WO2007107796A1

WO2007107796A1 - Improvements in treatment of dry powder formulations

Info

Publication number: WO2007107796A1
Application number: PCT/GB2007/050142
Authority: WO
Inventors: David Morton; Yorick Kamlag
Original assignee: Vectura Limited
Priority date: 2006-03-22
Filing date: 2007-03-22
Publication date: 2007-09-27
Also published as: CA2646420A1; GB0605676D0; JP2009530007A; EP1996264A1; CN101454039A

Abstract

The present invention relates to the treatment of dry powder formulations, doses of which are measured out and placed into receptacles such as blisters or capsules, to be dispensed by a dry powder inhaler device (DPI). In particular, the present invention relates to methods of agitating a dose of a dry powder formulation to ensure that any compacted powder is broken up. It is easier to extract a loose powder from a receptacle than it is to extract powder which is compacted and so ensuring that the powder in a receptacle is not compacted can, in turn, lead to improvements in the administration of the powder formulation to the lung of the patient.

Description

Improvements in Treatment of Dry Powder Formulations

The present invention relates to the treatment of dry powder formulations, doses of which are measured out and placed into receptacles such as blisters or capsules, to be dispensed by a dry powder inhaler device (DPI). In particular, the present invention relates to methods of agitating a dose of a dry powder formulation to ensure that any compacted powder is broken up It is easier to extract a loose powder from a receptacle than it is to extract powder which is compacted and so ensuring that the powder in a receptacle is not compacted can, in turn, lead to improvements in the administration of the powder formulation to the lung of the patient

DPIs commonly utilise receptacles, such as capsules or foil blisters, within which individual doses of the dry powder medicament are stored in a dry and protected environment. In order to ensure that a DPI provides an accurate dose of the pharmaceutically active agent, it is important that the correct amount of the dry powder formulation is loaded into the blister or capsule. Thereafter, it is important that substantially all of the powder is extracted consistently from the blister or capsule and that the extracted formulation includes the active agent in a form in which it can be inhaled and will reach the appropriate part of the respiratory tract.

Poor and irregular receptacle emptying appears to be a common problem in DPIs. This appears to be, at least in part, a result of the mechanisms frequently used to fill the receptacles with the dry powder. Doses of powder are generally measured out by machine as hand-filling is only practical on a small scale, for example for early phase clinical trials. Most mechanical filling processes work on the basis of a volumetric principle and operate by forming a powder plug or compact of a predetermined and constant volume, which is then transferred to the blister or capsule The powder must generally be compacted in order to ensure an accurate and reproducible volumetric fill.

In practice, problems can arise as a result of the inevitable compaction of the powder and the formation of robust plugs of compacted powder is frequently seen. lypical plugs formed by a standard mechanical measuring and filling process are shown in Figure 1. These compacts or plugs are often referred to as "standard" plugs

1 he formation of such compacts or plugs is undesirable or detrimental for a number of possible reasons. For example, the compacts may be too large to enter the exit conduit of the inhaler device, the compacts may become trapped under the foil flaps of conventional blisters, the compacts may become wedged into blister or capsule crevices, and/or combinations of these problems. Experiments have shown that the blister or capsule emptying may be improved by incorporating device modifications that are designed to allow the inhaler device to tolerate larger lumps of powder, for example by including a larger exit port. However, the compacts can still have a detrimental effect on the pulmonary delivery of the powder formulation, which is very much dependent on particle size.

Most notably, compacted masses or plugs tend to be formed when the powders include a high proportion of fine particles which have a particle size of about 20μm or less, and particularly of about lOμm or less. The issue with such fine powders is believed to be their tendency to agglomerate and to form one or more large compacted lumps of powder during machine-filling. Machine filling of dry powder formulations does not tend to present such a problem when the dry powder formulations include larger particles, such as large carrier particles with a particle size of 35μm or greater. These larger particles have a significant influence on the powder properties and in particular on the tendency of the powder particles to agglomerate and the flowability of the powder, with the larger particles acting a fluidismg means.

Sieving can improve blister or capsule emptying. A dry powder formulation including a high proportion of fine particles exhibits the above discussed compaction problems when doses are measured out and transferred to blisters or capsules mechanically However, when the same dry powder formulation is sieved or chopped and the blister or capsule is hand-filled, the inhaler exhibits drastically improved blibter or capsule emptying. However, sieving does not represent a practical solution to the problems associated with the compacted powder observed when blisters and capsules are machine filled. Sieving can only be practically conducted prior to loading powder into the filling machine Sieving cannot be conducted after filling as powder may be lost upon contact with the sieve and filling accuracy may therefore be compromised. Indeed, any direct physical contact with the powder to provide mechanical dispersion of compacts appears to be potentially undesirable.

