U.S. patent application number 14/970261 was filed with the patent office on 2016-06-09 for manufacture of pharmaceutical compositions.
The applicant listed for this patent is VECTURA LIMITED. Invention is credited to DAVID MORTON, JOHN STANIFORTH.
Application Number | 20160158150 14/970261 |
Document ID | / |
Family ID | 34317561 |
Filed Date | 2016-06-09 |
United States Patent
Application |
20160158150 |
Kind Code |
A1 |
MORTON; DAVID ; et
al. |
June 9, 2016 |
Manufacture of Pharmaceutical Compositions
Abstract
The present invention relates to particles and to methods of
making particles. In particular, the invention relates to methods
of making composite active particles comprising a pharmaceutically
active material for pulmonary inhalation, the method comprising a
jet milling process.
Inventors: |
MORTON; DAVID; (WILTSHIRE,
GB) ; STANIFORTH; JOHN; (WILTSHIRE, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
VECTURA LIMITED |
Wiltshire |
|
GB |
|
|
Family ID: |
34317561 |
Appl. No.: |
14/970261 |
Filed: |
December 15, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13337596 |
Dec 27, 2011 |
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14970261 |
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10571146 |
Jul 17, 2006 |
8182838 |
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PCT/GB04/03996 |
Sep 15, 2004 |
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13337596 |
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Current U.S.
Class: |
424/490 ; 241/5;
424/489; 514/217; 514/221; 514/284; 514/56 |
Current CPC
Class: |
A61K 9/1623 20130101;
A61K 31/473 20130101; A61K 9/1617 20130101; A61K 31/727 20130101;
A61K 9/1694 20130101; A61K 31/5513 20130101; A61K 31/55 20130101;
A61K 9/0075 20130101; A61K 9/50 20130101; A61K 9/16 20130101; A61K
9/008 20130101; B02C 19/06 20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 9/50 20060101 A61K009/50; B02C 19/06 20060101
B02C019/06; A61K 31/473 20060101 A61K031/473; A61K 31/55 20060101
A61K031/55; A61K 31/727 20060101 A61K031/727; A61K 31/5513 20060101
A61K031/5513; A61K 9/16 20060101 A61K009/16 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 15, 2003 |
GB |
0321607.4 |
Claims
1. A method for making composite active particles for use in a
pharmaceutical composition for pulmonary inhalation, the method
comprising jet milling active particles in the presence of
particles of additive material and, optionally, air or a
compressible gas or fluid.
2. A method as claimed in claim 1, wherein the additive material
comprises an amino acid, a metal stearate or a phospholipid.
3. A method as claimed in claim 2, wherein the additive material
comprises one or more of leucine, isoleucine, lysine, valine,
methionine, phenylalanine.
4. A method as claimed in claim 3, wherein the additive material
comprises leucine and preferably L-leucine.
5. A method as claimed in claim 2, wherein the additive material
comprises magnesium stearate.
6. A method as claimed in claim 2, wherein the additive material
comprises lecithin.
7. A method as claimed in any one of the preceding claims, wherein
the jet milling is carried out at an inlet pressure of between 0.1
and 3 bar.
8. A method as claimed in any one of claims 1-6, wherein the jet
milling is carried out at an inlet pressure of between 3 and 12
bar.
9. A method as claimed in any one of the preceding claims, wherein
at least 90% by volume of the active particles are less than 20
.mu.m in diameter prior to jet milling.
10. A method as claimed in any one of the preceding claims, wherein
at least 90% by volume of the additive particles are less than 20
.mu.m in diameter prior to jet milling.
11. A method as claimed in any one of the preceding claims, wherein
jet milling is carried out at temperatures below room
temperature.
12. A method as claimed in claim 11, wherein jet milling is carried
out at a temperature below 10.degree. C. and preferably below
0.degree. C.
13. A method as claimed in any one of the preceding claims, wherein
carrier particles are also jet milled with the active particles and
the particles of additive material.
14. A method as claimed in claim 13, wherein the carrier particles
have a particle size of at least 20 .mu.m.
15. A method as claimed in claim 13, wherein the carrier particles
have a particle size of less than 30 .mu.m, preferably less than 20
.mu.m and more preferably less than 10 .mu.m.
16. Composite active particles for use in a pharmaceutical
composition made using a method as claimed in any one of the
preceding claims.
17. Composite active particles as claimed in claim 16, for
pulmonary inhalation.
18. Composite active particles as claimed in either of claims 16
and 17, wherein the additive material forms a coating on the
surface of the additive particles.
19. Composite active particles as claimed in claim 18, wherein the
coating is a discontinuous coating.
20. Composite active particles as claimed in either of claims 18
and 19, wherein the coating of additive material is not more than 1
.mu.m in thickness.
21. Composite active particles as claimed in any one of claims
16-20, having an MMAD of not more than 10 .mu.m.
22. Composite active particles as claimed in claim 21, having an
MMAD of not more than 5 .mu.m, not more than 3 .mu.m, not more than
2 .mu.m, or not more than 1 .mu.m.
23. Composite active particles as claimed in any one of claims
16-22, wherein at least 90% by weight of the composite active
particles have a diameter of not more than 10 .mu.m.
24. Composite active particles as claimed in claim 23, wherein at
least 90% by weight of the particles have a diameter of not more
than 5 .mu.m, not more than 3 .mu.m, or not more than 1 .mu.m.
25. A pharmaceutical composition comprising composite active
particles as claimed in any one of claims 16-24.
26. A composition as claimed in claim 25, wherein the composition
is for pulmonary inhalation.
27. A composition as claimed in either of claims 25 and 26, wherein
the composition is a dry powder composition.
28. A composition as claimed in claim 27, wherein the composition
further comprises carrier particles.
29. A composition as claimed in any one of claims 25-28, wherein
the composition has a FPF(ED) of at least 70%.
30. A composition as claimed in claim 29, wherein the FPF(ED) is at
least 80%, at least 85%, or at least 90%.
