US20050051453A1 - Sealing a pharmaceutical formulation in a package - Google Patents

Abstract

An apparatus is provided for sealing a first layer to a second layer, the second layer comprising one or more cavities adapted to contain a pharmaceutical formulation. The apparatus comprises a roller comprising a heating element, and a surface adapted to support the first and second layers, the surface being translatable relative to the roller. The first layer may be heat sealed to the second layer when contacted by the roller to contain the pharmaceutical formulation within the one or more cavities.

Description

RELATED APPLICATIONS
• The present application claims the benefit of U.S. Provisional Application No. 60/343,310 filed on Dec. 21, 2001.
BACKGROUND
• The need for effective therapeutic treatment of patients has resulted in the development of a variety of pharmaceutical formulation delivery techniques. One traditional technique involves the oral delivery of a pharmaceutical formulation in the form of a pill, capsule, or the like. Inhaleable drug delivery, where an aerosolized pharmaceutical formulation is orally or nasally inhaled by a patient to deliver the formulation to the patient's respiratory tract, has also proven to be an effective manner of delivery. In one inhalation technique, a pharmaceutical formulation is delivered deep within a patient's lungs where it may be absorbed into the blood stream. Many types of inhalation devices exist including devices that aerosolize a dry powder.
• The pharmaceutical formulation is often packaged in a container from which it may be made available to a user. For example, a dose or a portion of a dose may be stored between layers of a multi-layered package, conventionally referred to as a blister or blister pack. Typically, a cavity is formed in a lower layer, the pharmaceutical formulation is deposited within the cavity, and an upper layer is sealed onto the lower layer, such as by heating and/or compressing the layers, to secure the pharmaceutical formulation within the cavity. The cavity may be designed so that the user may gain access to the cavity by separating the layers, by pushing the pharmaceutical formulation through the top layer or through a weakened portion of the top layer, by puncturing one of the layers with an instrument, or the like.
• It is often difficult to effectively package some pharmaceutical formulations in conventional blister-type packages. For example, when heat sealing the layers of the package, the application of heat to seal the layers may also cause the temperature of the cavity to increase, thereby heating the pharmaceutical formulation in the cavity which may affect its properties. Additionally, conventional sealing techniques often do not form a sufficiently protective seal to prevent environmental degradation of the pharmaceutical formulation.
• Therefore, it is desirable to be able to package a pharmaceutical formulation in a multi-layer package in an improved manner. It is further desirable to package a pharmaceutical formulation in a multi-layer package without substantially effecting the properties of the pharmaceutical formulation. It is still further desirable to improve the sealing of a multi-layer package to better protect a pharmaceutical formulation and/or to make the seal more consistent.
SUMMARY
• The present invention satisfies these needs. In one aspect of the invention layers of a multi-layered package are sealed by a heated roller to provide an improved pharmaceutical package.
• In another aspect of the invention, an apparatus for sealing a first layer to a second layer, the second layer comprising one or more cavities adapted to contain a pharmaceutical formulation, comprises a roller comprising a heating element; and a surface adapted to support the first and second layers, the surface being translatable relative to the roller; whereby the first layer may be heat sealed to the second layer when contacted by the roller to contain the pharmaceutical formulation within the one or more cavities.
• In another aspect of the invention, an apparatus for sealing a first layer to a second layer, the second layer comprising one or more cavities adapted to contain a pharmaceutical formulation, comprises a roller comprising a heating element; and a surface adapted to support the second layer, wherein at least a portion of the surface is substantially flat; whereby the first layer may be heat sealed to the second layer when contacted by the roller to contain the pharmaceutical formulation within the one or more cavities.
• In another aspect of the invention, a method of sealing a package comprises providing a first layer and a second layer on a surface, the second layer comprising one or more cavities containing a pharmaceutical formulation; compressing the layers together with a heated roller; and translating the heated roller relative to the surface, whereby the first layer may be heat sealed to the second layer when contacted by the roller to contain the pharmaceutical formulation within the one or more cavities.
• In another aspect of the invention, a pharmaceutical package is made by a process comprising providing a first layer and a second layer on a surface, the second layer comprising one or more cavities containing a pharmaceutical formulation; pressing the layers together with a heated roller; and translating the heated roller relative to the surface, whereby the first layer may be heat sealed to the second layer when contacted by the roller to contain the pharmaceutical formulation within the one or more cavities.
DRAWINGS
• These features, aspects, and advantages of the present invention will become better understood with regard to the following description, appended claims, and accompanying drawings which illustrate exemplary features of the invention. However, it is to be understood that each of the features can be used in the invention in general, not merely in the context of the particular drawings, and the invention includes any combination of these features, where:
• FIG. 1 is a schematic perspective view of a sealing apparatus of the present invention;
• FIGS. 2A through 2C are schematic perspective views of the sealing apparatus ofFIG. 1 performing a sealing process;
• FIG. 3A is a schematic sectional side view though line A-A ofFIG. 2B;
• FIG. 3B is a schematic sectional side view though line B-B ofFIG. 2C;
• FIG. 4 is a schematic sectional side view of a version of a multi-layered package that may be sealed with a sealing apparatus;
• FIG. 5 is a schematic sectional side view of another version of a multi-layered package that may be sealed with a sealing apparatus;
• FIG. 6A is a chart showing how temperature relates to position and contact portion in the sealing apparatus;
• FIG. 6B is a schematic showing locations of temperature detection in a test multi-layered package;
• FIG. 6C is a graph of the temperature at the locations shown inFIG. 6B as a function of time when using the present sealing apparatus;
• FIGS. 7A through 7D are graphs showing the temperature at locations shown inFIG. 6B as a function of time when using the present sealing apparatus and when using a uniform heating sealing appartus;
• FIG. 8 a graph of an Instron test of the seal strength of a multi-layered package sealed with a sealing apparatus of the present invention with four sampled multi-layered packages sealed with a uniform heating process;
• FIG. 9 is a graph showing contours of the peak cavity temperatures as a function of roller temperature and contact time;
• FIG. 10 is a schematic perspective view of a version of a sealing apparatus of the present invention;
• FIGS. 11A and 11B are schematic perspective views of versions of platforms of the sealing apparatus;
