U.S. patent application number 12/007041 was filed with the patent office on 2008-05-08 for method and apparatus for producing dry particles.
This patent application is currently assigned to Alkermes, Inc.. Invention is credited to Charles D. Blizzard, Marie Chung, Blair C. Jackson, Lloyd P. Johnston, Ernest E. Penachio, Jean Sung.
Application Number | 20080108554 12/007041 |
Document ID | / |
Family ID | 28040031 |
Filed Date | 2008-05-08 |
United States Patent
Application |
20080108554 |
Kind Code |
A1 |
Jackson; Blair C. ; et
al. |
May 8, 2008 |
Method and apparatus for producing dry particles
Abstract
Method and apparatus for producing dry particles. Two liquid
components are combined in a static mixer, atomized into droplets,
and the droplets dried to form dry particles. Use of the static
mixer enables incompatible liquid components to be rapidly and
homogeneously combined. The present invention optimizes process
conditions for increasing and controlling particle porosity. The
present invention also allows for optimization of particle size in
real-time during particle production.
Inventors: |
Jackson; Blair C.; (South
Grafton, MA) ; Johnston; Lloyd P.; (Belmont, MA)
; Penachio; Ernest E.; (Haverhill, MA) ; Blizzard;
Charles D.; (Westwood, MA) ; Chung; Marie;
(Cambridge, MA) ; Sung; Jean; (Concord,
MA) |
Correspondence
Address: |
COVINGTON & BURLING, LLP;ATTN: PATENT DOCKETING
1201 PENNSYLVANIA AVENUE, N.W.
WASHINGTON
DC
20004-2401
US
|
Assignee: |
Alkermes, Inc.
Cambridge
MA
|
Family ID: |
28040031 |
Appl. No.: |
12/007041 |
Filed: |
January 4, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10391199 |
Mar 19, 2003 |
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12007041 |
Jan 4, 2008 |
|
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10101563 |
Mar 20, 2002 |
7008644 |
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10391199 |
Mar 19, 2003 |
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Current U.S.
Class: |
424/489 ;
514/5.9 |
Current CPC
Class: |
A61K 9/1688 20130101;
A61K 9/0075 20130101; B01D 1/18 20130101; A61K 38/27 20130101; B01F
3/0803 20130101; B01F 5/0619 20130101; A61K 9/1694 20130101; A61K
9/1611 20130101; A61K 9/1617 20130101; B01J 2/04 20130101; A61K
38/28 20130101; B01J 2/10 20130101; A61K 31/137 20130101 |
Class at
Publication: |
514/003 |
International
Class: |
A61K 38/28 20060101
A61K038/28 |
Claims
1. A method for preparing a dry powder composition, comprising:
combining a first fluid component and a second fluid component in a
static mixer to form a mixed fluid solution, wherein the first
fluid component comprises a protein that is incompatible with the
second fluid component; atomizing the mixed fluid solution flowing
out of the static mixer to produce droplets, wherein the atomizing
step is carried out using an atomizer that comprises an internal
mixing nozzle; and drying the droplets in a dryer to form dry
particles, wherein the dry particles contain less than about 6% of
soluble dimer of the protein and have a Fine Particle Fraction (FPF
(3.3)) in the range of about 57-66.
2. The method of claim 1, wherein the atomizing step is performed
immediately after the combining step.
3. The method of claim 1, wherein the protein is insulin.
4. The method of claim 2, wherein the protein is insulin.
5. The method of claim 1, further comprising adding a surfactant to
the first fluid component, the second fluid component, or the mixed
fluid solution.
6. The method of claim 3, further comprising: adding DPPC to the
first fluid component, the second fluid component, or the mixed
fluid solution.
7. The method of claim 1, wherein the nozzle is a six-hole
nozzle.
8. The method of claim 3, wherein the nozzle is a six-hole
nozzle.
9. The method of claim 1, wherein a solids concentration of the
mixed fluid solution is more than about 2 g/L.
10. The method of claim 9, wherein the solids concentration of the
mixed fluid solution is more than about 5 g/L.
11. The method of claim 10, wherein the solids concentration of the
mixed fluid solution is less than about 60 g/L.
12. The method of claim 11, wherein the solids concentration of the
mixed fluid solution is less than about 30 g/L.
13. The method of claim 1, further comprising adding about 5-40 g/L
ammonium bicarbonate to the first fluid component, the second fluid
component, or the mixed fluid solution.
14. The method of claim 1, wherein the second fluid component is an
organic solution comprising approximately 60-70% water by volume
and wherein the mixed fluid solution comprises approximately 20%
organic phase by volume.
15. The method of claim 14, wherein the second fluid component is
an organic solution comprising approximately 60% water by volume
and wherein the mixed fluid solution comprises approximately 20%
organic phase by volume.
16. The method of claim 1, wherein the drying step is performed in
a dryer with an outlet temperature of 35-70.degree. C.
17. The method of claim 16, wherein the outlet temperature is
approximately 45.degree. C.
18. The method of claim 1, further comprising: ascertaining an
amount of solid ingredients necessary to achieve a solution
concentration; ascertaining an amount of liquid ingredients
necessary to achieve the solution concentration; combining the
liquid ingredients and the solid ingredients to form the first
fluid component.
19. The method of claim 1, wherein the atomizing step comprises
using an atomization gas rate of approximately 35-120 g/min.
20. The method of claim 19, wherein the atomization gas rate is
approximately 120 g/min.
21. The method of claim 1, wherein the atomizing step comprises
using a liquid feed rate of approximately 10-75 mL/min.
22. The method of claim 21, wherein the liquid feed rate is
approximately 10-20 mL/min.
23. The method of claim 1, wherein the drying step is performed
using a drying gas rate of approximately 80-125 kg/hr.
24. The method of claim 1, wherein the drying gas rate is
approximately 110 kg/hr.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 10/391,199, filed Mar. 19, 2003, which is a
continuation-in-part of U.S. patent application Ser. No.
10/101,563, filed Mar. 20, 2002, each of which is hereby
incorporated in its entirety in this patent application.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to a method and apparatus for
producing dry particles. More particularly, the present invention
relates to a method and apparatus for producing dry particles that
are suitable for inhalation into the lung, and which contain an
active agent.
[0004] 2. Related Art
[0005] Delivery of drugs and other active agents can be
accomplished through the use of dry powder compositions made from
particles containing the drug or active agent. In producing such
particles, it is often desirable to combine substances with
significantly different physical properties to achieve the desired
pharmaceutical effect in patients. Moreover, it is often desirable
to produce particles that are a combination of different
substances. One way to produce particles containing a combination
of different substances is to dissolve the substances in suitable
solvents, and then remove the solvents by, for example, evaporation
or drying, to yield the desired particles. A major difficulty with
this approach is that substances with differing physical properties
often have very different solubilities in solvents. Consequently,
co-solvents, or a larger mixture of solvents, may be needed to form
the solution from which the particles are produced. However, the
use of co-solvents can cause degradation of one of the components,
through chemical or physical incompatibility of the components in
solution.
[0006] One example of the incompatibility of components is the
production of particles that contain a hydrophobic component and a
hydrophilic component. The production of such particles is
described in U.S. Pat. No. 6,077,543 to Gordon et al. ("the Gordon
patent"). As described in the Gordon patent, a hydrophobic drug
solution and a hydrophilic excipient solution are spray dried
together to form dry powders containing the drug and the excipient.
To solve the incompatibility between the hydrophobic and
hydrophilic components, the hydrophilic and hydrophobic components
are separately dissolved in different solvents, and separately
directed simultaneously through a nozzle into a spray dryer. In
this method, the two liquid components are separately delivered to
the nozzle that atomizes the two liquid components into droplets
that are dried in a spray dryer to form dry particles.
[0007] One of the drawbacks of the method and apparatus of the
Gordon patent is that there is no complete mixing of the two liquid
components before being atomized into droplets. Thus, the droplets
that are produced are unlikely to be a homogeneous mixture of the
two liquid components, nor is there likely to be uniformity among
the droplets. Consequently, the particles that are produced are
unlikely to contain a homogeneous mixture of the drug and
excipients, and are unlikely to have uniformity among the particles
themselves. Thus, there is a need in the art for an improved method
and apparatus for producing dry particles that contain a homogenous
mixture of drug and excipient components, with improved uniformity
among the particles. There is a particular need in the art for such
a method and apparatus where the drug component and excipient
component are physically or chemically incompatible in the liquid
state.
[0008] One important application for dry powder compositions is
pulmonary drug delivery. Several properties of the dry particles
have been identified that correlate with enhanced delivery to the
pulmonary system. For example, it has been found that particles
having a tap density less than 0.4 g/cm.sup.3 and an aerodynamic
diameter that is between about 1 and about 3 microns (.mu.m) are
well suited for delivery to the alveoli or the deep lung. If
delivery to the central or upper airways is desired, particles
having larger aerodynamic diameters, ranging for example, from
about 3 to about 5 microns are preferred. Furthermore, particles
having a geometric diameter greater than about 5 microns are
believed to more successfully avoid phagocytic engulfment by
alveolar macrophages and clearance from the lungs.
[0009] There is a need in the art for improved methods for
producing particles having selected geometric and aerodynamic sizes
optimized for delivery to targeted sites of the pulmonary system.
There is a particular need for an apparatus and method that allows
for optimization of particle size in real-time, during the particle
production process.
[0010] The apparatus and method of the present invention, a
description of which is fully set forth below, solve the
aforementioned problems and difficulties with conventional
approaches to producing dry powder compositions.
SUMMARY OF THE INVENTION
[0011] The present invention is directed to a method and apparatus
for producing dry particles. The dry particles are advantageously
formed into dry powder compositions that can be administered to a
patient, such as a human patient, for therapeutic purposes. In a
preferred aspect of the present invention, the dry powder
compositions are formulated for inhalation by a patient for
delivery of an active agent through the pulmonary system.
[0012] In one aspect of the present invention, a method for
preparing a dry powder composition is provided. An embodiment of
the method of the present invention comprises combining a first
fluid component and a second fluid component in a mixer to form a
mixed fluid, wherein the first fluid component comprises an active
agent that is incompatible with the second fluid component,
atomizing the mixed fluid to produce droplets, and drying the
droplets to form dry particles. In some embodiments, the first
fluid component is hydrophilic and the second fluid component is
hydrophobic and the combining step comprises adding the first fluid
component to the second fluid component. In other embodiments, the
second fluid component is an organic solution comprising
approximately 60-70% water by volume, and the mixed fluid comprises
approximately 20% organic phase by volume. In yet other
embodiments, the method produces dry particles with less than about
6%, and preferably less than about 3%, high molecular weight
protein ("HMWP") and more than about 90% readily extractable
protein product ("RE").
[0013] In alternative embodiments of the method of the present
invention, the method comprises atomizing the mixed fluid with an
internal mixing nozzle, e.g., a single-hole nozzle or a six-hole
nozzle. In other embodiments, other types of nozzles may be
used.
[0014] In some embodiments of the method of the present invention,
the method further comprises adding a surfactant, for example, a
non-ionic surfactant or DPPC or Tween 80, to the first fluid
component, the second fluid component, or the mixed fluid. In some
embodiments, at least 0.2 wt % of Tween 80 is added. In other
embodiments, 0.2-2.8 wt % of Tween 80 is added.
[0015] In yet other embodiments of the method of the present
invention, the method comprises using a total solids concentration
for the mixed fluid of about 1-60 g/L.
[0016] In yet other embodiments of the method of the present
invention, the method comprises adding about 5-40 g/L ammonium
bicarbonate to the first fluid component, the second fluid
component, or the mixed fluid.
[0017] In another embodiment of the method of the present
invention, the method comprises performing the drying step in a
dryer with an outlet temperature of 35-70.degree. C. In alternative
embodiments, a drying gas rate of approximately 80-125 kg/hr is
used.
[0018] Alternative embodiments of the method of the present
invention comprise ascertaining the amount of solid and liquid
ingredients necessary to achieve the first solution concentration
and combining the liquid and solid ingredients together to form the
first fluid component.
[0019] In yet other alternative embodiments of the method of the
present invention, the method comprises using an atomization gas
rate of approximately 35-120 g/min.
[0020] In other embodiments of the method of the present invention,
the method comprises using a liquid feed rate of approximately
10-75 mL/min during the atomization step.
[0021] In an aspect of the apparatus of the present invention, an
apparatus for preparing a dry powder composition is provided. An
embodiment of the apparatus of the present invention comprises a
static mixer operative to combine a first fluid component with a
second fluid component to form a mixed fluid, wherein the first
fluid component comprises an active agent that is incompatible with
the second fluid component. The apparatus further comprises an
atomizer in fluid communication with the static mixer, whereby the
mixed fluid is atomized to form droplets, and a dryer wherein the
droplets are dried to form dry particles. In some embodiments of
the apparatus of the present invention, the atomizer comprises an
internal mixing nozzle, e.g., a single-hole nozzle or a six-hole
nozzle. In other aspects of the invention, a sheeting action nozzle
or a pressure nozzle may also be used.
[0022] In yet another aspect of the present invention, a method for
preparing a dry powder composition is provided. In such a method, a
hydrophilic component and a hydrophobic component are prepared, one
of which comprises an active agent. The hydrophobic and hydrophilic
components are combined in a static mixer to form a combination.
The combination is atomized to produce droplets, which are dried to
form dry particles. In a preferred aspect of this method, the
atomizing step is performed immediately after the components are
combined in the static mixer. In another preferred aspect of this
method, the hydrophilic component comprises an active agent that
may include, for example, insulin, albuterol sulfate, L-DOPA,
humanized monoclonal antibody (for example, IgG1), human growth
hormone (hGH), epinephrine, and ipatropium bromide monohydrate.
[0023] In a further aspect of the present invention, a method for
preparing a dry powder composition is provided. In such a method,
first and second components are prepared, one of which comprises an
active agent. The first and second components are combined in a
static mixer to form a combination. The first and second components
are such that combining them causes degradation in one of the
components. In a preferred aspect, the active agent is incompatible
with the other component. The combination is atomized to produce
droplets that are dried to form dry particles. In a preferred
aspect of such a method, the first component comprises an active
agent dissolved in an aqueous solvent, and the second component
comprises an excipient dissolved in an organic solvent.
[0024] In yet a further aspect of the present invention, a method
for preparing a dry powder composition is provided. In such a
method, a first phase is prepared that comprises human growth
hormone, sodium phosphate, and ammonium bicarbonate. A second phase
is prepared that comprises ethanol. The first and second phases are
combined in a static mixer to form a combination. The combination
is atomized to produce droplets that are dried to form dry
particles. In another aspect of such a method, the second phase
further comprises 1,2-dipalmitoyl-sn-glycero-3-phosphatidylcholine
(DPPC). In a further aspect of such a method, the resulting dry
particles consist essentially of about 93% human growth hormone and
about 7% sodium phosphate by weight of total human growth hormone
and sodium phosphate. In still a further aspect of such a method,
the resulting particles consist essentially of about 79% human
growth hormone, about 7% sodium phosphate, and about 14% DPPC by
weight of total human growth hormone, sodium phosphate, and
DPPC.
[0025] In still a further aspect of the present invention, a method
for preparing a dry powder composition is provided. In such a
method, a hydrophilic component is combined with an organic solvent
in a static mixer to form a combination. The combination is
atomized to produce droplets that are dried to form dry particles.
In a preferred aspect of such a method, the hydrophilic component
comprises an active agent. In a further aspect of such a method,
the hydrophilic component further comprises an excipient.
[0026] In yet a further aspect of the present invention, an
apparatus for preparing a dry powder composition is provided. The
apparatus includes a static mixer having an inlet end and an outlet
end. The static mixer is operative to combine an aqueous component
with an organic component to form a combination. Means are provided
for transporting the aqueous component and the organic component to
the inlet end of the static mixer. An atomizer is in fluid
communication with the outlet end of the static mixer to atomize
the combination into droplets. The droplets are dried in a dryer to
form dry particles. In one aspect of the present invention, the
atomizer is a rotary atomizer. Such a rotary atomizer may be
vaneless, or may contain a plurality of vanes. In a further aspect
of the present invention, the atomizer is a two-fluid mixing
nozzle. Such a two-fluid mixing nozzle may be an internal mixing
nozzle or an external mixing nozzle. In one aspect of the present
invention, the means for transporting the aqueous and organic
components are two separate pumps. Alternatively, a single pump
could be used. In a further aspect, the apparatus also includes a
geometric particle sizer that determines a geometric diameter of
the dry particles, and an aerodynamic particle sizer that
determines an aerodynamic diameter of the dry particles.
[0027] In still a further aspect of the present invention, a method
for preparing dry particles having a selected volume median
geometric diameter is provided. Such a method comprises: [0028]
drying atomized liquid droplets to form dry particles; [0029]
selecting a particle density (.rho.); [0030] measuring a measured
mass median aerodynamic diameter (d.sub.a.sup.m) of the dry
particles; [0031] measuring a measured volume median geometric
diameter (d.sub.g.sup.m) of the dry particles; [0032] calculating a
calculated volume median geometric diameter (d.sub.g.sup.c) from
the particle density and the measured mass median aerodynamic
diameter from the equation d.sub.a.sup.m=d.sub.g.sup.c {square root
over (.rho.)}; and [0033] adjusting the particle density until the
calculated volume median geometric diameter is substantially equal
to the measured volume median geometric diameter.
[0034] In another aspect of such a method, the adjusting-step
comprises: [0035] comparing the calculated volume median geometric
diameter to the measured volume median geometric diameter to
determine a differential; and [0036] responsive to the
differential, changing a particle density value in an aerodynamic
particle sizer.
[0037] In still another aspect of such a method, a liquid feed is
atomized to form the atomized liquid droplets. In a preferred
aspect, a first liquid component and a second liquid component are
combined in a static mixer to form the liquid feed.
[0038] In yet a further aspect of the present invention, a system
for preparing dry particles having a selected geometric diameter is
provided. The system includes a dryer that dries liquid droplets to
form dry particles. The system also includes a geometric particle
sizer coupled to the dryer that determines a measured geometric
diameter (d.sub.g.sup.m) of the dry particles. The system also
includes an aerodynamic particle sizer coupled to the dryer that
determines a measured aerodynamic diameter (d.sub.a.sup.m) of the
dry particles responsive to a density (.rho.) of the dry particles.
A further component of the system is a processor coupled to the
aerodynamic particle sizer. The processor is responsive to a
program configured for calculating a calculated geometric diameter
(d.sub.g.sup.c) from the density and the measured aerodynamic
diameter from the equation d.sub.a.sup.m=d.sub.g.sup.c {square root
over (.rho.)}, and adjusting the density until the calculated
geometric diameter is substantially equal to the measured geometric
diameter. In a further aspect of such a system, the program is
configured to carry out the adjusting by comparing the calculated
geometric diameter to the measured geometric diameter to determine
a differential, and, responsive to the differential, changing the
density used by the aerodynamic particle sizer. In a further aspect
of such a system, an atomizer is coupled to the dryer to atomize a
liquid feed to form the liquid droplets. In still a further aspect
of such a system, a static mixer is in fluid communication with the
atomizer, the static mixer combining a first liquid component and a
second liquid component to form the liquid feed.