31. A composition as claimed in any one of claims 25-28, wherein
the composition has a FPF(MD) of at least 60%.
32. A composition as claimed in claim 29, wherein the FPF(MD) is at
least 70%, at least 80%, or at least 85%.
33. A dry powder inhaler containing a composition as claimed in any
one of claims 25-32.
34. Use of an additive material as a milling aid in the jet milling
of an active material.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 13/337,596 filed Dec. 27, 2011, which is a continuation of U.S.
application Ser. No. 10/571,146 filed Jul. 17, 2006, now patented
as U.S. Pat. No. 8,182,838 which issued May 22, 2012, which is a
United States national stage of International Application No.
PCT/GB2004/003996, filed Sep. 15, 2004, which was published as
International Publication No. WO 2005/025536, and which claims
benefit of United Kingdom Application No. 0321607.4 filed, Sep. 15,
2003, the entire contents of which are hereby expressly
incorporated herein by reference thereto.
[0002] The present invention relates to particles and to methods of
making particles. In particular, the invention relates to methods
of making composite particles comprising a pharmaceutically active
material and an additive material, for pulmonary inhalation, the
methods comprising a co-jet milling process.
[0003] The lung provides an obvious target for local administration
of formulations which are intended to cure or alleviate respiratory
or pulmonary diseases, such as cystic fibrosis (CF), asthma, lung
cancer, etc. The lung also provides a route for delivery of
systemically acting formulations to the blood stream, for example,
for delivery of active agents which are not suitable for oral
ingestion, such as agents that degrade in the digestive tract
before they can be absorbed, and those requiring an extremely rapid
onset of their therapeutic action.
[0004] It is known to administer pharmaceutically active agents to
a patient in the form of fine, dry particles (active particles),
for example, by pulmonary administration of a particulate
medicament composition which is inhaled by the patient. Known
devices for the administration of drugs to the respiratory system
include pressurised metered dose inhalers (pMDIs) and dry powder
inhalers (DPIs).
[0005] The size of the active particles is of great importance in
determining the site of the absorption in the lung. In order for
the particles be carried deep into the lungs, the particles must be
very fine, for example having a mass median aerodynamic diameter
(MMAD) of less than 10 .mu.m. Particles having aerodynamic
diameters greater than about 10 .mu.m are likely to impact the
walls of the throat and generally do not reach the lung. Particles
having aerodynamic diameters in the range of about 5 .mu.m to about
2 .mu.m will generally be deposited in the respiratory bronchioles
whereas smaller particles having aerodynamic diameters in the range
of about 3 to about 0.05 .mu.m are likely to be deposited in the
alveoli and to be absorbed into the bloodstream.
[0006] Fine particles, that is those with an MMAD of less than
about 10 .mu.m tend to be increasingly thermodynamically unstable
due to their high surface area to volume ratio, which provides an
increasing surface free energy with this decreasing particle size,
and consequently increases the tendency of particles to agglomerate
and the strength of the agglomerate. In the inhaler, agglomeration
of fine particles and adherence of such particles to the walls of
the inhaler are problems that result in the fine particles leaving
the inhaler as large, stable agglomerates, or being unable to leave
the inhaler and remaining adhered to the interior of the device, or
even clogging or blocking the inhaler.
[0007] The uncertainty as to the extent of formation of stable
agglomerates of the particles between each actuation of the
inhaler, and also between different inhalers and different batches
of particles, leads to poor dose reproducibility. Furthermore, the
formation of agglomerates means that the MMAD of the active
particles can be vastly increased, with agglomerates of the active
particles not reaching the required part of the lung.
[0008] The metered dose (MD) of a dry powder formulation is the
total mass of active agent present in the metered form presented by
the inhaler device in question. For example, the MD might be the
mass of active agent present in a capsule for a Cyclohaler (trade
mark), or in a foil blister in an Aspirair (trade mark) device.
[0009] The emitted dose (ED) is the total mass of the active agent
emitted from the device following actuation. It does not include
the material left inside or on the surfaces of the device. The ED
is measured by collecting the total emitted mass from the device in
an apparatus frequently referred to as a dose uniformity sampling
apparatus (DUSA), and recovering this by a validated quantitative
wet chemical assay.
[0010] The fine particle dose (FPD) is the total mass of active
agent which is emitted from the device following actuation which is
present in an aerodynamic particle size smaller than a defined
limit
[0011] This limit is generally taken to be Si.tm if not expressly
stated to be an alternative limit, such as 3 .mu.m or 1 .mu.m, etc.
The FPD is measured using an impactor or impinger, such as a twin
stage impinger (TSI), multi-stage liquid impinger (MSLI), Andersen
Cascade Impactor (ACI) or a Next Generation Impactor (NGI). Each
impactor or impinger has a pre-determined aerodynamic particle size
collection cut-off point for each stage. The FPD value is obtained
by interpretation of the stage-by-stage active agent recovery
quantified by a validated quantitative wet chemical assay where
either a simple stage cut is used to determine FPD or a more
complex mathematical interpolation of the stage-by-stage deposition
is used.
[0012] The fine particle fraction (FPF) is normally defined as the
FPD divided by the ED and expressed as a percentage. Herein, the
FPF of ED is referred to as FPF(ED) and is calculated as
FPF(ED)=(FPD/ED).times.100%.
[0013] The fine particle fraction (FPF) may also be defined as the
FPD divided by the MD and expressed as a percentage. Herein, the
FPF of MD is referred to as FPF(MD), and is calculated as
FPF(MD)=(FPD/MD).times.100%.
[0014] The terms "delivered dose" or "DD" and "emitted dose" or
"ED" are used interchangeably herein. These are measured as set out
in the current EP monograph for inhalation products.
[0015] "Actuation of an inhaler" refers to the process during which
a dose of the powder is removed from its rest position in the
inhaler. That step takes place after the powder has been loaded
into the inhaler ready for use.