• FIG. 12 is a schematic perspective view of another version of a sealing apparatus; and
• FIG. 13 is a schematic perspective view of another version of a sealing apparatus.
DESCRIPTION
• The present invention relates to package sealing. Although the process is illustrated in the context of packaging a pharmaceutical formulation in a multi-layered package, the present invention can be used in other processes and should not be limited to the examples provided herein.
• Asealing apparatus100 according to the present invention is shown schematically inFIG. 1. The sealing apparatus comprises aplatform105 and aroller110. Theplatform105 includes asurface115 which supports an object that is to be sealed. Theroller110 is translatable relative to thesurface115 so that theroller110 may pass over at least a portion of thesurface115. Theroller110 includes aroller surface120 that rolls over at least a portion of the object on thesurface115. In one version, theroller110 includes aheating element125 which is capable of heating theroller surface120 to a desired temperature. Theheating element125 may be positioned in theroller110, as shown inFIG. 1. Alternatively, theheating element125 may be separated from but in communication with theroller110 so as to be able to heat theroller surface120.
• In one version, the sealingapparatus100 is adapted to seal a pharmaceutical formulation within a multi-layer package, such as a blister. For example, the sealingapparatus100 may seal a plurality of layers to one another with the pharmaceutical formulation contained between the layers. An exemplary sealing process is shown inFIGS. 2A through 2C. Alower layer130 of a multi-layered package is placed on theplatform surface115. In the version shown, thelower layer130 comprises acavity135 which may contain a pharmaceutical formulation. Thecavity135 is positioned within arecess140 in thesurface115 while arim portion145 rests on thesurface115. Thecavity135 may be formed on theplatform105 and/or the pharmaceutical formulation may be inserted into thecavity135 while thelower layer130 is positioned on thesurface115. Alternatively, alower layer130 with a preformedcavity135 prefilled with the pharmaceutical formulation may be positioned onto thesurface115. Anupper layer150 is then, or previously, positioned over thelower layer130, as shown inFIG. 2B. When the layers are positioned on theplatform105, theroller surface120 is heated to a desired temperature, and theplatform surface115 is translated relative to theroller110 to cause theroller110 to pass over the layers. The heating and/or compression of the layers seals the layers to one another and secures the pharmaceutical formulation within the sealedmulti-layered package155.
• The sealing process is further illustrated inFIGS. 3A and 3B, which show cross-sectional views through lines A-A ofFIG. 2B and B-B ofFIG. 2C, respectively. InFIG. 3A, thelower layer130 is positioned on theplatform surface110 with thecavity135, which is filled with a pharmaceutical formulation, positioned within therecess140. Theupper layer150 is positioned over thelower layer130. Between theupper layer150 thelower layer130 is a sealing material that may cause a seal to be formed between theupper layer150 and thelower layer130 when heated and/or compressed. To seal the layers, theplatform105 is translated relative to theroller110 in the direction shown by thearrow160. As the layers pass between theroller110 and theplatform105, aseal165 is formed between the layers, for example by being formed between therim portion145 of thelower layer130 and the portion of theupper layer150 which contacts therim portion145. Alternatively to the configuration shown, therecess140 may be shaped to more closely resemble the contour of thecavity135.
• Theroller110 may apply compression between theupper layer150 and thelower layer130. For example, in one version, the separation distance, d, between theroller110 and theplatform surface115 is less than the combined thickness of thelower layer130 and theupper layer150 so that the layers are compressed as they pass between theroller110 and thesurface115. For example, the distance, d, may be from about 0% to about 100% of the combined thickness of the layers, more preferably from about 30% to about 98%, and most preferably from about 60% to about 95%. In another version, theroller110 may rest on theplatform surface115 and the mass of theroller110 may serve to compress the layers together. Additionally, theroller110 may be designed to rotate in the direction of thearrow170. In one version, an actuator, such as a rotary motor, may be provided to cause theroller110 to rotate. The motor may control the rotation of theroller110 in accordance with the translation of thesurface115 relative to theroller110. Alternatively, the motor may rotate theroller110 to cause the translation. In another version, theroller110 freely rotates so that the translation of thesurface115 and the friction of the object and/or the platform causes theroller110 to rotate. In yet another version, gearing may be provided so that translation of theplatform105 causes rotation of theroller110 or so that rotation of theroller110 causes translation of theplatform105. In one particular version, the surface velocity is substantially zero, relative to a grounded reference.
• Theroller110 may comprise aheating element125 to provide heat to the layers to facilitate the sealing process. For example, in the version shown inFIGS. 3A and 3B, theheating element125 may be positioned within theroller110. Theheating element125 is adapted to heat theroller surface120, primarily by conducting heat through theroller110. Theheated surface120 then contacts the layers as the layers are passed between theroller110 and theplatform105. Accordingly, theroller surface120 can be heated to a predetermined temperature which is determined to apply sufficient heat for a translation velocity to be used. Theheating element125 may comprise a heat generating element, such as a cylindrical resistive heater cartridge, placed within a cylindrical hole that extends along the roller's axis of rotation. Theroller110 may comprise a high heat conducting material, such as metal, in order to ensure a substantially uniform temperature profile across theroller surface120. Theroller110 may be of any suitable radius. Preferably, the radius of the roller is selected so that the rotation of theroller110 during a sealing process is less than about 360 degrees, and more preferably less than about 270 degrees, for temperature stability. In another version, the heating element is exterior to theroller110. For example, the heating element may be positioned so that it transfers heat to the exterior surface of theroller surface120, such as by convection and/or radiation.
• The sealing material is positioned between theupper layer150 and thelower layer130 and comprises a material that can seal theupper layer150 to thelower layer130 when heat and/or compression is applied to the sandwiched layers. For example, in one version, the sealing material comprises a layer of heat activated sealer, such as lacquer, or polymethyl methacrylate (PMMA), or the like. The heat activated sealer may be provided on thelower surface175 of theupper layer150. When heated to a sufficient temperature, such as at least about 140° C., and often at least about 160° C., the heat activated sealer changes state so that when cooled, theupper layer150 is sealed to thelower layer130. Alternatively, the heat activated sealer may be provided on an upper surface of thelower layer130 or may be a separate sheet positioned between theupper layer150 and thelower layer130. In another version, the heat activated sealer may be the material of theupper layer150 and/or thelower layer130. In this version, sufficient heat may be applied to melt the material between the layers so that the layers may be fused to one another upon cooling. Theroller110 may provide compression to the heat activated sealer during the sealing process to more evenly distribute the sealer and/or to help bond theupper layer150 to thelower layer130. Alternatively, the sealing material may comprise an adhesive or bonding material that does not require heat to activate. Accordingly, in this version, theroller110 may be used to compress the layers and improve the sealing of the layers.