Features and Advantages
[0039] It is a feature of the present invention that a static mixer
is used to combine two liquid components to form a combination that
is atomized into droplets that are dried to form particles. The
static mixer advantageously provides rapid and homogeneous mixing
of the two liquid components. This is particularly advantageous
when the two liquid components are physically and/or chemically
incompatible with each other. Because of the homogeneous mixing
provided by the static mixer, the particles resulting from use of
the apparatus and method of the present invention advantageously
have substantially the same composition at the particle scale. A
mixer other than a static mixer may be used to achieve similar
results. When the two liquid components are physically and/or
chemically incompatible with each other, the mixture should be
removed from the nonstatic mixer as quickly as possible in order to
minimize degradation of product and then immediately atomized.
[0040] It is a further feature of the present invention that the
liquid feed solution to be atomized is fully mixed prior to
atomization. The present invention also advantageously minimizes
the time that the liquid feed solution to be atomized remains in
its combined state prior to atomization.
[0041] Another feature of the present invention is that it can be
used to produce particles that contain a hydrophilic active agent,
and hydrophilic or hydrophobic excipients.
[0042] Another feature of the present invention is that it can be
used to produce dry particles that are particularly well adapted
for inhalation into the lung, particularly the deep lung. As one
example, the present invention advantageously optimizes process
conditions for increasing and controlling particle porosity. As
another example, the formulations of the present invention
advantageously include ammonium bicarbonate that increases particle
porosity. As yet another example, the present invention provides a
method and apparatus that can be used to optimize particle size in
real-time during the particle production process. In this manner,
process conditions for particles of selected geometric and/or
aerodynamic size can advantageously be optimized using a minimal
amount of material.
BRIEF DESCRIPTION OF THE FIGURES
[0043] The present invention is described with reference to the
accompanying drawings. In the drawings, like reference numbers
indicate identical or functionally similar elements. The left most
digit(s) of a reference number indicates the figure in which the
reference number first appears.
[0044] FIG. 1A illustrates flow through a static mixer
[0045] FIG. 1B shows a static mixer suitable for use with the
present invention;
[0046] FIG. 2 illustrates one embodiment of a system of the present
invention for producing dry particles;
[0047] FIG. 3 shows a vaned rotary atomizer suitable for use with
the present invention;
[0048] FIG. 4A illustrates one embodiment of an internal mixing
nozzle suitable for use with the present invention;
[0049] FIG. 4B illustrates another embodiment of an internal mixing
nozzle suitable for use with the present invention;
[0050] FIG. 4C illustrates yet another embodiment of an internal
mixing nozzle suitable for use with the present invention;
[0051] FIG. 4D illustrates still another embodiment of an internal
mixing nozzle suitable for use with the present invention;
[0052] FIG. 4E illustrates another embodiment of a nozzle suitable
for use with the present invention;
[0053] FIG. 5 illustrates one embodiment of an external mixing
nozzle suitable for use with the present invention;
[0054] FIG. 6 illustrates an alternate embodiment of a system of
the present invention for producing dry particles;
[0055] FIG. 7 shows a flow chart of one embodiment of a process of
the present invention for optimizing particle size;
[0056] FIG. 8 illustrates one embodiment of a computer system
suitable for use with the present invention;
[0057] FIG. 9 shows a graph of mass median aerodynamic diameter
(MMAD) as measured using the system and method of the present
invention versus MMAD measured using a multi-stage liquid impinger
(MSLI); and
[0058] FIG. 10. shows a graph that illustrates the effect of the
order of addition on soluble aggregate (dimer) levels as a function
of ethanol concentration.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Overview
[0059] The present invention is directed to apparatus and methods
for preparing dry particles.
[0060] The present invention has particular applicability for
preparing dry particles, and dry powder compositions, for
inhalation into the lung for therapeutic purposes. Particularly,
preferred dry particles include those described and disclosed in
the following eleven applications: "Inhalable Sustained Therapeutic
Formulations," Appl. No. 60/366,479 (filed Mar. 20, 2002);
"Inhalable Salmeterol and Ipratropium Compositions," Appl. No.
60/366,449 (filed Mar. 20, 2002); "Inhalable Salmeterol and
Ipratropium Compositions," Appl. No. 60/366,354 (filed Mar. 20,
2002); "Inhalable Salmeterol and Ipratropium Compositions," Appl.
No. 60/366,470 (filed Mar. 20, 2002); "Inhalable Salmeterol and
Ipratropium Compositions," Appl. No. 60/366,487 (filed Mar. 20,
2002); "Inhalable Salmeterol and Ipratropium Compositions," Appl.
No. 60/366,440 (filed Mar. 20, 2002); "hGH (Human Growth Hormone)
Formulations for Pulmonary Administration," Appl. No. 60/366,488
(filed Mar. 20, 2002); "Pulmonary Delivery for LevoDOPA," Appl. No.
60/366,471 (filed Mar. 20, 2002); "Inhalable Sustained Therapeutic
Formulations," Appl. No. ______, Attorney Docket No. 2685.2034-001
US (filed Mar. 19, 2003); "hGH (Human Growth Hormone) Formulations
for Pulmonary Administration," Appl. No. ______, Attorney Docket
No. 2685.2040-001 US (filed Mar. 19, 2003); and "Pulmonary Delivery
for LevoDOPA," Appl. No. ______, Attorney Docket No. 2685.2044-001
US (filed Mar. 19, 2003), the entirety of each of which is
incorporated herein by reference. The description that follows will
provide examples of preparing such dry particles. However, it
should be understood by one skilled in the art that the present
invention is not limited to preparing dry particles, or dry powder
compositions, suitable for inhalation into the lung, and that dry
particles for other purposes can be prepared. As used herein, the
term "dry" refers to particles that have a moisture and/or residual
solvent content such that the powder is physically and chemically
stable in storage at room temperature, and is readily dispersible
in an inhalation device to form an aerosol. The moisture and
residual solvent content of the particles can be below 10 wt %, can
be below 7 wt %, or can be lower.
[0061] The present invention solves the problems associated with
preparing dry particles that contain incompatible components by
providing a method and apparatus that ensures a homogeneous mixture
of the components in the finished dry particle product, and
improves uniformity among the particles themselves. As used herein,
"incompatible components" refers to components that may be
chemically or physically incompatible with each other when in
contact. One example of incompatible components is a protein in
aqueous solution in which the protein is stable, and an organic
solution containing hydrophobic substances. The aqueous protein
solution is incompatible with the hydrophobic organic solution
since the organic solution will cause degradation of the protein.
In the method of the present invention, the incompatible
components, such as a hydrophilic component and a hydrophobic
component, are prepared and maintained separately from each other
until just prior to the particle production process. The term
"hydrophobic component" refers to materials that are insoluble or
sparingly or poorly soluble in water. Such compositions typically
have a solubility below 5 mg/ml, usually below 1 mg/ml, in water.
The term "hydrophilic component" refers to materials that are
highly soluble in water. Typical aqueous solubilities of
hydrophilic components will be greater than 5 mg/ml, usually
greater than 50 mg/ml, and can be greater than 100 mg/ml. The
incompatible hydrophobic and hydrophilic components are combined in
a static mixer to form a combination that is a homogeneous mixture
of the incompatible components. Immediately thereafter, the
combination is atomized into droplets that are dried to form the
dry particles. Through the use of the static mixer, the
incompatible components can be very rapidly combined into a
homogeneous mixture. The use of the static mixer significantly
reduces the amount of time the incompatible components are in
contact with each other, thereby minimizing or eliminating the
degradation effects resulting from such contact. The use of the
static mixer also ensures a complete mixing of the incompatible
components before atomization so that each droplet, and thus each
finished dry particle, has substantially the same composition.
Uniformity in the composition of the particles at the particle
scale is a significant factor in the efficacy of the dry particles
when used for therapeutic purposes.
[0062] When preparing dry particles and dry powder compositions for
inhalation, it is desirable to increase the porosity of the
particles so that the particles can be inhaled into the lung,
preferably into the deep lung. The present invention advantageously
optimizes process conditions for increasing and controlling
particle porosity. In a preferred embodiment of the present
invention, an internal mixing two-fluid nozzle is used to atomize a
liquid feed stream to form atomized droplets. In an internal mixing
two-fluid nozzle, one or more gas streams impinge upon a liquid
feed stream to atomize the liquid feed stream into atomized
droplets that exit the nozzle. Such a nozzle allows for intimate
contact between the gas (such as nitrogen) and the liquid feed
stream. This increases the amount of gas in the liquid feed stream
and the resulting droplets. When the droplets are dried, the
exiting gas contributes to the porosity of the finished dry
particles. Increased gas in the droplets can also be achieved
through the use of ammonium bicarbonate, or other volatile salts,
in the liquid feed stream. In alternative embodiments of the
present invention, a variety of nozzle types may be used, including
but not limited to a single-hole nozzle, a six-hole nozzle, and a
pressure nozzle.
[0063] If dry particles are being produced for inhalation into the
lung, then it is important to control the size of the particles
during the production process. The particles can be characterized
by aerodynamic diameter (d.sub.a) and geometric diameter (d.sub.g).
Aerodynamic diameter can be determined using a "time-of-flight"
measurement system that accelerates the particles being measured
past two points. The time of travel is measured, and correlated to
an aerodynamic size through the following relationship:
d.sub.a=d.sub.g {square root over (.rho.)}, where .rho. is the
density of the particles. A suitable device for determining
aerodynamic diameter is an aerodynamic particle sizer, such as the
APS Model 3321, available from TSI, Inc., St. Paul, Minn. Such a
device measures the mass median aerodynamic diameter (MMAD) of the
particles, as well as complete particle size distributions
(PSD).
[0064] Laser diffraction techniques can be used to determine
particle geometric diameter. One such device is the Insitec online
particle sizer, available from Malvern Instruments Ltd. The Insitec
device consists of an optical sensor head, a signal processing
unit, and a computer for instrument control and data collection and
analysis. The Insitec device measures volume median geometric
diameter (VMGD) of the particles in real-time as they are produced.
In addition to VMGD, the Insitec device generates complete particle
size distributions (PSD), which allows an operator to visually
determine the polydispersity of the particles being generated.
[0065] Through the apparatus and method of the present invention,
optimization of particle size is accomplished in real-time during
particle production. In the process of the present invention, the
density (.rho.) of the particles is used as an optimization
variable. The density of the particles is adjusted until the
measured geometric diameter is equal to the geometric diameter
calculated from the equation d.sub.a=d.sub.g {square root over
(.rho.)}. One significant advantage of this method is that the
liquid stream to be atomized and dried into particles needs to be
sprayed for only about three minutes to collect sufficient data to
optimize the process variables. This allows for the rapid screening
of multiple process conditions using a minimal amount of material.
Moreover, the total length of spraying time and material required
is significantly reduced.
[0066] The size distribution of airborne particles can be measured
through gravimetric analysis through the use of, for example, an
Andersen Cascade Impactor (ACI), Anderson Instruments, Smyrna, Ga.
The ACI is a multi-stage device that separates aerosols into
distinct fractions based on aerodynamic size. The size cutoffs of
each stage are dependent upon the flow rate at which the ACI is
operated. For the examples and discussion herein, a flow rate of 60
L/min is used, unless indicated otherwise.
[0067] At each stage of the ACI, an aerosol stream passes through a
series of nozzles, and impinges upon an impaction plate. Particles
with sufficient inertia impact the plate, while those with
insufficient inertia to impact the plate remain in the aerosol
stream, and are carried to the next stage. Each successive stage
has a higher aerosol velocity in the nozzle so that smaller
diameter particles are collected at each successive stage.
Particles too small to be collected on the last stage are collected
on a collection filter.
[0068] A two-stage ACI (ACI-2) is particularly advantageous for
characterizing and optimizing dry particles for inhalation. The
first fraction is referred to as "FPF(5.6)", or Fine Particle
Fraction (5.6). This fraction corresponds to the percentage of
particles having an aerodynamic diameter of less than 5.6 .mu.m.
The fraction of the particles that passes this stage and is
deposited on the collection filter is referred to as "FPF(3.4)", or
Fine Particle Fraction (3.4). This fraction corresponds to the
percentage of particles having an aerodynamic diameter of less than
3.4 .mu.m. FPF(5.6) has been demonstrated to correlate to the
fraction of the dry particles that is capable of inhalation into
the lung of a patient. FPF(3.4) has been demonstrated to correlate
to that fraction that is capable of reaching the deep lung of a
patient. The foregoing correlations provide a quantitative
indicator that can be used with the process of the present
invention to optimize the production process and the resulting
finished dry particles for inhalation into the lung.
[0069] In a further embodiment, a three-stage ACI (ACI-3) is used
for particle characterization and optimization. The ACI-3 consists
of only the top three stages of the eight-stage ACI and allows for
the collection of three separate powder fractions. For example, the
ACI-3 configuration can consist of 20 .mu.m pore (stages -1 and 1)
and 150 .mu.m pore (stage 2) stainless steel screens which can be
saturated with methanol. The fraction of the powder that passes the
final stage of ACI-3 is referred to as FPF(3.3)
Apparatus and Methods of the Present Invention
[0070] The apparatus and methods of the present invention will now
be described with reference to the accompanying figures. As will be
described below in more detail with respect to FIG. 2, a static
mixer is used to combine two liquid components to form a
combination. The combination is atomized to produce droplets that
are dried to form dry particles. In one embodiment of the present
invention, the two liquid components are a hydrophilic component
and a hydrophobic component. In another embodiment, the two
components are such that combining the two causes degradation in
one of the components. In yet another embodiment, one component is
a hydrophilic component and the other component is an organic
solvent.
[0071] Static or motionless mixers consist of a conduit or tube in
which is received a number of static mixing elements. Static mixers
provide uniform mixing in a relatively short length of conduit, and
in a relatively short period of time. With static mixers, the fluid
moves through the mixer, rather than some part of the mixer, such
as a blade, moving through the fluid. Flow through one embodiment
of a static mixer is illustrated in FIG. 1A. A pump (not shown)
introduces a stream of one or more fluids into an inlet end of a
static mixer 10 as shown generally at 1. The stream is split and
forced to opposite outside walls as shown generally at 2. A vortex
is created axial to the centerline of static mixer 10, as shown
generally at 3. The vortex is sheared and the process recurs, but
with the opposite rotation, as shown generally at 4. The
clockwise/counter-clockwise motion ensures a homogeneous product
that exits an outlet end of static mixer 10.
[0072] One embodiment of a static mixer is shown in FIG. 1B. Static
mixer 10 includes a number of stationary or static mixing elements
14 arranged in a series within a conduit or pipe 12. The number of
elements can range from, for example, 4 to 32 or more. Conduit 12
is circular in cross-section and open at opposite ends for
introducing (inlet end 18) and withdrawing (outlet end 16) fluids.
Mixing element 14 comprises segments 142. Each segment 142 consists
of a plurality of generally flat plates or vanes 144. The two
substantially identical segments 142 are preferably axially
staggered with respect to each other. A static mixer as shown in
FIG. 1B is more fully described in U.S. Pat. No. 4,511,258, the
entirety of which is incorporated herein by reference.
[0073] Turning now to FIG. 2, one embodiment of a system of the
present invention for producing dry particles is shown. The system
includes a first feed vessel 210 and a second feed vessel 220. As
will be explained in more detail below with respect to the various
examples, feed vessel 210 can contain, for example, a hydrophilic
component, an aqueous solution, or other suitable liquid component.
Feed vessel 220 can contain, for example, a hydrophobic component,
an organic solution, or other suitable liquid component. The
contents of feed vessel 210 and feed vessel 220 are transported,
via suitable means, to an inlet end of a static mixer 230. In one
embodiment of the present invention, the means for transporting is
a first pump 212 for the contents of feed vessel 210, and a second
pump 222 for the contents of feed vessel 220. Alternatively, a
single pump could be used to transport the contents of feed vessels
210 and 220 to the inlet end of static mixer 230. As would be
readily apparent to one skilled in the art, other means for
transporting the contents of feed vessels 210 and 220 could be
used. In one embodiment of the present invention, feed vessels 210
and 220 contain the same volume of liquid, and pumps 212 and 222
are operated at substantially the same rate. In other embodiments,
pumps 212 and 222 are operated at different rates. Pumps 212 and
222 may be gear pumps, or other types of pumps as would be apparent
to one skilled in the art.
[0074] The contents of feed vessels 210 and 220 are combined in
static mixer 230 to form a combination. The combination is a
homogeneous mixture of the liquid components entering the inlet end
of static mixer 230. As illustrated in FIG. 2, static mixer 230 may
be oriented in a horizontal configuration, i.e., a central axis of
static mixer 230 is perpendicular to a central axis of a spray
dryer 250. Preferably, static mixer 230 is oriented in a vertical
configuration, as shown, for example, in FIG. 6 (discussed in more
detail below). Static mixers suitable for use with the present
invention are illustrated in FIGS. 1A and 1B, and include model
1/4-21 made by Koflo Corporation and the ISG (Interfacial Surface
Generator) Mixer (Catalog #S01-012) made by Ross Engineering, Inc.,
Savannah, Ga. The ISG Mixer comprises mixing elements enclosed in a
pipe housing and shaped so that adjacent elements form a
tetrahedral chamber. Holes through the elements provide the flow
path.
[0075] An outlet end of static mixer 230 is in fluid communication
with an atomizer 240. Atomizer 240 atomizes the combination flowing
out of static mixer 230 into droplets. Because the combination
flowing out of static mixer 230 is a homogeneous mixture of the
input liquid components, the droplets formed by atomizer 240 will
also contain a homogeneous mixture of the input liquid components.
Atomizers suitable for use with the present invention include, but
are not limited to, rotary atomizers, two-fluid mixing nozzles, and
pressure, ultrasonic, vibrating plate, and electrostatic nozzles,
and combinations of the foregoing. Atomizers suitable for use with
the present invention will be described in more detail below with
respect to FIGS. 3-5.
[0076] In a preferred embodiment of the present invention, the
combination formed in static mixer 230 is atomized immediately
after the combination is formed. That is, the outflow of static
mixer 230 flows into atomizer 240 for atomization. This is
particularly advantageous when first feed vessel 210 and second
feed vessel 220 contain incompatible components since the contact
between the incompatible components will be minimized.
[0077] The droplets formed by atomizer 240 are dried in spray dryer
250 to form dry particles. Because the droplets formed by atomizer
240 contain a homogeneous mixture of the input liquid components,
the dry particles formed by spray dryer 250 will also contain a
homogeneous mixture of the input liquid components. Spray dryers
suitable for use with the present invention include a Mobile Minor,
EX Model manufactured by Niro, Columbia, Md. Other commercially
available spray dryers from suppliers such as Niro, APV Systems,
Denmark (e.g., the APV Anhydro Model), and Swenson, Harvey, Ill.,
also can be employed, as can scaled-up spray dryers suitable for
industrial capacity production lines.
[0078] A drying gas is used in spray dryer 250 to dry the droplets
to form dried particles. Examples of gases suitable for use with
the present invention include, but are not limited to, air,
nitrogen, argon, carbon dioxide, helium, and combinations or
mixtures thereof. In a preferred embodiment, nitrogen gas is used.
As illustrated in FIG. 2, a nitrogen gas supply 252 is coupled to
spray dryer 250, through suitable valves and regulators as would be
apparent to one skilled in the art.