[0016] The tendency of fine particles to agglomerate means that the
FPF of a given dose can be highly unpredictable and a variable
proportion of the fine particles will be administered to the lung,
or to the correct part of the lung, as a result. This is observed,
for example, in formulations comprising pure drug in fine particle
form. Such formulations exhibit poor flow properties and poor
FPF.
[0017] In an attempt to improve this situation and to provide a
consistent FPF and FPD, dry powder formulations often include
additive material.
[0018] The additive material is intended to reduce the adhesion and
cohesion experienced by the particles in the dry powder
formulation. It is thought that the additive material interferes
with the weak bonding forces between the small particles, helping
to keep the particles separated and reducing the adhesion of such
particles to one another, to other particles in the formulation if
present and to the internal surfaces of the inhaler device. Where
agglomerates of particles are formed, the addition of particles of
additive material decreases the stability of those agglomerates so
that they are more likely to break up in the turbulent air stream
and collisions created on actuation of the inhaler device,
whereupon the particles are expelled from the device and inhaled.
As the agglomerates break up, the active particles may return to
the form of small individual particles or agglomerates of small
numbers of particles which are capable of reaching the lower
lung.
[0019] In the prior art, dry powder formulations are discussed
which include distinct particles of additive material (generally of
a size comparable to that of the fine active particles). In some
embodiments, the additive material may form a coating, generally a
discontinuous coating, on the active particles and/or on any
carrier particles.
[0020] Preferably, the additive material is an anti-adherent
material and it will tend to reduce the cohesion between particles
and will also prevent fine particles becoming attached to the inner
surfaces of the inhaler device. Advantageously, the additive
material is an anti-friction agent or glidant and will give the
powder formulation better flow properties in the inhaler. The
additive materials used in this way may not necessarily be usually
referred to as anti-adherents or anti-friction agents, but they
will have the effect of decreasing the adhesion and cohesion
between the particles or improving the flow of the powder. The
additive materials are sometimes referred to as force control
agents (FCAs) and they usually lead to better dose reproducibility
and higher FPFs.
[0021] Therefore, an additive material or FCA, as used herein, is a
material whose presence on the surface of a particle can modify the
adhesive and cohesive surface forces experienced by that particle,
in the presence of other particles and in relation to the surfaces
that the particles are exposed to. In general, its function is to
reduce both the adhesive and cohesive forces.
[0022] The reduced tendency of the particles to bond strongly,
either to each other or to the device itself, not only reduces
powder cohesion and adhesion, but can also promote better flow
characteristics. This leads to improvements in the dose
reproducibility because it reduces the variation in the amount of
powder metered out for each dose and improves the release of the
powder from the device. It also increases the likelihood that the
active material, which does leave the device, will reach the lower
lung of the patient.
[0023] It is favourable for unstable agglomerates of particles to
be present in the powder when it is in the inhaler device. As
indicated above, for a powder to leave an inhaler device
efficiently and reproducibly, the particles of such a powder should
be large, preferably larger than about 40 .mu.m. Such a powder may
be in the form of either individual particles having a size of
about 40 .mu.m or larger and/or agglomerates of finer particles,
the agglomerates having a size of about 40 .mu.m or larger. The
agglomerates formed can have a size of as much as about 100 .mu.m
and, with the addition of the additive material, those agglomerates
are more likely to be broken down efficiently in the turbulent
airstream created on inhalation. Therefore, the formation of
unstable agglomerates of particles in the powder may be favoured
compared with a powder in which there is substantially no
agglomeration.
[0024] The reduction in the cohesion and adhesion between the
active particles can lead to equivalent performance with reduced
agglomerate size, or even with individual particles.
[0025] In a further attempt to improve extraction of the dry powder
from the dispensing device and to provide a consistent FPF and FPD,
dry powder formulations often include coarse carrier particles of
excipient material mixed with fine particles of active material.
Rather than sticking to one another, the fine active particles tend
to adhere to the surfaces of the coarse carrier particles whilst in
the inhaler device, but are supposed to release and become
dispersed upon actuation of the dispensing device and inhalation
into the respiratory tract, to give a fine suspension. The carrier
particles preferably have MMADs greater than about 60 .mu.m.
[0026] The inclusion of coarse carrier particles is also very
attractive where very small doses of active agent are dispensed. It
is very difficult to accurately and reproducibly dispense very
small quantities of powder and small variations in the amount of
powder dispensed will mean large variations in the dose of active
agent where the powder comprises mainly active particles.
[0027] Therefore, the addition of a diluent, in the form of large
excipient particles will make dosing more reproducible and
accurate.
[0028] Carrier particles may be of any acceptable excipient
material or combination of materials. For example, the carrier
particles may be composed of one or more materials selected from
sugar alcohols, polyols and crystalline sugars. Other suitable
carriers include inorganic salts such as sodium chloride and
calcium carbonate, organic salts such as sodium lactate and other
organic compounds such as polysaccharides and oligosaccharides.
Advantageously, the carrier particles comprise a polyol. In
particular, the carrier particles may be particles of crystalline
sugar, for example mannitol, dextrose or lactose. Preferably, the
carrier particles are composed of lactose.
[0029] However, a further difficulty is encountered when adding
coarse carrier particles to a composition of fine active particles
and that difficulty is ensuring that the fine particles detach from
the surface of the large particles upon actuation of the delivery
device.
[0030] The step of dispersing the active particles from other
active particles and from carrier particles, if present, to form an
aerosol of fine active particles for inhalation is significant in
determining the proportion of the dose of active material which
reaches the desired site of absorption in the lungs. In order to
improve the efficiency of that dispersal, it is known to include in
the composition additive materials of the nature discussed above.
Compositions comprising fine active particles and additive
materials are disclosed in WO 97/03649 and WO 96/23485.
[0031] It is an aim of the present invention to provide a method of
producing dry powder compositions which have physical and chemical
properties which lead to an enhanced FPF and FPD. This will lead to
greater dosing efficiency, with a greater proportion of the active
agent being dispensed and reaching the desired part of the lung for
achieving the required therapeutic effect.
