present invention are normally stored in volume storage devices and recovered from their temporary storage in RAM when executed by the CPU.

The software implementation and the computer program code product of the present invention can be stored in a memory device, such as an EPROM, and recovered in RAM during controller execution. The computer program code can be written in conventional computer-readable programming languages, such as, for example, language language, C, C ", Pascal, or native assembler. The appropriate program code is entered into a single file, or multiple files, using a conventional text editor and stored or incorporated into a computer-usable medium, such as a computer system memory.If the code text entered is in a high-level language, the code is compiled into a compiler code that is linked to an object code of precompiled window collection routines.To execute the compiled or linked object code, the system user invokes the object code, causing the computer system to load the code into memory to develop the tasks identified in the computer program.

In one version, the controller may comprise a microprocessor or ASIC of sufficiently small size and power consumption to be housed in or in the powder filling apparatus 100. For example, microprocessors suitable for use as a local microprocessor include the MC68HC711E9 by Motorola, the PIC16C74 by Microchip, and the 82930AX by Intel Corporation. The microprocessor may include a microprocessor chip, multiple processors and / or coprocessor chips, and / or digital signal processor (DSP) capability.

In a particularly useful implementation, the powder filling apparatus 100 can be used to fill a pharmaceutical receptacle, such as a blister, capsule, bottle, bottle, or the like, with a pharmaceutical powder formulation. For example, the powder filling apparatus 100 has proven to be particularly advantageous in inhalable pharmaceutical formulations of dry filler powder in receptacles from which the pharmaceutical formulation can be aerosolized for inhalation by a user. For example, when in powder form, the powder may initially be stored in the sealed package, which is opened before aerosolization of the powder, as described in US Patent 5,785,049, US Patent 5,415,162, and US Patent Application 09 / 583,312. Alternatively, the powder may be contained in a capsule, as described in U.S. Patent 4,995,385, U.S. Patent 3,991,761, U.S. Patent 6,230,707, and PCT Publication WO 97/27892, the capsule can be opened before, during, or after insertion of the capsule in an aerosolization device. In the bulk, blister, capsule, or the like form the powder can be aerosolized by any active element, such as compressed air, as described in US Patent 5,458,135, US Patent 5,785,049, and US Patent 6,257,233, or propellant, as described in US Patent Application 09 / 556,262, filed on April 24, 2000, and entitled "Aerosolization Apparatus and Methods", and in PCT Publication WO 00/72904. Alternatively, the powder can be aerosolized in response to user inhalation, as described for example in US Patent Application 09 / 583,312 and US Patent 4,995,385. All of the above references are incorporated herein by reference in their entirety.

The pharmaceutical formulation may comprise an active agent. The active agent described herein includes in agent, drug, compound, composition of matter or mixture thereof that provides some frequently beneficial pharmacological effect. This includes foods, food supplements, nutrients, drugs, vaccines, vitamins, and other beneficial agents. As used herein, the terms additionally include any physiologically or pharmacologically active substance that produces a localized or systemic effect on a patient. An active agent for incorporation into the pharmaceutical formulation described herein may be an inorganic or organic compound, which includes, without limitation, drugs acting on: peripheral nerves, adrenergic receptors, cholinergic receptors, skeletal muscles, the cardiovascular system, smooth muscles, the blood circulatory system, synoptic sites, neuro-effector binding sites, endocrine and hormone systems, the immune system, the reproductive system, the skeletal system, pulmonary system, autacoid systems, food and excretory systems, the histamine system, and the system central nervous Suitable active agents can be selected from, for example, hypnotics and sedatives, psychic energizers, tranquilizers, respiratory drugs, anticonvulsants, muscle relaxants, anti-parkinson agents (dopamine antagonists), analgesics, anti-inflammatories, anti-anxiety drugs (anxiolytic), suppressants appetite, antimigraphic agents, muscle contractors, anti-infective antiarthritics (antibiotics, antivirals, antifungals, vaccines), antimalarials, antiemetics, anepileptics, bronchodilators, cytokines, growth factors, antineoplastic agents, antithrombotic agents, antihypertensives, cardiovascular drugs antioxidants, anti-asthma agents, hormonal agents including contraceptives, sympathomimetics, diuretics, lipid regulating agents, antiandrogenic agents, antiparasitic agents, anticoagulants, neoplastic, antineoplastic, hypoglycemic, nutritional agents and supplements, growth supplements, antienteritic agents, vaccines, antibodies, diagnostic agents, and contrast agents. The active agent, when administered by inhalation, can act locally or systemically.