• It has been discovered that the sealingapparatus100 of the present invention provides for advantageous sealing of multi-layered packages. For example, the use of aroller110 that is translatable relative to aplatform surface115 is advantageous over a flat compression and/or heating member that uniformly or substantially uniformly engages theupper layer150. As can be seen inFIG. 3B, theroller surface120 contacts only a portion of theupper layer150. The contact portion, c, is the portion of theupper layer150 that contacts theroller surface120. This contact portion, c, has a length that is less than the length of theupper layer150. This shortened contact portion assures that a greater percentage of the surface is compressed, and the sealing material is more evenly distributed across the sealing area. As a result, the effects of material discontinuities or imperfections are minimized.
• Furthermore, it has been determined that high temperatures can adversely affect some pharmaceutical formulations. For example, some pharmaceutical formulations undergo degradation when exposed to temperatures of about 100° C. or greater, and others are at least partially altered when exposed to temperatures of about 80° C. or greater. High temperatures have been found to be particularly undesirable for powdered pharmaceutical formulations that are to be aerosolized in that the elevated temperature may lead to agglomerations and less than desirable aerosol performance and/or may lead to morphological degradation. In addition, excessive heat can morphologically change other types of pharmaceutical formulations. It has been discovered that localized heating of a portion of the layers to be sealed, such as by using aroller110 comprising aheating element125, unexpectedly lowers the temperature of thecavity135 during the sealing process and thereby lowers the temperature experienced by a pharmaceutical formulation within thecavity135 during the sealing process when compared to a uniform heating process. Additionally, it has been unexpectedly discovered that a higher sealing temperature can be used without significantly raising the temperature of thecavity135 when using thepresent sealing apparatus100.
• In one version, the sealingapparatus100 may be used to seal a multi-layered package around a pharmaceutical formulation that is susceptible to degradation and/or reduced aerosol performance when exposed to excessive amounts of moisture. For example, the multi-layered package may comprise one or more layers that comprise a moisture barrier material. The moisture barrier material comprises one or more metals, such as aluminum, or the like and/or other moisture barrier materials, such as polyamides, poly vinyl chlorides and the like. The moisture barrier may be provided below and above the pharmaceutical formulation to provide additional moisture protection. For example, as shown in the version ofFIG. 4, themulti-layered package155 may comprise alower layer130 comprising ametal containing layer180 and anupper layer150 comprising ametal containing layer185. Themetal containing layers180,185 may be sufficiently thick to substantially prevent a significant amount of moisture from passing therethrough. For example, themetal containing layers180,185 may be from about 10 μm to about 100 μm, and more preferably from about 20 μm to about 80 μm. Thelower layer130 and theupper layer150 are sealed together by a layer of sealing material, such as a layer of lacquer that may be from about 1 μm to about 20 μm. Within thecavity135 is a pharmaceutical formulation, such as a pharmaceutical formulation indry powder form195 that may be aerosolized. Alternatively, the pharmaceutical formulation may be in capsule, pill, elixir, or the like form. Thelower layer130 and/or theupper layer150 of themulti-layered package155 may optionally include additional materials that serve to improve the sealing or moldability of the layers. For example,FIG. 5 shows a particular version of amulti-layered package155 useful in providing a moisture barrier package for a pharmaceutical formulation. In this version, thelower layer130 comprises afirst layer200 comprising polymeric material, such as polyvinyl chloride, and having a thickness of about 60 μm, asecond layer205 comprising a polyamide, such as nylon, and having a thickness of about 25 μm, athird layer210 comprising a metal, such as aluminum, and having a thickness of about 60 μm, and afourth layer215 comprising a polymeric material, such as polyvinyl chloride, and having a thickness of about 60 μm. Theupper layer150 comprises afirst layer220 comprising a metal, such as aluminum, and having a thickness of about 25 μm, and asecond layer225 comprising a sealing material, such as lacquer, and having a thickness of about 6 μm.
• The moisture protection provided by the packages ofFIGS. 4 and 5 is improved by using thepresent sealing apparatus100 to seal theupper layer150 to thelower layer130. It has been determined that with conventional sealing techniques, a pharmaceutical formulation within the cavity is sufficiently protected from moisture for from about 15 to about 20 days. However, with thepresent sealing apparatus100, the moisture protection is significantly improved. Though the precise mechanism for the improvement is unknown, it is believed that one or more of the following contributes to the added moisture protection: 1) localized compression and rolling decreases the amount of entrapped air in the seal, 2) the effects of different coefficients of expansion is less pronounced, 3) improved reorientation of the polymeric materials under localized heat and pressure, and 4) partial combination of polymeric compression, flow and recovery provided by the roller leaves voids.
• It has been further discovered that by using thepresent sealing apparatus100, thermal degradation of a pharmaceutical formulation within acavity135 is reduced. As shown inFIG. 6A, the use of aroller110 comprising aheating element125 localizes the application of heat to a particular portion along the length of themulti-layered package155. The temperature of themulti-layered package155 is at a maximum at the contact portion, c, and is sharply reduced at the portions not directly in contact with theroller110. In one version, for a cavity that is from about 0.4 inches to about 0.5 inches in length, the contact portion may be from about 0.1 to about 1.0 inches, more preferably from about 0.05 to about 0.4 inches, more preferably from about 0.8 inches to about 0.20 inches, and most preferably about 0.12 inches. For different sized cavities, the contact portion may be altered accordingly. As shown inFIG. 