[0032] It is also an aim of the present invention to provide a
method of producing powders wherein the method achieves a further
reduction in the size of the active particles, preferably so that
the particles are of an appropriate size for administration to the
deep lung by inhalation. Preferably, this is possible using both
active dry powder inhaler devices and passive dry powder inhaler
devices.
[0033] In particular, the present invention seeks to optimise the
preparation of particles of active agent used in the dry powder
composition by engineering the particles making up the dry powder
composition and, in particular, by engineering the particles of
active agent. It is proposed to do this by adjusting and adapting
the milling process used to form the particles of active agent.
[0034] According to a first aspect of the present invention, a
method is provided for making composite active particles for use in
a pharmaceutical composition for pulmonary inhalation, the method
comprising jet milling active particles in the presence of additive
material, preferably wherein the jet milling is conducted using air
or a compressible gas or fluid. Preferably, the additive material
is a force control agent, as defined herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0035] FIG. 1 is a graph presenting the life dose uniformity for
formulation "6C".
[0036] FIG. 2 is a graph presenting the life dose uniformity for
formulation "12A".
[0037] FIG. 3 shows the particle size distribution of the raw
material micronized lactose.
[0038] FIG. 4 shows the particle size distribution of the raw
material apomorphine.
[0039] FIG. 5 shows the particle size distribution of the raw
material clobozam.
[0040] FIG. 6 shows the particle size distribution of the clobozam
formulation comprising 95% clobozam and 5% mechanofused magnesium
stearate.
[0041] FIG. 7 shows the particle size distribution of the clobozam
formulation comprising 95% clobozam and 5% co-jet milled
Aerocine.
[0042] FIG. 8 shows the particle size distribution of the clobozam
formulation comprising 95% clobozam and 5% co-jet milled
leucine.
[0043] FIG. 9 shows the particle size distribution of the
apomorphine formulation comprising 75% lactose, 20% apomorphine and
5% co-jet milled leucine.
[0044] FIG. 10 also shows the particle size distribution of the
apomorphine formulation comprising 75% lactose, 20% apomorphine and
5% co-jet milled leucine.
[0045] In the conventional use of the word, "milling" means the use
of any mechanical process which applies sufficient force to the
particles of active material that it is capable of breaking coarse
particles (for example, particles with an MMAD greater than 100
.mu.m) down to fine particles (for example, having an MMAD not more
than 50 .mu.n). In the present invention, the term "milling" also
refers to deagglomeration of particles in a formulation, with or
without particle size reduction. The particles being milled may be
large or fine prior to the milling step.
[0046] In the prior art, co-milling or co-micronising active agents
and additive materials have been suggested. It is stated that
milling can be used to substantially decrease the size of particles
of active agent. However, if the particles of active agent are
already fine, for example have an MMAD of less than 20 .mu.m prior
to the milling step, the size of those particles may not be
significantly reduced where the milling of these active particles
takes place in the presence of an additive material. Rather,
milling of fine active particles with additive particles using the
methods described in the prior art (for example, in WO 02/43701)
will result in the additive material becoming deformed and being
smeared over or fused to the surfaces of the active particles. The
resultant composite active particles have been found to be less
cohesive after the milling treatment. However, there is still the
disadvantage that this is not combined with a significant reduction
in the size of the particles.
[0047] The prior art mentions two types of processes in the context
of co-milling or co-micronising active and additive particles.
[0048] First, there is the compressive type process, such as
mechanofusion, cyclomixing and similar methods. As the name
suggests, mechanofusion is a dry coating process designed to
mechanically fuse a first material onto a second material. The
first material is generally smaller and/or softer than the second.
The mechanofusion and cyclomixing working principles are distinct
from alternative milling techniques in having a particular
interaction between an inner element and a vessel wall, and are
based on providing energy by a controlled and substantial
compressive force. The term mechanofusion is used here to encompass
any process which operates in such a manner, and applies in a
rotational vessel a controlled and substantial compressive force.
"Food processor" type mixers are not considered useful for the
processes required in the present invention. Such mixers do not
provide the necessary compressive forces. They include conventional
mixing blades and these are not arranged with a small enough gap
between the blades and the vessel wall.
[0049] When fine active particles and additive particles are fed
into the mechanofusion driven vessel (such as a MechanoFusion
system (Hosokawa Micron Ltd)), they are subject to a centrifugal
force and are pressed against the vessel inner wall. The powder is
compressed between the fixed clearance of the drum wall and an
inner element with high relative speed between drum and element.
The inner wall and the element together form a gap or nip in which
the particles are pressed together. As a result, the particles
experience very high shear forces and very strong compressive
stresses as they are trapped between the inner drum wall and the
inner element. The particles are pressed against each other with
enough energy to locally heat and soften, break, distort, flatten
and wrap the additive particles around the core particle to form a
coating. The energy is generally sufficient to break up
agglomerates and some degree of size reduction of both components
may occur.
[0050] These mechanofusion and cyclomixing processes apply a high
enough degree of force to separate the individual particles of
active material and to break up tightly bound agglomerates of the
active particles such that effective mixing and effective
application of the additive material to the surfaces of those
particles is achieved. An especially desirable aspect of the
described co-milling processes is that the additive material
becomes deformed in the milling and may be smeared over or fused to
the surfaces of the active particles.
[0051] However, in practice, this compression process produces
little or no milling (i.e. size reduction) of the drug particles,
especially where they are already in a micronised form (i.e. <10
.mu.m), the only physical change which may be observed is a plastic
deformation of the particles to a rounder shape.
[0052] Secondly, there are the impact milling processes involved in
ball milling and the use of a homogenizer.
[0053] Ball milling is a suitable milling method for use in the
prior art co-milling processes. Centrifugal and planetary ball
milling are especially preferred methods. Alternatively, a high
pressure homogeniser may be used in which a non-compressible fluid
containing the particles is forced through a valve at high pressure
producing conditions of high shear and turbulence. Such
homogenisers may be more suitable than ball mills for use in large
scale preparations of the composite active particles.
