U.S. patent application number 10/301820 was filed with the patent office on 2005-03-10 for sealing a pharmaceutical formulation in a package.
This patent application is currently assigned to Inhale Therapeutic Systems, Inc.. Invention is credited to Alston, William W., Rasmussen, Dennis R., Schuler, Carlos E..
Application Number | 20050051453 10/301820 |
Document ID | / |
Family ID | 23345560 |
Filed Date | 2005-03-10 |
United States Patent
Application |
20050051453 |
Kind Code |
A1 |
Schuler, Carlos E. ; et
al. |
March 10, 2005 |
Sealing a pharmaceutical formulation in a package
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.
Inventors: |
Schuler, Carlos E.;
(Cupertino, CA) ; Alston, William W.; (San Jose,
CA) ; Rasmussen, Dennis R.; (Boca Raton, FL) |
Correspondence
Address: |
NEKTAR THERAPEUTICS
150 INDUSTRIAL ROAD
SAN CARLOS
CA
94070
US
|
Assignee: |
Inhale Therapeutic Systems,
Inc.
San Carlos
CA
|
Family ID: |
23345560 |
Appl. No.: |
10/301820 |
Filed: |
November 20, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60343310 |
Dec 21, 2001 |
|
|
|
Current U.S.
Class: |
206/528 ;
206/531; 53/329.3; 53/478 |
Current CPC
Class: |
B65B 51/16 20130101;
B65B 7/164 20130101; B65B 7/2878 20130101 |
Class at
Publication: |
206/528 ;
053/478; 053/329.3; 206/531 |
International
Class: |
B65B 051/10; B65D
083/04 |
Claims
What is claimed is:
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 to claim 1 wherein at least a portion of
the surface is substantially flat.
3. An apparatus according to claim 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 to claim 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 to claim 6 wherein the surface is
substantially flat.
8. A method according to claim 6 wherein the first layer comprises
a metal.
9. A method according to claim 6 wherein the second layer comprises
a metal.
10. A method according to claim 6 wherein the first layer and the
second layer each comprise a metal.
11. A method according to claim 6 wherein the pharmaceutical
formulation comprises a dry powder.
12. A method according to claim 6 wherein the pharmaceutical
formulation comprises an aerosolizable dry powder.
13. A method according to claim 6 wherein the pharmaceutical
formulation is within a capsule.
14. A method according to claim 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 to claim 15 wherein the
surface is substantially flat.
17. A pharmaceutical package according to claim 15 wherein the
first layer comprises a metal.
18. A pharmaceutical package according to claim 15 wherein the
second layer comprises a metal.
19. A pharmaceutical package according to claim 15 wherein the
first layer and the second layer each comprise a metal.
20. A pharmaceutical package according to claim 15 wherein the
pharmaceutical formulation comprises a dry powder.
21. A pharmaceutical package according to claim 15 wherein the
pharmaceutical formulation comprises an aerosolizable dry
powder.
22. A pharmaceutical package according to claim 15 wherein the
pharmaceutical formulation is within a capsule.
23. A pharmaceutical package according to claim 15 wherein the
pharmaceutical formulation comprises an aerosolizable dry powder
within a capsule.
Description
RELATED APPLICATIONS
[0001] The present application claims the benefit of U.S.
Provisional Application No. 60/343,310 filed on Dec. 21, 2001.
BACKGROUND
[0002] 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.
[0003] 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.
[0004] 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.
[0005] 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
[0006] 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.
[0007] 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.
[0008] 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.
[0009] 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.