A number of different approaches to breaking up compacted powder have been previously suggested, as illustrated, for example, in WO 01 /43802. In this patent application, it is suggested that at least one pulse of energy be provided to the receptacle carrying the powder. In preferred embodiments, a blister containing the powder is struck or flicked by mechanical means, and this is preferably achieved within the inhaler device itself. However, the methods and systems proposed m this and other documents suffer from a number of drawbacks. Whilst approaches previously proposed usually break up the powder compacts, the condition of the powder following this treatment is often not ideal for subsequent dispensing using a DPI This is due to a failure to apply the energy in a controlled and effective manner. The disclosure in the prior art is not specific enough and gives the skilled person little or no guidance to identify how to achieve satisfactory results. This appears to primarily result from a lack of appreciation or understanding of the interplay between the important parameters involved.

Further drawbacks of the approaches described in the prior art are that they could result in damage to the receptacle, which is commonly formed from very soft materials This means that care needs to be taken to minimise the energy the receptacle is exposed to.

In addition, it appears to be preferred in the prior art for the compacts to be broken up immediately prior to actuation of the DPI This will mean that the powder plugs are left untreated for long periods of time and this will allow an increase the inter- particulate bonds formed and can therefore reduce the efficiency of the deaggregation techniques disclosed

In light of the foregoing, it is clearly desirable to provide a method of treating a measured dose of dry powder formulation so that the presence of compacted powder in a filled receptacles is avoided, thereby improving the subsequent emptying of the receptacle and increasing lung deposition of the powder when dispensed using a DPI. The method needs to be effective, not only in breaking up compacted powder, but preferably also m ensuring that the powder does not become coated or caked on the inner surface of the receptacle within which it is stored. Preferably, the powder also does not become segregated.

Thus, according to the first aspect of the present invention, a method is provided for agitating a measured dose of a dry powder formulation, so that any compacted powder is broken up and is present in a respirable form. By respirable form, it is meant that the powder is in a deaggregated form and that, upon being dispensed by a DPI, the powder will be dispensed so that the active agent present in the powder is in the form of particles or particle agglomerates of respirable size (preferably having a diameter of 10 μm or less). The powder in respirable form may include small agglomerates of particles, as are present in an ordered mixture, for example where the powder comprises fine particles of a pharmaceutically active agent and larger particles of a carrier material, to which the fine particles adhere. Any agglomerates present in the powder in respirable form may be broken up by the turbulence created upon actuation of the DPI.

The respirable nature of the resultant powder may be ascertained by ACI (Anderson Cascade Impactor) data, such as that shown in Example 7 The data shows that the powder plug is not in respirable form prior to agitation in accordance with the invention, but it is considered to be respirable after such treatment. In some embodiments, the respirable powder has a Fine Particle Fraction of greater than 50. In another embodiment, there is a significant improvement of the FPF compared to the FPF prior to the agitation. In one embodiment of the invention, the step of breaking up compacted powder involves agitating the powder with force sufficient to break up the compacted powder. The force is preferably applied once the powder has been placed into the receptacle and more preferably once the receptacle has been sealed, thereby ensuring that the agitation step does not result in any loss of the measured dose of powder. Receptacles are containers, such as blisters and capsules, into which measured or metered doses of dry powder formulations are placed for storage and from which the dose of powder may be dispensed by a DPI.

According to a second aspect of the present invention, a method is provided for agitating a measured dose of a dry powder formulation which is in a sealed receptacle, the method comprising indirectly applying a vibrational force to the powder, for example via the air within the sealed receptacle. Preferably, this is achieved by applying the vibrational force to a flexible wall of the receptacle. This has two advantages. Firstly, it makes it easier to transmit the vibrations to the air within the receptacle. Secondly, it allows the vibrational force that is transmitted through the body of the receptacle to be minimised. This is important because the vigorous "shaking" of the powder, which results from vibration of the receptacle wall which is in direct contact with the powder, can lead to some of the disadvantages associated with the prior art methods and can have detrimental effects on the powder itself and on its extraction from the blister.

Preferred embodiments which apply to both of these first and second aspects of the invention are described in detail below.

The inventors have identified that the key features for achieving this when applying the agitation using a probe transmitting vibrational force (also referred to herein as a sonotrode) are: (i) the probe shape, (li) the pressure of the probe applied to the blister, (in) the frequency of the vibration of the probe, (iv) the amplitude of the vibration of the probe and (v) the duration of the energy burst. In one preferred embodiment, the agitation involves applying a vibrational force using a vibrational means, wherein the vibrational force is not applied directly to the receptacle at the point where the powder contacts the receptacle.

The powder is preferably agitated following the powder-measuring step, which is usually carried out by a blister or capsule-filling machine.

The vibrational force may be provided in the form of sonication, including acoustic and ultrasound agitation (including resonant frequency matching), shaking, impacts and percussion effects. In each case, the vibration may be applied to the outside of the sealed receptacle, and is communicated to the powder compact held inside the receptacle, preferably through the air in the receptacle (in preference to the vibration being communicated through the body of the receptacle, at least part of which will be in direct contact with the powder compact.