[0054] Suitable homogensiers include EmulsiFlex high pressure
homogenisers which are capable of pressures up to 4000 bar, Niro
Soavi high pressure homogenisers (capable of pressures up to 2000
bar), and Microfluidics Microfluidisers (capable of pressures up to
2750 bar). The milling step may, alternatively, involve a high
energy media mill or an agitator bead mill, for example, the
Netzsch high energy media mill, or the DYNO-mill (Willy A. Bachofen
AG, Switzerland).
[0055] These processes create high-energy impacts between media and
particles or between particles. In practice, while these processes
are good at making very small particles, it has been found that
neither the ball mill nor the homogenizer was effective in
producing dispersion improvements in resultant drug powders in the
way observed for the compressive process. It is believed that the
second impact processes are not as effective in producing a coating
of additive material on each particle.
[0056] Conventional methods comprising co-milling active material
with additive materials (as described in WO 02/43701) result in
composite active particles which are fine particles of active
material with an amount of the additive material on their surfaces.
The additive material is preferably in the form of a coating on the
surfaces of the particles of active material. The coating may be a
discontinuous coating. The additive material may be in the form of
particles adhering to the surfaces of the particles of active
material.
[0057] At least some of the composite active particles may be in
the form of agglomerates. However, when the composite active
particles are included in a pharmaceutical composition, the
additive material promotes the dispersal of the composite active
particles on administration of that composition to a patient, via
actuation of an inhaler.
[0058] Jet mills are capable of reducing solids to particle sizes
in the low-micron to submicron range. The grinding energy is
created by gas streams from horizontal grinding air nozzles.
Particles in the fluidized bed created by the gas streams are
accelerated towards the centre of the mill, colliding with slower
moving particles. The gas streams and the particles carried in them
create a violent turbulence and as the particles collide with one
another they are pulverized.
[0059] In the past, jet milling has not been considered attractive
for co-milling active and additive particles, processes like
mechanofusion and cyclomixing or equivalent being clearly
preferred. The collisions between the particles in a jet mill are
somewhat uncontrolled and those skilled in the art, therefore,
considered it unlikely for this technique to be able to provide the
desired deposition of a coating of additive material on the surface
of the active particles. Moreover, it was believed that, unlike the
situation with mechanofusion, cyclomixing and similar processes,
segregation of the powder constituents occurred in jet mills, such
that the finer particles, that were believed to be the most
effective, could escape from the process. In contrast, it could be
clearly envisaged how techniques such as mechanofusion would result
in the desired coating.
[0060] It should also be noted that it was also previously believed
that the compressive or impact milling processes must be carried
out in a closed system, in order to prevent segregation of the
different particles. This has also been found to be untrue and the
co-jet milling processes according to the present invention do not
need to be carried out in a closed system. Even in an open system,
the co-jet milling has surprisingly been found not to result in the
loss of the small particles, even when using leucine as the
additive material.
[0061] It has now unexpectedly been discovered that composite
particles of active and additive material can be produced by co-jet
milling these materials. The resultant particles have excellent
characteristics which lead to greatly improved performance when the
particles are dispensed from a DPI for administration by
inhalation. In particular, co-jet milling active and additive
particles can lead to further significant particle size reduction.
What is more, the composite active particles exhibit an enhanced
FPD and FPF, compared to those disclosed in the prior art.
[0062] The effectiveness of the promotion of dispersal of active
particles has been found to be enhanced by using the co-jet milling
methods according to the present invention in comparison to
compositions which are made by simple blending of similarly sized
particles of active material with additive material. The phrase
"simple blending" means blending or mixing--using conventional
tumble blenders or high shear mixing and basically the use of
traditional mixing apparatus which would be available to the
skilled person in a standard laboratory.
[0063] It has been found that, contrary to previous belief, co-jet
milling can be used to produce sufficiently complete coatings of
additive material, which have now been observed to substantially
improve the dispersion of the powders from an inhaler. The jet
milling process can also be adjusted to tailor the composite
particles to the type of inhaler device to be used to dispense the
particles. The inhaler device may be an active inhaler device, such
as Aspirair (trade mark) or it may be a passive device.
[0064] Further, the co-jet milling process may optionally also be
arranged so as to significantly mill the active particles, that is,
to significantly reduce the size of the active particles: The
co-jet milling of the present invention may even, in certain
circumstances, be more efficient in the presence of the additive
material than it is in the absence of the additive material. The
benefits are that it is therefore possible to produce smaller
particles for the same mill, and it is possible to produce milled
particles with less energy. Co-jet milling should also reduce the
problem of amorphous content by both creating less amorphous
material, as well as hiding it below a layer of additive
material.
[0065] The impact forces of the co-jet milling are sufficient to
break up agglomerates of drug, even micronised drug, and are
effective at distributing the additive material to the consequently
exposed faces of the particles. This is an important aspect of the
present invention. It has been shown that if the energy of the
process is not sufficient to break up the agglomerates of drug (for
example, as will be the case when one uses a conventional blender),
the additive material merely coats the agglomerates and these
agglomerates can even be compressed, making them even more
difficult to disperse. This is clearly undesirable when one is
seeking to prepare a dry powder for administration by
inhalation.
[0066] Fine particles of active material suitable for pulmonary
administration have often been prepared by milling in the past.
However, when using many of the known milling techniques, once the
particles reach a minimum size, referred to as the "critical size",
they tend to re-combine at the same rate as being fractured, or do
not fracture effectively and therefore no further reduction in the
particle size is achieved. Critical sizes are specific to
particular mills and sets of milling conditions.
[0067] Thus, manufacture of fine particles by milling can require
much effort and there are factors which consequently place limits
on the minimum size of particles of active material which can be
achieved, in practice, by such milling processes.
[0068] The present invention consequently relates to the provision
of a high-energy impact process that is effective in producing
improvements in the resultant drug powders.