[0079] A bag house 260 is coupled to an outlet end 254 of spray
dryer 250. Disposed within bag house 260 is a bag filter 262. A
gas-solid stream, made up of the drying gas and the dry particles,
exits outlet end 254. Exhaust lines 266 provide exhaust for spray
dryer 250 and bag house 260. The gas-solid stream exiting spray
dryer 250 enters bag house 260. Bag filter 262 retains the dry
particles, and allows the hot gas stream, containing the drying
gas, and evaporated water and solvents, to pass. Preferably, bag
filter 262 is made from a material such as Gore-Tex.RTM., available
from W.L. Gore & Associate, Inc., Newark, Del. Dry particles
are collected at a product collection point 264 by running a back
pulse of nitrogen across bag filter 262.
[0080] The collected particles can then be screened, for example,
using size screening methods known to one skilled in the art. In
one embodiment of the present invention, single dosages of the
collected dry particles are measured, and the single dosages are
then packaged, using techniques well known to one skilled in the
art. In this manner, a unit dose of a dry powder composition can be
formed by placing a therapeutically effective amount of dry powder
composition made up of particles into a unit dose receptacle.
[0081] One embodiment of an atomizer suitable for use with the
system depicted in FIG. 2 is a vaned rotary atomizer, such as
rotary atomizer 300 illustrated in FIG. 3. Rotary atomizer 300
includes a spinning wheel 320 that spins about an axis 330. Liquid
feed enters rotary atomizer 300 at an inlet point 302, and is
distributed across wheel 320, as depicted generally at 304. Wheel
320 disperses the liquid feed into a spray of fine droplets. The
spin rate of the wheel is controlled, as is the liquid feed rate.
By controlling the spin rate and liquid feed rate, the
characteristics of the spray can be controlled, such as droplet
size. Rotary atomizer 300 is configured with 24 vanes 310. It
should be readily apparent to one skilled in the art that rotary
atomizers with other number of vanes 310 can be used with the
present invention. For example, a rotary atomizer having 4 vanes,
or a vaneless rotary atomizer, could also be used.
[0082] Alternate embodiments of an atomizer suitable for use with
the system shown in FIG. 2 are shown in FIGS. 4A, 4B, 4C, 4D, 4E,
and 5. FIGS. 4A, 4B, 4C, 4D, and 5 depict two-fluid nozzles that
atomize a liquid feed stream through the use of one or more gas
streams that impinge upon the liquid feed stream. One example of an
internal mixing nozzle 400, is illustrated in FIG. 4A. In the
internal mixing nozzle 400, gas 420 impinges on a liquid feed
stream 410 in a mixing chamber 430 that is internal to internal
mixing nozzle 400. A spray of atomized droplets 440 exits internal
mixing nozzle 400 through a single hole. As would be apparent to
one skilled in the art, any number of gas streams, including a
single gas stream, could be used.
[0083] FIG. 4B illustrates another example of an internal mixing
nozzle, a single-hole nozzle 450. The single-hole nozzle 450
operates under the same principles as the internal mixing nozzle
400 depicted in FIG. 4A. The gas is supplied through inlet 451, and
the liquid is supplied through inlet 452. The gas impinges on the
liquid in a mixing chamber 458 in air cap 453. A spray of atomized
droplets 457 exits the single-hole nozzle 450 through a single
hole. The single-hole nozzle comprises an air cap 453, a fluid cap
454, a retainer ring 455, and a gasket 456.
[0084] FIG. 4C illustrates another example of an internal mixing
nozzle, a six-hole nozzle 460. The six-hole nozzle operates under
the same principles as the single-hole nozzle, except that the air
cap 461 in the six-hole nozzle has six holes 462. The gas is
supplied through inlet 463, and the liquid is supplied through
inlet 464. The gas impinges on the liquid in a mixing chamber 468
in air cap 461. Sprays of atomized droplets 469 exit the six-hole
nozzle 460 through holes 462. The six-hole nozzle comprises an air
cap 461, a fluid cap 465, a retainer ring 466, and a gasket
467.
[0085] FIG. 4D illustrates yet another example of an internal
mixing nozzle, a sheeting action nozzle 470. While this nozzle
operates under principles similar to the single-hole and six-hole
nozzles, the different configuration of the nozzle depicted in FIG.
4D results in a different atomizing effect. In nozzle 470, the
liquid feed stream 471 enters the mixing chamber 472 in a direction
angular, and preferably lateral, to the nozzle's longitudinal axis.
Liquid feed stream 471 enters the mixing chamber 472 through a
liquid feed inlet 476, which is at an angle to the longitudinal
axis of the nozzle 470. The liquid flows to and down the sides of
the mixing chamber 472 in a thin sheet. The gas 473 impinges upon
the thin sheet of liquid at the nozzle hole 474. A spray of
atomized droplets 475 exits the nozzle 470. One example of a nozzle
similar in design to the nozzle depicted in FIG. 4D is the Flomax
series of nozzles (Catalog #FM1) manufactured by Spraying Systems
Co., Wheaton, Ill.
[0086] FIG. 4E illustrates yet another example of a nozzle, a
pressure nozzle 480, suitable for use with the system shown in FIG.
2. The pressure nozzle 480 does not need a gas stream to atomize
droplets. Instead, it uses the pressure of the liquid to spray
atomized droplets from the nozzle 480. Pressure applied to the
liquid within the nozzle 480 forces the liquid out of the nozzle
hole 481. A rotational force is imparted to the liquid before it
reaches the nozzle hole 481. This rotational force may be applied,
for example, by a slotted insert 482 featuring multiple small
cross-sectional feed inserts 483 leading to the nozzle hole 481. In
the example depicted in FIG. 4E, the cross-sectional feed inserts
483 are aligned on a diagonal to the nozzle hole 481. The spray of
atomized droplets from each of the cross-sectional feed inserts 483
therefore exits the nozzle hole 481 with angular momentum.
Collectively, the angular momentum in the sprays from each of the
cross-sectional feed inserts 483 yields a conical spray of atomized
droplets.
[0087] FIG. 5 depicts an external mixing nozzle 500. In external
mixing nozzle 500, two gas streams 520 impinge on a liquid feed
stream 510 in a mixing zone 530 that is adjacent to the external
edge of external mixing nozzle 500. A spray of atomized droplets
540 is formed external to external mixing nozzle 500. As would be
apparent to one skilled in the art, other numbers of gas streams,
including a single gas stream, could be used.
[0088] In order to produce particles optimized for inhalation and
pulmonary drug delivery, optimization experiments were conducted to
enhance porosity during the atomization step of the dry particle
production process. Through these experiments it was determined
that changing the mode of atomization affects porosity, and that
porosity can be controlled through the selection of the type of
atomizer.
[0089] Three rotary atomizers were tested, all of which had a
configuration substantially as shown in FIG. 3. The three atomizers
differed in the number of vanes 310 on wheel 320. One had four
vanes ("V4"), one had 24 vanes ("V24"), and one was vaneless. The
V4 and the V24 wheels were operated using similar process
conditions, shown below in Table 1, to obtain particles with
similar geometric sizes, shown below in Table 2. Because of the
increased number of vanes, the V24 wheel could not be operated at
as a high an rpm as the V4 wheel. TABLE-US-00001 TABLE 1 Outlet
Drying Gas Atomizer Inlet Temperature Atomizer Pressure Feed Rate
Wheel Temperature (.degree. C.) (.degree. C.) Speed (rpm)
(mmH.sub.2O) (mL/min) V4 120 55 50000 98 63 V24 120 62 34000 110
60
[0090] TABLE-US-00002 TABLE 2 Geometric Size Measured @ Fine
Particle Fraction (%) Run Number Wheel Type 0.5 bar 2 bar 3 bar 4
bar <5.6 .mu.m <3.4 .mu.m 294053 V4 9.5 8.9 8 6.7 72 56
294054 V24 9.2 7.5 6.5 5.3 65 48
[0091] The data in Table 2 suggest that particles produced using
the V4 wheel are larger and more porous (e.g., have higher FPF(5.6)
and FPF(3.4)) than particles produced using the V24 wheel. One
reason for this difference could be differences in "air pumping"
between the two atomizers. "Air pumping" occurs with rotary
atomizers because, as the wheels spin, the wheels act as a fan,
drawing air through the wheel. At the flow or feed rates to the
atomizers typically used with the present invention, the V24 vanes
do not completely fill with liquid. Consequently, there is a path
for the air to flow over the liquid in the vane, with only a
portion being entrained in the liquid to be atomized. The V4 vanes
operate similarly, but because the vanes are physically smaller,
the V4 vanes are usually filled with liquid during operation.
Consequently, the air and atomization gas must both pass
simultaneously through the vane, rather than over the vane. This
allows for a more intimate contact between the air and liquid to be
atomized. This intimate contact between gas and liquid induces more
porosity in the resulting dry particle.
[0092] The increase of porosity in the particles resulting from the
gas/liquid contact can be seen by comparing the particles produced
with vaned atomizers with particles produced using a vaneless
atomizer. Vaneless atomizers do not generate a strong air pumping
effect. A V4 and a vaneless atomizer were operated using similar
process conditions, shown below in Table 3. As can be seen from
Table 4, the particles produced using the vaneless atomizer were
both smaller and more dense (lower FPF(5.6) and FPF(3.4)) than the
particles produced using the V4 atomizer. TABLE-US-00003 TABLE 3
Outlet Drying Gas Atomizer Inlet Temperature Atomizer Pressure Feed
Rate Wheel Temperature (.degree. C.) (.degree. C.) Speed (rpm)
(mmH.sub.2O) (mL/min) V4 155 63 60000 98 52.5 Vaneless 155 63 50000
98 52.5
[0093] TABLE-US-00004 TABLE 4 Geometric Size Measured @ Fine
Particle Fraction (%) Run Number Wheel Type 0.5 bar 2 bar 3 bar 4
bar <5.6 .mu.m <3.4 .mu.m 294088 V4 14.2 12.5 11.2 9.9 70 55
294089 Vaneless 5.4 5 4.8 4.2 63 40
[0094] In a preferred embodiment of the present invention, a
two-fluid nozzle is used to increase the contact between gas and
liquid during the atomization step to increase the porosity of the
resulting dry particles. As described above, a two-fluid nozzle is
configured to allow for mixing of two fluids, such as a gas and a
liquid, during atomization. The mixing can occur either externally
(using, for example, a nozzle such as that shown in FIG. 5) or
internally (using, for example, a nozzle such as that shown in FIG.
4A, 4B, 4C, or 4D) with respect to the nozzle itself. Examples
using the mixing nozzles shown in FIG. 4A, 4B, 4C, 4D, or 4E are
disclosed below in connection with Tables 14-25.
[0095] Experiments were conducted with an external mixing nozzle
substantially as shown in FIG. 5 at nozzle or system pressures
ranging from 15 to 40 psi. As shown below in Table 5, the FPF(5.6)
ranged from 76 to 81% and the FPF(3.4) ranged from 59 to 63%.
Changes in porosity as a function of increasing gas rates were not
observed with external mixing nozzles. TABLE-US-00005 TABLE 5
System Nozzle Geometric Size Measured @ Fine Particle Fraction (%)
Run Number Pressure (psi) 0.5 bar 2 bar 3 bar 4 bar <5.6 .mu.m
<3.4 .mu.m 294141 15 9.4 8.4 7.3 5.3 81 63 294132C 20 9.5 7.5
6.7 4.9 77 61 294132B 40 8.4 9.4 7.1 6.4 76 59
[0096] Experiments were conducted using an internal mixing nozzle
substantially as shown in FIG. 4A. Use of internal mixing nozzles
likely allows for more intimate contact between the liquid and gas,
thereby resulting in dry particles having higher porosity, as
evidenced by higher FPF(5.6) and FPF(3.4). Experiments were
conducted to test the effect of nozzle pressure and the effect of
the mass flow ratio of gas to liquid. As evidenced by the data in
Table 6 below, more porous particles can be obtained at higher
operating pressures with an internal mixing nozzle. The pressure
effect may be a reflection of the higher gas/liquid ratio of run
294152A (1.8) compared to that of run 294151 (1.3). As evidenced by
the data in Table 7 below, more porous particles can be obtained at
higher gas:liquid flow rates with an internal mixing nozzle. The
operating conditions for use with an internal mixing nozzle that
optimized the geometric size and the porosity/fine particle
fraction are shown below in Table 8. TABLE-US-00006 TABLE 6 System
Nozzle Geometric Size Measured @ Fine Particle Fraction (%) Run
Number Pressure (psi) 0.5 bar 2 bar 3 bar 4 bar <5.6 .mu.m
<3.4 .mu.m 294151 68 12 10.3 8.8 7.2 76 64 294152A 100 11.5 8.8
8.3 7.4 86 79
[0097] TABLE-US-00007 TABLE 7 Gas/Liquid Geometric Size Measured @
Fine Particle Fraction (%) Run Number Ratio 0.5 bar 2 bar 3 bar 4
bar <5.6 .mu.m <3.4 .mu.m 294150A 1 12.9 12.3 10.1 8.1 76 64
294150C 1.5 14 11.8 9.8 7.8 82 70
[0098] TABLE-US-00008 TABLE 8 Run Gas/Liquid System Nozzle
Geometric Size Measured @ Fine Particle Fraction (%) Number Ratio
Pressure (psi) 0.5 bar 2 bar 3 bar 4 bar <5.6 .mu.m <3.4
.mu.m 342012B 1.9 58 10.8 10.4 8 6.5 90 81
[0099] As noted above, the present invention advantageously
optimizes process conditions for increasing and controlling the
porosity of the dry particles through the use of the internal
mixing two-fluid nozzle. In another aspect of the present
invention, particle porosity is increased through the use of
volatile salts. Carbonation of one of the liquid components used to
form the dry particles induces porosity in the resulting dried
particles by nucleation of carbon dioxide (CO.sub.2). The
nucleation of CO.sub.2 induces multiple phases (gas and liquid) in
an atomized droplet, with the gas phase being inaccessible for the
excipients. Such heterogeneous nature of the atomized droplet leads
to increased porosity in the resulting dry particle once drying is
complete. The tap density of the dry particles can be used as a
measure of porosity. The more porous the dry particles, the lower
the observed tap density. It has been found that particles spray
dried from a carbonated formulation solution have much lower tap
density than particles spray dried from an otherwise identical
solution.
[0100] An experiment was conducted using a formulation of
60/18/18/4 (DPPC/Lactose/Albumin/Albuterol sulfate). Four batches
were prepared. The aqueous phase of two batches were sparged with
CO.sub.2, the other two were not treated with CO.sub.2. The spray
dry conditions were well controlled for all four batches so that
they were operated at the same process condition. A vaned rotary
atomizer (V24) was used in this experiment. The results are shown
in Table 9 below. TABLE-US-00009 TABLE 9 Outlet T Feed Rate
Atomizer Tap Density Batch No. Sparging CO.sub.2 Inlet T (.degree.
C.) (.degree. C.) (ml/min) Speed (rpm) (g/cc) 1 No 110 56-57 40
18000 0.09 2 Yes 110 56-57 40 18000 0.065 3 No 110 56-57 40 18000
0.091 4 Yes 110 56-57 40 18000 0.059
[0101] From the data shown in Table 9 above, it is quite clear that
particles manufactured by the solution sparged with CO.sub.2 have
lower tap density, with a more porous structure. Therefore,
sparging the spray drying solution with CO.sub.2 helps to increase
porosity of the particles.
[0102] In a preferred aspect of the present invention, increased
porosity, and consequently lower tap density, can be achieved
through the use of ammonium bicarbonate (NH.sub.4HCO.sub.3) in one
of the liquid components used to form the dry particles. In an
alternate embodiment of the present invention, carbonation of one
of the liquid components, or of the combination solution, could be
achieved by sparging with CO.sub.2 at reduced temperature
(4.degree. C.) or pressurizing with CO.sub.2, also preferably at
reduced temperature. The carbonate components
(HCO.sub.3.sup.-/CO.sub.3.sup.2-/CO.sub.2) would not remain in the
final dry particles as they are volatile species. They would be
eliminated during the drying process. Use of carbonate components
or other volatile salts have the advantage of avoiding the use of
higher temperatures for inducing porosity. Additionally, carbonate
components can advantageously be used over mild pH ranges where
protein stability is maximized. Moreover, the pH of the resulting
dry particles can be adjusted through the addition of appropriate
counter ions.
[0103] As described above, the addition of volatile salts to the
solution used to form dry particles increases the porosity of the
particles. The addition of volatile salts also increases the
production of insoluble complexes, the production of which can be
used to control the release rate of the active agent in the
particles, both proteins and small molecules. The formation of an
insoluble complex begins with the interaction between, for example,
two species when they are dissolved together. In solution,
molecules of opposite charge are attracted to each other via
electrostatic forces. When the ionic species are limited to
oppositely charged forms A and B, then A and B will attract to each
other. If A and B interact strongly enough, they are likely to form
an insoluble complex A.sub.xB.sub.y, where x and y are the
stoichiometric coefficients describing the ratio(s) with which A
and B tend to associate. This complex can stay in suspension, or
may form a precipitate that will settle or flocculate. If
additional ionic species are present, the additional species will
compete with A and B on a charge basis and tend to reduce the
strength of the interaction between A and B, thereby decreasing the
tendency of A and B to form an insoluble complex. If the additional
ionic species can be selectively removed, A and B will then form an
insoluble complex.
[0104] Insoluble material can interfere with the production of
large porous particles that are of particular utility for pulmonary
drug delivery. It is often desirable to have large porous particles
that contain species A and B, where A and B have the tendency to
form an insoluble complex A.times.B.sub.y. Higher ionic strength
decreases the strength of the interaction between A and B,
rendering A and B more soluble in the process solution. As the
material is spray dried, the volatile salt is preferentially
removed from the droplets as the dry particles are formed. The
insoluble complex A.sub.xB.sub.y may subsequently form in the
nearly-dried particles, but the porous structure has already formed
in those particles.
[0105] The following non-limiting examples illustrate the use of
ammonium bicarbonate to produce particles having a low aerodynamic
diameter, which results in a low tap density and high porosity. It
should be understood by one skilled in the art that the present
invention is not limited to the use of ammonium bicarbonate, and
that other suitable volatile salts could also be used without
departing from the scope of the invention.
EXAMPLES
Porous Bovine Albumin Particles
[0106] 350 mg of bovine serum albumin, 100 mg of anhydrous sodium
citrate, 66 mg of calcium chloride dihydrate, and 10 g of ammonium
bicarbonate were dissolved in 500 mL of sterile water. The
resulting feed solution was spray dried using a Niro spray dryer
equipped with a rotary atomizer. The drying gas (dry nitrogen) was
delivered at a flow rate of approximately 100 kg/h with a
170.degree. C. inlet temperature, and a 61.degree. C. outlet
temperature. The feed solution was delivered to the atomizer/spray
dryer at 60 ml/min liquid flow rate. The atomizer was operated at
29,000 rpm, with -2 inches of water pressure in the spraying
chamber of the spray dryer. The resulting dry particles had a mass
mean aerodynamic diameter of 4.03 .mu.m, and a volume mean
geometric diameter of 7.76 .mu.m at 1 bar.
[0107] 48 mg of bovine serum albumin, 20 mg of anhydrous sodium
citrate, 13 mg of calcium chloride dihydrate, 28 mg of maltodextrin
(M100) and 10 g of ammonium bicarbonate were dissolved in 1000 mL
of sterile water. The resulting feed solution was spray dried using
a Niro spray dryer equipped with a rotary atomizer. The drying gas
(dry nitrogen) was delivered at a flow rate of approximately 100
kg/h with a 170.degree. C. inlet temperature, and a 56.degree. C.
outlet temperature. The feed solution was delivered to the
atomizer/spray dryer at 60 ml/min liquid flow rate. The atomizer
was operated at 29,000 rpm, with -2 inches of water pressure in the
spraying chamber of the spray dryer. The resulting dry particles
had a mass mean aerodynamic diameter of 3.97 .mu.m, and a volume
mean geometric diameter of 15.01 .mu.m at 1 bar.