6B, heat that is applied to therim portion145 of a multi-layered package is conducted250 to thecavity135 where it exposes the pharmaceutical formulation to heat. This conduction of heat is particularly pronounced when one or more of thelayers130,150 comprises a metal-containing layer. By providing localized heating with the sealingapparatus100, the resulting conduction is reduced. During a test process, the temperature during the sealing process was taken at four points on the multi-layered package155: on the rim portion and spaced from thecavity135, T₁; within thecavity135 and in proximity to therim portion145, T₂; within thecavity135 and below the level of a pharmaceutical formulation, T₃; and at the deepest portion of thecavity135, T₄. The temperature of aroller110 having a radius of about 2 inches was set to 180° C. and theplatform105 androller110 were translated160 at a velocity of about 0.8 inches/second to seal the multi-layered package shown inFIG. 5 having a cavity with a length of about 0.45 inches and depth of about 0.1 inches The resulting temperature curves at the four points during the sealing process are shown inFIG. 6C. As can be seen, T₁reaches a maximum of about 140° C. when in contact with theroller110, but the heat quickly dissipates as theroller110 progresses beyond the point. The local relatively high temperatures quickly diffuse throughout the layers to achieve an average temperature that is a reduced value. As a result of the shortened heating period at points along therim portion145, the heat conducted to thecavity135 is reduced, and the temperatures within the cavity, T₂, T₃, T₄, are held below about 65° C. and do not significantly alter a pharmaceutical formulation within thecavity135.
• This reduction in heating profiles is illustrated inFIGS. 7A through 7D which compare the temperatures during sealing using the localized heating provided by thepresent sealing apparatus100 with the temperatures during sealing using an apparatus that uniformly heats the top of themulti-layered package155. The uniform heating process was carried out using a sealing plate heated to about 170° C. that contacts themulti-layered package155 for about 0.6 seconds. As can be seen inFIG. 7A, the maximum temperature reached at T₁is significantly less using the process according to the present invention than the temperature at T₁using the uniform heating process, and the high temperatures are maintained for significantly less time using the present process. The lower maximum temperature and the shortened time provide less heat for conduction to thecavity135, and as a result the temperatures in thecavity135 are reduced. For example, as shown inFIG. 7B, the temperature at T₂for the uniform heating process is above 100° C. for a significant duration of the sealing process. Temperatures about 100° C. are damaging to some pharmaceutical formulations. As further shown inFIGS. 7C and 7D, the cavity temperatures even deeper within the cavity approach or reach 100° C. for the uniform heating process. In contrast, the localized heating using the process of the present invention results in cavity temperatures below about 65° C., thereby providing the ability to package pharmaceutical formulations that undergo heat damage at temperatures thereabove. In addition, it has been determined that the heat damage to a pharmaceutical formulation within thecavity135 can be further reduced by provided a space between the top of the pharmaceutical formulation and theupper layer150. This prevents heat from passing directly from theupper layer150 to the pharmaceutical formulation.
• Unexpectedly, the quality of the sealing of themulti-layered package155 is improved using thesealing apparatus100 of the present invention. For example, as shown inFIG. 8, which shows a graph of an Instron test of the seal strength of a multi-layered package sealed according to thepresent process270 with four sampled multi-layered packages sealed according to the uniform heating process described above. Even though theroller110 in the present process was maintained at a lower temperature than the sealing plate of the uniform heating process and even though the maximum temperature reached along therim portion145 is lower with the present process, the strength of the seal is higher. Accordingly, with the present process, an improved seal is achieved while also preventing undesired alteration of a pharmaceutical formulation being packaged. An additional unexpected result of the present invention is illustrated inFIG. 9 which shows contours of the peak cavity temperatures as a function of roller temperature and contact time (the length of the contact portion, c, divided by the velocity of translation of the roller). As can be seen, the peak cavity temperature is more affected by contact time than by roller temperature. Accordingly, assuming the contact time is held sufficiently low, very high roller temperatures may be employed without adversely heating thecavity135. Also,FIG. 9 demonstrates that the process is unexpectedly easy to control since contact time may be a more controllable variable than roller temperature.
• A particular version of asealing apparatus100 is shown inFIG. 10. In this version, astage300 is provided to support theplatform105 and theroller110 and to provide for translation and/or rotation between theplatform105 and theroller110. In this version, theplatform105 is removably insertable onto atop surface305 of thestage300. On the top surface is one ormore indexing members310 that receive theplatform105 to assure proper alignment of theplatform105 on thestage300. Thestage300 also comprises one or more guide rails315. The guide rails support aroller carrier320 so that the roller carrier230 may translate relative to thetop surface305 of thestage300. Theroller carrier320 comprises one or moreroller supporting members325. In the version shown, tworoller supporting members325 have a throughhole330 for rotatably receiving anextension335 of theroller310. Theroller carrier320 may also comprise anopening340 through which the bottom portion of theroller110 may extend. In one version, the size and thickness of theopening340 is selected so that substantially only the contact area, c, portion of theroller surface120 extends belowside panels345 of theroller carrier320. In this way, theside panels345 serve as a heat shield to aid in localizing the application of heat to the contact area, c. Accordingly, when a multi-layer package is positioned on thesurface115 of theplatform105 and when theplatform105 is positioned on thestage300, theroller surface120 contacts the multi-layered package to seal the layers, as discussed above. This contact may be provided by positioning the roller110 a predetermined distance above thetop surface305 of thestage300 or above thesurface115 of theplatform105. Alternatively, the contact may be provided by providing a mechanism, such as a spring, that biases theplatform105 toward theroller110 or that biases theroller110 toward thestage300. The spring may be sized and shaped to provide a predetermined amount of pressure to be applied to the package. Alternatively, the amount of pressure may be controlled by selection of size and/or weight of theroller110. In another version, theplatform105 may be pivotably connected to thestage300 so that theplatform105 may pivot about an axis parallel to its longitudinal axis. In this way, misalignment between theroller110 and theplatform105 may be accommodated. Alternatively, theroller110 may be able to pivot.