[0010] 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
[0011] 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:
[0012] FIG. 1 is a schematic perspective view of a sealing
apparatus of the present invention;
[0013] FIGS. 2A through 2C are schematic perspective views of the
sealing apparatus of FIG. 1 performing a sealing process;
[0014] FIG. 3A is a schematic sectional side view though line A-A
of FIG. 2B;
[0015] FIG. 3B is a schematic sectional side view though line B-B
of FIG. 2C;
[0016] FIG. 4 is a schematic sectional side view of a version of a
multi-layered package that may be sealed with a sealing
apparatus;
[0017] FIG. 5 is a schematic sectional side view of another version
of a multi-layered package that may be sealed with a sealing
apparatus;
[0018] FIG. 6A is a chart showing how temperature relates to
position and contact portion in the sealing apparatus;
[0019] FIG. 6B is a schematic showing locations of temperature
detection in a test multi-layered package;
[0020] FIG. 6C is a graph of the temperature at the locations shown
in FIG. 6B as a function of time when using the present sealing
apparatus;
[0021] FIGS. 7A through 7D are graphs showing the temperature at
locations shown in FIG. 6B as a function of time when using the
present sealing apparatus and when using a uniform heating sealing
appartus;
[0022] 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;
[0023] FIG. 9 is a graph showing contours of the peak cavity
temperatures as a function of roller temperature and contact
time;
[0024] FIG. 10 is a schematic perspective view of a version of a
sealing apparatus of the present invention;
[0025] FIGS. 11A and 11B are schematic perspective views of
versions of platforms of the sealing apparatus;
[0026] FIG. 12 is a schematic perspective view of another version
of a sealing apparatus; and
[0027] FIG. 13 is a schematic perspective view of another version
of a sealing apparatus.
DESCRIPTION
[0028] 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.
[0029] A sealing apparatus 100 according to the present invention
is shown schematically in FIG. 1. The sealing apparatus comprises a
platform 105 and a roller 110. The platform 105 includes a surface
115 which supports an object that is to be sealed. The roller 110
is translatable relative to the surface 115 so that the roller 110
may pass over at least a portion of the surface 115. The roller 110
includes a roller surface 120 that rolls over at least a portion of
the object on the surface 115. In one version, the roller 110
includes a heating element 125 which is capable of heating the
roller surface 120 to a desired temperature. The heating element
125 may be positioned in the roller 110, as shown in FIG. 1.
Alternatively, the heating element 125 may be separated from but in
communication with the roller 110 so as to be able to heat the
roller surface 120.
[0030] In one version, the sealing apparatus 100 is adapted to seal
a pharmaceutical formulation within a multi-layer package, such as
a blister. For example, the sealing apparatus 100 may seal a
plurality of layers to one another with the pharmaceutical
formulation contained between the layers. An exemplary sealing
process is shown in FIGS. 2A through 2C. A lower layer 130 of a
multi-layered package is placed on the platform surface 115. In the
version shown, the lower layer 130 comprises a cavity 135 which may
contain a pharmaceutical formulation. The cavity 135 is positioned
within a recess 140 in the surface 115 while a rim portion 145
rests on the surface 115. The cavity 135 may be formed on the
platform 105 and/or the pharmaceutical formulation may be inserted
into the cavity 135 while the lower layer 130 is positioned on the
surface 115. Alternatively, a lower layer 130 with a preformed
cavity 135 prefilled with the pharmaceutical formulation may be
positioned onto the surface 115. An upper layer 150 is then, or
previously, positioned over the lower layer 130, as shown in FIG.
2B. When the layers are positioned on the platform 105, the roller
surface 120 is heated to a desired temperature, and the platform
surface 115 is translated relative to the roller 110 to cause the
roller 110 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 sealed multi-layered package
155.
[0031] The sealing process is further illustrated in FIGS. 3A and
3B, which show cross-sectional views through lines A-A of FIG. 2B
and B-B of FIG. 2C, respectively. In FIG. 3A, the lower layer 130
is positioned on the platform surface 110 with the cavity 135,
which is filled with a pharmaceutical formulation, positioned
within the recess 140. The upper layer 150 is positioned over the
lower layer 130. Between the upper layer 150 the lower layer 130 is
a sealing material that may cause a seal to be formed between the
upper layer 150 and the lower layer 130 when heated and/or
compressed. To seal the layers, the platform 105 is translated
relative to the roller 110 in the direction shown by the arrow 160.
As the layers pass between the roller 110 and the platform 105, a
seal 165 is formed between the layers, for example by being formed
between the rim portion 145 of the lower layer 130 and the portion
of the upper layer 150 which contacts the rim portion 145.
Alternatively to the configuration shown, the recess 140 may be
shaped to more closely resemble the contour of the cavity 135.