[0108] Porous Humanized IgG Antibody Particles
[0109] 47.35 ml of 50.7 mg/ml humanized monoclonal IgG1 antibody
solution was added to 1000 mL water (pH=6.4). 1.6 g of DPPC was
added to 1000 mL isopropyl alcohol. The two solutions were mixed by
slowly adding the ethanol solution to the aqueous solution
immediately prior to spray drying. The resulting feed solution was
spray dried using a Niro spray dryer equipped with a rotary
atomizer. The drying gas (dry nitrogen) was delivered at a flow
rate of approximately 110 kg/h with a 100.degree. C. inlet
temperature, and a 45.degree. C. outlet temperature. The feed
solution was delivered to the atomizer/spray dryer at 50 ml/min
liquid flow rate. The atomizer was operated at 34,500 rpm, with -2
inches of water pressure in the spraying chamber of the spray
dryer. The resulting dry particles had a mass mean aerodynamic
diameter of 3.01 .mu.m, and a volume mean geometric diameter of
9.17 .mu.m at 1 bar.
[0110] Porous Human Growth Hormone Particles
[0111] 2.63 g hGH, 1.03 g sucrose, 1.58 g leucine, 368 mg sodium
phosphate, 26.25 mg Tween-20, and 52.5 g ammonium bicarbonate was
added to 3675 mL water (pH=7.4). 1575 mL of ethanol was slowly
added to the aqueous solution immediately prior to spray drying.
The resulting feed solution was spray dried using a Niro spray
dryer equipped with a rotary atomizer. The drying gas (dry
nitrogen) was delivered at a flow rate of approximately 110 kg/h
with a 139.degree. C. inlet temperature, and a 62.degree. C. outlet
temperature. The feed solution was delivered to the atomizer/spray
dryer at 60 ml/min liquid flow rate. The atomizer was operated at
34,000 rpm, with -5 inches of water pressure in the spraying
chamber of the spray dryer. The resulting dry particles had a mass
mean aerodynamic diameter of 1.94 .mu.m, and a volume mean
geometric diameter of 5.8 pm at 1 bar.
[0112] Particles containing 93 wt % hGH and 7 wt % sodium phosphate
were prepared as follows. The aqueous solution was prepared by
adding 328 mg of sodium phosphate monobasic to 400 mL of water for
irrigation (Braun). The pH was adjusted to 7.4 using 1.0 N NaOH. 15
g of ammonium bicarbonate (Spectrum Chemicals) was added to the
sodium phosphate buffer. 200 mL of ethanol (Pharmco) was added to
complete the aqueous solution. The aqueous solution was combined in
a static mixer with 400 mL of 14 g/L hGH solution (5.6 g hGH
dissolved in sodium phosphate buffer at pH=7.4). The combined
solution was spray dried under the following process
conditions:
[0113] Inlet temperature .about.115.degree. C.
[0114] Outlet temperature from the drying drum .about.70.degree.
C.
[0115] Nitrogen drying gas=110 kg/hr
[0116] Nitrogen atomization gas=46 g/min
[0117] 2 Fluid internal mixing nozzle atomizer
[0118] Nitrogen atomization pressure .about.65 psi
[0119] Liquid feed rate=25 ml/min
[0120] Liquid feed temperature .about.22.degree. C.
[0121] Pressure in drying chamber=-2.0 in water
[0122] The resulting particles had a FPF(5.6) of 84%, and a
FPF(3.4) of 77%, both measured using a 2-stage ACI. The volume mean
geometric diameter was 8.9 .mu.m at 1.0 bar.
[0123] Porous Albuterol Sulfate Particles
[0124] 80 mg of albuterol sulfate, 460 mg of maltodextrin, 350 mg
of leucine, 110 mg of Pluronic F68, and 10 g of ammonium
bicarbonate were dissolved in 500 mL of sterile water. The aqueous
solution was mixed with 500 mL of ethanol. The resulting feed
solution was spray dried using a Niro spray dryer equipped with a
rotary atomizer. The drying gas (dry nitrogen) was delivered at a
flow rate of approximately 100 kg/h with a 150.degree. C. inlet
temperature, and a 62.degree. C. outlet temperature. The feed
solution was delivered to the atomizer/spray dryer at 65 ml/min
liquid flow rate. The atomizer was operated at 22,000 rpm, with 39
mm of water pressure in the spraying chamber of the spray dryer.
The resulting dry particles had a mass mean aerodynamic diameter of
3.33 .mu.m, and a volume mean geometric diameter of 11.5 .mu.m at 4
bar.
[0125] Porous Danazol Particles
[0126] 800 mg of danazol, 1.6 g of maltodextrin, 1.2 g leucine, 400
mg of polyethyleneglycol (PEG) 1500, and 40 g of ammonium
bicarbonate were dissolved in 2 L of sterile water. The aqueous
solution was mixed with 2 L of ethanol. The resulting feed solution
was spray dried using a Niro spray dryer equipped with a rotary
atomizer. The drying gas (dry nitrogen) was delivered at a flow
rate of approximately 100 kg/h with a 155.degree. C. inlet
temperature, and a 64.degree. C. outlet temperature. The feed
solution was delivered to the atomizer/spray dryer at 70 ml/min
liquid flow rate. The atomizer was operated at 22,000 rpm, with 39
mm of water pressure in the spraying chamber of the spray dryer.
The resulting dry particles had a mass mean aerodynamic diameter of
2.69 .mu.m, and a volume mean geometric diameter of 10.6 .mu.m at 4
bar.
[0127] Turning now to FIG. 6, an alternate embodiment of a system
600 for producing dry particles is shown. System 600 will be
explained for the exemplary situation of combining an aqueous
solution 610 with an ethanol solution 620 to form dry particles. As
would be readily apparent to one skilled in the art, system 600 is
not limited to use of an aqueous solution and an ethanol solution.
For example, system 600 could be used to combine other hydrophilic
and hydrophobic components, other aqueous and organic components,
or a hydrophilic component and an organic solvent, to form dry
particles. System 600 could also be used to combine two components
to form dry particles where the combination of the two components
causes degradation in one of the components.
[0128] As illustrated in FIG. 6, aqueous solution 600 is
transported via a gear pump 614 and a flow meter 612 to a static
mixer 630. Ethanol (EtOH) solution 620 is transported via a gear
pump 624 and a flow meter 622 to static mixer 630. In one
embodiment of the present invention, the same volume of aqueous
solution 610 and ethanol solution 620 is used, and pumps 614 and
624 are operated at substantially the same rate to deliver the
respective solutions to static mixer 630 at substantially the same
rate. In other embodiments, pumps 614 and 624 are operated at
different rates. As would be apparent to one skilled in the art,
the concentration of components in the final dry particles can be
used to determine the pump rates for pumps 614 and 624. For
example, in one embodiment of the present invention, the volumes of
aqueous solution 610 and ethanol solution 620 are selected to each
be completely consumed during the spray drying process. In such an
embodiment, the pump rates for pumps 614 and 624 are selected so
that solutions 610 and 620 are both used up. As would be
appreciated by one skilled in the art, other types of pumps, or
other means for transporting the solutions to static mixer 630
could be used. Alternatively, a single pump could be used to
deliver both solutions to static mixer 630. In the embodiment shown
in FIG. 6, static mixer 630 is oriented in a vertical
configuration, i.e., a central axis of static mixer 630 is parallel
to a central axis of a spray dryer 650. Alternatively, static mixer
630 could be configured in an inclined configuration, at an acute
angle with respect to the central axis of spray dryer 650. The
inclined or vertical configuration of static mixer 630 helps ensure
laminar flow, with any bubbling or gassing at the top. Preferably,
the inputs to the static mixer flow upwards to provide more
homogeneous mixing, and to prevent channeling. Static mixers
suitable for use with the present invention are illustrated in
FIGS. 1A and 1B, and include model 1/4-21, made by Koflo
Corporation.
[0129] An outlet end of static mixer 630 is in fluid communication
with a two-fluid nozzle 640 that is used to atomize the combination
flowing out of static mixer 630 into droplets. In an alternative
embodiment of system 600, a rotary atomizer, such as rotary
atomizer 300 depicted in FIG. 3, is used in place of nozzle 640.
Because the combination flowing out of static mixer 630 is a
homogeneous mixture of the input liquid components (aqueous
solution and ethanol solution), the droplets formed by nozzle 640
will also contain a homogeneous mixture of the input liquid
components. Nozzle 640 can be an internal mixing nozzle such as
that shown in FIG. 4, or an external mixing nozzle such as that
shown in FIG. 5. Preferably, nozzle 640 is an internal mixing
nozzle.
[0130] In the embodiment shown in FIG. 6, a nitrogen gas stream 642
is input to nozzle 640 to atomize the combination flowing out of
static mixer 630. As discussed above with respect to FIGS. 4 and 5,
nitrogen gas stream 642 can be a single gas stream, or divided into
a plurality of gas streams, to impinge upon the liquid combination
to atomize it into droplets. As would be readily apparent to one
skilled in the art, other gases could be used to atomize the liquid
combination into droplets, and the present invention is not limited
to the use of nitrogen as the atomizing gas stream.
[0131] The atomized droplets from nozzle 640 are dried in spray
dryer 650. Nitrogen from a nitrogen gas supply 652 is heated by a
heater 654 and input to spray dryer 650. A flow meter 656 and a
temperature measurement point 658 are used to monitor the flow and
temperature of the nitrogen gas input to spray dryer 650. As would
be readily apparent to one skilled in the art, other drying gases
could be used in spray dryer 650, such as, but not limited to, air,
argon, carbon dioxide, helium, and combinations or mixtures
thereof. In an alternate embodiment of the present invention, the
drying gas input to spray dryer 650 is the same input used to
atomize the liquid combination in nozzle 640. A mixture of gas and
dried particles or powder exits from spray dryer 650 at an outlet
659. A flow conditioner 660 and temperature measurement point 662
are used to condition and monitor the characteristics of the
gas-powder mixture exiting spray dryer 650. A flow conditioner
suitable for use with the present invention is made by Vortab, San
Marcos, Calif.
[0132] Flow conditioner 660 conditions the gas-powder mixture
exiting spray dryer 650 so that the particles contained in the gas
stream can be characterized by measuring the geometric diameter and
the aerodynamic diameter of the particles. Flow conditioner 660
provides a more homogeneous powder distribution in the piping by
imparting turbulent conditions to the gaseous stream. The more
homogeneous powder distribution prevents selective or skewed
sampling in the downstream sizers. After conditioning by flow
conditioner 660, a sample of the gas-powder mixture flows through a
geometric sizer 670 and an aerodynamic sizer 672, the operation of
which will be discussed in more detail below. The sample of the
gas-powder mixture is used to determine geometric and aerodynamic
size. After sizing, the sample is deposited on a filter (not shown)
for later disposal. The bulk of the gas-powder mixture flows
directly out of flow conditioner 660 and the dry particles are
collected on a bag filter 680 that retains the dry particle product
while allowing the gas to pass through to an exhaust 684 and for
solvent stripping. The dry particle product is removed from bag
filter 680, such as by running a back pulse of nitrogen across bag
filter 680, and is collected in a product collection vessel
682.
[0133] Geometric sizer 670 preferably measures volume median
geometric diameter (VMGD) of the particles. An exemplary geometric
sizer is the Insitec online particle sizer, available from Malvern
Instruments Ltd. The Insitec device consists of an optical sensor
head, a signal processing unit, and a computer for instrument
control and data collection and analysis. Aerodynamic sizer 672
preferably measures mass median aerodynamic diameter (MMAD) of the
particles. An exemplary aerodynamic sizer is the PS Model 3321,
available from TSI, Inc., St. Paul, Minn. In one embodiment of the
present invention, a computer 674 is coupled to geometric sizer 670
and to aerodynamic sizer 672. Computer 674 is used to carry out the
optimization process of the present invention, described in more
detail below with respect to FIG. 7. In an alternate embodiment of
the present invention, a computer or processor that is part of
aerodynamic sizer 672 or geometric sizer 670 is used to carry out
the optimization process of the present invention.
[0134] Conventional optimization of a spray drying process is a
time consuming and material intensive process, requiring the
manipulation of multiple process variables, such as inlet
temperature, outlet temperature, atomizer speed, drum pressure, gas
flow rate, and liquid feed rate, and multiple product formulations.
A typical optimization run would involve selecting a formulation
and a set of process conditions, spraying the material under the
selected conditions, collecting the finished dry particle powder,
and characterizing the dry particles using various in vitro
techniques, such as laser diffraction techniques (HELOS
diffractometer and a RODOS disperser) to measure geometric
diameter, an aerosizer to measure aerodynamic diameter, an ACI to
measure size distribution, and measurement of tap density. Once the
results of the characterization tests were complete, then the
process parameters could be adjusted to optimize the
characteristics of the particles. Approximately 2-3 g of material,
and about two hours, are required for each such optimization run.
To completely optimize process conditions to obtain final desired
powder characteristics, hundreds of runs may be required. Thus,
conventional optimization of the spray drying process is
inefficient, time consuming, and expensive.
[0135] The system and method of the present invention significantly
decreases the time and material required to optimize the spray
drying process. Using the system and method of the present
invention, an operator can evaluate particle characteristics in
real time during the spray drying process without having to run the
traditional in vitro characterization assays after the fact. Using
the system and method of the present invention, process conditions
can be modified in real time to optimize particle size to produce
particles having a desired geometric and/or aerodynamic
diameter.
[0136] Geometric sizer 670 can be used to measure the geometric
diameter of the particles, and aerodynamic sizer 672 can be used to
measure the aerodynamic diameter of the particles. However, in
order for the aerodynamic measurement to be made, the density of
the particles must be known prior to the measurement. Density
(.rho.), geometric diameter (d.sub.g), and aerodynamic diameter
(d.sub.a) are related by the following equation: d.sub.a=d.sub.g
{square root over (.rho.)}. The process of the present invention
uses density as the optimization variable to achieve particles
having the desired aerodynamic and/or geometric diameters.
[0137] One embodiment of a process of the present invention for
optimizing particle size is illustrated in FIG. 7. In a step 710,
an initial particle density is selected, and provided to
aerodynamic sizer 672. In a preferred embodiment of the present
invention for preparation of dry particles suitable for inhalation
into the lung, preferably into the deep lung, an initial particle
density of 0.06 g/cm.sup.3 is used. It should be apparent to one
skilled in the art that other initial particle densities can be
selected, depending upon the particular particle to be produced. In
a step 720, a measured aerodynamic diameter (d.sub.a.sup.m) and a
measured geometric diameter (d.sub.g.sup.m) are obtained using
aerodynamic sizer 672 and geometric sizer 670, respectively. In a
step 730, a calculated geometric diameter (d.sub.g.sup.c) is
calculated from the initial particle density and the measured
aerodynamic diameter using the equation d.sub.a.sup.m=d.sub.g.sup.c
{square root over (.rho.)}
[0138] If the estimated initial particle density (e.g., 0.06
g/cm.sup.3) was correct for the particles being produced, then the
calculated geometric diameter should be substantially equal to the
measured geometric diameter measured by geometric sizer 670. If the
calculated geometric diameter and the measured geometric diameter
do not match, then a new density is input into aerodynamic sizer
672 and processing returns to step 730 to re-calculate geometric
diameter. This process continues until the calculated geometric
diameter and the measured geometric diameter match. This iterative
process is illustrated in FIG. 7. In a step 740, it is determined
whether d.sub.g.sup.c=d.sub.g.sup.m. The calculated geometric
diameter is compared to the measured geometric diameter to
determine a differential. If there is a differential, then, in a
step 760, the particle density is adjusted, and processing returns
to step 730 to again calculate geometric diameter using the
adjusted value for particle density. Increasing the density
decreases the geometric diameter. Decreasing the density increases
the geometric diameter. The geometric diameter is again calculated
in step 730, and compared to the measured geometric diameter in
step 740. This process repeats until in step 740 it is determined
that the calculated geometric diameter is substantially equal to
the measured geometric diameter, at which point the particle
production process continues, as shown in a step 750.
[0139] When using the process of the present invention as shown in
FIG. 7, solutions are spray dried to form dry particles, and the
aerodynamic and geometric diameters are measured. Process
conditions (flow rates, temperatures, etc.) are held constant
during the measurement of the aerodynamic and geometric diameters.
Once the measurements are made, solvents can then be run through
the spray drying system while the density iteration is calculated
(steps 730, 740, and 760 in FIG. 7). This represents a significant
savings of costly material, such as the aqueous solution containing
active agent.
[0140] In one embodiment of the present invention, the density
iteration is done with aerodynamic diameter as a fixed variable. In
such an embodiment, the density is changed until the calculated
geometric diameter is substantially equal to the measured geometric
diameter. Once the density iteration is complete, then the density,
aerodynamic diameter, and geometric diameter of the particles are
known. At that point, process conditions (gas and/or liquid flow
rates, temperatures, process solutions) can be changed to achieve a
different density, aerodynamic, or geometric diameter.
Alternatively, a process condition or process solution can be
modified to determine its affect on density, aerodynamic diameter
and geometric diameter.
[0141] In another embodiment of the present invention, the density
iteration is done with geometric diameter as a fixed variable. In
such an embodiment, process conditions, such as gas flow rate, are
adjusted to achieve a desired measured geometric diameter.
Aerodynamic diameter is measured. Density is then changed until the
calculated geometric diameter is substantially equal to the
measured geometric diameter. Once the density iteration is
complete, then the density, aerodynamic diameter, and geometric
diameter of the particles are known. By fixing geometric diameter
in the density optimization process, particles having the same
geometric diameter can be produced under different process
conditions to facilitate comparisons between particles of the same
geometric diameter.
[0142] Once the process reaches step 750, an operator has three
values to use in decisions regarding the dry particles that have
been produced to that point: geometric diameter; aerodynamic
diameter; and density. One advantage of the method of the present
invention is that the liquid combination from static mixer 630
needs to be atomized into spray dryer 650 for only about three
minutes for the data to be collected and step 750 reached for a
particular set of process conditions. In this manner, multiple sets
of process conditions can be rapidly screened using a minimal
amount of material. For example, once step 750 is reached, the
density, geometric diameter, and aerodynamic diameter of the
particles are known for a given set of process conditions and
process solutions. If the desired density, geometric diameter, or
aerodynamic diameter has not been achieved, then the process
conditions can be modified and the density iteration process
repeated. Alternatively, a particular process condition or process
material can be changed, and its affect on density, aerodynamic
diameter, and geometric diameter determined.