• Theplatform105 may have asurface115 having one ormore recesses140 therein. For example, in the version ofFIG. 10, alower layer130 having a formedcavity135 may be positioned on thesurface115 so that thecavity135 is positioned within the recess. Alternatively, the recess may be used as a mold by which thecavity135 may be formed, such as by cold forming. In another version, a plurality ofrecesses140 are provided in the platform, as shown inFIG. 11A. In this version, theroller110 is sufficiently wide to contact two or more multi-layered packages positioned on theplatform105. In another version, an array ofrecesses140 may be provided, as shown inFIG. 11B. In this version, the translation of theroller110 along theplatform105 extends a sufficient length to contact an array of multi-layered packages that are positioned on theplatform105. In another version, theplatform105 may comprise an array of recesses, and theroller110 may be adapted to only seal a portion of the array. The balance of the recesses may be sealed by one or more additional rollers or by the first roller making one or more additional passes across the array. Theplatform105 may be positionable on thestage300 by a mechanism, such as a robotic mechanism, or may be positioned by hand. Alternatively, theplatform105 may be fixed to thestage300, and the multi-layered package or an array of multi-layered packages may be positioned onto theplatform105 by a mechanism or by hand. Thesurface115 may be made of a material selected so that theroller110 provides a predetermined amount of pressure on the multi-layered package. For example, the surface may be made of a material having a durometer of from about 10 to about 100. In one version, the surface comprises a fluoroelastomer, such as Viton™ available from E.I. Dupont de Nemours, having a durometer of about 70. The Viton™ surface is also advantageous in that is offers excellent heat resistance. In one version, thesurface115 may be substantially flat to provide ease in indexing and more precise control of the relative movements.
• The relative rotation and/or translation of theroller110 and theplatform105 may be controlled by acontroller350, as shown for example inFIGS. 12 and 13. In the version ofFIG. 12, arotary motor360 is provided on aroller support member325 in a manner where it may rotatably engage theroller110, such as by receiving and engaging theextension335. Themotor360 may be cause rotation of theextension335 and thereby cause rotation of theroller110. Thecontroller350 is in communication with themotor360 and is adapted to control the operation of theroller110, such as by causing the roller to rotate at a predetermined rotational velocity. In this way, the rotation of theroller110 may drive the translation of theroller110 relative to theplatform105 by causing theroller carrier320 to slide along the guide rails315. In another version, the translation of theroller110 may be provided by amotor370 that forces theroller carrier320 to slide along the guidedrails315, as shown inFIG. 13. Alternatively, a linear motor may be provided that acts directly on theroller carrier320. In the version shown, themotor370 is a rotary motor that rotates a drive shaft375 which in engages a projection380 extending from theroller carrier110 in a manner that translates rotation of the drive shaft375 into translation of the projection380, such as by providing teeth and grooves on respective members. In this version, theroller110 may be freely rotatable within theroller support325 so that the translation of theroller carrier320 and the resulting friction between theroller surface120 and the multi-layered package causes the rotation of theroller110. Thecontroller350 may control themotor370 of the version ofFIG. 13 in order to control the velocity of the translation. In another version, both the rotation of theroller110 and the translation of theroller110 relative to theplatform105 may be controlled. This version is advantageous in that there are reduced stresses applied to the components and/or to the package. Alternatively, theroller110 may be translated relative to theplatform105 by hand. A variety of motors which are available in the commercial market are suitable for use. the motors may include one or more of stepper motors, servo motors, pneumatic actuators, etc. In addition, the motors may also provide input to thecontroller350 by sensing the position of theroller110 or theroller carrier320 in order to provide added control to the process. Such sensors can include encoded wheel transducers, potentiometers, etc. Hybrid or bidirectional transducers often pair input and output functions together. In addition, a temperature sensor may be provided. The temperature sensor may be adapted to detect the temperature of theroller surface120 or other surface. The temperature sensor may be in communication with thecontroller350 and the controller may control the sealing process in accordance with the detected temperature.
• Thecontroller350 may control the operation of thesealing apparatus100 as discussed above. Although thecontroller350 has been illustrated by way of an exemplary single controller device to simplify the description of present invention, it should be understood that thecontroller350 may be a plurality of controller devices that may be connected to one another or a plurality of controller devices that may be connected to different components of thesealing apparatus100.
• In one embodiment, thecontroller350 comprises electronic hardware including electrical circuitry comprising integrated circuits that is suitable for operating or controlling thesealing apparatus100. Generally, thecontroller350 is adapted to accept data input, run algorithms, produce useful output signals, and may also be used to detect data signals from one or more sensors and other device components, and to monitor or control the process in thesealing apparatus100. However, thecontroller350 may merely perform one of these tasks. In one version, thecontroller350 may comprise one or more of (i) a computer comprising a central processor unit (CPU) which is interconnected to a memory system with peripheral control components, (ii) application specific integrated circuits (ASICs) that operate particular components of thesealing apparatus100 or operate a particular process, and (iii) one or more controller interface boards along with suitable support circuitry. Typical CPUs include the PowerPC™, Pentium™, and other such processors. The ASICs are designed and preprogrammed for particular tasks, such as retrieval of data and other information from the sealingapparatus100 and/or operation of particular device components. Typical support circuitry 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 often operates in conjunction with a random access memory (RAM), a read-only memory (ROM) and other storage devices well known in the art. The RAM can be used to store the software implementation of the present invention during process implementation. The programs and subroutines of the present invention are typically stored in mass storage devices and are recalled for temporary storage in RAM when being executed by the CPU.
• The software implementation and computer program code product of the present invention may be stored in a memory device, such as an EPROM, and called into RAM during execution by thecontroller350. The computer program code may be written in conventional computer readable programming languages, such as for example, assembly language, C, C″, Pascal, or native assembly. Suitable program code is entered into a single file, or multiple files, using a conventional text editor and stored or embodied in a computer-usable medium, such as a memory of the computer system. If the entered code text is in a high level language, the code is compiled to a compiler code which is linked with an object code of precompiled windows library routines. To execute the linked and compiled object code, the system user invokes the object code, causing the computer system to load the code in memory to perform the tasks identified in the computer program.
• In one version, thecontroller350 may comprise a microprocessor or ASIC of sufficiently small size and power consumption to be housed on or in theaerosolization device100. For example, suitable microprocessors for use as a local microprocessor include the MC68HC711E9 by Motorola, the PIC16C74 by Microchip, and the 82930AX by Intel Corporation. The microprocessor can include one microprocessor chip, multiple processors and/or co-processor chips, and/or digital signal processor (DSP) capability.
