U.S. patent application number 15/960634 was filed with the patent office on 2018-08-23 for dry powder pharmaceutical compositions and methods.
This patent application is currently assigned to 3M Innovative Properties Company. The applicant listed for this patent is 3M INNOVATIVE PROPERTIES COMPANY. Invention is credited to ADAM S. CANTOR, JACQUELINE M. GANSER, MICHAEL W. MUETING, STEPHEN W. STEIN.
Application Number | 20180235880 15/960634 |
Document ID | / |
Family ID | 41137181 |
Filed Date | 2018-08-23 |
United States Patent
Application |
20180235880 |
Kind Code |
A1 |
CANTOR; ADAM S. ; et
al. |
August 23, 2018 |
DRY POWDER PHARMACEUTICAL COMPOSITIONS AND METHODS
Abstract
A method of making a dry powder pharmaceutical composition
comprising: providing inactive ingredient particles; providing a
micronized active ingredient; mixing the inactive ingredient
particles with surface-modified nanoparticles to provide an
inactive ingredient comprised of particles having surfaces with the
surface-modified nanoparticles deposited on the surfaces; and/or
mixing the micronized active ingredient with surface-modified
nanoparticles to provide a micronized active ingredient comprised
of particles having surfaces with the surface-modified
nanoparticles deposited on the surfaces; and then mixing the
micronized active ingredient with the inactive ingredient; the dry
powder compositions made by the method; a method of delivering
medicament to the lungs of a mammal by administering a therapeutic
amount of the dry powder pharmaceutical composition, and a dry
powder inhalation device comprising a mouth piece, a powder
containment system, and the dry powder pharmaceutical composition
are disclosed.
Inventors: |
CANTOR; ADAM S.; (RIVER
FALLS, WI) ; GANSER; JACQUELINE M.; (WHITE BEAR LAKE,
MN) ; MUETING; MICHAEL W.; (HUDSON, WI) ;
STEIN; STEPHEN W.; (LINO LAKES, MN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
3M INNOVATIVE PROPERTIES COMPANY |
St. Paul |
MN |
US |
|
|
Assignee: |
3M Innovative Properties
Company
|
Family ID: |
41137181 |
Appl. No.: |
15/960634 |
Filed: |
April 24, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12995319 |
Nov 30, 2010 |
9956170 |
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PCT/US09/48096 |
Jun 22, 2009 |
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15960634 |
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61075942 |
Jun 26, 2008 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 11/06 20180101;
A61K 31/00 20130101; A61K 9/0075 20130101; A61P 29/00 20180101;
A61K 31/58 20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 31/00 20060101 A61K031/00; A61K 31/58 20060101
A61K031/58 |
Claims
1. A method of making a dry powder pharmaceutical composition
comprising: providing inactive ingredient particles; providing a
micronized active ingredient; mixing the inactive ingredient
particles with surface-modified nanoparticles to provide an
inactive ingredient comprised of particles having surfaces with the
surface-modified nanoparticles deposited on the surfaces; then
mixing the micronized active ingredient with the inactive
ingredient comprising particles having surfaces with the
surface-modified nanoparticles deposited on the surfaces.
2. (canceled)
3. The method of making a composition of claim 1, further
comprising mixing the micronized active ingredient with
surface-modified nanoparticles prior to mixing the micronized
active ingredient with the inactive ingredient comprising particles
having surfaces with the surface-modified nanoparticles deposited
on the surfaces.
4. The method of making a composition of claim 3, further
comprising dry blending inactive ingredient particles without
surface-modified nanoparticles with the inactive ingredient
comprised of particles having surfaces with the surface-modified
nanoparticles deposited on the surfaces, wherein the dry blending
is carried out prior to mixing the micronized active ingredient
with the inactive ingredient.
5-13. (canceled)
14. The method of making a composition of claim 1, wherein mixing
the inactive ingredient particles with the surface-modified
nanoparticles is carried out in a liquid, and then the liquid is
removed to provide the inactive ingredient comprised of particles
having surfaces with the surface-modified nanoparticles deposited
on the surfaces; and wherein the inactive ingredient particles are
substantially insoluble in the liquid, and the surface-modified
nanoparticles are dispersible in the liquid.
15. The method of making a composition of claim 14, wherein the
liquid is removed by spray drying, rotary evaporation, bulk
evaporation, or freeze drying.
16. The method of making a composition of claim 1, wherein mixing
the active ingredient with the inactive ingredient is carried out
by dry blending.
17. The method of making a composition of claim 1, wherein the
inactive ingredient is comprised of particles having a mean
physical diameter of less than 200 micrometers.
18. The method of making a composition of claim 1, wherein the
active ingredient is comprised of particles having a mean
aerodynamic diameter of less than 5 micrometers.
19. The method of making a composition of claim 18, wherein the
mean physical diameter of the particles comprising the inactive
ingredient is at least 10 fold greater than the mean aerodynamic
diameter of the particles comprising the active ingredient.
20. The method of making a composition of claim 1, wherein the
active ingredient and the inactive ingredient are each present in
an amount such that the weight ratio of the amount of active
ingredient to the amount of the inactive ingredient is not more
than 1:3.
21. The method of making a composition of claim 1, wherein the
inactive ingredient is selected from the group consisting of
lactose, trehalose, sucrose, mannitol, or a combination
thereof.
22. The method of making a composition of claim 1, wherein the
active ingredient is selected from the group consisting of
antiallergics, antiasthmatics, antiinflammatories, bronchodilators,
steroids, anticholinergics, salts thereof, solvates thereof,
enantiomers thereof, and a combination thereof
23. The method of making a composition of claim 22, wherein the
active ingredient is selected from the group consisting of
budesonide, albuterol, formoterol, fluticasone, salmeterol,
mometasone, tiotropium, beclomethasone, salts thereof, solvates
thereof, enantiomers thereof, and a combination thereof
24. The method of making a composition of claim 1, wherein the
surface-modified nanoparticles comprise a core, the core comprising
an inorganic material selected from the group consisting of silica,
titania, alumina, an oxide of zinc, an oxide of iron, metal
phosphates, metal sulfates, metal chlorides, or a combination
thereof
25. The method of making a composition of claim 1, wherein the
surface-modified nanoparticles comprise a core, the core comprising
an organic polymer.
26. The method of making a composition of claim 1, wherein a
surface of the core is modified with a compound selected from the
group consisting of alkylsilanes, carboxylic acids, phosphonic
acids, sulfonates, polyethylene glycols, sugars, and a combination
thereof
27. The method of making a composition of claim 1, or the device of
any one of claims 9 through 26, wherein the nanoparticles have a
mean diameter of not more than 20 nanometers.
28. The method of making a composition of claim 1, wherein the
amount of surface-modified nanoparticles in the composition is at
least 0.02 percent and not more than 5 percent by weight of the
composition.
29. The method of making a composition of claim 1, wherein the
composition has a respirable fraction which is at least 20 percent
greater than a composition with the same ingredients without
nanoparticles and a composition made by adding the nanoparticles to
the same ingredients at the same time.
30. The method of making a composition of claim 1, wherein the
composition has an active ingredient delivery efficiency which is
at least 10 percent greater than a composition with the same
ingredients without nanoparticles and a composition made by adding
the nanoparticles to the same ingredients at the same time.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application No. 61/075942, filed Jun. 26, 2008, which is
incorporated herein by reference in its entirety.
BACKGROUND
[0002] The preparation or delivery of pharmaceutical drugs and
medicaments as powders is demanding Pharmaceutical applications
must take careful account of various particle or powder
characteristics, and pharmaceutical compositions often are prepared
as powders as an intermediate step to final formulation in many
forms for delivery to the patient. Pharmaceutical compositions can
be tableted or encapsulated for oral gastro-intestinal ingestion
and delivery. Powder pharmaceutical compositions also can be
incorporated into a dry powder inhaler (DPI) for delivery to the
respiratory tract. Dry powder inhalation of a pharmaceutical
composition requires unique and challenging physical property
profiles for a powder. For efficient and efficacious delivery to
the lung in powder form, drug particles must be sufficiently small
and deagglomerated. Lung deposition improves substantially for
particles less than 5 microns in aerodynamic diameter and decreases
substantially for particles with an aerodynamic diameter greater
than 5 microns. However, below 5 microns in particle diameter,
deagglomeration efficiency declines markedly.
[0003] Balancing these competing effects, in one example, has
involved adsorbing small respirable drug particles onto larger
inert carrier particles which provide for bulk deagglomeration but
which require additional energy to release the drug from the
surface of the carrier particles. Recent advances in improving the
flowability characteristics of powders by adding surface-modified
nanoparticles are disclosed in International Publication No. WO
2007/019229, entitled "Compositions Exhibiting Improved
Flowability" (incorporated herein by reference).
[0004] There is a continuing need for compositions and methods that
provide for more efficient and efficacious delivery of
pharmaceutical compositions in powder form.
SUMMARY
[0005] It has now been found that delivery efficiency of an active
ingredient in a dry powder pharmaceutical composition containing
both the active ingredient and an inactive ingredient can be
increased by treating either or both ingredients separately with
surface-modified nanoparticles. The active and inactive ingredients
are then combined to provide a dry powder composition. For certain
embodiments, a relatively large proportion of the composition can
comprise the inactive ingredient, thereby allowing delivery of a
small amount of drug, while delivering an amount of composition
which can be reproducibly metered. Such compositions can be used in
a dry powder inhaler to deliver the active ingredient to the lung
of a mammal.