[0069] Furthermore, contrary to conventional thinking, the
processes of the present invention do not need to be carried out in
a closed system. Even where the additive material being co-jet
milled is leucine, there is no observed loss of additive material
or reduction in coating where the jet milling is not carried out in
a closed system. Rather, in one embodiment of the invention, the
method of the present invention is carried out in a flow-through
system, without any loss in performance of the resultant composite
particles. This is an economically important feature, as it can
significantly increase the rate of production of the powders of the
invention.
[0070] In one embodiment of the present invention, 90% by mass of
the active particles jet-milled are initially less than 20 .mu.m in
diameter. More preferably, 90% by mass of the active particles
jet-milled are initially less than 10 .mu.m in diameter, and most
preferably less than 5 .mu.m in diameter.
[0071] In another embodiment, 90% by mass of the additive particles
jet-milled are initially less than 20 .mu.m in diameter. More
preferably, 90% by mass of the additive particles jet-milled are
initially less than 10 .mu.m in diameter, and most preferably less
than 5 .mu.m in diameter or less than 3 .mu.m in diameter.
[0072] The terms "active particles" and "particles of active
material" and the like are used interchangeably herein. The active
particles comprise one or more pharmaceutically active agents. The
preferred active agents include:
[0073] 1) steroid drugs such as alcometasone, beclomethasone,
beclomethasone dipropionate, betamethasone, budesonide, clobetasol,
deflazacort, diflucortolone, desoxymethasone, dexamethasone,
fludrocortisone, flunisolide, fluocinolone, fluometholone,
fluticasone, fluticasone proprionate, hydrocortisone,
triamcinolone, nandrolone decanoate, neomycin sulphate, rimexolone,
methylprednisolone and prednisolone;
[0074] 2) antibiotic and antibacterial agents such as
metronidazole, sulphadiazine, triclosan, neomycin, amoxicillin,
amphotericin, clindamycin, aclarubicin, dactinomycin, nystatin,
mupirocin and chlorhexidine;
[0075] 3) systemically active drugs such as isosorbide dinitrate,
isosorbide mononitrate, apomorphine and nicotine;
[0076] 4) antihistamines such as azelastine, chlorpheniramine,
astemizole, cetirizine, cinnarizine, desloratadine, loratadine,
hydroxyzine, diphenhydramine, fexofenadine, ketotifen,
promethazine, trimeprazine and terfenadine;
[0077] 5) anti-inflammatory agents such as piroxicam, nedocromil,
benzydamine, diclofenac sodium, ketoprofen, ibuprofen, heparinoid,
nedocromil, cromoglycate, fasafungine and iodoxamide;
[0078] 6) anticholinergic agents such as atropine, benzatropine,
biperiden, cyclopentolate, oxybutinin, orphenadine hydrochloride,
glycopyrronium, glycopyrrolate, procyclidine, propantheline,
propiverine, tiotropium, tropicamide, trospium, ipratropium bromide
and oxitroprium bromide;
[0079] 7) anti-emetics such as bestahistine, dolasetron, nabilone,
prochlorperazine, ondansetron, trifluoperazine, tropisetron,
domperidone, hyoscine, cinnarizine, metoclopramide, cyclizine,
dimenhydrinate and promethazine;
[0080] 8) hormonal drugs such as protirelin, thyroxine, salcotonin,
somatropin, tetracosactide, vasopressin or desmopressin;
[0081] 9) bronchodilators such as salbutamol, fenoterol and
salmeterol;
[0082] 10) sympathomimetic drugs such as adrenaline, noradrenaline,
dexamfetamine, dipirefin, dobutamine, dopexamine, phenylephrine,
isoprenaline, dopamine, pseudoephedrine, tramazoline and
xylometazoline;
[0083] 11) anti-fungal drugs such as amphotericin, caspofungin,
clotrimazole, econazole nitrate, fluconazole, ketoconazole,
nystatin, itraconazole, terbinafine, voriconazole and
miconazole;
[0084] 12) local anaesthetics such as amethocaine, bupivacaine,
hydrocortisone, methylprednisolone, prilocaine, proxymetacaine,
ropivacaine, tyrothricin, benzocaine and lignocaine;
[0085] 13) opiates, preferably for pain management, such as
buprenorphine, dextromoramide, diamorphine, codeine phosphate,
dextropropoxyphene, dihydrocodeine, papaveretum, pholcodeine,
loperamide, fentanyl, methadone, morphine, oxycodone, phenazocine,
pethidine and combinations thereof with an anti-emetic;
[0086] 14) analgesics and drugs for treating migraine such as
clonidine, codine, coproxamol, dextropropoxypene, ergotamine,
sumatriptan, tramadol and non-steroidal anti-inflammatory
drugs;
[0087] 15) narcotic agonists and opiate antidotes such as naloxone,
and pentazocine;
[0088] 16) phosphodiesterase type 5 inhibitors, such as sildenafil
(Viagra (trade mark));
[0089] 17) antidepressants such as amesergide, amineptine,
amitriptyline, amoxapine, benactyzine, brofaromine, bupropion,
butriptyline, cianopramine, citalopram, clorgyline, clovoxamine,
demexiptiline, desipramine, dibenzepin, dimetacrine, dothiepin,
doxepin, etoperidone, femoxetine, fezolamine, fluoxetine,
fluvoxamine, ifoxetine, imipramine, iprindole, isocarboxazid,
levoprotiline, lofepramine, maprotiline, medifoxamine, melitracen,
metapramine, methylphenidate, mianserin, milnacipran, minaprine,
mirtazapine, moclobemide, nefazodone, nialamide, nomifensine,
nortriptyline, opipramol, oxaflozane, oxaprotiline, oxitriptan,
paroxetine, phenelzine, pirlindole, propizepine, protriptyline,
quinupramine, rolipram, selegiline, sertraline, setiptiline,
sibutramine, teniloxazine, tianeptine, tofenacin, toloxatone,
tranylcypromine, trazodone, trimipramine, tryptophan, venlafaxine,
viloxazine, viqualine and zimeldine;