• In one version, the sealingapparatus100 is adapted to seal a dry powder pharmaceutical formulation with thecavity135 of a multi-layered package. In one particular version, at least a portion of the dry powder pharmaceutical formulation directly contacts thebottom layer130 of the package, in which case it may be important to prevent thebottom layer130 from reaching excessive temperatures. Alternatively, a material, such as a capsular container may be provided between the dry powder pharmaceutical formulation and thelower layer130 of the package. In this case it may also be necessary to prevent excessive heat in the cavity because the heat may be conducted through the material and to the pharmaceutical formulation.
• Thecavity135 may contain the pharmaceutical formulation in a form where it may be aerosolized for inhalation by the user. For example, when in a powdered form, the powder may be initially stored in the sealed package, which is opened prior to aerosolization of the powder, as described in U.S. Pat. No. 5,785,049, U.S. Pat. No. 5,415,162, and U.S. patent application Ser. No. 09/583,312. Alternatively the powder may be contained in a capsule, as described in U.S. Pat. No. 4,995,385, U.S. Pat. No. 3,991,761, U.S. Pat. No. 6,230,707, and PCT Publication WO 97/27892, the capsule being openable before, during, or after insertion of the capsule into an aerosolization device. In either the bulk, blister, capsule, or the like form, the powder may be aerosolized by an active element, such as compressed air, as described in U.S. Pat. No. 5,458,135, U.S. Pat. No. 5,785,049, and U.S. Pat. No. 6,257,233, or propellant, as described in U.S. patent application Ser. No. 09/556,262, filed on Apr. 24, 2000, and entitled “Aerosolization Apparatus and Methods”, and in PCT Publication WO 00/72904. Alternatively the powder may be aerosolized in response to a user's inhalation, as described for example in the aforementioned U.S. patent application Ser. No. 09/583,312 and U.S. Pat. No. 4,995,385. All of the above references being incorporated herein by reference in their entireties.
• In a preferred version, the invention provides a system and method for aerosolizing a pharmaceutical formulation and delivering the pharmaceutical formulation to the lungs of the user. The pharmaceutical formulation may comprise powdered medicaments, liquid solutions or suspensions, and the like, and may include an active agent.
• The active agent described herein includes an agent, drug, compound, composition of matter or mixture thereof which provides some pharmacologic, often beneficial, effect. This includes foods, food supplements, nutrients, drugs, vaccines, vitamins, and other beneficial agents. As used herein, the terms further include any physiologically or pharmacologically active substance that produces a localized or systemic effect in a patient. An active agent for incorporation in the pharmaceutical formulation described herein may be an inorganic or an organic compound, including, without limitation, drugs which act on: the peripheral nerves, adrenergic receptors, cholinergic receptors, the skeletal muscles, the cardiovascular system, smooth muscles, the blood circulatory system, synoptic sites, neuroeffector junctional sites, endocrine and hormone systems, the immunological system, the reproductive system, the skeletal system, autacoid systems, the alimentary and excretory systems, the histamine system, and the central nervous system. Suitable active agents may be selected from, for example, hypnotics and sedatives, psychic energizers, tranquilizers, respiratory drugs, anticonvulsants, muscle relaxants, antiparkinson agents (dopamine antagnonists), analgesics, anti-inflammatories, antianxiety drugs (anxiolytics), appetite suppressants, antimigraine agents, muscle contractants, anti-infectives (antibiotics, antivirals, antifungals, vaccines) antiarthritics, antimalarials, antiemetics, anepileptics, bronchodilators, cytokines, growth factors, anti-cancer agents, antithrombotic agents, antihypertensives, cardiovascular drugs, antiarrhythmics, antioxicants, anti-asthma agents, hormonal agents including contraceptives, sympathomimetics, diuretics, lipid regulating agents, antiandrogenic agents, antiparasitics, anticoagulants, neoplastics, antineoplastics, hypoglycemics, nutritional agents and supplements, growth supplements, antienteritis agents, vaccines, antibodies, diagnostic agents, and contrasting agents. The active agent, when administered by inhalation, may act locally or systemically.
• The active agent may fall into one of a number of structural classes, including but not limited to small molecules, peptides, polypeptides, proteins, polysaccharides, steroids, proteins capable of eliciting 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, erythropoietin (EPO), Factor VII, Factor IX, ceredase, cerezyme, cyclosporin, granulocyte colony stimulating factor (GCSF), thrombopoietin (TPO), alpha-1 proteinase inhibitor, elcatonin, granulocyte macrophage colony stimulating factor (GMCSF), growth hormone, human growth hormone (HGH), growth hormone releasing hormone (GHRH), heparin, low molecular weight heparin (LMWH), interferon alpha, interferon beta, interferon gamma, interleukin-1 receptor, interleukin-2, interleukin-1 receptor antagonist, interleukin-3, interleukin-4, interleukin-6, luteinizing hormone releasing hormone (LHRH), factor IX, insulin, pro-insulin, insulin analogues (e.g., mono-acylated insulin as described in U.S. Pat. No. 5,922,675, which is incorporated herein by reference in its entirety), amylin, C-peptide, somatostatin, somatostatin analogs including octreotide, vasopressin, follicle stimulating hormone (FSH), insulin-like growth factor (IGF), insulintropin, macrophage colony stimulating factor (MCSF), nerve growth factor (NGF), tissue growth factors, keratinocyte growth factor (KGF), glial growth factor (GGF), tumor necrosis factor (TNF), endothelial growth factors, parathyroid hormone (PTH), glucagon-like peptide thymosin alpha 1, IIb/IIIa inhibitor, alpha-1 antitrypsin, phosphodiesterase (PDE) compounds, VLA-4 inhibitors, bisphosponates, respiratory syncytial virus antibody, cystic fibrosis transmembrane regulator (CFTR) gene, deoxyreibonuclease (Dnase), bactericidal/permeability increasing protein (BPI), anti-CMV antibody, 13-cis retinoic acid, macrolides such as erythromycin, oleandomycin, troleandomycin, roxithromycin, clarithromycin, davercin, azithromycin, flurithromycin, dirithromycin, josamycin, spiromycin, midecamycin, leucomycin, miocamycin, rokitamycin, andazithromycin, and swinolide 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 as gentamicin, netilmicin, paramecin, tobramycin, amikacin, kanamycin, neomycin, and streptomycin, vancomycin, teicoplanin, rampolanin, mideplanin, colistin, daptomycin, gramicidin, colistimethate, polymixins such as polymixin B, capreomycin, bacitracin, penems; penicillins including penicllinase-sensitive agents like penicillin G, penicillin V, penicillinase-resistant agents like methicillin, oxacillin, cloxacillin, dicloxacillin, floxacillin, nafcillin; gram negative microorganism active agents like ampicillin, amoxicillin, and hetacillin, cillin, and galampicillin; antipseudomonal penicillins like carbenicillin, ticarcillin, azlocillin, mezlocillin, and piperacillin; cephalosporins like cefpodoxime, cefprozil, ceftbuten, ceftizoxime, ceftriaxone, cephalothin, cephapirin, cephalexin, cephradrine, cefoxitin, cefamandole, cefazolin, cephaloridine, cefaclor, cefadroxil, cephaloglycin, cefuroxime, ceforanide, cefotaxime, cefatrizine, cephacetrile, cefepime, cefixime, cefonicid, cefoperazone, cefotetan, cefmetazole, ceftazidime, loracarbef, and moxalactam, monobactams like aztreonam; and carbapenems such as imipenem, meropenem, pentamidine isethiouate, albuterol sulfate, lidocaine, metaproterenol sulfate, beclomethasone diprepionate, triamcinolone acetamide, budesonide acetonide, fluticasone, ipratropium bromide, flunisolide, cromolyn sodium, ergotamine tartrate and where applicable, analogues, agonists, antagonists, inhibitors, and pharmaceutically acceptable salt forms of the above. In reference to peptides and proteins, the invention is intended to encompass synthetic, native, glycosylated, unglycosylated, pegylated forms, and biologically active fragments and analogs thereof.