[0006] Accordingly, in one embodiment, there is provided a method
of making a dry powder pharmaceutical composition comprising:
[0007] providing inactive ingredient particles; [0008] providing a
micronized active ingredient; [0009] mixing the inactive ingredient
particles with surface-modified nanoparticles to provide an
inactive ingredient comprised of particles having surfaces with the
surface-modified nanoparticles deposited on the surfaces; and/or
mixing the micronized active ingredient with surface-modified
nanoparticles to provide a micronized active ingredient comprised
of particles having surfaces with the surface-modified
nanoparticles deposited on the surfaces; and [0010] then mixing the
micronized active ingredient with the inactive ingredient.
[0011] The surface-modified nanoparticles may have a hydrophilic or
hydrophobic surface modification. Examples of core materials for
the nanoparticles include silicas, titania, iron oxides, zinc
oxides, alumina, metal phosphates such as a calcium phosphate,
metal sulfates, metal chlorides, and combinations thereof. For
certain embodiments, the mean diameter of the nanoparticles may be
20 nm or less.
[0012] The particles of the powder drug composition in certain
embodiments have a median particle size diameter less than 200
micrometers. The diameter of these particles, however, is
substantially larger than the diameter of the nanoparticles, for
example, 10 to 1000 times larger.
[0013] In another embodiment, there is provided a dry powder
pharmaceutical composition comprising: [0014] an inactive
ingredient comprised of particles; [0015] a micronized active
ingredient; and [0016] surface-modified nanoparticles; [0017]
wherein the composition is made by a process comprising: [0018]
providing inactive ingredient particles; [0019] mixing the inactive
ingredient particles with the surface-modified nanoparticles to
provide an inactive ingredient comprised of particles having
surfaces with the surface-modified nanoparticles deposited on the
surfaces; and/or mixing the micronized active ingredient with the
surface-modified nanoparticles to provide a micronized active
ingredient comprised of particles having surfaces with the
surface-modified nanoparticles deposited on the surfaces; and
[0020] then mixing the micronized active ingredient with the
inactive ingredient.
[0021] In another embodiment, there is provided a method of
delivering medicament to the lungs of a mammal by administering a
therapeutic amount of a dry powder pharmaceutical composition, the
composition comprising: [0022] an inactive ingredient comprised of
particles; [0023] a micronized active ingredient; and [0024]
surface-modified nanoparticles; [0025] wherein the composition is
made by a process comprising: [0026] providing inactive ingredient
particles; [0027] mixing the inactive ingredient particles with the
surface-modified nanoparticles to provide an inactive ingredient
comprised of particles having surfaces with the surface-modified
nanoparticles deposited on the surfaces; and/or mixing the
micronized active ingredient with the surface-modified
nanoparticles to provide a micronized active ingredient comprised
of particles having surfaces with the surface-modified
nanoparticles deposited on the surfaces; and [0028] then mixing the
micronized active ingredient with the inactive ingredient.
[0029] In another embodiment, there is provided a dry powder
inhalation device comprising a mouth piece, a powder containment
system, and a dry powder pharmaceutical composition, the
composition comprising: [0030] an inactive ingredient comprised of
particles; [0031] a micronized active ingredient; and [0032]
surface-modified nanoparticles; [0033] wherein the composition is
made by a process comprising: [0034] providing inactive ingredient
particles; [0035] mixing the inactive ingredient particles with the
surface-modified nanoparticles to provide an inactive ingredient
comprised of particles having surfaces with the surface-modified
nanoparticles deposited on the surfaces; and/or mixing the
micronized active ingredient with the surface-modified
nanoparticles to provide a micronized active ingredient comprised
of particles having surfaces with the surface-modified
nanoparticles deposited on the surfaces; and [0036] then mixing the
micronized active ingredient with the inactive ingredient.
DEFINITIONS
[0037] The term "nanoparticle" as used herein refers to particles,
groups of particles, particulate molecules (i.e., small individual
groups or loosely associated groups of molecules) and groups of
particulate molecules that while potentially varied in specific
geometric shape have an effective, average, or mean diameter of
less than 100 nanometers.
[0038] The term "mean" as applied herein to a diameter, in certain
embodiments, preferably is mass mean. For example, mean physical
diameter as used herein, in certain embodiments, preferably is mass
mean physical diameter.
[0039] The term "comprising" and variations thereof (e.g.,
comprises, includes, etc.) do not have a limiting meaning where
these terms appear in the description and claims.
[0040] As used herein, "a," "an," "the," "at least one," and "one
or more" are used interchangeably, unless the context clearly
dictates otherwise.
[0041] The words "preferred" and "preferably" refer to embodiments
of the invention that may afford certain benefits, under certain
circumstances. However, other embodiments may also be preferred,
under the same or other circumstances. Furthermore, the recitation
of one or more preferred embodiments does not imply that other
embodiments are not useful, and is not intended to exclude other
embodiments from the scope of the invention.
[0042] Unless otherwise indicated, all numbers expressing feature
sizes, amounts, and physical properties used in the specification
and claims are to be understood as being modified in all instances
by the term "about." Accordingly, unless indicated to the contrary,
the numerical parameters set forth in the present specification and
attached claims are approximations that can vary depending upon the
desired properties sought to be obtained by those skilled in the
art utilizing the teachings disclosed herein.
[0043] Also herein, the recitation of numerical ranges by endpoints
includes all numbers subsumed within that range (e.g. 1 to 5
includes 1, 1.5, 2, 2.75, 3, 3.80, 4, and 5; between 1 and 5
includes 1.1, 1.5, 2, 2.75, 3, 3.80, 4, and 4.5) and any range
within that range.
[0044] The above summary of the present invention is not intended
to describe each disclosed embodiment or every implementation of
the present invention. The description that follows more
particularly exemplifies illustrative embodiments.
DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
[0045] Unexpectedly, Applicants have found that, in a dry powder
pharmaceutical composition containing both an active ingredient and
an inactive ingredient which can be present as a carrier or bulking
agent, by treating either the active or inactive ingredient or both
ingredients separately with surface-modified nanoparticles, an
increase in delivery efficiency, respirable fraction, or both may
be obtained. After the treatment with the surface modified
nanoparticles, the active and inactive ingredients are combined to
provide the dry powder composition.
[0046] For certain embodiments, a relatively large proportion of
the composition can comprise the inactive ingredient, thereby
allowing delivery of a small amount of drug, while delivering an
amount of composition which can be reproducibly metered to minimize
variability between doses. In addition, certain manufacturing
limitations, for example, the inability to accurately fill blisters
or capsules (or other single dose containers) with doses of powder
less than about 1 mg, are overcome by using larger powder doses of
the present compositions. For certain embodiments, the powder dose
is 2 to 20 mg. For certain of these embodiments, the powder dose is
2 to 10 mg.
[0047] Compositions described herein can be used in a dry powder
inhaler to deliver the active ingredient to the lung of a mammal.
For certain embodiments, preferably the respirable fraction of the
composition is increased by at least 20 percent using the present
compositions as compared with the same compositions except without
the nanoparticles or as compared with the same composition except
that the nanoparticles are combined with the active and inactive
ingredients at the same time, that is when the active and inactive
ingredients are already combined. For certain of these embodiments,
the respirable fraction is increased by at least 30 percent. For
certain of these embodiments, the respirable fraction is increased
by at least 50 percent or by at least 75 percent.
[0048] For certain embodiments, including any one of the above
embodiments, preferably active ingredient delivery efficiency is
increased by at least 10 percent using the present compositions as
compared with the same compositions except without the
nanoparticles or as compared with the same composition except that
the nanoparticles are combined with the active and inactive
ingredients at the same time, that is when the active and inactive
ingredients are already combined. For certain of these embodiments,
the delivery efficiency is increased by at least 20 percent. For
certain of these embodiments, the delivery efficiency is increased
by at least 50 percent.
[0049] Dry powder pharmaceutical compositions described herein are
made by a method comprising providing inactive ingredient
particles; providing a micronized active ingredient; mixing the
inactive ingredient particles with surface-modified nanoparticles
to provide an inactive ingredient comprised of particles having
surfaces with the surface-modified nanoparticles deposited on the
surfaces; and/or mixing the micronized active ingredient with
surface-modified nanoparticles to provide a micronized active
ingredient comprised of particles having surfaces with the
surface-modified nanoparticles deposited on the surfaces; and then
mixing the micronized active ingredient with the inactive
ingredient. It is believed that when either ingredient, but not the
other, is treated with the surface-modified nanoparticles, after
mixing the ingredients, some portion of the nanoparticles
associated with the treated ingredient become associated with the
surface of the ingredient not previously treated with the
nanoparticles. For certain of these embodiments, preferably the
method comprises mixing the inactive ingredient particles with
surface-modified nanoparticles to provide an inactive ingredient
comprised of particles having surfaces with the surface-modified
nanoparticles deposited on the surfaces; and then mixing the
micronized active ingredient with the inactive ingredient. For
certain of these embodiments, the method further comprises mixing
the micronized active ingredient with surface-modified
nanoparticles prior to mixing the micronized active ingredient with
the inactive ingredient.
[0050] For certain embodiments, including any one of the above
methods, the method further comprises dry blending inactive
ingredient particles without surface-modified nanoparticles with
the inactive ingredient comprised of particles having surfaces with
the surface-modified nanoparticles deposited on the surfaces,
wherein the dry blending is carried out prior to mixing the
micronized active ingredient with the inactive ingredient. A
variety of compositions with various amounts of inactive
ingredient, or various combinations of inactive ingredient can
thereby be conveniently provided at a lower cost, using a single
batch of inactive ingredient (or combination of inactive
ingredients) treated with surface-modified nanoparticles.