Known means may be used to focus or transfer the vibrational forces, such as an acoustic lens, or transmitting media to improve contact with the sealed receptacle. In some embodiments, the means used to apply the vibrational force may be an acoustic lens. In preferred embodiments of the invention, the means of applying the vibrational force is a sonotrode.

Preferred agitation methods include applying a vibrational force to the powder in the receptacles at frequencies of less than about 1 megahertz. Preferably, the frequency is from about 1 Hz to about 500 kHz, from about 1 kHz to about 250 kHz, from about 10 kHz to about 100 kHz, from about 15 kHz to about 50 kHz, or from about 20 kHz to about 40 kHz.

It is desirable to select vibration which will completely break up the powder compacts to provide a finely divided loose powder, but which will not have a detrimental effect on the powder formulation, for example by causing undesirable segregation of the powder or caking of the powder on the inner surface of the receptacle The skilled person would have no difficulty in ascertaining the suitable frequency in order to break up powder compacts without having a detrimental effect on the powder, based upon the nature of the powder, the nature of the compacts formed during receptacle filling and the nature of the receptacle.

In one embodiment, the agitation may be provided by contacting the filled receptacle with an ultrasonic probe, for example a probe which is operating at a frequency range of between about 10 and about 40 kHz.

The amplitude of oscillation of the vibrational force is also a key factor. It has been found that application of a vibrational force with a particular amplitude to a receptacle improves the break up of powder compacts and can assist in subsequent emptying of the receptacle.

Preferably, the amplitude of the vibrational force should be between about 10 to about 100%, more preferably from about 50 to about 100%. Especially preferred amplitudes range from about 75 to about 100%, from about 80 to about 100%, from about 85 to about 100% or from about 90 to about 100%. The skilled person would have no difficulty in ascertaining the suitable amplitude in order to break up powder compact, based upon the nature of the powder, the nature of the compacts formed during receptacle filling and the nature of the receptacle.

The pressure with which the vibrational force is applied to the receptacle has been found to be an important factor in achieving effective break up of powder compacts and improving the emptying of the receptacle upon actuation of the DPI.

Preferred pressures include ranges from about 0.1 to about 1.5 bar, from about 0.2 to about 1.2 bar and most preferably from about 0.2 to about 0.6 bar. The value of the pressure parameter lies in its application to a sealed environment.

Finally, the duration for which the vibrational force applied to the receptacle has been found to also be an important factor in achieving effective break up of powder compacts and improving the emptying of the receptacle. Preferably, the vibrational force should be applied for between about 0.01 and 10 seconds. The vibrational force needs to be applied for long enough to allow complete break up or deaggregation of the compacted powder, but must not be so long as to have any detrimental effects on the powder, for example by causing ordered mixtures to segregate. Preferably, the vibrational force is applied for between about 0.025 to about 1 second. The duration may need to be adjusted, depending upon the other parameters. For example, a lower frequency vibrational force may need to be applied for longer in order to have the desired effect. The skilled person would have no difficulty in establishing the optimum duration, without requiring inventive input or overly onerous experimentation.

In some embodiments of the invention, positioning the vibrational surface of the vibrational means against the receptacle creates a cavity, an empty space between the surfaces. This cavity is preferably sealed, and most preferably, an airtight seal is formed. The vibrational force causes the air within the cavity to vibrate and this vibration is transmitted to the air within the receptacle.

In especially preferred embodiments of the present invention, the vibrational force is provided by a probe which has a recessed surface, for example a concave vibrational surface. The vibrational force is generated by the probe causes the air to vibrate within the cavity of the probe formed by this recessed surface.

Upon contact of the probe with the sealed surface of the receptacle (for example, a blister), a sealed air entity is created. The air withm the temporarily sealed unit is able to expand and contract with each oscillation of the sonotrode. These expansions and contractions of the air within the probe cavity are then transferred through the lid of the blister into the blister contents namely air and powder. Provided enough flexibility is afforded to the blister a synchronous expansion- contraction of the air occurs within the sealed blister unit. The difference between this invention and the approaches described in the prior art is that rather than using simple vibrations to shake the blister and powder to attempt to deaggregate the powder compact, the air in the blister is also shared with the air within the powder compact and any expansion and contraction of air in the blister will affect the air in the powder plug The initial expansion-contraction sequences which resound throughout the blister contents initially resulting in minor air movements, but synchronised oscillations throughout the entirety of the powder plug impart an exponential effect with minimal energy input.

The specific arrangements of the vibrational means and the receptacle and/or powder are now further described, by way of example only, and with reference to

Figures 1 to 16, in which:

Figure 1 is a photograph of standard powder plugs in unsealed receptacles; Figure 2 is a schematic representation of a standard blister for use in a DPI;

Figure 3 is a schematic, partial representation of a vibrational means, including the vibrational surface;

Figure 4 is a schematic representation of a shaped or bespoke vibrational surface of a vibrational means; Figure 5 to 8 are schematic representations of the various different arrangements by which a sonotrode may be applied to a blister in order to agitate powder held within the blister;

Figure 9 is a schematic diagram of the different shape sonotrode that is useful in the present invention; Figure 10 is a photograph of a blister containing a dose of powder after treatment using a method according to the present invention; and

Figures 11 to 16 are graphs showing the results of the experiments described in

Examples 1 to 6.