[0090] 18) serotonin agonists such as 2-methyl serotonin,
buspirone, ipsaperone, tiaspirone, gepirone, lysergic acid
diethylamide, ergot alkaloids,
8-hydroxy-(2-N,N-dipropylamino)-tetraline,
1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane, cisapride,
sumatriptan, m-chlorophenylpiperazine, trazodone, zacopride and
mezacopride;
[0091] 19) serotonin antagonists including ondansetron,
granisetron, metoclopramide, tropisetron, dolasetron,
trimethobenzamide, methysergide, risperidone, ketanserin,
ritanserin, clozapine, amitryptiline,
R(+)-.alpha.-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidi-
ne-methanol, azatadine, cyproheptadine, fenclonine,
dexfenfluramine, fenfluramine, chlorpromazine and mianserin;
[0092] 20) adrenergic agonists including methoxamine,
methpentermine, metaraminol, mitodrine, clonidine, apraclonidine,
guanfacine, guanabenz, methyldopa, amphetamine, methamphetamine,
epinephrine, norepinephrine, ethylnorepinephrine, phenylephrine,
ephedrine, pseudo-ephedrine, methylphenidate, pemoline,
naphazoline, tetrahydrozoline, oxymetazoline, xylometazoline,
phenylpropanolamine, phenylethylamine, dopamine, dobutamine,
colterol, isoproterenol, isotharine, metaproterenol, terbutaline,
metaraminol, tyramine, hydroxyamphetamine, ritodrine, prenalterol,
albuterol, isoetharine, pirbuterol, bitolterol, fenoterol,
formoterol, procaterol, salmeterol, mephenterine and
propylhexedrine;
[0093] 21) adrenergic antagonists such as phenoxybenzamine,
phentolamine, tolazoline, prazosin, terazosin, doxazosin,
trimazosin, yohimbine, ergot alkaloids, labetalol, ketanserin,
urapidil, alfuzosin, bunazosin, tamsulosin, chlorpromazine,
haloperidol, phenothiazines, butyrophenones, propranolol, nadolol,
timolol, pindolol, metoprolol, atenolol, esmolol, acebutolol,
bopindolol, carteolol, oxprenolol, penbutolol, carvedilol,
medroxalol, naftopidil, bucindolol, levobunolol, metipranolol,
bisoprolol, nebivolol, betaxolol, carteolol, celiprolol, sotalol,
propafenone and indoramin;
[0094] 22) adrenergic neurone blockers including bethanidine,
debrisoquine, guabenxan, guanadrel, guanazodine, guanethidine,
guanoclor and guanoxan;
[0095] 23) benzodiazepines including alprazolam, brotizolam,
chlordiazepoxide, clobazepam, clonazepam, clorazepate, demoxepam,
diazepam, estazolam, flurazepam, halazepam, lorazepam, midazolam,
nitrazepam, nordazapam, oxazepam, prazepam, quazepam, temazepam and
triazolam;
[0096] 24) mucolytics agents such as N-acetylcysteine, recombinant
human DNase, amiloride, dextrans, heparin and low molecular weight
heparin; and
[0097] 25) pharmaceutically acceptable salts of any of the
foregoing.
[0098] Preferably, the active agent is a small molecule, as opposed
to a macromolecule. Preferably, the active agent is not a protein,
and more preferably, the active agent is not insulin. In the case
of proteins and in particular insulin, there is little or no
benefit to be derived from the use of a force control agent in a
dry powder formulation for administration by inhalation. The reason
for this is that in the case of these active agents, the active
agent itself acts as a force control agent and the cohesive forces
of particles of these active agents are already only weak.
[0099] In preferred embodiments of the present invention, the
active agent is heparin (fractionated and unfractionated),
apomorphine, clobozam, clomipramine or glycopyrrolate.
[0100] The terms "additive particles" and "particles of additive
material" are used interchangeably herein. The additive particles
comprise one or more additive materials (or FCAs). Preferably, the
additive particles consist essentially of the additive
material.
[0101] Known additive materials usually consist of physiologically
acceptable material, although the additive material may not always
reach the lung. For example, where the additive particles are
attached to the surface of carrier particles, they will generally
be deposited, along with those carrier particles, at the back of
the throat of the user.
[0102] Advantageously, the additive material includes one or more
compounds selected from amino acids and derivatives thereof, and
peptides and derivatives thereof. Amino acids, peptides and
derivatives of peptides are physiologically acceptable and give
acceptable release of the active particles on inhalation.
[0103] It is particularly advantageous for the additive material to
comprise an amino acid. The additive material may comprise one or
more of any of the following amino acids: leucine, isoleucine,
lysine, valine, methionine, and phenylalanine. The additive may be
a salt or a derivative of an amino acid, for example aspartame or
acesulfame K. Preferably, the additive particles consist
substantially of an amino acid, more preferably of leucine,
advantageously L-leucine. The D-and DL-forms may also be used. As
indicated above, leucine has been found to give particularly
efficient dispersal of the active particles on inhalation.
[0104] The additive material may include one or more water soluble
substances. This helps absorption of the additive material by the
body if it reaches the lower lung. The additive material may
include dipolar ions, which may be zwitterions. It is also
advantageous to include a spreading agent as an additive material,
to assist with the dispersal of the composition in the lungs.
Suitable spreading agents include surfactants such as known lung
surfactants (e.g. ALEC, Registered Trade Mark), which comprise
phospholipids, for example, mixtures of DPPC (dipalmitoyl
phosphatidylcholine) and PG (phosphatidylglycerol).