[0032] The roller 110 may apply compression between the upper layer
150 and the lower layer 130. For example, in one version, the
separation distance, d, between the roller 110 and the platform
surface 115 is less than the combined thickness of the lower layer
130 and the upper layer 150 so that the layers are compressed as
they pass between the roller 110 and the surface 115. 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, the roller 110 may rest on the platform surface 115 and
the mass of the roller 110 may serve to compress the layers
together. Additionally, the roller 110 may be designed to rotate in
the direction of the arrow 170. In one version, an actuator, such
as a rotary motor, may be provided to cause the roller 110 to
rotate. The motor may control the rotation of the roller 110 in
accordance with the translation of the surface 115 relative to the
roller 110. Alternatively, the motor may rotate the roller 110 to
cause the translation. In another version, the roller 110 freely
rotates so that the translation of the surface 115 and the friction
of the object and/or the platform causes the roller 110 to rotate.
In yet another version, gearing may be provided so that translation
of the platform 105 causes rotation of the roller 110 or so that
rotation of the roller 110 causes translation of the platform 105.
In one particular version, the surface velocity is substantially
zero, relative to a grounded reference.
[0033] The roller 110 may comprise a heating element 125 to provide
heat to the layers to facilitate the sealing process. For example,
in the version shown in FIGS. 3A and 3B, the heating element 125
may be positioned within the roller 110. The heating element 125 is
adapted to heat the roller surface 120, primarily by conducting
heat through the roller 110. The heated surface 120 then contacts
the layers as the layers are passed between the roller 110 and the
platform 105. Accordingly, the roller surface 120 can be heated to
a predetermined temperature which is determined to apply sufficient
heat for a translation velocity to be used. The heating element 125
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. The roller 110 may
comprise a high heat conducting material, such as metal, in order
to ensure a substantially uniform temperature profile across the
roller surface 120. The roller 110 may be of any suitable radius.
Preferably, the radius of the roller is selected so that the
rotation of the roller 110 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 the roller 110. For example, the heating element may
be positioned so that it transfers heat to the exterior surface of
the roller surface 120, such as by convection and/or radiation.
[0034] The sealing material is positioned between the upper layer
150 and the lower layer 130 and comprises a material that can seal
the upper layer 150 to the lower layer 130 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
the lower surface 175 of the upper layer 150. When heated to a
sufficient temperature, such as at least about 140.degree. C., and
often at least about 160.degree. C., the heat activated sealer
changes state so that when cooled, the upper layer 150 is sealed to
the lower layer 130. Alternatively, the heat activated sealer may
be provided on an upper surface of the lower layer 130 or may be a
separate sheet positioned between the upper layer 150 and the lower
layer 130. In another version, the heat activated sealer may be the
material of the upper layer 150 and/or the lower layer 130. 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. The roller 110 may provide compression to the heat
activated sealer during the sealing process to more evenly
distribute the sealer and/or to help bond the upper layer 150 to
the lower layer 130. Alternatively, the sealing material may
comprise an adhesive or bonding material that does not require heat
to activate. Accordingly, in this version, the roller 110 may be
used to compress the layers and improve the sealing of the
layers.
[0035] It has been discovered that the sealing apparatus 100 of the
present invention provides for advantageous sealing of
multi-layered packages. For example, the use of a roller 110 that
is translatable relative to a platform surface 115 is advantageous
over a flat compression and/or heating member that uniformly or
substantially uniformly engages the upper layer 150. As can be seen
in FIG. 3B, the roller surface 120 contacts only a portion of the
upper layer 150. The contact portion, c, is the portion of the
upper layer 150 that contacts the roller surface 120. This contact
portion, c, has a length that is less than the length of the upper
layer 150. 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.
[0036] 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.degree. C. or greater, and others are
at least partially altered when exposed to temperatures of about
80.degree. 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 a
roller 110 comprising a heating element 125, unexpectedly lowers
the temperature of the cavity 135 during the sealing process and
thereby lowers the temperature experienced by a pharmaceutical
formulation within the cavity 135 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 the cavity
135 when using the present sealing apparatus 100.