The active agent can fall into a number of structural classes, including but not limited to small molecules, peptide, polypeptides, proteins, polysaccharides, steroids, proteins capable of causing physiological effects, nucleotides, oligonucleotides, polynucleotides, fats, electrolytes, and the like

Examples of active agents suitable for use in this invention include but are not limited to one or more of calcitonin, amphotericin B, erythropoietin (EPO), Factor VIII, Factor IX, ceredasa, cerezima, cycloporporin, granulocyte colony stimulating factor ( GCSF), thrombopoietin (TPO), alpha-1 proteinase inhibitor, elcatonin, factor that stimulates granulocyte macrophage colony (GMCSF), growth hormone, human growth hormone (HGH), growth hormone release hormone ( GHRH), heparin, low molecular weight heparin (LMWH), alpha interferon, beta interferon, gamma interferon, interleukin-1 receptor, interleukin-2 receptor antagonist, interleukin-1 receptor, interleukin-3, interleukin-4, interleukin -6, luteinizing hormone release hormone (LHRH), factor IX, insulin, pro-insulin, insulin analogues (eg, mono-acylated insulin as described in US Patent No. 5,922,675, which is ncorpora here as a reference in its entirety), amylin, C-peptide, somatostatin, somatostatin analogs including octreotide, vasopressin, follicle stimulating hormone (FSH), insulin-like growth factor (IGF), insulintropin, colony stimulating factor macrophage (M-CSF), nerve growth factor (NGF), tissue growth factors, keratinocyte growth factor (KGF), glial growth factor (GGF), tumor necrosis factor (TNF), factors Endothelial growth, parathyroid hormone (PTH), glucagon-like peptide alpha 1 thymosin, IIb / IIIa inhibitor, alpha-1 antitrypsin, phosphodiesterase compounds (PDE), VLA-4 inhibitors, bisphosphonates, respiratory syncytial virus antibody, regulatory gene of cystic fibrosis transmembrane (CFTR), deoxyribonuclease (Dnasa), protein that increases permeability / bactericide (BPI), anti-CMV antibody, 13cis retinoic acid, macrolides such as ertromycin, oleandomic ina, troleandomycin, roxithromycin, clarithromycin, davercin, azithromycin, flurithromycin, dithromromycin, josamycin, spiromycin, midecamycin, leucomycin, myocamycin, rokitamycin, andazithromycin, and swinolida A; fluoroquinolones such as ciprofloxacin, ofloxacin, levofloxacin, trovafloxacin, alatrofloxacin, moxifloxicin, norfloxacin, enoxacin, grepafloxacin, gatifloxacin, lomefloxacin, sparfloxacin, temafloxacin, pefloxacin, amifloxacin, fleroxacin, tosufloxacin, prulifloxacin, irloxacin, pazufloxacin, clinafloxacin, and sitafloxacin, aminoglycosides such such as gentamicin, netilmicin, paramecin, tobramycin, amicacin, kanamycin, neomycin, and streptomycin, vancomycin, teicoplanin, rampolanin, mideplanin, colistin, daptomycin, gramicidine, colistimethate, polymyxins such as polymyxin B, capromycin, penis, bacmycin, penis penicillins that include penicillin-sensitive agents such as penicillin G, penicillin V, penicillin-resistant agents such as methicillin, oxacillin, cloxacillin, dicloxacillin, floxacillin, naphcillin; gram negative microorganism active agents such as ampicillin, amoxicillin, and hetacillin, cilia, and galampicillin; antiseudomonal penicillins such as carbenicillin, ticarcillin, azlocillin, mezlocillin, and piperacillin; cephalosporins such as cefpodoxime, cefprozil, ceftbuten, ceftizoxime, ceftriaxone, cephalothin, cefapirin, cephalexin, cefradrine, cefoxitin, cephamandol, cephazoline, cephaloidin, cefaclor, cephadroxyl, cephaloximate cephalophaprin, cephaphthymus cephaphiraphine, cephaphthymus cephaphiraphthin, cephaphthymus cephaphiraphthin, cephaphthymus cephaphiraphthin, cephaphthymus cephaphiraphthin, cephaphthymus cephaphyrimine cefoperazone, cefotetan, cefmetazole, ceftazidime, loracarbef, and moxalactam, monobactams such as aztreonam; and carbapenems such as imipenem, meropenem, pentamidine isetiouate, albuterol sulfate, lidocaine, metaproterenol sulfate, beclomethasone dipropionate, triamcinolone acetamide, budesonide acetonide, fluticasone, ipratropine chlorateamine, sodium trichlorotrate, flratrium ammonium bromide applicable, analogs, agonists, antagonists, inhibitors, and pharmaceutically acceptable salt forms of the foregoing. With reference to peptides and proteins, the invention is intended to encompass synthetic, natural, glycosylated, non-glycosylated forms, pegylated forms, and biologically active fragments and analogs thereof.