• Active agents for use in the invention further include nucleic acids, as bare nucleic acid molecules, vectors, associated viral particles, plasmid DNA or RNA or other nucleic acid constructions of a type suitable for transfection or transformation of cells, i.e., suitable for gene therapy including antisense. Further, an active agent may comprise live attenuated or killed 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 upon the particular agent, its activity, the severity of the condition to be treated, the patient population, dosing requirements, and the desired therapeutic effect. The composition will generally contain anywhere from about 1% by weight to about 99% by weight active agent, typically from about 2% to about 95% by weight active agent, and more typically from about 5% to 85% by weight active agent, and will also depend upon 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 from 0.001 mg/day to 100 mg/day, preferably in doses from 0.01 mg/day to 75 mg/day, and more preferably in doses from 0.10 mg/day to 50 mg/day. It is to be 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 excipient or carrier which may be taken into the lungs with no significant adverse toxicological effects to the subject, and particularly to the lungs of the subject. In addition to the active agent, a pharmaceutical formulation may optionally include one or more pharmaceutical excipients which 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, such excipients will, in part, serve to further improve the features of the active agent composition, for example by providing more efficient and reproducible delivery of the active agent, improving the handling characteristics of powders, such as flowability and consistency, and/or facilitating manufacturing and filling of unit dosage forms. In particular, excipient materials can often function to further improve the physical and chemical stability of the active agent, minimize the residual moisture content and hinder moisture uptake, and to enhance particle size, degree of aggregation, particle surface properties, such as rugosity, ease of inhalation, and the targeting of particles to the lung. One or more excipients may also be provided to serve as bulking agents when it is desired to reduce the concentration of 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, derivatized sugars such as alditols, aldonic acids, esterified sugars, and sugar polymers, which may be present singly 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 temperatures (Tg) above about 35° C., preferably above about 40° C., more preferably above 45° C., most preferably above about 55° C.
• Exemplary protein excipients include albumins such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, hemoglobin, and the like. Suitable amino acids (outside of the dileucyl-peptides of the invention), which may also function in a buffering capacity, include alanine, glycine, arginine, betaine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, tyrosine, tryptophan, and the like. Preferred are amino acids and polypeptides that function as dispersing agents. Amino acids falling into this category include hydrophobic amino acids such as leucine, valine, isoleucine, tryptophan, alanine, methionine, phenylalanine, tyrosine, histidine, and proline. Dispersibility-enhancing peptide excipients 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 raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol), pyranosyl sorbitol, myoinositol and the like.
• The pharmaceutical formulation may also include a buffer or a pH adjusting agent, typically a salt prepared from an organic acid or base. Representative buffers include organic acid salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid, Tris, tromethamine hydrochloride, or phosphate buffers.
• The pharmaceutical formulation may also include polymeric excipients/additives, e.g., polyvinylpyrrolidones, derivatized celluloses such as hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylmethylcellulose, Ficolls (a polymeric sugar), hydroxyethylstarch, dextrates (e.g., cyclodextrins, such as 2-hydroxypropyl-β-cyclodextrin and sulfobutylether-β-cyclodextrin), polyethylene glycols, and pectin.
• The pharmaceutical formulation may further include flavoring agents, taste-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”, 19^thed., Williams & Williams, (1995), and in the “Physician's Desk Reference”, 52^nded., Medical Economics, Montvale, N.J. (1998), both of which are incorporated herein by reference in their entireties.
• “Mass median diameter” or “MMD” is a measure of mean particle size, since the powders of the invention are generally polydisperse (i.e., consist of a range of particle sizes). MMD values as reported herein are determined by centrifugal sedimentation, although any number of commonly employed techniques can be used for measuring mean particle size. “Mass median aerodynamic 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 settling behavior, and is the diameter of a unit density sphere having the same settling velocity, generally in air, as the particle. The aerodynamic diameter encompasses particle 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 cascade impaction.
• In one version, the powdered formulation for use in the present invention includes a dry powder having a particle size selected to permit penetration into the alveoli of the lungs, that is, preferably 10 μm mass median diameter (MMD), preferably less than 7.5 μm, and most preferably less than 5 μm, and usually being in the range of 0.1 μm to 5 μm in diameter. The delivered dose efficiency (DDE) of these powders may be greater than 30%, more preferably greater than 40%, more preferably greater than 50% and most preferably greater than 60% and the aerosol particle size distribution is about 1.0-5.0 μm mass median aerodynamic 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, all of which are all incorporated herein by reference in their entireties.
• Although the present invention has been described in considerable detail with regard to certain preferred versions thereof, other versions are possible, and alterations, permutations and equivalents of the version shown will become apparent to those skilled in the art upon a reading of the specification and study of the drawings. For example, the relative positions of the elements in the expedients for carrying out the relative movements may be changed. Also, the various features of the versions herein can be combined in various ways to provide additional versions of the present invention. Furthermore, certain terminology has been used for the purposes of descriptive clarity, and not to limit the present invention. For example, the use of the terms “upper” and “lower” may 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 as fall within the true spirit and scope of the present invention.