[0143] To produce dry particles that can penetrate deep into the
lung, the desired geometric diameter is in the range of from about
7 to about 10 .mu.m. Using the method and apparatus of the present
invention as depicted in FIGS. 6 and 7, the density used by
aerodynamic sizer 672 is adjusted to minimize particle density,
while the measured geometric diameter is held constant in the 7-10
.mu.m range. For example, dry particles containing hGH were made
using the apparatus substantially as shown in FIG. 6 by selecting
an initial particle density of 0.06 g/cm.sup.3. The desired
geometric diameter size range for reaching the deep lung is in the
range of from about 7 to about 10 .mu.m, and aerodynamic diameter
size range of from about 1 to about 3 .mu.m. The aerodynamic
diameter was measured using the initial particle density of 0.06
g/cm.sup.3, and the geometric diameter was measured. The geometric
diameter was calculated, and compared to the measured geometric
diameter. To reach the deep lung, the measured geometric diameter,
and consequently the calculated geometric diameter, should be in
the range of from about 7 to about 10 .mu.m. If the calculated
geometric diameter was not the same as the measured geometric
diameter, the density value used in the aerodynamic sizer was
reduced, and the process repeated. By minimizing particle density
and holding the geometric diameter constant in the desired range,
particles having the desired geometric diameter, as well as the
desired low aerodynamic diameter, were produced.
[0144] The use of density as a valid optimization variable for
producing particles of the desired aerodynamic diameter is
demonstrated by the graph shown in FIG. 9. FIG. 9 shows a graph of
mass median aerodynamic diameter (MMAD) in .mu.m as measured using
the system and method of the present invention described above with
reference to FIGS. 6 and 7, versus MMAD measured using a
conventional multi-stage liquid impinger (MSLI). A MSLI works on
the same basic principles as an ACI device described above.
However, instead of having dry metal plates for stages like an ACI,
a MSLI has liquid-containing stages. Each MSLI stage consists of an
ethanol-wetted glass frit. The wetted stage is used to prevent
bouncing and re-etrainment, which can occur using the ACI. The
purpose of the liquid is to eliminate the presence of bounce in the
system, typically leading to greater accuracy than an ACI. The MSLI
used for the data illustrated in FIG. 9 included 5 stages. As can
be seen from FIG. 9, the MMAD measured using the density iteration
process of the present invention (y-axis) correlated well with the
MMAD measured using an MSLI (x-axis), with the MMAD measured using
the density iteration process being a reliable predictor of trends
in MMAD measured using the MSLI.
[0145] As noted above with respect to FIGS. 6 and 7, a computer or
computer system can be used to control the aerodynamic and/or
geometric particle sizers, and to carry out the particle size
optimization process. An exemplary computer system suitable for use
with the present invention is shown in FIG. 8. The computer system
802 includes one or more processors, such as a processor 804. The
processor 804 is connected to a communication bus 806. After
reading this description, it will become apparent to a person
skilled in the relevant art how to implement the invention using
other computer systems and/or computer architectures.
[0146] The computer system 802 also includes a main memory 808,
preferably random access memory (RAM), and can also include a
secondary memory 810. The secondary memory 810 can include, for
example, a hard disk drive 812 and/or a removable storage drive
814, representing a floppy disk drive, a magnetic tape drive, an
optical disk drive, etc. The removable storage drive 814 reads from
and/or writes to a removable storage unit 818 in a well-known
manner. The removable storage unit 818, represents a floppy disk,
magnetic tape, optical disk, etc. which is read by and written to
by the removable storage drive 814. As will be appreciated, the
removable storage unit 818 includes a computer usable storage
medium having stored therein computer software and/or data.
[0147] In alternative embodiments, the secondary memory 810 may
include other similar means for allowing computer programs or other
instructions to be loaded into the computer system 802. Such means
can include, for example, a removable storage unit 822 and an
interface 820. Examples of such can include a program cartridge and
cartridge interface (such as that found in video game devices), a
removable memory chip (such as an EPROM, or PROM) and associated
socket, and other removable storage units 822 and interfaces 820
which allow software and data to be transferred from the removable
storage unit 822 to the computer system 802.
[0148] The computer system 802 can also include a communications
interface 824. The communications interface 824 allows software and
data to be transferred between the computer system 802 and external
devices. Examples of the communications interface 824 can include a
modem, a network interface (such as an Ethernet card), a
communications port, a PCMCIA slot and card, etc. Software and data
transferred via the communications interface 824 are in the form of
signals 826 that can be electronic, electromagnetic, optical or
other signals capable of being received by the communications
interface 824. Signals 826 are provided to communications interface
via a channel 828. A channel 828 carries signals 826 and can be
implemented using wire or cable, fiber optics, a phone line, a
cellular phone link, an RF link and other communications
channels.
[0149] In this document, the terms "computer program medium" and
"computer usable medium" are used to generally refer to media such
as the removable storage device 818, a hard disk installed in hard
disk drive 812, and signals 826. These computer program products
are means for providing software to the computer system 802.
[0150] Computer programs (also called computer control logic) are
stored in the main memory 808 and/or the secondary memory 810.
Computer programs can also be received via the communications
interface 824. Such computer programs, when executed, enable the
computer system 802 to perform the features of the present
invention as discussed herein. In particular, the computer
programs, when executed, enable the processor 804 to perform the
features of the present invention. Accordingly, such computer
programs represent controllers of the computer system 802.
[0151] In an embodiment where the invention is implemented using
software, the software may be stored in a computer program product
and loaded into the computer system 802 using the removable storage
drive 814, the hard drive 812 or the communications interface 824.
The control logic (software), when executed by the processor 804,
causes the processor 804 to perform the functions of the invention
as described herein.
[0152] In another embodiment, the invention is implemented
primarily in hardware using, for example, hardware components such
as application specific integrated circuits (ASICs). Implementation
of such a hardware state machine so as to perform the functions
described herein will be apparent to persons skilled in the
relevant art(s). In yet another embodiment, the invention is
implemented using a combination of both hardware and software.
[0153] In a preferred embodiment, the spray dried particles of the
invention have a tap density less than about 0.4 g/cm.sup.3.
Particles that have a tap density of less than about 0.4 g/cm.sup.3
are referred to herein as "aerodynamically light particles". More
preferred are particles having a tap density less than about 0.1
g/cm.sup.3. Tap density can be measured by using instruments known
to those skilled in the art such as, but not limited to, the Dual
Platform Microprocessor Controlled Tap Density Tester (Vankel
Technology, Cary, N.C.) or a GeoPyc.TM. instrument (Micrometrics
Instrument Corp., Norcross, Ga. 30093). Tap density is a standard
measure of the envelope mass density. Tap density can be determined
using the method of USP Bulk Density and Tapped Density, United
States Pharmacopoeia convention, Rockville, Md., 10.sup.th
Supplement, 4950-4951, 1999. Features that can contribute to low
tap density include irregular surface texture and porous
structure.
[0154] The envelope mass density of an isotropic particle is
defined as the mass of the particle divided by the minimum sphere
envelope volume within which it can be enclosed. In one embodiment
of the invention, the particles have an envelope mass density of
less than about 0.4 g/cm.sup.3.
[0155] Aerodynamically light particles have a preferred size, e.g.,
a volume median geometric diameter (VMGD) of at least about 5
.mu.m. In one embodiment, the VMGD is from about 5 .mu.m to about
30 .mu.m. In another embodiment of the invention, the particles
have a VMGD ranging from about 10 .mu.m to about 30 .mu.m. In other
embodiments, the particles have a median diameter, mass median
diameter (MMD), a mass median envelope diameter (MMED) or a mass
median geometric diameter (MMGD) of at least 5 .mu.m, for example
from about 5 .mu.m to about 30 .mu.m.
[0156] The diameter of the spray-dried particles, for example, the
VMGD, can be measured using a laser diffraction instrument (for
example Helos, manufactured by Sympatec, Princeton, N.J.). Other
instruments for measuring particle diameter are well known in the
art. The diameter of particles in a sample will range depending
upon factors such as particle composition and methods of synthesis.
The distribution of size of particles in a sample can be selected
to permit optimal deposition to targeted sites within the
respiratory tract.
[0157] Aerodynamically light particles preferably have "mass median
aerodynamic diameter" (MMAD), also referred to herein as
"aerodynamic diameter", between about 1 .mu.m and about 5 .mu.m. In
another embodiment of the invention, the MMAD is between about 1
.mu.m and about 3 .mu.m. In a further embodiment, the MMAD is
between about 3 .mu.m and about 5 .mu.m.
[0158] Experimentally, aerodynamic diameter can be determined by
employing a gravitational settling method, whereby the time for an
ensemble of particles to settle a certain distance is used to infer
directly the aerodynamic diameter of the particles. An indirect
method for measuring the mass median aerodynamic diameter (MMAD) is
the multi-stage liquid impinger (MSLI).
[0159] Particles that have a tap density, less than about 0.4
g/cm.sup.3, median diameters of at least about 5 .mu.m, and an
aerodynamic diameter of between about 1 .mu.m and about 5 .mu.m,
preferably between about 1 .mu.m and about 3 .mu.m, are more
capable of escaping inertial and gravitational deposition in the
oropharyngeal region, and are targeted to the airways, particularly
the deep lung. The use of larger, more porous particles is
advantageous since they are able to aerosolize more efficiently
than smaller, denser aerosol particles such as those currently used
for inhalation therapies.
[0160] In another embodiment of the invention, the particles have
an envelope mass density, also referred to herein as "mass density"
of less than about 0.4 g/cm.sup.3. Particles also having a mean
diameter of between about 5 .mu.m and about 30 .mu.m are preferred.
Mass density and the relationship between mass density, mean
diameter and aerodynamic diameter are discussed in U.S. application
Ser. No. 08/655,570, filed on May 24, 1996, which is incorporated
herein by reference in its entirety. In a preferred embodiment, the
aerodynamic diameter of particles having a mass density less than
about 0.4 g/cm.sup.3 and a mean diameter of between about 5 .mu.m
and about 30 .mu.m mass mean aerodynamic diameter is between about
1 .mu.m and about 5 .mu.m.
[0161] In comparison to smaller, relatively denser particles the
larger aerodynamically light particles, preferably having a median
diameter of at least about 5 .mu.m, also can potentially more
successfully avoid phagocytic engulfment by alveolar macrophages
and clearance from the lungs, due to size exclusion of the
particles from the phagocytes' cytosolic space. Phagocytosis of
particles by alveolar macrophages diminishes precipitously as
particle diameter increases beyond about 3 .mu.m. Kawaguchi, H., et
al., Biomaterials 7: 61-66 (1986); Krenis, L. J. and Strauss, B.,
Proc. Soc. Exp. Med., 107: 748-750 (1961); and Rudt, S, and Muller,
R. H., J. Contr. Rel., 22: 263-272 (1992). For particles of
statistically isotropic shape, such as spheres with rough surfaces,
the particle envelope volume is approximately equivalent to the
volume of cytosolic space required within a macrophage for complete
particle phagocytosis.
[0162] The particles may be fabricated with the appropriate
material, surface roughness, diameter and tap density for localized
delivery to selected regions of the respiratory tract such as the
deep lung or upper or central airways. For example, higher density
or larger particles may be used for upper airway delivery, or a
mixture of varying sized particles in a sample, provided with the
same or different therapeutic agent may be administered to target
different regions of the lung in one administration. Particles
having an aerodynamic diameter ranging from about 3 to about 5
.mu.m are preferred for delivery to the central and upper airways.
Particles having and aerodynamic diameter ranging from about 1 to
about 3 .mu.m are preferred for delivery to the deep lung.
[0163] Inertial impaction and gravitational settling of aerosols
are predominant deposition mechanisms in the airways and acini of
the lungs during normal breathing conditions. Edwards, D. A., J.
Aerosol Sci., 26: 293-317 (1995). The importance of both deposition
mechanisms increases in proportion to the mass of aerosols and not
to particle (or envelope) volume. Since the site of aerosol
deposition in the lungs is determined by the mass of the aerosol
(at least for particles of mean aerodynamic diameter greater than
approximately 1 .mu.m), diminishing the tap density by increasing
particle surface irregularities and particle porosity permits the
delivery of larger particle envelope volumes into the lungs, all
other physical parameters being equal.
[0164] The low tap density particles have a small aerodynamic
diameter in comparison to the actual envelope sphere diameter. The
aerodynamic diameter, d.sub.aer, is related to the envelope sphere
diameter, d (Gonda, I., "Physico-chemical principles in aerosol
delivery," in Topics in Pharmaceutical Sciences 1991 (eds. D. J. A.
Crommelin and K. K. Midha), pp. 95-117, Stuttgart: Medpharm
Scientific Publishers, 1992)), by the formula: d.sub.aer=d {square
root over (.rho.)} where the envelope mass p is in units of
g/cm.sup.3. Maximal deposition of monodispersed aerosol particles
in the alveolar region of the human lung (.about.60%) occurs for an
aerodynamic diameter of approximately d.sub.aer=3 .mu.m. Heyder, J.
et al., J. Aerosol Sci., 17: 811-825 (1986). Due to their small
envelope mass density, the actual diameter d of aerodynamically
light particles comprising a monodisperse inhaled powder that will
exhibit maximum deep-lung deposition is: d=3/ {square root over
(.rho.)}.mu.m (where .rho.<1 g/cm.sup.3); where d is always
greater than 3 .mu.m. For example, aerodynamically light particles
that display an envelope mass density, .rho.=0.1 g/cm.sup.3, will
exhibit a maximum deposition for particles having envelope
diameters as large as 9.5 .mu.m. The increased particle size
diminishes interparticle adhesion forces. Visser, J., Powder
Technology, 58: 1-10. Thus, large particle size increases
efficiency of aerosolization to the deep lung for particles of low
envelope mass density, in addition to contributing to lower
phagocytic losses.
[0165] The aerodynamic diameter can be calculated to provide for
maximum deposition within the lungs. Previously this was achieved
by the use of very small particles of less than about five microns
in diameter, preferably between about one and about three microns,
which are then subject to phagocytosis. Selection of particles
which have a larger diameter, but which are sufficiently light
(hence the characterization "aerodynamically light"), results in an
equivalent delivery to the lungs, but the larger size particles are
not phagocytosed.
[0166] In one embodiment of the invention, the particles include a
biologically active (bioactive) compound, for example a
therapeutic, prophylactic or diagnostic agent. Bioactive compounds
or agents also are referred to herein as drugs, active agents, or
medicaments. The amount of bioactive agent present in the particles
generally ranges between about 0.1% weight and about 100% weight,
preferably between about 1.0% weight and about 100% weight.
[0167] Examples of biologically active agents include synthetic
inorganic and organic compounds, proteins, peptides, polypeptides,
DNA and RNA nucleic acid sequences having therapeutic, prophylactic
or diagnostic activities. Nucleic acid sequences include genes,
antisense molecules which bind to complementary DNA or RNA and
inhibit transcription, and ribozymes. The agents to be incorporated
can have a variety of biological activities, such as vasoactive
agents, neuroactive agents, hormones, anticoagulants,
immunomodulating agents, cytotoxic agents, prophylactic agents,
antibiotics, antivirals, antisense, antigens, and antibodies.
Compounds with a wide range of molecular weight can be used, for
example, between 100 and 500,000 grams or more per mole.
[0168] The particles can include a therapeutic agent for local
delivery within the lung, such as agents for the treatment of
asthma, chronic obstructive pulmonary disease (COPD), emphysema, or
cystic fibrosis, or for systemic treatment. For example, genes for
the treatment of diseases such as cystic fibrosis can be
administered, as can beta agonists steroids, anticholinergics and
leukotriene modifiers for asthma. Other specific therapeutic agents
include, but are not limited to, human growth hormone, insulin,
calcitonin, gonadotropin-releasing hormone, luteinizing hormone
releasing hormone (LHRH), granulocyte colony-stimulating factor
("G-CSF"), parathyroid hormone and PTH-related peptide,
somatostatin, testosterone, progesterone, estradiol, nicotine,
fentanyl, norethisterone, clonidine, scopolamine, salicylate,
cromolyn sodium, salmeterol, formeterol, albuterol, epinephrine,
L-dopa, and diazepam, as well as medicaments that primarily target
the central nervous system, kidneys, heart or other organs.
[0169] Diagnostic agents include but are not limited to imaging
agents which include commercially available agents used in positron
emission tomography (PET), computer assisted tomography (CAT),
single photon emission computerized tomography, x-ray, fluoroscopy,
and magnetic resonance imaging (MRI).
[0170] Examples of suitable materials for use as contrast agents in
MRI include but are not limited to the gadolinium chelates
currently available, such as diethylene triamine pentacetic acid
(DTPA) and gadopentotate dimeglumine, as well as iron, magnesium,
manganese, copper and chromium.
[0171] Examples of materials useful for CAT and x-rays include
iodine based materials for intravenous administration, such as
ionic monomers typified by diatrizoate and iothalamate, non-ionic
monomers such as iopamidol, isohexyl, and ioversol, non-ionic
dimers, such as iotrol and iodixanol, and ionic dimers, for
example, ioxagalte.
[0172] The particles can include additional component(s). Such
additional components may be referred to herein as excipients, and
can include, for example, phospholipids, surfactants, amino acids,
and polymers. In a preferred embodiment, the particles include one
or more phospholipids, such as, for example, a phosphatidylcholine,
phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine,
phosphatidylinositol or a combination thereof. In one embodiment,
the phospholipids are endogenous to the lung. Specific examples of
phospholipids are shown in Table 10. Combinations of phospholipids
can also be employed. TABLE-US-00010 TABLE 10
Dilaurylolyphosphatidylcholine (C12:0) DLPC
Dimyristoylphosphatidylcholine (C14:0) DMPC
Dipalmitoylphosphatidylcholine (C16:0) DPPC
Distearoylphosphatidylcholine (C18:0) DSPC
Dioleoylphosphatidylcholine (C18:1) DOPC
Dilaurylolylphosphatidylglycerol DLPG
Dimyristoylphosphatidylglycerol DMPG
Dipalmitoylphosphatidylglycerol DPPG Distearoylphosphatidylglycerol
DSPG Dioleoylphosphatidylglycerol DOPG Dimyristoyl phosphatidic
acid DMPA Dimyristoyl phosphatidic acid DMPA Dipalmitoyl
phosphatidic acid DPPA Dipalmitoyl phosphatidic acid DPPA
Dimyristoyl phosphatidylethanolamine DMPE Dipalmitoyl
phosphatidylethanolamine DPPE Dimyristoyl phosphatidylserine DMPS
Dipalmitoyl phosphatidylserine DPPS Dipalmitoyl sphingomyelin DPSP
Distearoyl sphingomyelin DSSP
[0173] Charged phospholipids also can be employed. Examples of
charged phospholipids are described in U.S. patent application
entitled "Particles for Inhalation Having Sustained Release
Properties," 09/752,106 filed on Dec. 29, 2000, and in U.S. patent
application Ser. No. 09/752,109 entitled "Particles for Inhalation
Having Sustained Release Properties", filed on Dec. 29, 2000; the
entire contents of both are incorporated herein by reference.
[0174] The phospholipid can be present in the particles in an
amount ranging from about 5 weight percent (%) to about 95 weight
%. Preferably, it can be present in the particles in an amount
ranging from about 20 weight % to about 80 weight %.
[0175] The phospholipids or combinations thereof can be selected to
impart controlled release properties to the spray dried particles
produced by the methods of the invention. Particles having
controlled release properties and methods of modulating release of
a biologically active agent are described in U.S. Provisional
Patent Application No. 60/150,742 entitled "Modulation of Release
From Dry Powder Formulations by Controlling Matrix Transition,"
filed on Aug. 25, 1999 and U.S. Non-Provisional patent application
Ser. No. 09/644,736, filed on Aug. 23, 2000, with the title
"Modulation of Release From Dry Powder Formulations". The contents
of both are incorporated herein by reference in their entirety.