The active agents for use in the invention further include nucleic acids, such as naked nucleic acid molecules, vectors, associated viral particles, plasmid DNA or RNA or other nucleic acid constructs of a type suitable for transfection or transformation of cells. that is, suitable for gene therapy that includes antisense. Additionally, an active agent may comprise live dead or attenuated viruses suitable for use as vaccines. Other useful drugs include those listed within the Physician’s Desk Reference (most recent edition).

The amount of active agent in the pharmaceutical formulation will be that amount necessary to deliver a therapeutically effective amount of the active agent per unit dose to achieve the desired result. In practice, this will vary widely depending on the particular agent, its activity, the severity of the condition to be treated, the population of patients, dosage requirements, and the desired therapeutic effect. The composition will generally contain anywhere from about 1% by weight to about 99% by weight of active agent, usually from about 2% to about 95% by weight of active agent, and more typically from about 5% to 85% by weight of active agent, and will also depend on the relative amounts of additives contained in the composition. The compositions of the invention are particularly useful for active agents that are delivered in doses of 0.001 mg / day to 100 mg / day, preferably in doses of 0.01 mg / day to 75 mg / day, and more preferably in doses of 0.10 mg / day at 50 mg / day. It is understood that more than one active agent may be incorporated into the formulations described herein and that the use of the term "agent" in no way excludes the use of two or more such agents.

The pharmaceutical formulation may comprise a pharmaceutically acceptable carrier or excipient that can be taken in the lungs without significant adverse toxicological effects for the subject, and particularly with the subject's lungs. In addition to the active agent, a pharmaceutical formulation may optionally include one or more pharmaceutical excipients that are suitable for pulmonary administration. These excipients, if present, are generally present in the composition in amounts ranging from about

0.01% to about 95% percent by weight, preferably from about 0.5 to about 80%, and more preferably from about 1 to about 60% by weight. Preferably, said excipients, in part, will serve to further improve the characteristics of the active agent composition, for example by providing more efficient and reproducible delivery of the active agent, improving powder handling characteristics, such as flowability and consistency, and / or facilitate the manufacture and filling of unit dosage forms. In particular, the excipient materials can function frequently to further improve the physical and chemical stability of the active agent, minimize residual moisture content and hinder moisture uptake, and improve particle size, degree of aggregation, surface properties of particle, such as roughness, ease of inhalation, and the orientation of the particles towards the lung. One or more excipients that serve as volume forming agents can also be supplied 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-biological polymers, biological polymers, carbohydrates, such as sugars, derived sugars such as alditols, aldonic acid, esterified sugars, and polymers. of sugar, which may be present alone or in combination. Suitable excipients are those provided in WO 96/32096, which is incorporated herein by reference in its entirety. The excipient may have a glass transition temperature (Tg) above about 35 ° C, preferably above about 40 ° C, more preferably above 45 ° C, more preferably above about 55 ° C.