[0051] When mixing the inactive ingredient particles or the
micronized active ingredient with the surface-modified
nanoparticles in any of the above methods, any suitable,
conventional mixing or blending process can be used as long as the
nanoparticles are dispersed to the extent that the nanoparticles
are not aggregated or, if aggregated, the average diameter of the
aggregated particles is less than 100 nm or within any one of the
ranges stated herein for the nanoparticles. For certain
embodiments, including any one of the above embodiments, mixing the
micronized active ingredient with the surface-modified
nanoparticles is carried out in a liquid, and then the liquid is
removed. For certain of these embodiments, the micronized active
ingredient is substantially insoluble in the liquid, and the
surface-modified nanoparticles are dispersible in the liquid. For
certain embodiments, including any one of the above embodiments,
mixing the inactive ingredient particles with the surface-modified
nanoparticles is carried out in a liquid, and then the liquid is
removed to provide the inactive ingredient comprised of particles
having surfaces with the surface-modified nanoparticles deposited
on the surfaces; and wherein the inactive ingredient particles are
substantially insoluble in the liquid, and the surface-modified
nanoparticles are dispersible in the liquid.
[0052] The mixing can be carried out by dispersing the
surface-modified nanoparticles in the liquid, adding the inactive
ingredient particles or instead adding the micronized active
ingredient, mixing, and removing the liquid. The liquid can be
hydrophilic or hydrophobic. When the surface-modified nanoparticles
have a hydrophilic surface, the liquid is preferably hydrophilic,
for example, the liquid can be water, ethanol, isopropanol,
combinations thereof, and the like. When the nanoparticle surface
is hydrophobic, the liquid is preferably hydrophobic, for example
the liquid can be heptane, hexane, octane, toluene, combinations
thereof, or the like.
[0053] The liquid can be removed by known processes while avoiding
excessive heat that could degrade the active ingredient or cause
melting or dissolving of any of the ingredients. For certain
embodiments, including any one of the above embodiments where the
liquid is removed, the liquid is removed by spray drying, rotary
evaporation, bulk evaporation, or freeze drying.
[0054] Other methods of mixing the inactive ingredient particles or
the micronized active ingredient with the surface-modified
nanoparticles may be used. For example, the mixing may be carried
out by blending the nanoparticles with either of the ingredients as
powders, i.e., dry blending In another example, the
surface-modified nanoparticles may be dispersed in a liquid as
described above, and the resulting dispersion sprayed onto the
inactive ingredient particles or onto the micronized active
ingredient followed by quickly removing the liquid, for example, by
evaporation. Such methods are described in International
Application No. PCT/US2009/040892.
[0055] For certain embodiments, including any one of the above
embodiments, mixing the active ingredient with the inactive
ingredient is carried out by dry blending. Known dry blending
processes may be used. However, excessive heat that could degrade
the active ingredient or cause melting of any of the ingredients is
avoided. Suitable methods include shaking, roll mixing, stirring,
tumble mixing, and the like.
[0056] As indicated above, the dry powder pharmaceutical
compositions described herein are comprised of an inactive
ingredient comprised of particles; a micronized active ingredient;
and surface-modified nanoparticles; and the compositions are
prepared as described in any one of the above methods. For certain
of these embodiments, the composition comprises the inactive
ingredient comprised of particles having surfaces with the
surface-modified nanoparticles deposited on the surfaces; and the
micronized active ingredient; wherein the composition is made by a
process comprising providing inactive ingredient particles; mixing
the inactive ingredient particles with the surface-modified
nanoparticles to provide the inactive ingredient comprised of
particles having surfaces with the surface-modified nanoparticles
deposited on the surfaces; and then mixing the micronized active
ingredient with the inactive ingredient.
[0057] In another embodiment, there is provided a method of
delivering medicament to the lungs of a mammal by administering a
therapeutic amount of a dry powder pharmaceutical composition. The
composition is any one of the compositions described above.
[0058] In another embodiment, there is provided a dry powder
inhalation device comprising a mouth piece, a powder containment
system, and a dry powder pharmaceutical composition. The
composition is any one of the compositions described above, and the
composition may be placed in the containment system. Suitable dry
powder inhalation devices may contain either a single dose or
multiple doses. Multiple doses may be stored in a reservoir or in
multiple, individually packaged doses stored in, for example,
blisters or capsules. Examples of suitable devices include, but are
not limited to, the TURBUHALER (Astra Zeneca), CLICKHALER (Innovata
Biomed), EASYHALER (Orion), ACCUHALER, DISKUS, DISKHALER, ROTAHALER
(GlaxoSmithKline), HANDIHALER, INHALATOR, AEROHALER (Boehringer
Ingelheim), AEROLIZER(Schering Plough), and NOVOLIZER (ASTA
Medica).
[0059] The inactive ingredient is comprised of particles having a
mean physical diameter of less than 1,000 microns. Mean physical
diameter can be measured by known methods, for example, by laser
diffraction or microscopy. The particle size of the inactive
ingredient is selected to provide a well-mixed powder composition
that is stable from segregation and achieves sufficient
deagglomeration from the active ingredient during powder delivery
to maximize the respirability of the active ingredient. For certain
embodiments, including any one of the above embodiments, preferably
the inactive ingredient is comprised of particles having a mean
physical diameter of less than 200 micrometers. In certain
embodiments, the mean physical diameter is selected so as to reduce
interparticle adhesion and, thus, reduce the potential for particle
agglomeration, thereby improving the flowability of the powder
composition and the ability to easily and uniformly blend the
inactive ingredient powder with an active ingredient. For certain
of these embodiments, the mean physical diameter is at least 10
micrometers or at least 20 micrometers. In certain embodiments the
mean physical diameter is selected so as to minimize the likelihood
that a blend of inactive ingredient and active ingredient would
separate from each other due to differing mean particle sizes. For
certain of these embodiments, the mean physical diameter is less
than 100 micrometers or less than 60 micrometers. For certain of
these embodiments, the mean physical diameter is between 10 and 60
micrometers. For certain of these embodiments, the mean physical
diameter is between 20 and 60 micrometers.
[0060] The micronized active ingredient is comprised of particles
having a mean physical diameter no greater than 100 micrometers.
For certain embodiments, including any one of the above
embodiments, preferably the active ingredient is comprised of
particles having a mean physical diameter of less than 10
micrometers, more preferably less than 5 micrometers. In certain
embodiments, the particles may have a mean physical diameter of
between about 1 and 5 micrometers. In one embodiment, the
micronized active ingredient may be formed by processes, such as
milling, grinding, and high-pressure homogenization, that cause an
overall reduction in particle size of larger active ingredient
particles. In another embodiment, the micronized active ingredient
may, for example, be formed by processes, such as
recrystallization, lyophilization, and spray drying, that lead
directly to formation of particles of an appropriate particle size.
In still another embodiment, the micronized active ingredient may
result from controlled agglomeration or aggregation of smaller
active ingredient particles. It should be understood that the term
"micronized" is used to refer to relatively small particles of the
sizes described above and does not suggest that these particles are
prepared by any particular process.
[0061] The mean aerodynamic diameter of the micronized active
ingredient particles is typically no greater than 100 micrometers.
Mean aerodynamic diameter can be measured by known methods, for
example, by laser time of flight or by cascade impactor testing.
For certain embodiments, the particles have a mean aerodynamic
diameter which permits the active ingredient to be deposited in the
lower lung. For certain embodiments, including any one of the above
embodiments, preferably the active ingredient is comprised of
particles having a mean aerodynamic diameter of less than 10
micrometers, more preferably less than 5 micrometers.
[0062] In certain embodiments, the particles may have a mean
aerodynamic diameter of between about 1 and 5 micrometers.
[0063] In certain embodiments, the particles comprising the
inactive ingredient are sufficiently larger than the particles
comprising the active ingredient so that when a patient inhales the
dry powder composition a substantial portion of the respirable
active ingredient particles deposit in the patient's lung, whereas
the larger inactive ingredient particles and the nanoparticles on
the surface of the inactive ingredient particles collect in the
patient's mouth and throat. For certain embodiments, including any
one of the above embodiments, the mean physical diameter of the
particles comprising the inactive ingredient is at least 10 fold
greater than the mean aerodynamic diameter of the particles
comprising the active ingredient.
[0064] As indicated above, a relatively large portion of the
composition is comprised of the inactive ingredient to obviate
problems associated with delivering small doses of pure or
essentially pure drug. For certain embodiments, including any one
of the above embodiments, preferably the active ingredient and the
inactive ingredient are each present in an amount such that the
weight ratio of the amount of active ingredient to the amount of
the inactive ingredient is not more than 1:3. For certain of these
embodiments, the weight ratio is not more than 1:9. For certain of
these embodiments, the weight ratio is not more than 5:95 or 1:99.
For certain of these embodiments, the weight ratio is 1:9 to
0.01:99.99 and sometimes 1:99 to 0.1:99.9.
[0065] The dry powder pharmaceutical compositions described herein
include a blend of one or more active ingredients, which are drugs
or medicaments, with one or more inactive ingredients, which
include excipients or carriers. Suitable excipients are listed in
the Handbook of Pharmaceutical Excipients (Rowe, et al., APhA
Publications, 2003), examples of which include microcrystalline
cellulose, dicalcium phosphate, lactose (including lactose
monohydrate), trehalose, sucrose, mannose, mannitol, sorbitol,
calcium carbonate, starches, and magnesium or zinc stearates. For
certain embodiments, including any one of the above embodiments,
the inactive ingredient is selected from the group consisting of
lactose, trehalose, sucrose, mannitol, or a combination
thereof.