A conventional blister for use m a DPI is schematically shown in Figure 2 The blister 1 comprises a cup-shaped body 2, within which a dose of powder may be held The open end of this cup-shaped body is sealed by a foil covering 3 or lid, that is sealed to the body around a shoulder area 4.

Typically, when a vibrational means 10, such as a sonotrode as shown in Figure 3, is applied to a blister 1 in order to agitate the blister contents, the surface 11 of the vibrational means which contacts the blister is flat, as shown in Figure 3a In embodiments of the present invention, it is preferred to have the vibrational surface shaped so that a cavity is formed when the surface is contacted with the receptacle Some examples of the possible shapes of such recessed surfaces of the vibrational means, are shown in Figures 3b, 3c, 4a and 4b, wherein the shaped surfaces 12 shown in Figures 4a and b are preferred The direction m which the vibrational force is applied is indicated by the arrow V

Figure 5 shows how the shaped vibrational surface shown in Figure 4a might conventionally have been used The vibrational means is positioned in order to agitate the receptacle and its contents. The vibrational surface is placed in direct contact with the base of the blister When the blister contains a dose of powder, for example in the form of a powder plug, the powder will lie in contact with the base of the blister and will therefore be in contact with the part of the blister wall which is in contact with the vibrational means In these circumstances, the vibrational force is passed through the wall of the blister body and directly to the powder

In practice, it has been found that such "direct" application of the vibrational force to the powder can have negative effects. For example, it has been found that this results m vigorous and largely uncontrolled agitation of the powder. A serious consequence of this is that the powder may become coated or caked on the inner surface of the blister This can have a detrimental effect on powder extraction when the dose of powder is to be dispensed by the DPI. Another possible detrimental effect is the segregation of the powder as the vibration may disrupt the ordered mixture making up a powder which comprises particles of different sizes, for example, fine particles of pharmaceutically active material and larger carrier particles of inert excipient material This can have catastrophic effects on the delivery of the active agent to the lung. A further disadvantage is that this application of a vibrational force can weaken or damage the blister

The arrangement shown in Figure 6 provides less contact between the body of the receptacle and the vibrational surface and so it suffers less from the disadvantages discussed in connection with the arrangement shown m Figure 5. Nevertheless, as the vibrational surface is in direct contact with the part of the blister body wall with which the powder is also likely to be in contact, and so some direct agitation via the receptacle wall will occur This direct agitation resulting from contact between the probe and the part of the receptacle with which the powder compact is in contact will result in minor and inconsistent powder deaggregation The prior art has failed to recognise the importance of specific configuration according to the aspects of the present invention (a preferred example of which is illustrated in Figure 8) for optimal performance and/or has failed to appreciate how this configuration applies a completely different type of agitation to the powder, resulting in a much more controlled deaggregation of the powder compact which also avoids undesirable effects which can be associated with the vigorous and uncontrolled vibrations used in the prior art

The use of a sonotrode with a flat contact surface placed in direct contact with the blister lid, as illustrated in Figure 7, will impart vibrational energy to the blister and its contents but not in the most efficient manner. Powder deaggregation is observed but often at the expense of compromising the blister seal integrity and unnecessarily extending the duration of the sonication

The arrangement as outlined in Figure 7 is less tolerant of "extreme" parameters. Should frequency or energy duration be exceeded the foil seals are prone to rupturing and the plastic blister walls are susceptible to melting. The sonication arrangement outlined in Figure 7 would appear to be the sensible; however the sonication assembly is suboptimal as misdirected energy in the form of heat compromises blister seal integrity The energy from the flat surface of the sonotrode encounters the flat surface of the blister imparting high localised vibration energy on the foil and seal which conventional blister materials are not designed to withstand The advantage of the arrangement as outlined in Figure 8 is the energy is not focused on the blister foil but exploits the blister foil to convey the pressure waves via the air contained in the hermetically sealed blister into the air of the powder plug It has also been found that application of the flat surface of the vibrational means to the upper, flat surface of the blister, as demonstrated by Figure 7, does not provide optimal emptying of the blister. In this arrangement, the source of the energy and the powder are in close proximity. This orientation has resulted in the powder caking/melting with excessive energy and heat being created. This arrangement relies on the probe to impart the energy to the blister wall which then, in turn, imparts the energy to the powder. The blister in this arrangement requires securing before the energy can be applied. The securing apparatus will therefore absorb a proportion of the energy applied to the blister thereby rendering the process less efficient and consequently requiring greater energy input form the probe with complications outlined above and depicted in Figure 7, resulting in poor powder deaggregation.