[0176] In another embodiment of the invention particles include a
surfactant. As used herein, the term "surfactant" refers to any
agent which preferentially absorbs to an interface between two
immiscible phases, such as the interface between water and an
organic polymer solution, a water/air interface or organic
solvent/air interface. Surfactants generally possess a hydrophilic
moiety and a lipophilic moiety, such that, upon absorbing to
microparticles, they tend to present moieties to the external
environment that do not attract similarly-coated particles, thus
reducing particle agglomeration. Surfactants may also promote
absorption of a therapeutic or diagnostic agent and increase
bioavailability of the agent.
[0177] In addition to lung surfactants, such as, for example, the
phospholipids discussed above, suitable surfactants include but are
not limited to hexadecanol; fatty alcohols such as polyethylene
glycol (PEG); polyoxyethylene-9-lauryl ether; a surface active
fatty acid, such as palmitic acid or oleic acid; glycocholate;
surfactin; a poloxamer; a sorbitan fatty acid ester such as
sorbitan trioleate (Span 85), Tween 20 or Tween 80 (Polyoxyethylene
Sorbitan Monooleate); and tyloxapol.
[0178] The surfactant can be present in the particles in an amount
ranging from about 0.01 weight % to about 5 weight %. Preferably,
it can be present in the particles in an amount ranging from about
0.1 weight % to about 1.0 weight %.
[0179] Methods of preparing and administering particles including
surfactants, and, in particular phospholipids, are disclosed in
U.S. Pat. No. 5,855,913, issued on Jan. 5, 1999 to Hanes et al. and
in U.S. Pat. No. 5,985,309, issued on Nov. 16, 1999 to Edwards et
al. The teachings of both are incorporated herein by reference in
their entirety.
[0180] In another embodiment of the invention, the particles
include an amino acid. Hydrophobic amino acids are preferred.
Suitable amino acids include naturally occurring and non-naturally
occurring hydrophobic amino acids. Examples of amino acids which
can be employed include, but are not limited to: glycine, proline,
alanine, cysteine, methionine, valine, leucine, tyrosine,
isoleucine, phenylalanine, tryptophan. Preferred hydrophobic amino
acids, include but not limited to, leucine, isoleucine, alanine,
valine, phenylalanine, glycine and tryptophan. Amino acids which
include combinations of hydrophobic amino acids can also be
employed. Non-naturally occurring amino acids include, for example,
beta-amino acids. Both D, L and racemic configurations of
hydrophobic amino acids can be employed. Suitable hydrophobic amino
acids can also include amino acid analogs. As used herein, an amino
acid analog includes the D or L configuration of an amino acid
having the following formula: --NH--CHR--CO--, wherein R is an
aliphatic group, a substituted aliphatic group, a benzyl group, a
substituted benzyl group, an aromatic group or a substituted
aromatic group and wherein R does not correspond to the side chain
of a naturally-occurring amino acid. As used herein, aliphatic
groups include straight chained, branched or cyclic C1-C8
hydrocarbons which are completely saturated, which contain one or
two heteroatoms such as nitrogen, oxygen or sulfur and/or which
contain one or more units of unsaturation. Aromatic groups include
carbocyclic aromatic groups such as phenyl and naphthyl and
heterocyclic aromatic groups such as imidazolyl, indolyl, thienyl,
furanyl, pyridyl, pyranyl, oxazolyl, benzothienyl, benzofuranyl,
quinolinyl, isoquinolinyl and acridintyl.
[0181] Suitable substituents on an aliphatic, aromatic or benzyl
group include --OH, halogen (--Br, --Cl, --I and --F) --O
(aliphatic, substituted aliphatic, benzyl, substituted benzyl, aryl
or substituted aryl group), --CN, --NO.sub.2, --COOH, --NH2,
--NH(aliphatic group, substituted aliphatic, benzyl, substituted
benzyl, aryl or substituted aryl group), --N(aliphatic group,
substituted aliphatic, benzyl, substituted benzyl, aryl or
substituted aryl group)2, --COO(aliphatic group, substituted
aliphatic, benzyl, substituted benzyl, aryl or substituted aryl
group), --CONH2, --CONH(aliphatic, substituted aliphatic group,
benzyl, substituted benzyl, aryl or substituted aryl group)), --SH,
--S(aliphatic, substituted aliphatic, benzyl, substituted benzyl,
aromatic or substituted aromatic group) and --NH--C(.dbd.NH)--NH2.
A substituted benzylic or aromatic group can also have an aliphatic
or substituted aliphatic group as a substituent. A substituted
aliphatic group can also have a benzyl, substituted benzyl, aryl or
substituted aryl group as a substituent. A substituted aliphatic,
substituted aromatic or substituted benzyl group can have one or
more substituents. Modifying an amino acid substituent can
increase, for example, the lypophilicity or hydrophobicity of
natural amino acids which are hydrophilic.
[0182] A number of the suitable amino acids, amino acid analogs and
salts thereof can be obtained commercially. Others can be
synthesized by methods known in the art. Synthetic techniques are
described, for example, in Green and Wuts, "Protecting Groups in
Organic Synthesis", John Wiley and Sons, Chapters 5 and 7,
1991.
[0183] Hydrophobicity is generally defined with respect to the
partition of an amino acid between a nonpolar solvent and water.
Hydrophobic amino acids are those acids which show a preference for
the nonpolar solvent. Relative hydrophobicity of amino acids can be
expressed on a hydrophobicity scale on which glycine has the value
0.5. On such a scale, amino acids which have a preference for water
have values below 0.5 and those that have a preference for nonpolar
solvents have a value above 0.5. As used herein, the term
hydrophobic amino acid refers to an amino acid that, on the
hydrophobicity scale has a value greater or equal to 0.5, in other
words, has a tendency to partition in the nonpolar acid which is at
least equal to that of glycine.
[0184] Combinations of hydrophobic amino acids can also be
employed. Furthermore, combinations of hydrophobic and hydrophilic
(preferentially partitioning in water) amino acids, where the
overall combination is hydrophobic, can also be employed.
Combinations of one or more amino acids and one or more
phospholipids or surfactants can also be employed.
[0185] The amino acid can be present in the particles in an amount
from about 0 weight % to about 60 weight %. Preferably, the amino
acid can be present in the particles in an amount ranging from
about 5 weight % to about 30 weight %. The salt of a hydrophobic
amino acid can be present in the liquid feed in an amount from
about 0 weight % to about 60 weight %. Preferably, the amino acid
salt is present in the liquid feed in an amount ranging from about
5 weight % to about 30 weight %. Methods of forming and delivering
particles which include an amino acid are described in U.S. patent
application Ser. No. 09/382,959, filed on Aug. 25, 1999, entitled
"Use of Simple Amino Acids to Form Porous Particles During Spray
Drying" and in U.S. patent application Ser. No. 09/644,320 filed on
Aug. 23, 2000, entitled "Use of Simple Amino Acids to Form Porous
Particles"; the teachings of both are incorporated herein by
reference in their entirety.
[0186] In another embodiment of the invention, the particles
include a carboxylate moiety and a multivalent metal salt. One or
more phospholipids also can be included. Such compositions are
described in U.S. Provisional Application 60/150,662, filed on Aug.
25, 1999, entitled "Formulation for Spray-Drying Large Porous
Particles," and U.S. patent application Ser. No. 09/644,105 filed
on Aug. 23, 2000, entitled "Formulation for Spray-Drying Large
Porous Particles"; the teachings of both are incorporated herein by
reference in their entirety. In a preferred embodiment, the
particles include sodium citrate and calcium chloride.
[0187] Biocompatible, and preferably biodegradable polymers also
can be included in the particles. Particles including such
polymeric materials are described in U.S. Pat. No. 5,874,064,
issued on Feb. 23, 1999 to Edwards et al., the teachings of which
are incorporated herein by reference in their entirety, and in U.S.
Pat. No. 6,136,295, issued on Oct. 24, 2000 to Edwards et al., the
entire teachings of which are incorporated herein by reference.
[0188] The particles can also include a material such as, for
example, dextran, polysaccharides, lactose, trehalose,
cyclodextrins, proteins, peptides, polypeptides, fatty acids,
inorganic compounds, phosphates.
[0189] The total concentration of solids in the liquid feed from
which the particles are formed ranges from about 0.1% to about 0.5%
and higher. Solids can include biologically active agent,
excipient, phospholipid, surfactants, salts, buffers, metals, and
other compounds.
[0190] Particles produced by the methods of the invention and which
include a medicament, for example one or more of the bioactive
agents described above, can be administered to the respiratory
tract of a patient in need of treatment, prophylaxis or diagnosis.
Administration of particles to the respiratory system can be by
means known in the art. For example, particles are delivered from
an inhalation device. In a preferred embodiment, particles are
administered via a dry powder inhaler (DPI). Metered-dose-inhalers
(MDI), or instillation techniques, also can be employed.
[0191] Various suitable devices and methods of inhalation which can
be used to administer particles to a patient's respiratory tract
are known in the art. For example, suitable inhalers are described
in U.S. Pat. No. 4,069,819, issued Aug. 5, 1976 to Valentini, et
al., U.S. Pat. No. 4,995,385 issued Feb. 26, 1991 to Valentini, et
al., and U.S. Pat. No. 5,997,848 issued Dec. 7, 1999 to Patton, et
al. Other examples of suitable inhalers include, but are not
limited to, the Spinhaler.RTM. (Fisons, Loughborough, U.K.),
Rotahaler.RTM. (Glaxo-Wellcome, Research Triangle Technology Park,
North Carolina), FlowCaps.RTM. (Hovione, Loures, Portugal),
Inhalator.RTM. (Boehringer-Ingelheim, Germany), and the
Aerolizer.RTM. (Novartis, Switzerland), the Diskhaler.RTM.
(Glaxo-Wellcome, RTP, NC) and others known to those skilled in the
art. Yet other examples of suitable inhalers include those
disclosed in the following United States patent applications:
"Inhalation Device and Method," application Ser. No. 09/835,302
(filed Apr. 16, 2001) and "Inhalation Device and Method,"
application Ser. No. 10/268,059 (filed Oct. 10, 2002), the entirety
of each of which is incorporated herein by reference.
[0192] Preferably, particles administered to the respiratory tract
travel through the upper airways (oropharynx and larynx), the lower
airways which include the trachea followed by bifurcations into the
bronchi and bronchioli and through the terminal bronchioli which in
turn divide into respiratory bronchioli leading then to the
ultimate respiratory zone, the alveoli or the deep lung. In a
preferred embodiment of the invention, most of the mass of
particles deposits in the deep lung. In another embodiment of the
invention, delivery is primarily to the central airways. Delivery
to the upper airways can also be obtained.
[0193] In one embodiment of the invention, delivery to the
pulmonary system of particles is in a single, breath-actuated step,
as described in U.S. Non-Provisional Patent Application, "High
Efficient Delivery of a Large Therapeutic Mass Aerosol",
application Ser. No. 09/591,307, filed Jun. 9, 2000, which is
incorporated herein by reference in its entirety. In another
embodiment of the invention, at least 50% of the mass of the
particles stored in the inhaler receptacle is delivered to a
subject's respiratory system in a single, breath-activated step. In
a further embodiment, at least 5 milligrams and preferably at least
10 milligrams of a medicament is delivered by administering, in a
single breath, to a subject's respiratory tract particles enclosed
in the receptacle. Amounts as high as 15, 20, 25, 30, 35, 40 and 50
milligrams can be delivered.
[0194] As used herein, the term "effective amount" means the amount
needed to achieve the desired therapeutic or diagnostic effect or
efficacy. The actual effective amounts of drug can vary according
to the specific drug or combination thereof being utilized, the
particular composition formulated, the mode of administration, and
the age, weight, condition of the patient, and severity of the
symptoms or condition being treated. Dosages for a particular
patient can be determined by one of ordinary skill in the art using
conventional considerations, (e.g. by means of an appropriate,
conventional pharmacological protocol). In one example, effective
amounts of albuterol sulfate range from about 100 micrograms
(.mu.g) to about 1.0 milligram (mg).
[0195] Aerosol dosage, formulations and delivery systems also may
be selected for a particular therapeutic application, as described,
for example, in Gonda, I. "Aerosols for delivery of therapeutic and
diagnostic agents to the respiratory tract," in Critical Reviews in
Therapeutic Drug Carrier Systems, 6: 273-313, 1990; and in Moren,
"Aerosol dosage forms and formulations," in: Aerosols in Medicine.
Principles, Diagnosis and Therapy, Moren, et al., Eds, Esevier,
Amsterdam, 1985.
[0196] The particles of the invention can be employed in
compositions suitable for drug delivery to the pulmonary system.
For example, such compositions can include the particles and a
pharmaceutically acceptable carrier for administration to a
patient, preferably for administration via inhalation. The
particles may be administered alone or in any appropriate
pharmaceutically acceptable carrier, such as a liquid, for example
saline, or a powder, for administration to the respiratory system.
They can be co-delivered with larger carrier particles, not
including a therapeutic agent, the latter possessing mass median
diameters for example in the range between about 50 .mu.m and about
100 .mu.m.
[0197] The present invention will be further understood by
reference to the following non-limiting examples.
Examples
Preparation of Dry Particles Containing hGH
[0198] In a preferred aspect of the present invention, it was
desired to prepare inhalable dry particles containing hGH (human
growth hormone) that would maximize the amount of active hGH that
reached the alveolar space. To do so, it was determined that the
inhalable dry particles should have a FPF(5.6) of at least about
85% and a FPF(3.4) of at least about 55%. It was also desired to
have at least 95% of the hGH in the dry particles be "readily
extractable", that is, soluble in buffer solution. When the hGH is
exposed to incompatible components, for example, organic solutions
such as ethanol solution, the hGH degrades or denatures, resulting
in degradation products that include insoluble aggregates and
soluble dimer. The method and apparatus of the present invention
were developed to minimize the amount of insoluble aggregates and
soluble dimer in the finished dry particles by minimizing the
contact between the hGH solution and the incompatible ethanol
solution by combining them rapidly in a static mixer.
[0199] The following examples illustrate preparation of inhalable
dry particles containing hGH. Unless indicated otherwise, bulk raw
hGH was supplied by Eli Lilly, Inc. as lyophilized powder. 1,2
Dipalmitoyl-sn-Glycero-3-Phosphocholine (DPPC) was obtained from
Avanti Polar Lipids. USP grade 200 proof ethyl alcohol and USP
(United States Pharmacopeia) Sterile Water for Irrigation were
used.
56.1 wt % hGH/40.6 wt % DPPC/3.3 wt % sodium phosphate
[0200] The dry particles were prepared in accordance with the
following procedure, using equipment substantially the same as that
illustrated in FIG. 2. The lyophilized hGH powder was allowed to
warm to room temperature for at least hour. The hGH was dissolved
in 1.7 mM sodium phosphate buffer (pH 7.4) to form a concentrated
hGH solution. The pH of the hGH concentrate was increased to 7.4
using 1.0 N NaOH. The hGH concentrate was passed through a
Millipore 0.22 .mu.m Opticap filter. The concentration of the hGH
concentrate was determined using a Beckman Du.RTM. 640
spectrophotometer. The hGH concentrate solution was diluted with
1.7 mM sodium phosphate buffer (pH 7.4) to achieve an hGH
concentration of 3.57 g/Kg. The resulting aqueous solution was
transferred to a sealed vessel, such as feed vessel 210. The
organic solution was prepared by dissolving the DPPC in 200 proof
ethyl alcohol to a concentration of 1.40 g/Kg. The organic solution
was transferred into a sealed vessel, such as feed vessel 220.
[0201] The aqueous phase was pumped at 15 ml/min.+-.3 ml/min, and
the organic phase was pumped at 35 ml/min.+-.3 ml/min into a twelve
inch long static mixer, such as static mixer 230. The combination
liquid flowed from the static mixer into a rotary atomizer (such as
atomizer 240) using a 24 vaned rotary atomizer wheel (Niro)
operating at 34,500 rpm.+-.2000 rpm. The combination was atomized
into small droplets, which entered the Niro Size 1 spray dryer
(such as spray dryer 250) utilizing dry nitrogen gas flowing at 105
Kg/hr.+-.4 Kg/hr. The inlet temperature of the spray dryer was
maintained at 88.degree. C..+-.5.degree. C. such that the outlet
temperature fell within the range of 45.degree. C..+-.2.degree. C.
The particles were collected in a bag house, such as bag house 260.
The resulting dry particles had a mean MMAD of 2.52 .mu.m and a
mean VMGD of 10.20 .mu.m.
[0202] Size-exclusion HPLC was used to detect and quantitate
aggregate formation in the resulting dry particles. As described in
more detail below, samples were dissolved in 25 mM sodium phosphate
buffer, pH 7.0, and in 67% 25 mM sodium phosphate buffer, pH 7.0,
containing 33% n-propanol, and filtered through 0.45 .mu.m syringe
filters prior to chromatography. Using this technique, hGH elutes
as monomer (main peak) at a retention time of 12 to 17 minutes. The
appearance of a leading shoulder on the monomer main peak indicates
the presence of soluble dimer. The amount of soluble dimer and
soluble monomer can be obtained by determining their respective
peak areas. The amount of insoluble aggregate is calculated from
the following formula: Insoluble Aggregate (%)=(1-A/B.times.Area
Correction).times.100% [0203] A=Monomer Peak Area of hGH dry
particles dissolved in 25 mM sodium phosphate buffer. [0204]
B=Monomer Peak Area of hGH dry particles dissolved in 67% 25 mM
sodium phosphate buffer, pH 7.0 containing 33% n-propanol. [0205]
Area Correction=1.027 (accounts for the difference of the hGH
standard peak area between injections from 33% n-propanol and
buffer).
[0206] Size exclusion HPLC was carried out using a Waters 2690 HPLC
system operating in isocratic mode with a Waters 2487 UV Detector
and a Tosohas TSK G3000SW, 10 .mu.m (7.5 mm.times.300 mm) column.
The size exclusion column was run at 0.6 ml/min using a 0.063 M
sodium phosphate buffer:isopropyl alcohol (97:3) mobile phase, at
pH 7.0. UV detection was at 214 nm.
[0207] An alternative method for determining soluble and insoluble
aggregates in protein such as hGH is described below. This method
is performed using size exclusion HPLC with detection at 214 nm on
a Waters 2690 system with a Waters 2486 dual wavelength detector. A
TSK GEL 3000SW 7.5 mm.times.300 mm column is used for the
separation with a 63 mM potassium phosphate, pH 7.0 containing 3%
IPA mobile phase flowing at 0.6 mL/min for 30 min/run at room
temperature. Manual integration is performed to quantify monomer,
high molecular weight protein (soluble aggregates) and acid
dissolved hGH (insoluble aggregates) areas versus a hGH reference
standard calibration curve.
[0208] The procedure is as follows: [0209] Weigh 20 mg of hGH into
a scintillation vial and transfer in 20 ml of diluent (25 mM
potassium phosphate). This is approximately 0.8 mg/mL hGH monomer.
Gently disperse powder solution. [0210] Remove approximately 3 ml
and filter into an HPLC vial and inject 20 .mu.L onto the SE HPLC
column. This solution is used to determine the hGH monomer content
and the amount of high molecular weight protein (soluble
aggregates). [0211] Remove a further 1 ml and transfer to a
centrifuge tube. (Perform in duplicate.) [0212] Centrifuge for 10
minutes at 14,000 rpm. Remove and discard the supernatant. Wash the
pellet to remove soluble hGH with 1 ml of water, and centrifuge for
10 minutes. Repeat this three times. [0213] Following the third
washing and removal of the water, centrifuge the tubes one more
time to remove any remaining water. Do not disrupt the pellet.