[0066] The active ingredient of the present compositions can be
used for the diagnosis, treatment, cure, prevention, or mitigation
of disease. Examples of such drugs include but are not limited to
medicaments such as antiallergics, analgesics, bronchodilators,
antihistamines, therapeutic proteins and peptides, antitussives,
anticholinergics, anginal preparations, antibiotics,
anti-inflammatory preparations, diuretics, hormones, or
sulfonamides, such as, for example, a vasoconstrictive amine, an
enzyme, an alkaloid or a steroid, salts thereof, solvates thereof,
enantiomers thereof, and combinations of any one or more of these.
For certain embodiments, including any one of the above
embodiments, the active ingredient is selected from the group
consisting of antiallergics, antiasthmatics, antiinflammatories,
bronchodilators, steroids, anticholinergics, salts thereof,
solvates thereof, enantiomers thereof, and a combination
thereof.
[0067] Specific examples of medicaments include isoproterenol,
phenylephrine, phenylpropanolamine, glucagon, adrenochrome,
trypsin, epinephrine, ephedrine, narcotine, codeine, atropine,
heparin, morphine, dihydromorphinone, dihydromorphine, ergotamine,
scopolamine, methapyrilene, cyanocobalamin, terbutaline, rimiterol,
salbutamol (albuterol), isoprenaline, fenoterol, oxitropium,
tiotropium, reproterol, budesonide, flunisolide, ciclesonide,
formoterol, fluticasone propionate, salmeterol, procaterol,
ipratropium, triamcinolone acetonide, tipredane, mometasone
furoate, colchicine, pirbuterol, beclomethasone, beclomethasone
dipropionate, orciprenaline, fentanyl, diamorphine, and dilitiazem.
Other examples include antibiotics, such as neomycin,
cephalosporins, streptomycin, penicillin, procaine penicillin,
tetracycline, chlorotetracycline, hydroxytetracycline;
adrenocorticotropic hormone and adrenocortical hormones, such as
cortisone, hydrocortisone, hydrocortisone acetate and prednisolone;
antiallergy compounds such as cromolyn sodium and nedocromil;
protein and peptide molecules such as insulin, pentamidine,
calcitonin, amiloride, interferon, LHRH analogues, IDNAase,
heparin, and others.
[0068] For certain embodiments, including any one of the above
embodiments, the active ingredient is selected from the group
consisting of budesonide, albuterol, formoterol, fluticasone,
salmeterol, mometasone, tiotropium, beclomethasone, salts thereof,
solvates thereof, enantiomers thereof, and a combination
thereof.
[0069] For a specific application the drug or medicaments may be
used as either a free base or as one or more salts thereof The
choice of a free base or salt will be influenced by the biological
impact as well as the chemical and physical stability (e.g., its
tendency toward solvates, multiple polymorphs, friability, etc.) of
the drug or medicament in a given formulation. Examples of anionic
salts of drugs and medicaments that may be used in the present
compositions include acetate, benzenesulphonate, benzoate,
bicarbonate, bitartrate, bromide, calcium edetate, camsylate,
carbonate, chloride, citrate, dihydrochloride, edetate, edisylate,
estolate, esylate, fumarate, fluceptate, gluconate, glutamate,
glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride,
hydroxynaphthoate, iodide, isethionate, lactate, lactobionate,
malate, maleate, mandelate, mesylate, methylbromide, methylnitrate,
methylsulphate, mucate, napsylate, nitrate, pamoate (embonate),
pantothenate, phosphatediphosphate, polygalacturonate, salicylate,
stearate, subacetate, succinate, sulphate, tannate, tartrate, and
triethiodide.
[0070] Examples of cationic salts of a drug or medicament that may
be used in the present compositions include alkali metals, e.g.,
sodium and potassium; and ammonium salts and salts of amines known
in the art to be pharmaceutically acceptable, e.g., glycine,
ethylene diamine, choline, diethanolamine, triethanolamine,
octadecylamine, diethylamine, triethylamine, 1-amino-2-propanol,
2-amino-2-(hydroxymethyl)propane-1,3-diol, and
1-(3,4-dihydroxyphenyl)-2-isopropylaminoethanol.
[0071] The surface-modified nanoparticles used in the present
compositions are comprised of a core material and a surface that is
different (i.e., modified) from the core material. The core
material may be inorganic or organic and is selected such that it
is compatible with the active ingredient and with the inactive
ingredient and suitable for the application for which the dry
powder composition is intended. The selection of the core material
will also be governed at least in part by specific performance
requirements for the composition. For example, the performance
requirements for the composition might require that a given core
material have certain dimensional characteristics (e.g., size and
shape), compatibility with the surface modifying materials along
with certain stability requirements (e.g., insolubility in a
processing or mixing liquid, good dispersibility in a processing or
mixing liquid). Requirements can include, for example,
biocompatibility, biosolubility, biodegradability, and stability
under more extreme environments (e.g., higher temperatures during
processing or shipping, resistance to moisture uptake) as well as
the ability to dry the surface-modified nanoparticles down to a
powder and subsequently maintain the ability to re-disperse the
nanoparticles in a processing or mixing liquid.
[0072] Suitable inorganic nanoparticle core materials include metal
oxide nanoparticles such as silica, titania, alumina, iron oxide,
zinc oxide, antimony oxide, tin oxide, alumina/silica, ceria,
vanadia, metal phosphates, e.g., calcium phosphates including
hydroxyapatite, metal sulfates, metal chlorides, and combinations
thereof. For certain embodiments, including any one of the above
embodiments, the surface-modified nanoparticles comprise a core,
the core comprising an inorganic material selected from the group
consisting of silica, titania, alumina, an oxide of zinc, an oxide
of iron, metal phosphates, metal sulfates, metal chlorides, or a
combination thereof Metals such as gold, silver, or other precious
metals can also be utilized as solid particles or as coatings on
organic or inorganic particles.
[0073] Suitable organic nanoparticle core materials include, for
example, organic polymeric nanospheres, sugars such as lactose,
trehalose, glucose or sucrose, and aminoacids. For certain
embodiments, including any one of the above embodiments except
where the core material is inorganic, the surface-modified
nanoparticles comprise a core, the core comprising an organic
polymer. For certain of these embodiments, the core comprises
polystyrene. Organic polymeric nanospheres are known and include
nanospheres that comprise polystyrene, such as those available from
Bangs Laboratories, Inc. of Fishers, Indiana as powders or
dispersions. Such organic polymeric nanospheres will generally have
average particle sizes ranging from 20 nm to not more than 60
nm.
[0074] A selected nanoparticle core material may be used alone or
in combination with one or more other nanoparticle core materials
including mixtures and combinations of organic and inorganic
nanoparticle materials. Such combinations may be uniform or have
distinct phases which can be dispersed or regionally specific,
e.g., layered or of a core-shell type structure.
[0075] The nanoparticle core, whether inorganic or organic, and in
whatever form employed, will have an mean particle diameter of less
than 100 nm. For certain embodiments, the nanoparticles have a mean
particle diameter of not more than 50 nm, preferably not more than
20 nm; in certain embodiments from 2 nm to 20 nm; and in certain
other embodiments from 3 nm to 10 nm or more preferably from 4 nm
to 8 nm. If the chosen nanoparticle or combination of nanoparticles
are themselves aggregated, the maximum preferred cross-sectional
dimension of the aggregated particles will be within any one of
these stated ranges.
[0076] In an exemplary embodiment, another class of
surface-modified organic nanoparticles includes
buckminsterfullerenes (fullerenes), dendrimers, branched and
hyperbranched "star" polymers such as 4, 6, or 8 armed polyethylene
oxides (available, for example, from Aldrich Chemical Company of
Milwaukee, Wis. or Shearwater Corporation of Huntsville, Ala.)
whose surfaces have been chemically modified. Specific examples of
fullerenes include C.sub.60, C.sub.70, C.sub.82, and C.sub.84.
Specific examples of dendrimers include polyamidoamine (PAMAM)
dendrimers of Generations 2 through 10 (G2-G10), available also
from, for example, Aldrich Chemical Company of Milwaukee, Wis.
[0077] In many cases it may be desirable for the nanoparticles
utilized in the invention to be substantially spherical in shape.
In other applications, however, more elongated shapes may be
desired. Aspect ratios of not more than 10 are preferred, with
aspect ratios not more than 3 generally more preferred. The core
material will substantially determine the final morphology of the
particle and thus a significant influence in selection of the core
material may be the ability to obtain a desired size and shape in
the final particle.
[0078] The surface of the selected nanoparticle core material will
generally be chemically or physically modified in some manner. Both
direct modification of a core surface as well as modification of a
permanent or temporary shell on a core material are envisioned.