However, surprisingly, the greatest improvement in the break up of the powder compacts and subsequent improved blister emptying is achieved by the arrangement shown in Figure 8. The recessed, cup-shaped surface 12 of the vibrational means 10 is positioned so that it contacts the foil lid 3 of the blister 1, rather than the cup- shaped body 2 of the blister. Preferably, the cup-shaped portion of the vibrational means is substantially aligned with the cup-shaped portion of the blister or capsule, as illustrated in Figure 8.

This finding is contrary to current teaching in the art, which recommends the use of a transmitting media to improve the contact between the receptacle and the vibrational means.

In one embodiment, the cup-shaped portion of the receptacle is merely supported with no vibration.

In a particularly preferred embodiment of the invention, when the vibrational surface contacts the receptacle, there is a gap between at least part of the vibrational surface and the surface of the receptacle This gap may be described as a cavity and the cavity is preferably sealed, i.e. it is surrounded by no gap between the vibrational surface and the receptacle In one embodiment, this arrangement is achieved by the vibrational surface of the vibrational means being concave in shape.

It has also been found that the depth of the concave vibration surface or cup- shaped indentation in the vibrational means can affect deaggregation of the powder compact and subsequent emptying of the blister or capsule (see Figure 9). In particular, it would appear that the ratio between the cup-shaped indentation of the surface of the vibrational means and the depth of the cup of the blister is significant as this provides greater facility for oscillating the air within the blister.

In some embodiments, the depth of the indentation in the vibrational means (as illustrated by A in Figure 9) is between 0.01 and 99% greater than the depth of the blister or capsule (B in Figure 9), between 0.1 and 90% greater, between 1 and 80% greater, between 5 and 50% greater, or between 10 and 20% greater than the depth of the blister or capsule

The improvement in the break up of the powder compact, and the subsequent improvement in receptacle emptying, resulting from the use of a vibrational means which creates a cavity upon application to the receptacle, may be improved by an arrangement in which the cavity has a particular volume, preferably the volume is equivalent to at least 0.1% the volume of the blister. This may again result from the reduction in caking of the powder resulting from the distal location of the vibrating surface from the powder. In addition, the compression and rarefaction of air in the pocket between the vibrating surface of the vibrational means, and the blister or capsule surface, the volume of which is determined by the depth of the indentation, may also contribute to the improved emptying

I he means used to hold the blister or capsule during application of the vibrational force is also a factor in achieving optimal emptying of the receptacle upon actuation of the inhaler.

In a preferred embodiment, the cup-shaped portion of the receptacle is located in a similarly shaped (i.e. a cup shaped) holder. The vibrational means may then be applied to the opposite surface of the receptacle. It is believed that this arrangement (Figure 5) results in dissipation of the energy of vibration throughout the receptacle, as a result of the contact surface area between the receptacle and the receptacle. In the preferred embodiment (as shown in Figure 8) the cup-shaped portion of the receptacle should be supported by a similarly shaped holder as this provide support for the blister. Full contact between the holder and receptacle will dissipate energy if the holder is not the sonotrode.

Improvements in the break up of the powder compacts and in subsequent emptying of the receptacle may be achieved by optimisation of the means used to hold the receptacle. In particular, improved results may be achieved by proving a holder that directs or concentrates the energy of vibration onto one or more points of the receptacle. For example, the cup-shaped portion of the blister or capsule could be held in a holder comprising three-prongs. This obviously reduces the contact area between the holder and the receptacle.

For an optimised result, each of the parameters discussed above, namely the arrangement of the receptacle, vibrating means and holder, or the properties of the vibrational force generated by the vibrational means, have an influence. These parameters should be selected to provide a complete break up of the powder compacts, to provide a finely divided loose powder, but should not have a detrimental effect on the powder formulation, for example by causing undesirable segregation of the powder. The ideal combination of parameters may be established by the skilled person without inventive input and without the need for excessive trial and error, especially based upon the preferred embodiments set out below.

In relation to each of the parameters discussed above, the nature of the powder, the nature of the compacts formed during receptacle filling and the nature of the receptacle itself may affect the values selected for each parameter, as the skilled person would recognize. For example, some powder formulations may contain additive materials in order to reduce the cohesion and/or adhesion of ad_jacent particles The inclusion of additive materials may mean that the selected parameters may need to be different to those used in connection with a powder which does not contain additive materials.

In some embodiments of the present invention, particular arrangements of the receptacle, vibrating means and holder, and/or particular values within the preferred ranges are selected for two or more of the parameters specified above, in order to improve subsequent blister emptying. In preferred embodiments, particular arrangements of the receptacle, vibrating means and holder, and particular values within the preferred ranges are selected for all of the parameters specified above.

In a preferred embodiment of the present invention, the pressure with which the vibrational force is applied to the blister or capsule is between about 0.2 to about 0.6 bar; the frequency of vibration is between about 20 to about 35 kHz; the amplitude of vibration is between about 50 to about 100%; and/or the duration of application of the vibrational means is between about 0.01 and about 1 second.