Example protein excipients include albumin such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, hemoglobin, and the like. Suitable amino acids (outside the dileucil peptides of the invention), which can also function in a regulatory capacity, include 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 dispersing agents 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 improve dispersibility include dimers, trimers, tetramers, and pentamers comprising one or more hydrophobic amino acid components such as those described above.

Carbohydrate excipients suitable for use in the invention include, for example, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinous, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, sorbitol xylitol (glucitol), pyranosyl sorbitol, myoinositol and the like.

The pharmaceutical formulation may also include a regulator or a pH adjusting agent, usually a salt prepared from an organic acid or base. Representative regulators 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 regulators.

The pharmaceutical formulation may also include polymeric excipients / additives, for example, povidones, cellulose derivatives such as hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylmethylcellulose, Ficoles (a polymeric sugar), hydroxyethyl starch, dextrates (eg, cyclodextrins, such as 2-hydroxypropyl- cyclodextrin and sulfobutyl ether-cyclodextrin), polyethylene glycols, and pectin.

The pharmaceutical formulation may additionally include flavoring agents, flavor masking agents, inorganic salts (for example sodium chloride), antimicrobial agents (for example benzalkonium chloride), sweeteners, antioxidants, antistatic agents, surfactants (for example polysorbates such as " TWEEN 20 "and" TWEEN 80 "), sorbitan esters, lipids (for example phospholipids such as lecithin and other phosphatidylcholines, phosphatidylethanolamines), fatty acids and fatty esters, steroids (for example cholesterol), and chelating agents (for example EDTA, zinc and other such suitable cations). Other pharmaceutical excipients and / or additives suitable for use in the compositions according to the invention are listed in "Remington: The Science & Practice of Pharmacy", 19th ed., Williams & Williams, (1995), and in the "Physician's Desk Reference ", 52nd ed., Medical Economics, Montvale, NJ (1998), which are incorporated herein by reference in their entirety.

"Medium mass diameter" or "MMD" is a measurement of the average particle size, because the powders of the invention are generally polydispersed (ie, they consist of a range of particle sizes). MMD values as reported here are determined by centrifugal sedimentation, although any number of techniques commonly used to measure the average particle size can be used. "Medium aerodynamic mass diameter" or "MMAD" is a measure of the aerodynamic size of a dispersed particle. The aerodynamic diameter is used to describe an aerosolized powder in terms of its sedimentation behavior, and is the diameter of a sphere of unit density that has the same sedimentation rate, generally in air, as the particle. The aerodynamic diameter encompasses the shape, density and physical size of a particle. As used herein, MMAD refers to the midpoint or median of the aerodynamic particle size distribution of an aerosolized powder determined by the impact of the cascade.

In one version, the powder formulation for use in the present invention includes a dry powder having a particle size selected to allow penetration into the alveoli of the lungs, that is, preferably 10 μm of medium mass diameter (MMD) , preferably less than 7.5 μm, and more preferably less than 5 μm, and is usually in the range of 0.1 μm to 5 μm in diameter. The delivery dose efficiency (DDE) of these powders may be greater than 30%, more preferably greater than 40%, more preferably greater than 50% and more preferably greater than 60% and the aerosol particle size distribution is approximately 1.0 - 5.0 μm of mean aerodynamic mass diameter (MMAD), usually 1.5 -

4.5 μm MMAD and preferably 1.5 - 4.0 μm MMAD. These dry powders have a moisture content below about 10% by weight, usually below about 5% by weight, and preferably below about 3% by weight. Such powders are described in WO 95/24183, WO 96/32149, WO 99/16419, and WO 99/16422, which are incorporated herein by reference in their entirety.