[0037] In one version, the sealing apparatus 100 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 of FIG. 4, the multi-layered package 155 may comprise a
lower layer 130 comprising a metal containing layer 180 and an
upper layer 150 comprising a metal containing layer 185. The metal
containing layers 180, 185 may be sufficiently thick to
substantially prevent a significant amount of moisture from passing
therethrough. For example, the metal containing layers 180, 185 may
be from about 10 .mu.m to about 100 .mu.m, and more preferably from
about 20 .mu.m to about 80 .mu.m. The lower layer 130 and the upper
layer 150 are sealed together by a layer of sealing material, such
as a layer of lacquer that may be from about 1 .mu.m to about 20
.mu.m. Within the cavity 135 is a pharmaceutical formulation, such
as a pharmaceutical formulation in dry powder form 195 that may be
aerosolized. Alternatively, the pharmaceutical formulation may be
in capsule, pill, elixir, or the like form. The lower layer 130
and/or the upper layer 150 of the multi-layered package 155 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 a multi-layered package 155 useful in
providing a moisture barrier package for a pharmaceutical
formulation. In this version, the lower layer 130 comprises a first
layer 200 comprising polymeric material, such as polyvinyl
chloride, and having a thickness of about 60 .mu.m, a second layer
205 comprising a polyamide, such as nylon, and having a thickness
of about 25 .mu.m, a third layer 210 comprising a metal, such as
aluminum, and having a thickness of about 60 .mu.m, and a fourth
layer 215 comprising a polymeric material, such as polyvinyl
chloride, and having a thickness of about 60 .mu.m. The upper layer
150 comprises a first layer 220 comprising a metal, such as
aluminum, and having a thickness of about 25 .mu.m, and a second
layer 225 comprising a sealing material, such as lacquer, and
having a thickness of about 6 .mu.m.
[0038] The moisture protection provided by the packages of FIGS. 4
and 5 is improved by using the present sealing apparatus 100 to
seal the upper layer 150 to the lower layer 130. 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 the present sealing apparatus 100, 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.
[0039] It has been further discovered that by using the present
sealing apparatus 100, thermal degradation of a pharmaceutical
formulation within a cavity 135 is reduced. As shown in FIG. 6A,
the use of a roller 110 comprising a heating element 125 localizes
the application of heat to a particular portion along the length of
the multi-layered package 155. The temperature of the multi-layered
package 155 is at a maximum at the contact portion, c, and is
sharply reduced at the portions not directly in contact with the
roller 110. 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 in FIG. 6B, heat that is applied to the rim portion 145 of a
multi-layered package is conducted 250 to the cavity 135 where it
exposes the pharmaceutical formulation to heat. This conduction of
heat is particularly pronounced when one or more of the layers 130,
150 comprises a metal-containing layer. By providing localized
heating with the sealing apparatus 100, the resulting conduction is
reduced. During a test process, the temperature during the sealing
process was taken at four points on the multi-layered package 155:
on the rim portion and spaced from the cavity 135, T.sub.1; within
the cavity 135 and in proximity to the rim portion 145, T.sub.2;
within the cavity 135 and below the level of a pharmaceutical
formulation, T.sub.3; and at the deepest portion of the cavity 135,
T.sub.4. The temperature of a roller 110 having a radius of about 2
inches was set to 180.degree. C. and the platform 105 and roller
110 were translated 160 at a velocity of about 0.8 inches/second to
seal the multi-layered package shown in FIG. 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 in FIG. 6C. As can be seen, T.sub.1 reaches a
maximum of about 140.degree. C. when in contact with the roller
110, but the heat quickly dissipates as the roller 110 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 the rim portion 145, the heat conducted to
the cavity 135 is reduced, and the temperatures within the cavity,
T.sub.2, T.sub.3, T.sub.4, are held below about 65.degree. C. and
do not significantly alter a pharmaceutical formulation within the
cavity 135.
[0040] This reduction in heating profiles is illustrated in FIGS.
7A through 7D which compare the temperatures during sealing using
the localized heating provided by the present sealing apparatus 100
with the temperatures during sealing using an apparatus that
uniformly heats the top of the multi-layered package 155. The
uniform heating process was carried out using a sealing plate
heated to about 170.degree. C. that contacts the multi-layered
package 155 for about 0.6 seconds. As can be seen in FIG. 7A, the
maximum temperature reached at T.sub.1 is significantly less using
the process according to the present invention than the temperature
at T.sub.1 using 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 the cavity 135, and as a
result the temperatures in the cavity 135 are reduced. For example,
as shown in FIG. 7B, the temperature at T.sub.2 for the uniform
heating process is above 100.degree. C. for a significant duration
of the sealing process. Temperatures about 100.degree. C. are
damaging to some pharmaceutical formulations. As further shown in
FIGS. 7C and 7D, the cavity temperatures even deeper within the
cavity approach or reach 100.degree. 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.degree. 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 the cavity
135 can be further reduced by provided a space between the top of
the pharmaceutical formulation and the upper layer 150. This
prevents heat from passing directly from the upper layer 150 to the
pharmaceutical formulation.