The shape of the powder plug also appears to have an effect on the deaggregation methods. From the experimental data set out in the Examples below, it would appear that an elongated or "sausage-shaped" pellet is dispersed more effectively compared to "normal" plugs, examples of which are shown in Figure 1. As a result, in one embodiment, the method involves agitation of elongated powder pellets, plugs or compacts. These elongated compacts have a greater surface area to volume ratio than the standard compacts. They also preferably have an aspect ratio of greater than 1 :1, preferably greater than 4: 3 or greater than 2:1. Where the compacts are cylindrical in shape, the ratio of the length to diameter is greater than I -I , preferably greater than 4: 3, greater than 2:1 or greater than 3:1.

Another aspect to the powder is the air content of the compacted metered powder A dense, low air content powder will not have the same ability to compress and rarefact compared to powders with slightly higher air content. Highly compacted powders have particles in close proximity, greater surface contact between neighbouring particles, minimal air gaps and high interparticulate adhesion and cohesion forces. In contrast, powders with particles exhibiting less surface contact between neighbouring particles, will consequently have greater air spaces which can be exploited for the compression rarefaction cycles Naturally, dense plugs will require greater sonication exposure to generate the greater air gaps to generate the deaggregated powders suitable for predictable drug delivery.

In a preferred embodiment, the step of agitating the powder comes immediately after the receptacle is machine-filled Preferably, the vibrational means is provided as part of the machine used to fill the receptacles

In an alternative embodiment, the vibrational means is provided in the DPI, so that the powder is agitated immediately prior to dispensing the powder for pulmonary delivery to a patient The agitation may take place upon priming or actuating the DPI

According to a third aspect of the present invention, receptacles such as blisters and capsules are provided which have been filled and treated using the methods according to the first and second aspects of the invention.

According to a fourth aspect of the present invention, dry powder inhaler devices are provided which comprise receptacles such as blisters or capsules according to the third aspect of the invention.

The invention described herein is applicable to powder-filled receptacles such as blisters and capsules for use in both active dry powder inhaler devices, such as Aspirair® (Vectura Limited) and Exubera® (Nektar Therapeutics), as well as in passive devices such as the Diskus® (Glaxo) and GyroHaler® (Vectura Limited)

According to a fifth aspect of the invention, a receptacle-filling apparatus is provided, which measures doses of dry powders and places these into receptacles, and subsequently agitates the powder-filled receptacles, in accordance with the first and second aspects of the invention Naturally, multiple blisters could be agitated according to the first and second aspects of the invention at the same time Thus, the agitation methods could form part of the production line preparing filled receptacles.

Example 1: Sonication of blisters filled by table-top fillet Two dry powder formulations comprising micronised clomipramine and magnesium stearate were prepared by co-micronising the two components together. These powders comprised 2% or 5% magnesium stearate

The powders were then filled into foil blisters using a Harro-Hoffliger (HH) table- top mechanical filler, which meters the powders into plug-shaped forms.

Experience has indicated that emptying inconsistency occurred when blisters filled by this method were fired from an Aspirair device. The problems appeared to occur due to the presence of large agglomerates of these cohesive powders and the failure to achieve sufficient plug break up inside the blister on firing.

Consequently, we attempted to apply ultrasonic energy into the powder sealed within the filled blisters using a Hielscher VialTweeter UIS250L. This unit applies ultrasonic energy at 24 kHz, and energy was applied at maximum amplitude for this unit. Filled blisters were located inverted with the flat blister top surface on the vibrating element, allowing the plug to sit directly above this element. Sonication was applied for 30 seconds in this test. Figure 2 shows the effects of sonicating a blister containing a plug for a period of 30 seconds. The powder is broken up and in the form of a finely divided loose powder.

Plugs were typically 3mg fill weight. Two types of plug shape from the filler were evaluated: a regular plug shape and a longer aspect "sausage" shape. Also the air vacuum applied to form the plug was varied from 5 psi to 10 psi, with the higher value expected to form more compacted plugs.

The sonicated blisters were fired from an Aspirair device and the percentage of the mass emptied was measured The results, which are set out in Table 1 below, consistently show a better blister emptying when the filled blisters are sonicated, when the filling vacuum is lower, and when plug shape is elongated.

Figure 11 is a graph showing the results of the sonicating trial discussed above.

Table 1 - Sonicating Trial

In the following examples (Examples 2-6), the experiments were carried out using the following equipment and formulations:

Equipment Details: Supplier: Telsonic Ultrasonics (Poole, UK) Ultrasonic Welder Type: USP-750-4

Output: lOOOW max

Frequency: 30 / 36 kHz Control Unit Type: MPS-4 basic

35 kHz Generator Type: SG3510 2OkHz Generator Type- DHG20110

Sonotrode Details: 35 and 20 kHz custom made by Telsonic UK Ltd (Poole, UK) Blister Holder: Custom made Bottom Tool for Belco Sealer (Serial No. 3), manufactured by Bowtech, Cambridge. The formed blister is held in cup-shaped receptacle on the upper surface of the tool.