Such modifications may include, for example, covalent chemical
bonding, hydrogen bonding, electrostatic attraction, London forces,
and hydrophilic or hydrophobic interactions so long as the
interaction is maintained at least during the time period required
for the nanoparticles to achieve their intended utility. The
surface of a nanoparticle core material may be modified with one or
more surface modifying groups. The surface modifying groups may be
derived from various surface modifying agents. Schematically,
surface modifying agents may be represented by the following
general formula:
A-B (II)
[0079] The A group in Formula II is a linking group that is capable
of attaching to the surface of the nanoparticle. In those
situations where the nanoparticles and the inactive ingredient or
the nanoparticles and the active ingredient are processed in a
liquid, the B group is a compatibilizing group with the liquid. The
B group may also be a group or moiety that is capable of preventing
irreversible agglomeration of the nanoparticles. It is possible for
the A and B groups to be the same, e.g., the attaching group may
also be capable of providing the desired surface compatibility. The
compatibilizing group may be reactive, but is generally
non-reactive, with a component of the active or inactive
ingredients. The A group may be comprised of more than one
component or created in more than one step, e.g., the A group may
be comprised of an A' moiety which is reacted with the surface, and
an A'' moiety which can be reacted with B. The sequence of these
reactions is not important, as these reactions can be wholly or
partly performed prior to the attachment to the core. Further
description of nanoparticles in coatings can be found in
Linsenbuhler, M. et. al., Powder Technology, 158, 2003, p.
3-20.
[0080] Many suitable classes of surface-modifying compounds are
known to those skilled in the art and include, for example,
silanes, organic acids, organic bases, inorganic acids with organic
groups, and alcohols, and combinations thereof. For certain
embodiments, including any one of the above embodiments, a surface
of the core is modified with a compound selected from the group
consisting of alkylsilanes, carboxylic acids, phosphonic acids,
sulfonates, polyethylene glycols, sugars, and a combination
thereof.
[0081] For certain embodiments, the surface-modifying compound is a
silane. Examples of silanes include organosilanes such as, for
example, alkylchlorosilanes, alkoxysilanes, e.g.,
methyltrimethoxysilane, methyltriethoxysilane,
ethyltrimethoxysilane, ethyltriethoxysilane,
n-propyltrimethoxysilane, n-propyltriethoxysilane,
isopropyltrimethoxysilane, isopropyltriethoxysilane,
butyltrimethoxysilane, butyltriethoxysilane, hexyltrimethoxysilane,
octyltrimethoxysilane, 3-mercaptopropyltrimethoxysilane,
n-octyltriethoxysilane, phenyltriethoxysilane, polytriethoxysilane,
vinyltrimethoxysilane, vinyldimethylethoxysilane,
vinylmethyldiacetoxysilane, vinylmethyldiethoxysilane,
vinyltriacetoxysilane, vinyltriethoxysilane,
vinyltriisopropoxysilane, vinyltrimethoxysilane,
vinyltriphenoxysilane, vinyltri(t-butoxy)silane,
vinyltris(isobutoxy)silane, vinyltris(isopropenoxy)silane , and
vinyltris(2-methoxyethoxy)silane; trialkoxyarylsilanes;
isooctyltrimethoxy-silane; N-(3-triethoxysilylpropyl)
methoxyethoxyethoxy ethyl carbamate; N-(3-triethoxysilylpropyl)
methoxyethoxyethoxyethyl carbamate; silane functional
(meth)acrylates including, e.g.,
3-(methacryloyloxy)propyltrimethoxysilane,
3-acryloyloxypropyltrimethoxysilane,
3-(methacryloyloxy)propyltriethoxysilane,
3-(methacryloyloxy)propylmethyldimethoxysilane,
3-(acryloyloxypropyl)methyldimethoxysilane,
3-(methacryloyloxy)propyldimethylethoxysilane,
3-(methacryloyloxy)methyltriethoxysilane,
3-(methacryloyloxy)methyltrimethoxysilane,
3-(methacryloyloxy)propyldimethylethoxysilane,
3-(methacryloyloxy)propenyltrimethoxysilane, and
3-(methacryloyloxy)propyltrimethoxysilane; polydialkylsiloxanes
including, e.g., polydimethylsiloxane, arylsilanes including, e.g.,
substituted and unsubstituted arylsilanes, alkylsilanes including,
e.g., substituted and unsubstituted alkyl silanes including, e.g.,
methoxy and hydroxy substituted alkyl silanes, and combinations
thereof Methods of surface-modifying silica using silane functional
(meth)acrylates are known and are described, for example, in U.S.
Pat. No. 4,491,508 (Olson et al.); U.S. Pat. No. 4,455,205 (Olson
et al.); U.S. Pat. No. 4,478,876 (Chung); U.S. Pat. No. 4,486,504
(Chung); and U.S. Pat. No. 5,258,225 (Katsamberis) whose
descriptions are incorporated herein by reference for such purpose.
Surface-modified silica nanoparticles include silica nanoparticles
surface-modified with silane surface modifying agents including,
for example, acryloyloxypropyl trimethoxysilane,
3-methacryloyloxypropyltrimethoxysilane,
3-mercaptopropyltrimethoxysilane, n-octyltrimethoxysilane,
isooctyltrimethoxysilane, and combinations thereof Silica
nanoparticles can be treated with a number of surface modifying
agents including, for example, an alcohol, an organosilane
including, for example, alkyltrichlorosilanes,
trialkoxyarylsilanes, trialkoxy(alkyl)silanes, and combinations
thereof, and organotitanates, and mixtures thereof.
[0082] In another embodiment, the surface-modifying compound is an
organic acid or an inorganic acid with an organic group. Examples
of such compounds include oxyacids of carbon (e.g., carboxylic
acid), sulfur and phosphorus, acid derivatized poly(ethylene
glycols) (PEGs) and combinations of any of these. Suitable
phosphorus containing acids include phosphonic acids including, for
example, octylphosphonic acid, laurylphosphonic acid,
decylphosphonic acid, dodecylphosphonic acid, octadecylphosphonic
acid, monopolyethylene glycol phosphonate and phosphates including
lauryl or stearyl phosphate. Suitable sulfur containing acids
include sulfates and sulfonic acids including dodecyl sulfate and
lauryl sulfonate. Any such acids may be used in either acid or salt
forms.
[0083] Other surface modifying compounds with carboxyl groups
include acrylic acid, methacrylic acid, beta-carboxyethyl acrylate,
mono-2-(methacryloyloxyethyl) succinate,
mono(methacryloyloxypolyethyleneglycol) succinate and combinations
of one or more of such compounds. For certain embodiments,
surface-modifying agents which incorporate a carboxylic acid
functionality include, for example,
CH.sub.3O(CH.sub.2CH.sub.2O).sub.2CH.sub.2COOH (hereafter MEEAA),
2-(2-methoxyethoxy)acetic acid having the chemical structure
CH.sub.3OCH.sub.2CH.sub.2OCH.sub.2COOH (hereafter MEAA),
mono(polyethylene glycol) succinate in either acid or salt form,
octanoic acid, dodecanoic acid, steric acid, acrylic and oleic acid
or their acidic derivatives. In a further embodiment,
surface-modified iron oxide nanoparticles include those modified
with endogenous fatty acids, e.g., steric acid, or fatty acid
deriviatives using endogenous compounds, e.g., steroyl lactylate or
sarcosine or taurine derivatives.
[0084] In another embodiment, the surface-modifying compound is an
organic base. Examples of such compounds include alkylamines, e.g.,
octylamine, decylamine, dodecylamine, octadecylamine, and
monopolyethylene glycol amines.
[0085] In another embodiment, the surface-modifying compound is an
alcohol or thiol. Examples of such compounds include, for example,
aliphatic alcohols, e.g., octadecyl, dodecyl, lauryl and furfuryl
alcohol, alicyclic alcohols, e.g., cyclohexanol, and aromatic
alcohols, e.g., phenol and benzyl alcohol, and combinations thereof
Thiol-based compounds are especially suitable for modifying cores
with gold surfaces.
[0086] The surface-modified nanoparticles are selected in such a
way that compositions formed with them are free from a degree of
particle agglomeration or aggregation that would interfere with the
desired properties of the composition. The surface-modified
nanoparticles are generally selected to be either hydrophobic or
hydrophilic such that, depending on the character of the processing
liquid, the active ingredient, or the inactive ingredient, the
resulting mixture or blend exhibits substantially free flowing
properties. Suitable surface groups constituting the surface
modification of the utilized nanoparticles can thus be selected
based upon these considerations. When a processing liquid is
hydrophobic, for example, one skilled in the art can select from
among various hydrophobic surface groups to achieve a
surface-modified particle that is compatible with the hydrophobic
liquid; when the processing liquid is hydrophilic, one skilled in
the art can select from various hydrophilic surface groups; and,
when the solvent is a hydrofluorocarbon, one skilled in the art can
select from among various compatible surface groups; and so forth.
The nanoparticle can include two or more different surface groups
(e.g., a combination of hydrophilic and hydrophobic groups) that
combine to provide a nanoparticle having a desired set of
characteristics. The surface groups will generally be selected to
provide a statistically averaged, randomly surface-modified
nanoparticle.
[0087] The surface groups will be present on the surface of the
nanoparticle in an amount sufficient to provide surface-modified
nanoparticles with the properties necessary for compatibility with
processing liquid, the active ingredient, or the inactive
ingredient. In an exemplary embodiment, the surface groups are
present in an amount sufficient to form a monolayer, and in another
embodiment, a continuous monolayer, on at least a substantial
portion of the surface of the nanoparticle.
[0088] A variety of methods are available for modifying the
surfaces of nanoparticles. A surface modifying agent may, for
example, be added to nanoparticles (e.g., in the form of a powder
or a colloidal dispersion) and the surface modifying agent may be
allowed to react with the nanoparticles. One skilled in the art
will recognize that multiple synthetic sequences to bring the
nanoparticle together with the compatibilizing group are known and
can be used. For example, the reactive group/linker may be reacted
with the nanoparticle followed by reaction with the compatibilizing
group. Alternatively, the reactive group/linker may be reacted with
the compatibilizing group followed by reaction with the
nanoparticle. Other surface modification processes are described
in, e g., U.S. Pat. No. 2,801,185 (Iler) and U.S. Pat. No.