Claims (23)

1. An apparatus for sealing a first layer to a second layer, the second layer comprising one or more cavities adapted to contain a pharmaceutical formulation, the apparatus comprising:

a roller comprising a heating element; and

a surface adapted to support the first and second layers, the surface being translatable relative to the roller;

whereby the first layer may be heat sealed to the second layer when contacted by the roller to contain the pharmaceutical formulation within the one or more cavities.

2. An apparatus according toclaim 1 wherein at least a portion of the surface is substantially flat.

3. An apparatus according toclaim 1 wherein the surface comprises one or more recesses adapted to contain the one or more cavities.

4. An apparatus for sealing a first layer to a second layer, the second layer comprising one or more cavities adapted to contain a pharmaceutical formulation, the apparatus comprising:

a roller comprising a heating element; and

a surface adapted to support the second layer, wherein at least a portion of the surface is substantially flat;

whereby the first layer may be heat sealed to the second layer when contacted by the roller to contain the pharmaceutical formulation within the one or more cavities.

5. An apparatus according toclaim 4 wherein the surface comprises one or more recesses adapted to contain the one or more cavities.

6. A method of sealing a package, the method comprising:

providing a first layer and a second layer on a surface, the second layer comprising one or more cavities containing a pharmaceutical formulation;

compressing the layers together with a heated roller; and

translating the heated roller relative to the surface,

whereby the first layer may be heat sealed to the second layer when contacted by the roller to contain the pharmaceutical formulation within the one or more cavities.

7. A method according toclaim 6 wherein the surface is substantially flat.

8. A method according toclaim 6 wherein the first layer comprises a metal.

9. A method according toclaim 6 wherein the second layer comprises a metal.

10. A method according toclaim 6 wherein the first layer and the second layer each comprise a metal.

11. A method according toclaim 6 wherein the pharmaceutical formulation comprises a dry powder.

12. A method according toclaim 6 wherein the pharmaceutical formulation comprises an aerosolizable dry powder.

13. A method according toclaim 6 wherein the pharmaceutical formulation is within a capsule.

14. A method according toclaim 6 wherein the pharmaceutical formulation comprises an aerosolizable dry powder within a capsule.

15. A pharmaceutical package made by a process comprising:

providing a first layer and a second layer on a surface, the second layer comprising one or more cavities containing a pharmaceutical formulation;

pressing the layers together with a heated roller; and

translating the heated roller relative to the surface,

whereby the first layer may be heat sealed to the second layer when contacted by the roller to contain the pharmaceutical formulation within the one or more cavities.

16. A pharmaceutical package according toclaim 15 wherein the surface is substantially flat.

17. A pharmaceutical package according toclaim 15 wherein the first layer comprises a metal.

18. A pharmaceutical package according toclaim 15 wherein the second layer comprises a metal.

19. A pharmaceutical package according toclaim 15 wherein the first layer and the second layer each comprise a metal.

20. A pharmaceutical package according toclaim 15 wherein the pharmaceutical formulation comprises a dry powder.

21. A pharmaceutical package according toclaim 15 wherein the pharmaceutical formulation comprises an aerosolizable dry powder.

22. A pharmaceutical package according toclaim 15 wherein the pharmaceutical formulation is within a capsule.

23. A pharmaceutical package according toclaim 15 wherein the pharmaceutical formulation comprises an aerosolizable dry powder within a capsule.

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