Blister Details: Cold formed blister base sealed to lid using Belco Blister Sealer. Blister base material: Aluminium-PVC Laminate foil COS_VEC_017 (Alcan) Blister lid material: Aluminium-PVC Laminate foil COS_VEC_004 (Alcan)

Details of Formulation 1. Clomipramine Hydrochloride 97.5% w/w: Magnesium Stearate 2.5% w/w Materials co-jet milled using Hosokawa AS50

Blisters filled using Table Top Filler (Harro Hofliger, Germany) using 15.1mm³ drum.

Details of Formulation 2:

Apomorphine Hydrochloride 90% w/w: Magnesium Stearate 10% w/w

Particle size of API = D₅₀ 1.96μm (Malvern Mastersizer)

Materials were co-jet milled using Hosokawa AS50.

Example 2

The data provided in Table 2.1 demonstrates the effect of sonotrode frequency (kHz) upon the blister and plug shape as demonstrated by % blister emptying for Formulation 1 (mean ± s.d. n = 10).

Table 2 1

These results are set out in the graph shown in Figure 12 Example 3

The data in Table 3.1 demonstrate the effect of sonotrode pressure (bar) upon the blister and plug shape as demonstrated by % blister emptying for Formulation 1 (mean ± s.d. n = 10).

Table 3.1

These results are set out in the graph shown in Figure 13.

Example 4

The data m Table 4.1 demonstrate the effect of percentage sonotrode amplitude and plug shape as demonstrated by % blister emptying for Formulation 1 (mean ± s.d. n

= 10J.

Table 4.1

These results are set out in the graph shown m Figure 14.

Example 5 The data in Table 5.1 demonstrate the effect of duration of vibration (s) and plug shape as demonstrated by % blister emptying for Formulation 1 (mean ± s.d. n =

10).

Table 5.1

These results are set out in the graph shown in Figure 15

Example 6 The data in Table 6.1 demonstrate the effect of sonication on Formulation 2 as demonstrated by shot weight as a percentage of fill weight.

Table 6.1

These results are set out in the graph shown in Figure 16.

Example 7

Anderson Cascade Impactor data was analysed to test the respirable nature of the powder following agitation according to the present invention. The results, showing the effect of the agitation (sonication) on the Fine Particle Dose (<5μm) and Fine Particle Fraction (FPF) are shown in Table 7.1 below

Table 7 1

*n = 1

Blister sonication parameters varied. Pulse duration varied from 0.1 to 1 second, pressure 0 4 to 1 bar and amplitude varied from 50 to 100% in each of these. The formulation was: Apomorphine HCl 30% Respitose70% and the blisters were Table Top Filled using a 16.695 mm³ drum.

In addition to the agitation discussed above, the break-up of powder compacts formed upon filling receptacles may be further assisted by modifications made to the dry powder formulation itself.

According to one embodiment of the present invention, it has been found to be advantageous to sieve the powder prior to mechanical filling. Preferably, this sieving is coupled with agitation of the powder in a blister or capsule to break up the compacted powder, as outlined above. Sieving may be carried out by passing the powder through a sieve, preferably one with a size range of 50 to 1,000 μm. Alternatively, the powder may be passed through a CoMiIl (available from Quadro).

In one embodiment, the break up of compacted powder is assisted by the inclusion of a pelletisation step to form small metastable pellets prior to filling. The pellet stability or strength is an issue, as it must survive the filling process. However, it is also important that the individual pellets resist forming strong bonds with adjacent pellets, to reduce the likelihood of the formation of stable compacts. Various methods may be used to form the metastable pellets, including granulation, co- milling, extrusion, tumbling. The processes may be carried out in the presence of a volatile additive, to aid the process, or it may be a dry process.

The formation of small metastable pellets is particularly advantageous when used in conjunction with agitation described herein.

In a yet further embodiment of the present invention, the formation of compacted powder may be reduced by including an additive material in the dry powder formulation which reduces the cohesion and/or adhesion of adjacent particles. The coating of powder particles with such an additive material, which may also be referred to as a force control agent or FCA, does not necessarily prevent the formation of agglomerates of powder particles or compacted powder. However, it does reduce the cohesive forces between particles, thereby reducing the stability of the agglomerates and compacts so that they are more easily disrupted, for example by the agitation steps mentioned above. Suitable additive materials are discussed at length in International Patent Publication No. WO 02/43701 and these include anti- adherent or anti-friction agents including amino acids such as leucine, phospholipids such as lecithin and metal stearates such as magnesium stearate.

Further ways to ensure that the powder compacts formed are less stable and more easily disrupted include, for example, using powder particles with controlled particle shape, addition of large particles, preferably inert carrier particles, to assist in fluidisation of powders, or the inclusion of magnetic particles which could be agitated after filling. The modifications of the dry powder formulation described above may even be effective enough to ensure that the turbulence created in the receptacle (such as a blister or capsule) upon actuation of the inhaler device is adequate to disrupt the agglomeration or compaction of the powder without any additional agitation, such as that described above, being required. Alternatively, the inevitable shaking of the receptacle during manufacture, packaging, transport and use may be sufficient to disrupt compacted powders with the above mentioned modifications.