4,522,958 (Das et al.), whose descriptions are incorporated herein
by reference for such purpose.
[0089] Surface-modified nanoparticles or precursors to them may be
in the form of a colloidal dispersion. Some such dispersions are
commercially available as unmodified silica starting materials, for
example those nano-sized colloidal silicas available under the
product designations NALCO 1040, 1050, 1060, 2326, 2327, and 2329
colloidal silica from Nalco Chemical Co. of Naperville, IL. Metal
oxide colloidal dispersions include colloidal titanium oxide,
examples of which are described in U.S. Pat. Nos. 6,329,058 and
6,432,526 (Amey et al.), whose descriptions are also incorporated
by reference herein. Such particles are also suitable substrates
for further surface modification as described above.
[0090] For certain embodiments, including any one of the above
embodiments, the surface-modified nanoparticles have a mean
particle diameter of not more than 50 nm. For certain of these
embodiments, the surface-modified nanoparticles have a mean
diameter of not more than 20 nanometers. For certain of these
embodiments, the surface-modified nanoparticles have a mean
diameter of 2 nm to 20 nm; and in certain other embodiments from 3
nm to 10 nm or more preferably from 4 nm to 8 nm. If the chosen
surface-modified nanoparticle or combination of surface-modified
nanoparticles are themselves aggregated, the maximum preferred
cross-sectional dimension of the aggregated surface-modified
nanoparticles will be within any one of these stated ranges.
[0091] The surface-modified nanoparticles are present in the dry
powder compositions described herein in an amount effective to
enhance a property which is relevant to processing or delivering
the composition. For example, the degree of aggregation,
agglomeration or flocculation of the active ingredient, the
inactive ingredient, or both can be reduced or minimized by the
surface-modified nanoparticles. The amount of surface-modified
nanoparticle effective to achieve such purposes will depend, inter
alia, on the composition of the bulk material, the chosen
nanoparticle, the presence or absence of other adjuvants or
excipients and on the particular needs and requirements of the
application for which the active ingredient, the inactive
ingredient, or both are to be used. For example, the nature of the
nanoparticle surface, the morphology of the particle and particle
size may each influence the desired properties of the composition
and influence the selection of a nanoparticle and the amount or
concentration of nanoparticles used. The presence of as little as
0.0001 percent of nanoparticles by weight of the composition may
provide a desired effect. For certain embodiments, the amount of
surface-modified nanoparticles is at least 0.01 weight percent. The
surface-modified nanoparticles may be used in an amount not
exceeding 10 weight percent, and in certain embodiments in an
amount not more than 5 weight percent of the composition. For
certain embodiments, including any one of the above embodiments,
the amount of surface-modified nanoparticles in the composition is
at least 0.02 percent and not more than 5 percent by weight of the
composition. For certain of these embodiments, the amount of
surface-modified nanoparticles in the composition is 0.1 to 3
weight percent of the dry powder composition.
[0092] In certain applications it may be preferred that the
selected nanoparticles be substantially spherical. The
biocompatibility, including toxicology, and physical properties of
a selected surface-modified nanoparticle is considered according to
the skill in the art for the present dry powder compositions in
accordance with the contemplated use or application.
[0093] In one exemplary embodiment, the surface-modified
nanoparticles will not irreversibly associate with one another. The
term "associate with" or "associating with" includes, for example,
covalent bonding, hydrogen bonding, electrostatic attraction,
London forces, and hydrophobic interactions.
[0094] The surface-modified nanoparticles used in the present
compositions as described above can in certain embodiments provide
a significant increase in delivery efficiency of an active
ingredient, a significant increase in respirable fraction, or both.
For certain embodiments, including any one of the above
embodiments, the composition has a respirable fraction which is at
least 20 percent greater than 1) a composition with the same
ingredients without nanoparticles and 2) a composition made by
adding the nanoparticles to the same ingredients at the same time.
For certain of these embodiments, the respirable fraction is at
least 30 percent greater. For certain of these embodiments, the
respirable fraction is at least 50 percent greater or at least 75
percent greater.
[0095] For certain embodiments, including any one of the above
embodiments, the composition has an active ingredient delivery
efficiency which is at least 10 percent greater than 1) a
composition with the same ingredients without nanoparticles and 2)
a composition made by adding the nanoparticles to the same
ingredients at the same time. For certain of these embodiments, the
delivery efficiency is at least 20 percent greater. For certain of
these embodiments, the delivery efficiency is at least 50 percent
greater.
[0096] The surface-modified nanoparticles utilized in the dry
powder compositions described herein typically enhance and/or
maintain the flowability of the powder composition. Flowability
(also called free flow) refers generally to the ability of a
free-flowing material to flow steadily and consistently as
individual particles or groups of individual particles such as
would occur, for example, through a fine orifice. Relative
improvements (i.e., reductions) in aggregation, agglomeration,
attrition, flocculation, segregation, caking, bridging or in the
ability to achieve uniform blends indicate an improvement in
flowability.
[0097] The presence of nanoparticles in the present compositions
can also enhance floodability (also called floodable flow), which
refers to the tendency of a solid or powder material toward
liquid-like flow due to the material fluidization of a mass of
particles by a gaseous carrier.
[0098] Also, the presence of the surface-modified nanoparticles may
allow for higher tap densities, where a larger concentration of a
dry powder composition described herein may be contained in a
capsule, a blister, or a reservoir-based DPI device. For example,
this may contribute to more doses in a DPI device within the same
sized device, rather than changing the device's shape or size.
[0099] In another embodiment, the dry powder inhalation device
described herein may have the dry powder composition stored in a
storage device prior to dosing. This storage device may comprise,
for example, a reservoir, capsule, blister, or dimpled tape. In an
exemplary embodiment, the micronized active ingredient used in the
composition is a micronized crystalline powder, but may also be an
amorphous powder from a process such as spray drying. Additionally,
the active ingredient may be contained in particles that are a
matrix of drug and an excipient. The dry powder inhalation device
may be a multi-dose device or may be a single dose device. The dry
powder inhalation device may be either a passive device or an
active device.
[0100] In a further embodiment, the dry powder pharmaceutical
composition may be used for delivering medicament to the lungs of a
mammal by oral inhalation delivery.
[0101] Objects and advantages of this invention are further
illustrated by the following examples, but the particular materials
and amounts thereof recited in these examples, as well as other
conditions and details, should not be construed to limit the scope
of the present invention.
EXAMPLES
[0102] Unless otherwise indicated, all parts and percentages are by
weight.
Aerosol Performance Test Methods
[0103] The ability of the powder to be aerosolized was measured
using an inertial cascade impactor as follows. A small amount
(nominally 4 mg) of powder was weighed into a size three Shionogi
QUALI-V hydroxypropyl methylcellulose capsule (Shionogi Qualicaps,
Madrid, Spain) and loaded into an AEROLIZER device ("DPI" device,
commercially available as a FORADIL AEROLIZER product, available
from Schering Plough Co.), which was tested for pharmaceutical
performance using a Next Generation Pharmaceutical Impactor ("NGI")
(MSP Corporation, Shoreview, Minn.). For examples 1 through 5 and
comparative examples 1 and 2 the NGI was additionally fitted with a
preseparator (MSP Corporation, Shoreview, Minn.). A series of
diluted formulations having a nominal concentration of 5 weight %
budesonide, blended with a large particle size lactose as a bulking
agent, were tested for performance. The formulations differed by
the amount and type of surface-modified nanoparticles and/or the
way in which the surface-modified nanoparticles were added to the
formulation. At a 5% budesonide concentration, the 4 mg dose size
used for testing provided an effective dose of 200 .mu.g.
Comparator formulations consisting of a simple blend of untreated
budesonide with the large particle size lactose, and the same blend
treated with surface-modified nanoparticles by dispersing and
mixing all three components in solvent, were also tested. The NGI
was coupled with a USP throat (United States Pharmacopeia, USP 24
<601>Aerosols, Metered Dose Inhalers, and Dry Powder
Inhalers) and operated at a standard flow rate of 60 Lpm for a
collection time of four seconds. A suitable coupler was affixed to
the USP throat to provide an air-tight seal between the DPI device
and the throat. For all testing, the USP throat and stage cups 4-7
of the NGI were coated with a surfactant, a 10 mL aliquot of
diluent was placed in the preseparator, and a 3 mL aliquot of
diluent was placed in stage cups 1-3 of the NGI to prevent particle
bounce and re-entrainment. The amount of drug collected on each
component of the NGI testing apparatus was determined by rinsing
the component with a measured volume of an appropriate solvent and
subjecting the rinsed material to HPLC analysis with ultraviolet
detection to determine drug concentration. Data that was returned
from HPLC analysis was analyzed to determine the average amount of
drug collected on the DPI and capsule, the USP throat, and on each
component of the NGI per delivered dose.
[0104] Using the individual component values, the respirable
fraction and delivery efficiency were calculated for each powder
sample. Respirable mass was defined as the total delivered dose
that was measured to be smaller than the respirable limit of 4.5
micrometers in aerodynamic diameter. Respirable fraction was
defined as the percentage of a delivered dose that reached the
entry of the throat and was smaller than the respirable limit.