[0041] Unexpectedly, the quality of the sealing of the
multi-layered package 155 is improved using the sealing apparatus
100 of the present invention. For example, as shown in FIG. 8,
which shows a graph of an Instron test of the seal strength of a
multi-layered package sealed according to the present process 270
with four sampled multi-layered packages sealed according to the
uniform heating process described above. Even though the roller 110
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 the rim portion 145 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 in FIG. 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 the cavity 135. Also, FIG. 9 demonstrates
that the process is unexpectedly easy to control since contact time
may be a more controllable variable than roller temperature.
[0042] A particular version of a sealing apparatus 100 is shown in
FIG. 10. In this version, a stage 300 is provided to support the
platform 105 and the roller 110 and to provide for translation
and/or rotation between the platform 105 and the roller 110. In
this version, the platform 105 is removably insertable onto a top
surface 305 of the stage 300. On the top surface is one or more
indexing members 310 that receive the platform 105 to assure proper
alignment of the platform 105 on the stage 300. The stage 300 also
comprises one or more guide rails 315. The guide rails support a
roller carrier 320 so that the roller carrier 230 may translate
relative to the top surface 305 of the stage 300. The roller
carrier 320 comprises one or more roller supporting members 325. In
the version shown, two roller supporting members 325 have a through
hole 330 for rotatably receiving an extension 335 of the roller
310. The roller carrier 320 may also comprise an opening 340
through which the bottom portion of the roller 110 may extend. In
one version, the size and thickness of the opening 340 is selected
so that substantially only the contact area, c, portion of the
roller surface 120 extends below side panels 345 of the roller
carrier 320. In this way, the side panels 345 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
the surface 115 of the platform 105 and when the platform 105 is
positioned on the stage 300, the roller surface 120 contacts the
multi-layered package to seal the layers, as discussed above. This
contact may be provided by positioning the roller 110 a
predetermined distance above the top surface 305 of the stage 300
or above the surface 115 of the platform 105. Alternatively, the
contact may be provided by providing a mechanism, such as a spring,
that biases the platform 105 toward the roller 110 or that biases
the roller 110 toward the stage 300. 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 the roller 110. In
another version, the platform 105 may be pivotably connected to the
stage 300 so that the platform 105 may pivot about an axis parallel
to its longitudinal axis. In this way, misalignment between the
roller 110 and the platform 105 may be accommodated. Alternatively,
the roller 110 may be able to pivot.
[0043] The platform 105 may have a surface 115 having one or more
recesses 140 therein. For example, in the version of FIG. 10, a
lower layer 130 having a formed cavity 135 may be positioned on the
surface 115 so that the cavity 135 is positioned within the recess.
Alternatively, the recess may be used as a mold by which the cavity
135 may be formed, such as by cold forming. In another version, a
plurality of recesses 140 are provided in the platform, as shown in
FIG. 11A. In this version, the roller 110 is sufficiently wide to
contact two or more multi-layered packages positioned on the
platform 105. In another version, an array of recesses 140 may be
provided, as shown in FIG. 11B. In this version, the translation of
the roller 110 along the platform 105 extends a sufficient length
to contact an array of multi-layered packages that are positioned
on the platform 105. In another version, the platform 105 may
comprise an array of recesses, and the roller 110 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. The platform
105 may be positionable on the stage 300 by a mechanism, such as a
robotic mechanism, or may be positioned by hand. Alternatively, the
platform 105 may be fixed to the stage 300, and the multi-layered
package or an array of multi-layered packages may be positioned
onto the platform 105 by a mechanism or by hand. The surface 115
may be made of a material selected so that the roller 110 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.TM. available
from E.I. Dupont de Nemours, having a durometer of about 70. The
Viton.TM. surface is also advantageous in that is offers excellent
heat resistance. In one version, the surface 115 may be
substantially flat to provide ease in indexing and more precise
control of the relative movements.
[0044] The relative rotation and/or translation of the roller 110
and the platform 105 may be controlled by a controller 350, as
shown for example in FIGS. 12 and 13. In the version of FIG. 12, a
rotary motor 360 is provided on a roller support member 325 in a
manner where it may rotatably engage the roller 110, such as by
receiving and engaging the extension 335. The motor 360 may be
cause rotation of the extension 335 and thereby cause rotation of
the roller 110. The controller 350 is in communication with the
motor 360 and is adapted to control the operation of the roller
110, such as by causing the roller to rotate at a predetermined
rotational velocity. In this way, the rotation of the roller 110
may drive the translation of the roller 110 relative to the
platform 105 by causing the roller carrier 320 to slide along the
guide rails 315. In another version, the translation of the roller
110 may be provided by a motor 370 that forces the roller carrier
320 to slide along the guided rails 315, as shown in FIG. 13.