Claims

1 A method for agitating a measured dose of a dry powder formulation, so that any compacted powder is broken up, wherein the powder is in respirable form.

2 A method as claimed in claim 1 , wherein the step of breaking up the compacted powder involves agitating the powder with force sufficient to break up the compacted powder.

3 A method as claimed in claim 2, wherein the force is a vibrational force.

4 A method as claimed in claim 2 or 3, wherein the force is applied once the powder has been placed into a receptacle and preferably once the receptacle has been sealed.

5 A method for agitating a measured dose of a dry powder formulation which is in a sealed receptacle, the method comprising indirectly applying a vibrational force to the powder within the sealed receptacle.

6. A method as claimed in claim 5, wherein the vibrational force is applied to the powder via the air in the receptacle.

7 A method as claimed in claim 5 or 6, wherein the vibrational force is applied to a flexible wall of the receptacle, preferably so that the vibrational force transmitted through the body of the receptacle is minimised.

8 A method as claimed in any one of the preceding claims, wherein the agitation does not involve applying a vibrational force directly to the receptacle at the point where the powder contacts the receptacle.

9 A method as claimed in any one of the preceding claims, wherein the powder is agitated following a powder-measuring step.

10 A method as claimed in any one of the preceding claims, wherein the vibrational force is provided m the form of sonication, including acoustic and ultrasound agitation (including resonant frequency matching), shaking, impacts and percussion effects.

1 1. A method as claimed in any one of the preceding claims, wherein the vibrational forces are transmitted or focussed using means such as an acoustic lens, or transmitting media to improve contact with the receptacle.

12. A method as claimed in any one of the preceding claims, wherein vibrational force is applied by a sonotrode.

13 A method as claimed in any one of the preceding claims, wherein the agitation involves applying a vibrational force to the powder in the receptacle at frequencies of less than about 1 megahertz.

14 A method as claimed m claim 13, wherein the frequency is from about 1 Hz to about 500 kHz, from about 1 kHz to about 250 kHz, from about 10 kHz to about 100 kHz, from about 15 kHz to about 50 kHz, or from about 20 kHz to about 40 kHz.

15. A method as claimed in any one of the preceding claims, wherein the agitation may be provided by contacting a powder-filled receptacle with an ultrasonic probe, preferably wherein the probe is operating at a frequency range of between about 10 and about 40 kHz.

16 A method as claimed in any one of the preceding claims, wherein the agitation involves applying a vibrational force to the powder in the receptacle with an amplitude of oscillation of between about 10 to about 100%, from about 50 to about 100%, from about 75 to about 100%, from about 80 to about 100%, from about 85 to about 100% or from about 90 to about 100%.

17 A method as claimed in any one of the preceding claims, wherein the agitation involves applying the vibrational force to the receptacle with a pressure in the range of from about 0.1 to about 1.5 bar, from about 0.2 to about 1.2 bar, or from about 0 2 to about 0.6 bar.

18 A method as claimed in any one of the preceding claims, wherein the agitation involves applying the vibrational force for a duration of between about 0 025 to about 1 second.

19 A method as claimed in any one of the preceding claims, wherein the agitation involves applying a vibrational force and the vibrational force is generated by a vibrational means having a vibrational surface which, upon contacting the receptacle, creates a cavity between the vibrational surface and the receptacle surface

20. A method as claimed in claim 19, wherein the cavity is sealed to create a sealed air entity.

21. A method as claimed in claim 19 or 20, wherein the receptacle wall contacted by the vibrational means transmits the vibration generated within the cavity to the air within the receptacle.

22. A method as claimed in any one of the preceding claims, wherein the receptacle is a blister

23 A method as claimed in any one of the preceding claims, wherein the powder is pelletised prior to the agitation step, to form small metastable pellets

24 A method as claimed in any one of the preceding claims, further comprising a pelletising step to form small metastable powder pellets

25 A method as claimed m any one of the preceding claims, wherein the dry powder formulation comprises an additive material which reduces the cohesion and/or adhesion of the powder particles

26 A method as claimed in any one of the preceding claims, wherein the dry powder composition comprises particles of a size and/or shape that form compacted powder which is less stable and more easily broken up.

27 A method as claimed in any one of the preceding claims, wherein the dry powder composition comprises a compact or plug that is elongated in shape.

28 A method substantially as described herein.

29. A blister or capsule for use in a dry powder inhaler device, which has been filled with a dose of a dry powder formulation using a method as claimed in any one of the preceding claims.

30. A dry powder inhaler device comprising a blister or capsule as claimed in claim 29.

31. A receptacle-filling apparatus comprising a vibrational means in order to perform the method claimed in any one of claims 1 to 28.

32. An apparatus as claimed in claim 31 , wherein the apparatus measures doses of dry powders and places these into receptacles, and subsequently agitates the powder-filled receptacles.