[0214] Reconstitute the pellet with 1 ml of 0.01N HCl, and allow it
to dissolve for 15 minutes. [0215] Transfer the solution to a HPLC
vial and inject 100 .mu.L onto the column.
[0216] The buffer soluble hGH content is determined from the
injection of the first solution. The insoluble hGH content is
determined from injection of the second solution in 0.01 N HCl. The
percent readily extractable hGH is calculated as buffer soluble hGH
divided by total hGH content (soluble plus insoluble hGH).
[0217] Three experimental runs were made to determine the effect of
time in the incompatible ethanol solution on the integrity of the
hGH protein. For two of the experiments, a static mixer was not
used. Rather, the aqueous and organic solutions were combined, and
the combination was maintained for a period of time prior to
atomization and spray drying. In the first experiment (sample 2 in
Table 11 below), the aqueous and the organic solutions were
combined prior to spraying, such that the final volume was 1.25 L,
and the resulting combination was spray dried over a period of 25
minutes. In the second experiment (sample 1 in Table 11 below), the
aqueous and organic solutions were combined prior to spraying, such
that the final volume was 28 L, and the resulting combination was
spray dried over a period of 8 hours (560 minutes). In the third
experiment, (sample 3 in Table 11 below), the static mixer was used
so that the exposure of the hGH to ethanol was about 6 seconds (0.1
minute). The total batch size for sample 3 was 0.375 L of the
aqueous solution and 0.875 L of the ethanol solution.
TABLE-US-00011 TABLE 11 Static Maximum Exposure Soluble Insoluble
Sample Mixer Time (minutes) Aggregate Aggregate 1 No 560 1.60% 26%
2 No 25 5.40% 14% 3 Yes 0.1 3.90% 9%
[0218] All of the samples in Table 11 were prepared under the same
conditions, with the exception of the amount of exposure time
between the aqueous and ethanol solutions prior to spray drying. As
can be seen from the results in Table 11, the insoluble aggregate
of the hGH monomer increased as a function of exposure time to 70%
(v/v) ethanol solution. Use of the static mixer decreased the
insoluble aggregates by about 17%.
93.5 wt % hGH/6.5 wt % Sodium Phosphate: 10 g/L Ammonium
Bicarbonate; 12 g/L Solids
[0219] Lipid-free particles with a formulation containing hGH and
sodium phosphate monohydrate were prepared as follows using
apparatus substantially as shown in FIG. 6. The aqueous solution
was prepared by preparing a bulk sodium phosphate solution at 100
mM at pH 7.4 and a bulk ammonium bicarbonate solution at 50 g/L. 52
mL of 100 mM sodium phosphate buffer at pH 7.4 was added to 268 mL
of water for irrigation. To this was added 200 mL of the 50 g/L
ammonium bicarbonate solution and 200 mL of ethanol. The resulting
solution was combined in a static mixer with 280 mL of bulk hGH at
40 g/L in 1.7 mM sodium phosphate buffer at pH=7.4. Solute
concentration in the combined solution was 12 g/L. The combined
solution was spray dried under the following process conditions:
[0220] Inlet temperature .about.74.degree. C. [0221] Outlet
temperature from the drying drum .about.40.degree. C. [0222]
Nitrogen drying gas=110 kg/hr [0223] Nitrogen atomization gas=64
g/min [0224] 2 Fluid internal mixing nozzle atomizer [0225]
Nitrogen atomization pressure .about.90 psi [0226] Liquid feed
rate=25 ml/min [0227] Liquid feed temperature .about.22.degree. C.
[0228] Pressure in drying chamber=-2.0 in water [0229] The
resulting particles had a FPF(5.6) of 75%, and a FPF(3.4) of 70%,
both measured using a 2-stage ACI. The volume mean geometric
diameter was 8 .mu.m at 1.0 bar. The resulting particles had a
soluble dimer fraction of 1.2% and a readily extractable hGH
fraction of 97.5%.
[0230] The combination solution flowing out of the static mixer was
fed into a two-fluid nozzle atomizer located above the spray dryer,
such as atomizer 640. The contact between the atomized droplets
from the atomizer and the heated nitrogen caused the liquid to
evaporate from the droplets, resulting in dry porous particles. The
resulting gas-solid stream was fed to bag filter 680 that retained
the resulting dry particles, and allowed the hot gas stream
containing the drying gas (nitrogen), evaporated water, and ethanol
to pass. The dry particles were collected into product collection
vessel 682.
[0231] In order to obtain dry particles of particular physical and
chemical characteristics, in vitro characterization tests can be
carried out on the finished dry particles, and the process
parameters adjusted accordingly, as would be apparent to one
skilled in the art. Particles produced using the apparatus shown in
FIG. 2 had a VMGD of 8.4 .mu.m, FPF(5.6) of 89% to 93%, readily
extractable hGH fraction of 95.5%, and a soluble dimer fraction of
3%. Particles containing 93.5 wt % hGH and 6.5 wt % sodium
phosphate were produced using the apparatus substantially as shown
in FIG. 6. In this manner, the desired aerodynamic diameter,
geometric diameter, and particle density could be obtained for
these particles in real-time, during the production process.
80 wt % hGH/14 wt % DPPC/6 wt % Sodium Phosphate; 15 g/L Ammonium
Bicarbonate; 6 g/L Solids
[0232] Particles with a formulation containing hGH, DPPC, and
sodium phosphate were prepared as follows using apparatus
substantially as shown in FIG. 6. The aqueous solution was prepared
by preparing a bulk sodium phosphate solution at pH 7.4 and a bulk
ammonium bicarbonate solution. 280 mg of sodium phosphate monobasic
was added to 457 mL of water for irrigation. The pH was adjusted to
7.4 using 1.0 N NaOH. To this was added 15 g of ammonium
bicarbonate and 200 mL of ethanol. 343 mL of 14 g/L hGH bulk
solution (4.8 g of hGH in 1.7 mM sodium phosphate buffer at pH 7.4)
was added to complete the aqueous solution. 840 mg of DPPC was
added to 200 mL of ethanol to form the ethanol solution. The
aqueous solution was combined in a static mixer with the ethanol
solution using a flow rate of 24 mL/min for the aqueous solution
and a flow rate of 6 mL/min for the ethanol solution. Solute
concentration in the combined solution was 6 g/L. The combined
solution was spray dried under the following conditions:
[0233] Inlet temperature .about.120.degree. C.
[0234] Outlet temperature from the drying drum .about.70.degree.
C.
[0235] Nitrogen drying gas=110 kg/hr.
[0236] Nitrogen atomization gas=40 g/min.
[0237] 2 fluid internal mixing nozzle atomizer.
[0238] Nitrogen atomization pressure .about.65 psi.
[0239] Liquid feed rate=30 mL/min (24 mL/min aqueous and 6 mL/min
ethanol).
[0240] Liquid feed temperature .about.22.degree. C.
[0241] Pressure in drying chamber=-2.0 in water.
[0242] The resulting particles had a FPF (5.6) of 89%, and a FPF
(3.4) of 76%, both measured using a 2-stage ACI. The volume mean
geometric diameter was 7.4 .mu.m at 1.0 bar. The resulting
particles had a soluble dimer fraction of 3.5% and a readily
extractable hGH fraction of 95.6%.
[0243] Through the process of the present invention, the formation
of protein aggregates can be minimized. For example, reduced
protein aggregation is achieved through, among other things, using
the static mixer and controlling the level of ethanol in the
ethanol solution.
[0244] A comparison of powders produced with either batch or static
mixing is shown below in Table 12. All of the lots were produced
using substantially the same process materials, and process
conditions. The five combined lots produced with batch mixing
generate a lower level of high molecular weight (HMW) protein
(soluble dimer=HMW protein) than is generated using a static mixing
process (n=4 lots). Batch mixing of the spray-dry solution
containing 20% ethanol appears beneficial, as it might allow time
to disrupt hydrophobic interactions between the hGH molecules, and
thus reduce hGH aggregation. When ethanol is added to the diluted
hGH aqueous phase via the static mixer, a prolonged ethanol-aqueous
interface occurs and this results in powders having somewhat higher
levels of soluble aggregates. This occurs because the hGH in the
aqueous phase is exposed to higher than optimal ethanol levels
which can cause the hGH to unfold and denature. If a static mixer
is used for the mixing process, then the hGH is preferably added as
a concentrate to a diluted ethanol/aqueous phase. This is
equivalent to adding the hGH last in batch mixing. This is
preferred because it eliminates exposing the hGH to high ethanol
levels which can perturb its protein structure. The effect of the
order of addition on soluble aggregate (dimer) levels as a function
of ethanol concentration is shown in FIG. 10. The soluble
aggregates level is reduced by adding the hGH last (right column),
until the ethanol concentration exceeds about 20%. TABLE-US-00012
TABLE 12 Insoluble Lots N = hGH Monomer HMW Protein Aggregates
Mixing 5 79.6% 3.3% 4.4% batch 4 78.4% 5.0% 5.9% static
[0245] Conversely, at higher levels of ethanol (>20%),
destabilization of the protein structure may occur, and static
mixing was demonstrated to be a better method of mixing because it
reduces the time of exposure of the hGH to the ethanol phase (Table
13). This results in powders with lower levels of insoluble
aggregates. It has been demonstrated (data not shown) that the time
of exposure of the hGH to the ethanol can affect the level of
soluble aggregate formed in the spray-drying formulation solution.
TABLE-US-00013 TABLE 13 Insoluble Lot Number HMW Protein Aggregates
Organic, Excipient, Mixing 3-63063 5.4% 14.0% 70%, EtOH, batch
3-10697 3.9% 9.0% 70%, EtOH, static
93.5 wt % hGH/6.5 wt % Sodium Phosphate
[0246] Lipid-free particles with a formulation containing hGH and
sodium phosphate monohydrate were prepared as follows using an
apparatus substantially as shown in FIG. 6. The aqueous solution
was prepared by dissolving 0.78 g sodium phosphate dibasic in 500
mL of Water for Irrigation (WFI). To this was added 11.74 bulk hGH
lyophilization powder with water content of 4.4%. The organic
solution was prepared by dissolving 30 g of ammonium bicarbonate in
300 mL of water for irrigation, then combined with 200 mL of
ethanol. The aqueous solution, at a pH of about 7 and the organic
solution were combined in a static mixer prior to being introduced
to the spray dryer nozzle. Solute concentration in the combined
solution was 12 g/L. The combined solution was spray dried under
the following process conditions:
[0247] Inlet temperature .about.74.degree. C.
[0248] Outlet temperature from the drying drum .about.40.degree.
C.
[0249] Nitrogen drying gas=110 kg/hr
[0250] Nitrogen atomization gas=80 g/min
[0251] 2 Fluid internal mixing nozzle atomizer
[0252] Nitrogen atomization back pressure .about.100 psi
[0253] Liquid feed rate=25 ml/min
[0254] Liquid feed temperature .about.22.degree. C.
[0255] Pressure in drying chamber=-2.0 in water
[0256] The resulting particles had a FPF(3.3) of 69%, measured
using a 3-stage wetted screen ACI. The volume mean geometric
diameter was 7.0 .mu.m at 1.0 bar. The resulting particles had a
HMWP of 1.5% and a readily extractable hGH fraction of 96%.
[0257] The combination solution flowing out of the static mixer was
fed into a two-fluid nozzle atomizer located above the spray dryer,
such as atomizer 640. The contact between the atomized droplets
from the atomizer and the heated nitrogen caused the liquid to
evaporate from the droplets, resulting in dry porous particles. The
resulting gas-solid stream was fed to bag filter 680 that retained
the resulting dry particles, and allowed the hot gas stream
containing the drying gas (nitrogen), evaporated water, and ethanol
to pass. The dry particles were collected into product collection
vessel 682.
[0258] In order to obtain dry particles of particular physical and
chemical characteristics, in vitro characterization tests can be
carried out on the finished dry particles, and the process
parameters adjusted accordingly, as would be apparent to one
skilled in the art. Particles containing 93.5 wt % hGH and 6.5 wt %
sodium phosphate were produced using the apparatus substantially as
shown in FIG. 6. In this manner, the desired aerodynamic diameter,
geometric diameter, and particle density could be obtained for
these particles in real-time, during the production process.
[0259] The apparatus and method of the present invention may be
adjusted in a variety of ways, including but not limited to those
described in this example, in order to adjust powder
characteristics. For example, lipid-free particles with a
formulation containing hGH and sodium phosphate monohydrate were
prepared as prescribed in Tables 14, 15, and 16, using an apparatus
substantially as shown in FIG. 6. The hGH powders obtained from
these methods are characterized in Table 17. TABLE-US-00014 TABLE
14 FORMULATIONS USED Sheeting Single-hole Six-hole Action Pressure
Composition Nozzle Nozzle Nozzle Nozzle hGH concentration, 93.5
93.5 93.5 93.5 wt. % Sodium phosphate 6.5 6.5 6.5 6.5
concentration, wt. % Tween concen- 0-11.2 0-0.1 0 0 tration, wt. %
Solids concen- 6-30 6-60 15 5-12 tration, g/L Ammonium 0-30 0-40
30-40 30 Bicarbonate concentration, g/L Overall ethanol 20 20 20 20
concentration, vol. % Overall WFI 80 80 80 80 concentration, vol. %
Concentration of 60-70 60 60 60 WFI in organic phase, vol. %
[0260] TABLE-US-00015 TABLE 15 SOLUTION PREPARATION Sheeting
Single-hole Six-hole Action Pressure Nozzle Nozzle Nozzle Nozzle
Mixer Type Batch and Static Static Static Static (Two Solutions)
(Two Solutions) (Two Solutions) Order of Solution Organic Phase:
Organic Phase: Organic Phase: Organic Phase: Preparation 1. Amm.
Bicarb 1. Amm. Bicarb 1. Amm. Bicarb 1. Amm. Bicarb 2. WFI 2. WFI
2. WFI 2. WFI 3. Ethanol 3. Ethanol 3. Ethanol 3. Ethanol Aqueous
Phase: Aqueous Phase: Aqueous Phase: Aqueous Phase: 1. Sodium Phos.
1. Sodium Phos. 1. Sodium Phos. 1. Sodium Phos. 2. WFI 2. WFI 2.
WFI 2. WFI 3. hGH 3. hGH 3. hGH 3. hGH Method of Solution Wet and
Dry Wet and Dry Dry Dry Preparation
[0261] As indicated in Table 15, "wet" and "dry" methods of
solution preparation were used. The wet method comprises mixing
multiple solutions (including a concentrated hGH solution and
various buffer concentrations) in order to form the final solutions
that are mixed in the batch or static mixer. This method requires
multiple in-process calculations and mixing many solutions,
including a concentrated hGH solution and various buffer
concentrations, to produce the final solutions.
[0262] The dry method comprises dissolving dry ingredients directly
in the final solutions that are mixed in the batch or static mixer.
The dry method eliminates in-process calculations and removes the
need for different buffer preparations. Instead, the dry method
requires initial calculations of the amount of sodium phosphate
dibasic, hGH lyophilization powder and water needed to achieve the
desired solution concentrations, taking into account the moisture
content of the beginning bulk powder. Those amounts are then
dissolved in the appropriate solutions. TABLE-US-00016 TABLE 16
PROCESS CONDITIONS Sheeting Single-hole Six-hole Action Pressure
Nozzle Nozzle Nozzle Nozzle Operating Pressure -2 -2 -2 -2 in Spray
Dryer, W.C. Spray Dryer Outlet 35-70 35-65 45-65 50-71 Temperature,
.degree. C. Atomization Gas 38-120 50-120 200-315 N/A Rate, g/min.
Aqueous Feed Rate, 4-37.5 5-20 5-40 35 mL/min. Organic Flow Rate,
7.5-37.5 5-20 5-40 35 mL/min. Total Feed Rate, 10-75 10-40 10-80 70
mL/min. Drying Gas Rate, 80-125 110 110 110-120 kg/hr. Mass Gas to
Feed 1.5-11.1 1.4-13.3 4.2-17.5 N/A Ratio
[0263] In this example, a spray dryer operating pressure of -2''
water column ("W.C.") was used. As is apparent to one of skill in
the art, other spray drying pressures (for example, +2'' W.C.) may
be used, depending upon variations in equipment or other production
parameters. TABLE-US-00017 TABLE 17 RANGE OF CHARACTERIZATION
RESULTS Sheeting Single-hole Six-hole Action Pressure Nozzle Nozzle
Nozzle Nozzle VMGD @1 bar 4.3-17.4 9.0-25.4 9.8-10.6 21.6 FPF
<3.3 micron 29-75/49-84 50/66 .sup. 45-48 0 FPF Method ACI-3 @
ACI-3 @ ACI-3 @ ACI-3 @ 28.3 lpm/60 lpm 28.3 lpm/ 28.3 lpm 28.3 lpm
60 lpm Readily 91-96 92.6-98.3 96.6-98.1 98 Extractable HMWP
0.9-1.7 0.8-3.4 1.6-2.6 1.6
[0264] The single-hole, two-fluid nozzle depicted in FIG. 4B was
used in this example. Sample parameters used and powder properties
obtained in this example using the single-hole nozzle are set forth
in Tables 18 and 19. TABLE-US-00018 TABLE 18 SAMPLE SOLUTION AND
PROCESS CONDITIONS FOR SINGLE-HOLE NOZZLE Feed Solution Solids
Concentration 12 g/L Ammonium Bicarbonate conc. 30 g/L Solvent:
Ethanol/Water (vol/vol %) 20/80 Process Feed Rate 25 mL/min.
Conditions Atomization Gas Rate 80 g/min. Drying Gas Rate 110
kg/hr. Spray Dryer Outlet Temperature 40.degree. C.
[0265] TABLE-US-00019 TABLE 19 SAMPLE POWDER PROPERTIES WITH
SINGLE-HOLE NOZZLE VMGD n = 14 HMWP RE (1 bar) FPF.sub.TD <3.3
.mu.m Method Average 1.5 95.9 6.7 69 ACI-3, AIR1, 60 lpm StDev 0.3
0.8 0.9 4 ACI-3, AIR1, 60 lpm Range 1.1-2.4 94.4-97.5 5.3-8.1 61-75
ACI-3, AIR1, 60 lpm
[0266] The six-hole nozzle depicted in FIG. 4C was also used in
this example. The six-hole nozzle generally produced powders with
larger geometric size and lower density than those produced with
the single-hole nozzle. The six-hole nozzle can also process higher
solids concentrations, which increases production rates and helps
with readily extractable values. Sample parameters used and powder
properties obtained from this example using the six-hole nozzle are
set forth in Tables 20 and 21. TABLE-US-00020 TABLE 20 SAMPLE
SOLUTION AND PROCESS CONDITIONS FOR SIX-HOLE NOZZLE Feed Solution
Ammonium Bicarbonate conc. 30 g/L Solvent: Ethanol/Water (vol/vol
%) 20/80 Process Conditions Atomization Gas Rate 120 g/min. Drying
Gas Rate 110 kg/hr. Spray Dryer Outlet Temperature 45.degree.
C.