Alternatively, a linear motor may be provided that acts directly on
the roller carrier 320. In the version shown, the motor 370 is a
rotary motor that rotates a drive shaft 375 which in engages a
projection 380 extending from the roller carrier 110 in a manner
that translates rotation of the drive shaft 375 into translation of
the projection 380, such as by providing teeth and grooves on
respective members. In this version, the roller 110 may be freely
rotatable within the roller support 325 so that the translation of
the roller carrier 320 and the resulting friction between the
roller surface 120 and the multi-layered package causes the
rotation of the roller 110. The controller 350 may control the
motor 370 of the version of FIG. 13 in order to control the
velocity of the translation. In another version, both the rotation
of the roller 110 and the translation of the roller 110 relative to
the platform 105 may be controlled. This version is advantageous in
that there are reduced stresses applied to the components and/or to
the package. Alternatively, the roller 110 may be translated
relative to the platform 105 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
the controller 350 by sensing the position of the roller 110 or the
roller carrier 320 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 the roller surface 120 or other surface.
The temperature sensor may be in communication with the controller
350 and the controller may control the sealing process in
accordance with the detected temperature.
[0045] The controller 350 may control the operation of the sealing
apparatus 100 as discussed above. Although the controller 350 has
been illustrated by way of an exemplary single controller device to
simplify the description of present invention, it should be
understood that the controller 350 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
the sealing apparatus 100.
[0046] In one embodiment, the controller 350 comprises electronic
hardware including electrical circuitry comprising integrated
circuits that is suitable for operating or controlling the sealing
apparatus 100. Generally, the controller 350 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
the sealing apparatus 100. However, the controller 350 may merely
perform one of these tasks. In one version, the controller 350 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
the sealing apparatus 100 or operate a particular process, and
(iii) one or more controller interface boards along with suitable
support circuitry. Typical CPUs include the PowerPC.TM.,
Pentium.TM., and other such processors. The ASICs are designed and
preprogrammed for particular tasks, such as retrieval of data and
other information from the sealing apparatus 100 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.
[0047] 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 the
controller 350. 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.
[0048] In one version, the controller 350 may comprise a
microprocessor or ASIC of sufficiently small size and power
consumption to be housed on or in the aerosolization device 100.
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.
[0049] In one version, the sealing apparatus 100 is adapted to seal
a dry powder pharmaceutical formulation with the cavity 135 of a
multi-layered package. In one particular version, at least a
portion of the dry powder pharmaceutical formulation directly
contacts the bottom layer 130 of the package, in which case it may
be important to prevent the bottom layer 130 from reaching
excessive temperatures. Alternatively, a material, such as a
capsular container may be provided between the dry powder
pharmaceutical formulation and the lower layer 130 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.
[0050] The cavity 135 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.
[0051] 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.
[0052] 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.
[0053] 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.
[0054] 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.
[0055] 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).
[0056] 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.
[0057] 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.
[0058] 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.degree.
C., preferably above about 40.degree. C., more preferably above
45.degree. C., most preferably above about 55.degree. C.
[0059] 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.
[0060] 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.
[0061] 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.
[0062] 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-.beta.-cyclodextrin and
sulfobutylether-.beta.-cyclodextr- in), polyethylene glycols, and
pectin.
[0063] 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.sup.th
ed., Williams & Williams, (1995), and in the "Physician's Desk
Reference", 52.sup.nd ed., Medical Economics, Montvale, N.J.
(1998), both of which are incorporated herein by reference in their
entireties.
[0064] "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.
[0065] 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 .mu.m mass median diameter (MMD), preferably less
than 7.5 .mu.m, and most preferably less than 5 .mu.m, and usually
being in the range of 0.1 .mu.m to 5 .mu.m 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 .mu.m mass median
aerodynamic diameter (MMAD), usually 1.5-4.5 .mu.m MMAD and
preferably 1.5-4.0 .mu.m 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.
[0066] 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.
* * * * *