Delivery efficiency was defined as the respirable mass divided by
the total delivered dose. When using the NGI, respirable mass was
collected in cups 3, 4, 5, 6, and 7, and on the filter. Mass
collected in the throat, preseparator, and cups 1 and 2 were
considered non-respirable.
Example 1
[0105] Hydrophobic silica surface-modified nanoparticles (SMN) were
prepared by mixing 600 grams of Nalco 2326 colloidal silica, 56.8
grams of isooctyltrimethoxysilane (Gelest, Inc.), 540 grams of
ethanol, and 135 grams of methanol in a 2 liter flask at
approximately 82.degree. C. for 4 hours. The resulting white
particulate product was isolated and oven dried at 120.degree. C. A
surface-modified nanoparticle dispersion was prepared by adding
5.0028 grams of the hydrophobic silica SMN to 500 mL of heptane and
stirring until the SMN had completely dispersed. The resulting
SMN-heptane dispersion had a nominal concentration of 0.010 g/mL.
Lactose (INHALAC 230, lactose monohydrate, approximate particle
sizes: d10=60 .mu.m, d50 =100 .mu.m, d90=140 .mu.m, available from
Meggle GmbH, Wasserburg, Germany) (20.0118 grams) was added to a
500 mL round bottom flask. An aliquot of 41 mL of the SMN-heptane
dispersion was added to the flask along with an additional 50 mL of
heptane. The mixture was then sonicated for approximately 15
seconds to ensure uniform mixture in the flask. The flask was then
placed onto a rotary evaporator to remove the solvent. The rotary
evaporator was set to a nominal temperature of 60.degree. C. and
operated under a vacuum. After removal of all of the visible
solvent, the flask was then placed into a vacuum oven at
approximately 45.degree. C. for approximately 1 hour to remove
further residual solvent. The resulting powder was sieved with a
No. 70 mesh sieve (210 micron openings) to break up any
agglomerated material. The sieved material was then collected and
placed in a container for later use. The lactose-SMN powder blend
had a nominal concentration of surface-modified nanoparticles of
2.0 percent by weight of the powder blend (% w/w).
[0106] Micronized budesonide (approximate particle sizes: d10=1.116
.mu.m, d50=1.878 .mu.m, d90=3.200 .mu.m, available from Onbio Inc.,
Ontario, Canada) (0.1597 grams) and 3.0067 grams of the lactose-SMN
powder blend were added to a 4 inch by 4 inch (10 cm.times.10 cm)
plastic bag with a ZIPLOCK seal. The contents of the bag were mixed
first by gently kneading the contents of the bag followed by
shaking the contents of the bag. This cycle of kneading-shaking was
repeated approximately five times during a total mixing time of
approximately three minutes. The contents of the bag were then
transferred into a 20 mL glass vial. Care was taken to minimize the
amount of residual powder left in the bag. The powder transferred
to the vial was then further mixed on a vortex mixer for
approximately 15 sec. The resulting budesonide-lactose-SMN powder
blend had a nominal budesonide concentration of 5.0 w/w and a
nominal SMN concentration of 2.0% w/w. Aerosol performance testing
as described in the section above was performed, and the resulting
respirable fraction was 53%, and the delivery efficiency was
33%.
Example 2
[0107] A lactose-SMN powder blend was prepared as in Example 1 with
the exception that the nominal concentration of surface-modified
nanoparticles was adjusted to be 0.5 w/w. This powder was blended
with micronized budesonide as in Example 1 to prepare a powder
blend having a nominal budesonide concentration of 5.0 w/w and a
nominal SMN concentration of 0.5% w/w. Aerosol performance testing
as described in the section above was performed, and the resulting
respirable fraction was 63%, and the delivery efficiency was
43%.
Example 3
[0108] A surface-modified nanoparticle dispersion was prepared by
adding 5.0028 grams of hydrophobic silica SMN prepared as described
in Example 1 to 500 mL of heptane and stirring until the SMN had
completely dispersed. The resulting SMN-heptane dispersion had a
nominal concentration of 0.010 g/mL. Budesonide (approximate
particle sizes: d10=1.116 .mu.m, d50=1.878 .mu.m, d90=3.200 .mu.m,
available from Onbio Inc., Ontario, Canada) (10.0131 grams) was
added to a 250 mL round bottom flask. An aliquot of 21 mL of the
SMN-heptane dispersion was added to the flask along with an
additional 60 mL of heptane. The mixture was then sonicated for
approximately 30 seconds to ensure uniform mixture in the flask.
The flask was then placed onto a rotary evaporator to remove the
solvent. The rotary evaporator was set to a nominal temperature of
60.degree. C. and operated under a vacuum. After removal of all of
the visible solvent, the flask was then placed into a vacuum oven
at approximately 45.degree. C. for approximately 1 hour to remove
further residual solvent. The resulting powder was sieved with a
No. 140 mesh sieve (106 micron openings) to break up any
agglomerated material. The sieved material was then collected and
placed in a container for later use. The budesonide-SMN powder
blend had a nominal concentration of surface-modified nanoparticles
of 2.0% w/w. A lactose-SMN powder blend with a nominal
concentration of surface-modified nanoparticles of 2.0% w/w was
prepared as in Example 1.
[0109] Budesonide-SMN powder blend (0.1609 grams) and 3.0046 grams
of the lactose-SMN powder blend were added to a 4 inch by 4inch (10
cm.times.10 cm) plastic bag with a ziplock seal. The contents of
the bag were mixed first by gently kneading the contents of the bag
followed by shaking the contents of the bag. This cycle of
kneading-shaking was repeated approximately five times during a
total mixing time of approximately three minutes. The contents of
the bag were then transferred into a 20 mL glass vial. Care was
taken to minimize the amount of residual powder left in the bag.
The powder transferred to the vial was then further mixed on a
vortex mixer for approximately 15 sec. This blend had a nominal
budesonide concentration of 5.0 w/w and a nominal SMN concentration
of 2.0% w/w. Aerosol performance testing as described in the
section above was performed, and the resulting respirable fraction
was 72%, and the delivery efficiency was 44%.
Example 4
[0110] A lactose-SMN powder blend with a nominal concentration of
surface-modified nanoparticles of 0.5 w/w was prepared was prepared
as in Example 2. A budesonide-SMN powder blend with a nominal
concentration of surface-modified nanoparticles of 2.0% w/w was
prepared as in Example 3.
[0111] Budesonide-SMN powder blend (0.1602 grams) and 3.0029 grams
of the lactose-SMN powder blend were added to a 4 inch by 4 inch
(10 cm.times.10 cm) plastic bag with a ZIPLOCK seal. The contents
of the bag were mixed first by gently kneading the contents of the
bag followed by shaking the contents of the bag. This cycle of
kneading-shaking was repeated approximately five times during a
total mixing time of approximately three minutes. The contents of
the bag were then transferred into a 20 mL glass vial. Care was
taken to minimize the amount of residual powder left in the bag.
The powder transferred to the vial was then further mixed on a
vortex mixer for approximately 15 sec. This blend had a nominal
budesonide concentration of 5.0 w/w and a nominal SMN concentration
of 0.5 w/w. Aerosol performance testing as described in the section
above was performed, and the resulting respirable fraction was 63%,
and the delivery efficiency was 43%.
Example 5
[0112] A budesonide-SMN powder blend with a nominal concentration
of surface-modified nanoparticles of 2.0% w/w was prepared as in
Example 3. Budesonide-SMN powder blend (0.1607 grams) and 3.0107
grams of lactose (INHALAC 230, lactose monohydrate, approximate
particle sizes: d10=60 .mu.m, d50=100 .mu.m, d90=140 .mu.m,
available from Meggle GmbH, Wasserburg, Germany) were added to a 4
inch by 4 inch (10 cm.times.10 cm) plastic bag with a ZIPLOCK seal.
The contents of the bag were mixed first by gently kneading the
contents of the bag followed by shaking the contents of the bag.
This cycle of kneading-shaking was repeated approximately five
times during a total mixing time of approximately three minutes.
The contents of the bag were then transferred into a 20 mL glass
vial. Care was taken to minimize the amount of residual powder left
in the bag. The powder transferred to the vial was then further
mixed on a vortex mixer for approximately 15 sec. This blend had a
nominal budesonide concentration of 5.0% and a nominal SMN
concentration of 0.1% w/w. Aerosol performance testing as described
in the section above was performed, and the resulting respirable
fraction was 44%, and the delivery efficiency was 31%.
Comparative Example 1
[0113] Micronized budesonide (approximate particle sizes: d10=1.116
.mu.m, d50=1.878 .mu.m, d90=3.200 .mu.m, available from Onbio Inc.,
Ontario, Canada) (0.1597 grams) and 3.0040 grams of lactose
(INHALAC 230, lactose monohydrate, approximate particle sizes:
d10=60 .mu.m, d50=100 .mu.m, d90=140 .mu.m, available from Meggle
GmbH, Wasserburg, Germany) were added to a 4 inch by 4 inch (10
cm.times.10 cm) plastic bag with a ZIPLOCK seal. The contents of
the bag were mixed first by gently kneading the contents of the bag
followed by shaking the contents of the bag. This cycle of
kneading-shaking was repeated approximately five times during a
total mixing time of approximately three minutes. The contents of
the bag were then transferred into a 20 mL glass vial. Care was
taken to minimize the amount of residual powder left in the bag.
The powder transferred to the vial was then further mixed on a
vortex mixer for approximately 15 sec. This blend had a nominal
budesonide concentration of 5.0 w/w. Aerosol performance testing as
described in the section above was performed, and the resulting
respirable fraction was 33%, and the delivery efficiency was
27%.