[0267] TABLE-US-00021 TABLE 21 SAMPLE POWDER PROPERTIES WITH
SIX-HOLE NOZZLE Solids Liquid Concen- Feed VMGD FPF.sub.TD <
tration Rate HMWP RE (1 bar) 3.3 .mu.m Method 30 10 1.9 97.7 8.2 66
ACI-3, AIR1, 60 lpm 30 20 1.7 97.7 9.3 63 ACI-3, AIR1, 60 lpm 60 10
1.5 97.4 7.3 57 ACI-3, AIR1, 60 lpm 60 20 1.6 97.9 8.8 58 ACI-3,
AIR1, 60 lpm
[0268] The sheeting action nozzle depicted in FIG. 4D was also used
in this example. This nozzle appears to be a gentler nozzle on the
protein, as seen in higher readily extractable value. Adjusting the
size of this nozzle can yield higher FPF values and smaller VMGD
values. Sample parameters used and powder properties obtained from
this example using the nozzle depicted in FIG. 4D are set forth in
Tables 22 and 23. TABLE-US-00022 TABLE 22 SAMPLE SOLUTION AND
PROCESS CONDITIONS FOR SHEETING ACTION NOZZLE Feed Solids
Concentration 15 g/L Solution Ammonium Bicarbonate conc. 30 g/L
Solvent: Ethanol/Water (vol/vol %) 20/80 Process Feed Rate 20
mL/min. Conditions Atomization Gas Rate 315 g/min. Drying Gas Rate
110 kg/hr. Spray Dryer Outlet Temperature 45.degree. C.
[0269] TABLE-US-00023 TABLE 23 SAMPLE POWDER PROPERTIES WITH
SHEETING ACTION NOZZLE VMGD HMWP RE (1 bar) FPF.sub.TD <3.3
.mu.m Method 1.7 98.1 10.3 48 ACI-3, Ch H, 28.3 lpm
[0270] The pressure nozzle depicted in FIG. 4E was also used in
this example. The pressure nozzle is less damaging to the chemical
integrity of the hGH in the powder because there is no atomizing
gas to produce an air-liquid interface. Sample parameters used and
powder properties obtained from this example using the pressure
nozzle are set forth in Tables 24 and 25. TABLE-US-00024 TABLE 24
SAMPLE SOLUTION AND PROCESS CONDITIONS FOR PRESSURE NOZZLE Nozzle
Nozzle hole diameter (in.) 0.016 Core no. 206 Feed Solids
Concentration 12 g/L Solution Ammonium Bicarbonate conc. 30 g/L
Solvent: Ethanol/Water (vol/vol %) 20/80 Process Feed Rate 68
mL/min. Conditions Atomization Gas Rate 315 g/min. Drying Gas Rate
110 kg/hr. Spray Dryer Outlet Temperature 70.degree. C.
[0271] TABLE-US-00025 TABLE 25 SAMPLE POWDER PROPERTIES WITH
PRESSURE NOZZLE VMGD HMWP RE (1 bar) FPF.sub.TD <3.3 .mu.m
Method 1.6 98.0 21.6 0 ACI-3, AIR1, 60 lpm
[0272] The addition of non-ionic surfactants to solutions
containing hGH significantly reduces the formation of insoluble
aggregates during exposure to an air/liquid interface. In
particular, use of the surfactant Tween 80 (which is approved for
use in a commercial inhalation product for the treatment of asthma
(Pulmicort Respules)) reduces the amount of insoluble aggregates of
hGH in solution. Non-ionic surfactants, such as Tween 80,
preferentially adsorb to air-water interfaces and stabilize
proteins against aggregate during processing, such as spray drying.
However, excessive use of non-ionic surfactants such as Tween 80 is
not preferred in pulmonary products. The addition of low levels of
Tween 80 (.about.0.2-2.8 wt %) to hGH formulations made with the
single-hole nozzle increased the readily extractable protein
product in the powder to >99%. The addition of 0.1-0.2 wt %
Tween 80 had some effect but did not provide as much protection. A
sample of results from this example are set forth in Table 26.
TABLE-US-00026 TABLE 26 Tween 80 RE 0.1 97.1 0.2 97.1 2.8 99.9 5.6
99.9 11.2 99.9
[0273] The solids concentration is the total concentration of hGH
plus any non-volatile excipients used in the formulation solution.
Increasing solids concentration tends to increase readily
extractable hGH and powder production and tends to reduce FPF. The
range of solids concentration explored for the single-hole nozzle
was 2-30 g/L and for the six-hole nozzle was 6-60 g/L.
Representative results from this example are set forth in Tables 27
and 28. TABLE-US-00027 TABLE 27 Nozzle Solids Conc. HMWP Insoluble
Aggregates Single-hole 2 3.5 13.0 Single-hole 3 5.0 6.8 Single-hole
5 6.1 2.2
[0274] TABLE-US-00028 TABLE 28 Solids VMGD FPF.sub.TD <
FPF.sub.TD < Nozzle Conc. HMWP RE (1 bar) 3.3 .mu.m 3.4 .mu.m
Single-hole 8 3.2 98.2 6.1 82 Single-hole 12 1.8 98.2 7.3 69
Single-hole 12 1.5 97.7 8.2 77 Single-hole 30 1.1 96.1 6.2 65
Six-hole 15 1.2 97.0 12.7 65 Six-hole 60 1.6 97.9 8.8 58
[0275] Ammonium bicarbonate is used as a volatile solid in the
spray drying solution to help achieve desirable physical
characteristics in the final particles. As the concentration of
ammonium bicarbonate increases, FPF and powder dispersibility
improve. However, higher levels increase the HMWP and decrease the
readily extractable protein product. The range of ammonium
bicarbonate concentration explored for the single-hole nozzle was
0-30 g/L and for the six-hole nozzle was 0-40 g/L. A sample of
results from this example are set forth in Table 29. TABLE-US-00029
TABLE 29 Ammonium Ricarb VMGD FPF.sub.TD < FPF.sub.TD <
Nozzle Conc. HMWP RE (1 bar) 3.3 .mu.m 3.4 .mu.m Single-hole 10 1.1
97.9 9.1 69 Single-hole 29 2.0 96.6 7.6 77 Single-hole 0 1.2 95.5
12.4 52 Single-hole 30 1.2 95.5 5.6 70
[0276] The addition of alcohol as a co-solvent to the aqueous phase
in appropriate amounts helps achieve desired physical
characteristics and reduces protein aggregation. Too much alcohol
content, however, results in detrimental structural changes in the
protein. There are two alcohol levels that can affect the hGH:
overall alcohol content of the solvent system and alcohol content
that the hGH is exposed to upon mixing. The optimum overall alcohol
content for the combined solvents was found to be 20/80 (v/v %)
ethanol/water. Contact between hGH and high concentration ethanol
was minimized by diluting the ethanol with water prior to combining
it with the aqueous hGH solution. First, the ethanol was diluted to
40 vol % and mixed with an equal amount of 100% aqueous hGH
solution to create a final feed solution of 20 vol % ethanol. This
procedure improved the end product. To test the effects of further
dilution of the organic phase, further tests were conducted
lowering the ethanol content to 30 vol % and then mixed with the
aqueous hGH phase at a ratio of 2:1 organic:aqueous. In both cases,
the single-hole nozzle was used. Representative results from this
example are set forth in Table 30. TABLE-US-00030 TABLE 30 Water
Content in Organic: Organic Aqueous VMGD Phase (vol %) Ratio HMWP
RE (1 bar) FPF.sub.TD < 3.3 .mu.m Method 60 1:1 1.6 95.4 6.1 70
ACI-3, AIR1, 60 lpm 70 2:1 1.6 95.9 6.5 68 ACI-3, AIR1, 60 lpm
[0277] Spray dryer outlet temperature is the temperature at the
outlet of the spray drying drum. As the outlet temperature
increases, the HMWP and the FPF increase and the moisture content
decreases. The range of spray dryer outlet temperature explored for
the single-hole nozzle was 35-70.degree. C. and for the six-hole
nozzle was 35-65.degree. C. Sample results from this example are
set forth in Table 31. TABLE-US-00031 TABLE 31 VMGD Nozzle
T.sub.out, sd HMWP RE (1 bar) FPF.sub.TD < 3.3 .mu.m Method
Single-hole 40 1.5 97.2 7.1 57 ACI-3, Ch H, 28.3 lpm Single-hole 60
2.1 96.3 6.6 65 ACI-3, Ch H, 28.3 lpm
[0278] Atomization gas rate is the rate of the high-velocity gas
that creates the liquid droplets in two-fluid atomization. The mass
gas to liquid ratio (atomization gas to liquid feed rate) affects
mean droplet size. Increase in the ratio decreases droplet size,
which may in turn increase FPF. Thus, as atomization gas rate
increases, the VMGD tends to decrease as the FPF increases. The
range of atomization gas rate explored for the single-hole nozzle
was 38-120 g/min and for the six-hole nozzle was 50-120 g/min.
Representative results from this example are set forth in Table 32.
TABLE-US-00032 TABLE 32 Atomization VMGD FPF.sub.TD < FPF.sub.TD
< Nozzle Gas Rate HMWP RE (1 bar) 3.3 .mu.m 3.4 .mu.m
Single-hole 46 1.2 97.5 9.6 60 Single-hole 64 1.1 97.9 9.1 69
Single-hole 64 1.2 97.9 7.9 71 Single-hole 80 1.3 98.6 8.1 78
Single-hole 46 1.6 94.0 9.3 54 Single-hole 120 2.4 95.3 7.9 58
[0279] The liquid feed rate is the rate at which the liquid
solutions are pumped into the atomizer and spray dryer. As the feed
rates increase, the gas to liquid ratio decreases and thus the VMGD
tends to increase as the FPF decreases. The range of liquid feed
rates explored for the single-hole nozzle was 10-75 mL/min and for
the six-hole nozzle was 10-40 mL/min. Representative results from
this example are set forth in Table 33. TABLE-US-00033 TABLE 33
Liquid VMGD FPF.sub.TD < FPF.sub.TD < Nozzle Feed Rate HMWP
RE (1 bar) 3.3 .mu.m 3.4 .mu.m Single-hole 15 2.2 97.3 7.5 77
Single-hole 50 1.8 96.6 8.4 66 Six-hole 25 3.4 97.4 10.2 66
Six-hole 40 3.0 97.3 15.1 43
[0280] The drying gas rate is the rate of the heating gas used to
dry the droplets. This rate also controls the residence time within
the dryer. The range of drying gas rate explored for the
single-hole nozzle was 80-125 kg/hr. Sample results from this
example are set forth in Table 34. TABLE-US-00034 TABLE 34 Drying
VMGD Nozzle Gas Rate HMWP RE (1 bar) FPF.sub.TD < 3.4 .mu.m
Method Single-hole 80 1.7 97.9 N/A N/A N/A Single-hole 110 2.1 97.8
N/A N/A N/A Single-hole 110 2.8 N/A 7.3 71 ACI-2, AIR1, 60 lpm
Single-hole 125 2.4 N/A 8.0 70 ACI-2, AIR1, 60 lpm
[0281] As would be apparent to one of skill in the art, other
drying gas rates may be used, depending upon variations in
equipment or other production parameters (for example, the size of
the dryer). In this example a size 1 dryer was used. Use of other
size dryers may entail approximately the same liquid feed to drying
gas ratio (mL liq/kg gas), which ranged from 4.8 to 56.25 mL liq/kg
gas in this example.
Preparation of Dry Particles Containing Insulin
[0282] Particles with a formulation containing insulin, DPPC, and
sodium citrate were prepared using apparatus substantially as shown
in FIG. 2, and as described above for hGH. The resulting particles
contained 60 wt % DPPC, 30 wt % insulin, and 10 wt % sodium
citrate. A 1 L total combination volume was used, with a total
solute concentration of 3 g/L in 60/40 ethanol/water. The aqueous
solution was prepared as follows. 630 mg of citric acid monohydrate
was added to 1.0 L of USP water to form 1.0 L of 3.0 mM citrate
buffer. The pH was adjusted to 2.5 with 1.0 N HCl. 900 mg insulin
was dissolved in 400 mL of the citrate buffer. The pH was adjusted
to pH 6.7 using 1.0 N NaOH. The organic solution was prepared by
dissolving 1.8 g of DPPC in 600 mL of ethanol. 400 mL of water was
added to the organic solution for a total volume of 1 L.
[0283] The aqueous insulin solution and the organic solution were
combined in a static mixer, such as static mixer 230. The outflow
of the static mixer flowed into rotary atomizer 240, and the
resulting atomized droplets were spray dried in spray dryer 250.
The resulting 60 wt % DPPC, 30 wt % insulin, and 10 wt % sodium
citrate particles were collected from bag house 260 into a
container.
[0284] In order to obtain dry particles of particular physical and
chemical characteristics, in vitro characterization tests can be
carried out on the finished dry particles, and the process
parameters adjusted accordingly, as would be apparent to one
skilled in the art. Alternatively, particles containing 60 wt %
DPPC, 30 wt % insulin, and 10 wt % sodium citrate could be produced
using the apparatus substantially as shown in FIG. 6. In this
manner, the desired aerodynamic diameter, geometric diameter, and
particle density could be obtained for these particles in
real-time, during the production process.
Preparation of Dry Particies Containing Humanized Monoclonal IgG1
Antibody
[0285] Particles with a formulation containing humanized monoclonal
IgG1 antibody and DPPC were prepared using apparatus substantially
as shown in FIG. 2, and as described above for hGH. The resulting
particles contained 80 wt % humanized monoclonal IgG1 antibody and
20 wt % DPPC. A 2 L total combination volume was used, with a total
solute concentration of 1.0 g/L in 30/70 ethanol/water. The aqueous
solution was prepared as follows. 25.0 mL of 47.8 mg/mL humanized
monoclonal IgG1 antibody solution was added to 1400 mL of USP
water. The organic solution was prepared by mixing 0.8 g DPPC with
600 mL of ethanol.
[0286] The aqueous solution and the organic solution were combined
in a static mixer, such as static mixer 230. The outflow of the
static mixer flowed into rotary atomizer 240, and the resulting
atomized droplets were spray dried in spray dryer 250. The
resulting particles were collected from bag house 260 into a
container.
[0287] In order to obtain dry particles of particular physical and
chemical characteristics, in vitro characterization tests can be
carried out on the finished dry particles, and the process
parameters adjusted accordingly, as would be apparent to one
skilled in the art. Alternatively, particles containing 80 wt %
humanized monoclonal IgG1 antibody and 20 wt % DPPC could be
produced using the apparatus substantially as shown in FIG. 6. In
this manner, the desired aerodynamic diameter, geometric diameter,
and particle density could be obtained for these particles in
real-time, during the production process.
Preparation of Dry Particles Containing Epinephrine
[0288] Particles with a formulation containing epinephrine and
leucine were prepared using apparatus substantially as shown in
FIG. 2, and as described above for hGH. The resulting particles
contained 18 wt % epinephrine bitartrate and 82 wt % leucine. An
aqueous solution was prepared as follows: 900 mg epinephrine
bitartrate and 4.1 g leucine were added to 300 mL of USP water and
dissolved by stirring.
[0289] The 300 mL of aqueous solution and 700 mL of ethanol were
combined in a static mixer, such as static mixer 230. This resulted
in spray drying a 1.0 liter total combination volume, with a total
solute concentration of 5.0 g/L in 70/30 ethanol/water. The outflow
of the static mixer flowed into an atomizer, such as rotary
atomizer 240, at an atomization rate of 19.5 g/min and a feed rate
of 65 ml/min. The resulting atomized droplets were spray dried
using dry nitrogen as the drying gas in spray dryer 250. The
resulting particles were collected from bag house 260 into a
container.
[0290] In order to obtain dry particles of particular physical and
chemical characteristics, in vitro characterization tests can be
carried out on the finished dry particles, and the process
parameters adjusted accordingly, as would be apparent to one
skilled in the art. Alternatively, particles containing 18 wt %
epinephrine and 82 wt % leucine could be produced using the
apparatus substantially as shown in FIG. 6. In this manner, the
desired aerodynamic diameter, geometric diameter, and particle
density could be obtained for these particles in real-time, during
the production process.
Preparation of Dry Particles Containing Salmeterol Xinafoate
[0291] Particles with a formulation containing salmeterol
xinafoate, leucine, and DSPC were prepared using apparatus
substantially as shown in FIG. 2, and as described above for hGH.
The resulting particles contained 74.55 wt % DSPC, 24 wt % leucine,
and 1.45 wt % salmeterol xinafoate. A 1 L total combination volume
was used, with a total solute concentration of 1.0 g/L in 70/30
ethanol/water. The aqueous solution was prepared as follows. 240 mg
leucine was dissolved in 300 mL of USP water. The organic solution
was prepared by dissolving 745.5 mg DSPC in 700 mL of ethanol. 14.5
mg salmeterol xinafoate was dissolved in the DSPC/ethanol solution.
Both solutions were separately heated to 50.degree. C.
[0292] The aqueous solution and the organic solution were combined
in a static mixer, such as static mixer 230. The outflow of the
static mixer flowed into rotary atomizer 240, and the resulting
atomized droplets were spray dried in spray dryer 250. The
resulting particles were collected from bag house 260 into a
container.
[0293] In order to obtain dry particles of particular physical and
chemical characteristics, in vitro characterization tests can be
carried out on the finished dry particles, and the process
parameters adjusted accordingly, as would be apparent to one
skilled in the art. Alternatively, particles containing 74.55 wt %
DSPC, 24 wt % leucine, and 1.45 wt % salmeterol xinafoate could be
produced using the apparatus substantially as shown in FIG. 6. In
this manner, the desired aerodynamic diameter, geometric diameter,
and particle density could be obtained for these particles in
real-time, during the production process.
Preparation of Dry Particles Containing Other Active Agents
[0294] Based upon the above examples and description, it would be
readily apparent to one skilled in the art how to prepare dry
particles containing other active agents using the methods and
apparatus of the present invention. For example, the apparatus of
FIGS. 2 and 6 could be used to prepare dry particles containing a
combination of salmeterol and ipatroprium bromide in substantially
the same manner as described above for salmeterol. The apparatus of
FIGS. 2 and 6 can also be used, for example, to prepare dry
particles containing albuterol sulfate, DPPC, DSPC, and leucine.
The aqueous solution would be prepared by dissolving 200 mg leucine
in 300 mL water to form an aqueous phase, and dissolving 40 mg of
albuterol sulfate in the aqueous phase to form the aqueous
solution. The organic solution would be prepared by dissolving 380
mg DPPC in 700 mL of ethanol to form an organic phase, and
dissolving 380 mg DSPC in the organic phase to form the organic
solution. The aqueous solution and the organic solution would be
heated separately to 50.degree. C. The aqueous solution and the
organic solution would be combined in a static mixer, such as
static mixer 230. The outflow of the static mixer would flow into
rotary atomizer 240, and the resulting atomized droplets would be
spray dried in spray dryer 250. The resulting particles would be
collected from bag house 260 into a container. The resulting
particles would contain 38 wt % DPPC, 38 wt % DSPC, 20 wt %
leucine, and 4 wt % albuterol sulfate.
CONCLUSION
[0295] While various embodiments of the present invention have been
described above, it should be understood that they have been
presented by way of example only, and not limitation. The present
invention is not limited to the preparation of dry particles for
inhalation, nor is it limited to a particular active agent,
excipient, or solvent, nor is the present invention limited to a
particular scale, batch size or particle size. Thus, the breadth
and scope of the present invention should not be limited by any of
the above-described exemplary embodiments, but should be defined
only in accordance with the following claims and their
equivalents.
* * * * *