Although the present invention has been described in considerable detail with respect to certain preferred versions thereof, other versions are possible, and alterations, permutations and equivalents of the version shown will become apparent by those skilled in the art after a reading of the specification and study of the drawings. For example, the relative positions of the items in the files can be changed to carry out the relative movements. Also, the various features of the versions can be combined here in various ways to provide additional versions of the present invention. Additionally, certain terminology has been used for descriptive clarity purposes, and not to limit the present invention. For example, the use of terms such as "up" and "down" and "first" and "second" can be reversed in the specification. Therefore, the appended claims should not be limited to the description of the preferred versions contained herein and should include all such alterations, permutations, and equivalents when it falls within the spirit and true scope of the present invention.

Claims (20)

1. A pharmaceutical powder filling apparatus for use in packaging a pharmaceutical powder formulation, the apparatus (100) comprises: a hopper (105) adapted to contain a pharmaceutical powder formulation (115), the hopper (105) comprises an outlet (120), a vibrating member and an actuator (140) adapted to cause the vibrating member to vibrate so that dust flows from the outlet such that a chamber (125) can be filled with dust (115) flowing through the output (120); Y characterized in that the vibrating member comprises a membrane (155) positioned in, on, or near the hopper (105) such that the vibrating member separates from the dust (115) in the hopper, the vibrating member, in use, is excited by the actuator to produce vibrations continuously, or periodically in short intervals, to alter a medium inside the hopper and therefore keep the powder in the hopper (105) in a constantly fluidized state such that it flows through the output (120). 2. The apparatus according to claim 1 further comprising a second vibrating member (250) comprising a member (260) adapted to contact the powder (115).

3.

The apparatus according to claim 2 wherein the second vibrating member (250) has a longitudinal axis and wherein the second vibrating member vibrates in a direction parallel to the longitudinal axis.

Four.

The apparatus according to claim 1 further comprising a chamber and wherein the chamber is adapted to transport the powder to a receptacle.

5.

The apparatus according to 4 wherein the camera is a measuring chamber.

6.

The apparatus according to claim 4 wherein the chamber is in a rotating member (205).

7.

The apparatus according to claim 6 wherein the rotating member (205) can rotate between a dust receiving position and a dust ejection position.

8.

The apparatus according to claim 1 wherein the medium (145) comprises a gas.

9.

The apparatus according to 8 wherein the medium (145) comprises air.

10.

The apparatus according to claim 1 wherein the vibrating membrane (155) is adapted to vibrate at a frequency of about 10 Hz to about 1000 Hz.

eleven.

The apparatus according to claim 1 wherein the hopper (105) comprises an enclosure having side walls.

12.

A method for filling a chamber (125), the method comprises:

provide a chamber to be filled; provide a pharmaceutical powder formulation (115); providing a filling apparatus comprising a hopper having an outlet and a vibrating member comprising a membrane; The pharmaceutical powder formulation is located in the hopper and the apparatus arranged in such a way that the vibrating member (155) is positioned in, on, or near the hopper (105) such that the vibrating member is separated from the powder ( 115) in the hopper; arrange the chamber in such a way that the dust flowing from the outlet will flow into the chamber; vibrate the vibrating member continuously, or periodically in short intervals, to alter a medium inside the hopper and therefore keep the powder in the hopper (105) in a constantly fluidized state such that it flows through the outlet ( 120); Y allow dust to flow through the outlet inside the chamber. 13. The method according to claim 12 wherein the member (155) vibrates at a frequency of 10 Hz to about 1000 Hz. 14. The method according to claim 12 further comprising vibrating a second member 5 (250), the second member is contacted with the powder (115).

fifteen.

The method according to claim 12 wherein the medium (145) comprises a gas.

16.

The method according to claim 15 wherein the medium (145) comprises air.

17.

The method according to claim 12 wherein the chamber (125) comprises a receptacle (175) and the method further comprises sealing the receptacle.

The method according to claim 12 further comprising transferring the powder (115) from the chamber to a receptacle. 19. The method according to claim 12, comprising rotating the chamber from a dust receiving position to a dust ejection position. 20. The method according to claim 12, wherein the chamber (125) comprises a receptacle (175). The method according to claim 12, wherein the receptacle (175) is a blister pack. 22. The method according to claim 12, wherein the receptacle is a capsule.