Comparative Example 2
[0114] A surface-modified nanoparticle dispersion was prepared by
adding 5.0028 grams of hydrophobic silica SMN prepared as described
in Example 1 to 500 mL of heptane and stirring until the SMN had
completely dispersed. The resulting SMN-heptane dispersion had a
nominal concentration of 0.010 g/mL. Budesonide (approximate
particle sizes: d10=1.116 .mu.m, d50=1.878 .mu.m, d90=3.200 .mu.m,
available from Onbio Inc., Ontario, Canada) (0.2646 grams) was
added to a 50 mL beaker. Approximately 10 mL heptane was added to
the beaker to wet the budesonide. An aliquot of 3 mL of the
SMN-heptane dispersion was added to the beaker. The
budesonide-SMN-heptane mixture was then sonicated for approximately
5 seconds to ensure uniform mixture in the beaker.
[0115] Lactose (INHALAC 230, lactose monohydrate, approximate
particle sizes: d10=60 d50=100 .mu.m, d90=140 .mu.m, available from
Meggle GmbH, Wasserburg, Germany) (5.0327 grams) was added to a 250
mL round bottom flask. An aliquot of 8 mL of the SMN-heptane
dispersion was added to the flask along with an additional 30 mL of
heptane. The mixture was then sonicated for approximately 5 seconds
to ensure uniform mixture in the flask.
[0116] The budesonide-SMN-heptane mixture was then added to the 250
mL round bottom flask along with an additional 30 mL of heptane.
The resulting SMN-budesonide-lactose-heptane dispersion was then
sonicated for approximately 20 seconds to ensure uniform mixture in
the flask. The flask was then placed onto a rotary evaporator to
remove the solvent. The rotary evaporator was set to a nominal
temperature of 60.degree. C. and operated under a vacuum. After
removal of all of the visible solvent, the flask was then placed
into a vacuum oven at approximately 45.degree. C. for approximately
1 hour to remove further residual solvent. The resulting powder was
sieved with a No. 70 mesh sieve (210 micron openings) to break up
any agglomerated material. The sieved material was then collected
and placed in a container for later use. The dried
lactose-budesonide-SMN powder blend had a nominal budesonide
concentration of 5.0 w/w and a nominal concentration of
surface-modified nanoparticles of 2.0% w/w. Aerosol performance
testing as described in the section above was performed, and the
resulting respirable fraction was 35%, and the delivery efficiency
was 25%.
Example 6
[0117] Hydrophobic calcium phosphate surface-modified nanoparticles
(SMN) were prepared by mixing 25 grams of calcium chloride
hexahydrate (Fluka) and 80.25 grams of isooctyltrimethoxysilane
(Gelest, Inc.) in a 0.5 liter flask at approximately 110.degree. C.
under a stream of nitrogen until phase separation was observed,
then adding a solution of phosphoric acid (11.18 grams in 5 grams
of methanol with 80.65 grams trioctylamine (Alfa Aesar)). Heptane
(100 mL) was then added to the reaction mixture, which was held at
110.degree. C. for an additional two hours. The heptane was removed
via a Dean-Stark collector, and the hot reaction mixture was poured
into a 1 liter flask containing 800 mL of methanol, resulting in
precipitation of a white solid. The solid was isolated by decanting
the liquid, and was then washed by adding an ethanol/methanol
mixture and stirring overnight, followed by centrifugation to
isolate the solid. The solid was then dried in a 110.degree. C.
oven for one hour. The dried solid was redispersed in hexanes and
centrifuged, which was then washed a second time by adding to 400
mL of ethanol and stirring overnight. The solids were isolated by
centrifugation and decantation of the supernatant, and were then
dried in a 110.degree. C. oven for two hours. The solid was then
washed a third time by adding ethanol and stirring overnight. The
solids were isolated by centrifugation and decantation of the
supernatant, and were then dried in a 110.degree. C. oven for two
hours.
[0118] A surface-modified nanoparticle dispersion was prepared by
adding 1.0002 grams of the hydrophobic calcium phosphate SMN to 200
mL of heptane and sonicating until the SMN had completely
dispersed. The resulting SMN-heptane dispersion had a nominal
concentration of 0.005 g/mL. Lactose (INHALAC 250, lactose
monohydrate, approximate particle sizes: d10=20 .mu.m, d50=55 pm,
d90=95 .mu.m, available from Meggle GmbH, Wasserburg, Germany)
(49.868 grams) was added to a 500 mL round bottom flask. An aliquot
of 25 mL of the SMN-heptane dispersion was added to the flask along
with an additional 200 mL of heptane. The mixture was then
sonicated briefly to ensure uniform mixture in the flask. The flask
was then placed onto a rotary evaporator to remove the solvent. The
rotary evaporator was set to a nominal temperature of 50.degree. C.
and operated under a vacuum. After removal of all of the visible
solvent, the flask was then placed into a DESPATCH oven at
approximately 120.degree. C. for approximately 1 hour to remove
further residual solvent. The resulting powder was sieved with a
No. 60 mesh sieve (250 micron openings) to break up any
agglomerated material. The sieved material was then collected and
placed in a container for later use. The lactose-SMN powder blend
had a nominal concentration of surface-modified nanoparticles of
0.25 percent by weight of the powder blend (% w/w).
[0119] Micronized budesonide (approximate particle sizes: d10=1.116
.mu.m, d50=1.878 .mu.m, d90=3.200 .mu.m, available from Onbio Inc.,
Ontario, Canada) (0.2496 grams) and 4.7503 grams of the lactose-SMN
powder blend were added to a 20 mL glass vial. The contents of the
vial were mixed on a vortex mixer for approximately 3 minutes at
setting 8. This blend had a nominal budesonide concentration of 5.0
w/w and a nominal SMN concentration of 0.25% w/w. Aerosol
performance testing as described in the section above was
performed, and the resulting respirable fraction was 39%, and the
delivery efficiency was 24%.
Example 7
[0120] A lactose-SMN powder blend was prepared as in Example 6 with
the exception that the nominal concentration of surface-modified
nanoparticles was adjusted to be 0.5 w/w. This powder was blended
with micronized budesonide as in Example 6 to prepare a powder
blend having a nominal budesonide concentration of 5.0 w/w and a
nominal SMN concentration of 0.5% w/w. Aerosol performance testing
as described in the section above was performed, and the resulting
respirable fraction was 38%, and the delivery efficiency was
43%.
Example 8
[0121] A surface-modified nanoparticle dispersion was prepared by
adding 2.0002 grams of the hydrophobic calcium phosphate SMN to 200
mL of heptane and sonicating until the SMN had completely
dispersed. The resulting SMN-heptane dispersion had a nominal
concentration of 0.0100 g/mL. Lactose (INHALAC 250, lactose
monohydrate, approximate particle sizes: d10=20 .mu.m, d50=55
.mu.m, d90=95 .mu.m, available from Meggle GmbH, Wasserburg,
Germany) (49.495 grams) was added to a 500 mL round bottom flask.
An aliquot of 50 mL of the SMN-heptane dispersion was added to the
flask along with an additional 200 mL of heptane. The mixture was
then sonicated briefly to ensure uniform mixture in the flask. The
flask was then placed onto a rotary evaporator to remove the
solvent. The rotary evaporator was set to a nominal temperature of
50.degree. C. and operated under a vacuum. After removal of all of
the visible solvent, the flask was then placed into a Despatch oven
at approximately 120.degree. C. for approximately 1 hour to remove
further residual solvent. The resulting powder was sieved with a
No. 60 mesh sieve (250 micron openings) to break up any
agglomerated material. The sieved material was then collected and
placed in a container for later use. The lactose-SMN powder blend
had a nominal concentration of surface-modified nanoparticles of
1.0 percent by weight of the powder blend (% w/w).
[0122] This powder was blended with micronized budesonide as in
Example 6 to prepare a powder blend having a nominal budesonide
concentration of 5.0% w/w and a nominal SMN concentration of 1.0%
w/w. Aerosol performance testing as described in the section above
was performed, and the resulting respirable fraction was 42%, and
the delivery efficiency was 26%.
[0123] Comparative Example 3
[0124] Micronized budesonide (approximate particle sizes: d10
=1.116 .mu.m, d50 =1.878 .mu.m, d90=3.200 .mu.m, available from
Onbio Inc., Ontario, Canada) (0.2503 grams) and 4.7482 grams of
lactose (INHALAC 250, lactose monohydrate, approximate particle
sizes: d10=20 .mu.m, d50=55 .mu.m, d90=95 um, available from Meggle
GmbH, Wasserburg, Germany) were added to a 20 mL glass vial. The
contents of the vial were mixed on a vortex mixer for approximately
3 minutes at setting 8. This blend had a nominal budesonide
concentration of 5.0 w/w. Aerosol performance testing as described
in the section above was performed, and the resulting respirable
fraction was 29%, and the delivery efficiency was 16%.
[0125] Various modifications and alterations to this invention will
become apparent to those skilled in the art without departing from
the scope and spirit of this invention. It should be understood
that this invention is not intended to be unduly limited by the
illustrative embodiments and examples set forth herein and that
such examples and embodiments are presented by way of example only
with the scope of the invention intended to be limited only by the
claims set forth herein.
[0126] The complete disclosures of the patents, patent documents,
and publications cited herein are incorporated by reference in
their entirety or the portions of each that are indicated as if
each were individually incorporated.
* * * * *