[0105] The phospholipids used in accordance with the invention may
have acyl substituents on the phosphatidyl groups. As in their
natural counterparts, the acyl groups may comprise identical or
different, saturated or unsaturated acyl radicals, generally
C14-22, especially C16-20, acyl radicals. Thus, the phospholipids
may comprise, by way of acyl radicals, the saturated radicals
palmitoyl C16:0 and stearoyl C18:0 and/or the unsaturated radicals
oleoyls C18:1 and C18:2. Diacyl substitution is preferred and the
phospholipids used in the compositions in accordance with the
invention more particularly comprise two identical saturated acyl
radicals, especially dipalmitoyl and distearoyl or a mixture of
phospholipids in which such radicals predominate, in particular
mixtures in which dipalmitoyl is the major diacy component. Thus,
phosphatidyl choline (PC) and PG may be used may be used with the
same diacylphosphatidyl profile as in PC and PG extracted from
human or animal or vegetable sources, but if synthetic sources are
used the dipalmitoyl component may predominate, as in the DPPC
mentioned above.
[0106] Suitable surfactants include, for example, dipalmitoyl
phosphatidylethanolamine (DPPE), dipalmitoyl phosphatidylinositol
(DPPI). Further exemplary phospholipids include
1-palmitoyl-2-oleoyl-SN-glycero-3-phosphoglycerol (POPG),
phosphoglycerides such as disteroylphosphatidylcholine,
diarachidoylphosphatidylcholine dibehenoylphosphatidylcholine,
diphosphatidylglycerol, short-chain phosphatidylcholines,
long-chain saturated phosphatidylethanolamines, long-chain
saturated phosphatidylserines, long-chain saturated
phosphatidylglycerols, long-chain saturated
phosphatidylinositols.
[0107] The additive material may comprise a phospholipid or a
derivative thereof. Lecithin has been found to be a good material
for the additive material.
[0108] The additive material may comprise a metal stearate, or a
derivative thereof, for example, sodium stearyl fumarate or sodium
stearyl lactylate. Advantageously, the additive material comprises
a metal stearate. For example, zinc stearate, magnesium stearate,
calcium stearate, sodium stearate or lithium stearate. Preferably,
the additive material comprises magnesium stearate.
[0109] The additive material may include or consist of one or more
surface active materials, in particular materials that are surface
active in the solid state, which may be water soluble or water
dispersible, for example lecithin, in particular soya lecithin, or
substantially water insoluble, for example solid state fatty acids
such as oleic acid, lauric acid, palmitic acid, stearic acid,
erucic acid, behenic acid, or derivatives (such as esters and
salts) thereof such as glyceryl behenate. Specific examples of such
materials are: phosphatidylcholines, phosphatidylethanolamines,
phosphatidylglycerols and other examples of natural and synthetic
lung surfactants; lauric acid and its salts, for example, sodium
lauryl sulphate, magnesium lauryl sulphate; triglycerides such as
Dynsan 118 and Cutina HR; and sugar esters in general.
Alternatively, the additive may be cholesterol.
[0110] Other possible additive materials include sodium benzoate,
hydrogenated oils which are solid at room temperature, talc,
titanium dioxide, aluminium dioxide, silicon dioxide and
starch.
[0111] In one embodiment of the invention, the additive material
comprises an amino acid, a metal stearate or a phospholipid.
Preferably, the additive material comprises one or more of L-, D-
or DL-forms of leucine, isoleucine, lysine, valine, methionine,
phenylalanine, or Aerocine, lecithin or magnesium stearate. In
another embodiment, the additive material comprises leucine and
preferably l-leucine.
[0112] In general, the optimum amount of additive material to be
included in a dry powder formulation will depend on the chemical
composition and other properties of the additive material and of
the active material, as well as upon the nature of other particles,
such as carrier particles, if present. In general, the efficacy of
the additive material is measured in terms of the FPF of the
composition.
[0113] In one embodiment of the present invention, composite active
particles produced by co-jet milling according to the present
invention are mixed with carrier particles made of an inert
excipient material.
[0114] Where the powder composition comprises an active material,
additive material and excipient material, this is referred to as a
3-component system. In contrast, a 2-component system comprises
just active and additive materials.
[0115] Excipient materials may be included in powders for
administration by pulmonary inhalation for a number of reasons. On
the one hand, the inclusion of particles of excipient material of
an appropriate size can enhance the flow properties of the powder
and can enhance the powder's handleability. Excipient material is
also added to powder formulations as a diluent. It can be very
difficult to accurately and reproducibly administer a very small
amount of powder. Where low doses of drug are required, this can
pose a problem and so it can be desirable to add a diluent to the
powder, to increase the amount of powder to be dispensed.
[0116] In one embodiment of the present invention, the excipient
material is in the form of relatively large or coarse carrier
particles. Advantageously, substantially all (by weight) of the
carrier particles have a diameter which lies between about 20 .mu.m
and about 1000 .mu.m, more preferably about 50 .mu.m and about 1000
.mu.m. Preferably, the diameter of substantially all (by weight) of
the carrier particles is less than about 355 .mu.m and lies between
about 20 .mu.m and about 250 .mu.m.
[0117] Preferably at least about 90% by weight of the carrier
particles have a diameter between from about 40 .mu.m to about 180
.mu.m. The relatively large diameter of the carrier particles
improves the opportunity for other, smaller particles to become
attached to the surfaces of the carrier particles and provides good
flow and entrainment characteristics and improved release of the
active particles in the airways to increase deposition of the
active particles in the lung.
[0118] Conventional thinking regarding carrier particles is that
they improve the poor flowability of formulations comprising fine
particles of less than 10 .mu.m. The poor flowability is due to the
agglomeration of the fine particles which occurs due to the strong
attractive forces between the small particles. In the presence of
large carrier particles, these attractive forces cause the fine
particles to become attached to the surface of the large carrier
particles, forming (usually discontinuous) coatings. This
arrangement of the large and fine particles leads to better flow
characteristics than is observed with a formulation made up solely
of fine active particles.
[0119] The carrier particles to be added to the composite active
particles of the present invention are relatively large particles
of an excipient material, such as lactose.
[0120] The ratios in which the carrier particles and composite
active particles are mixed will, of course, depend on the type of
inhaler device used, the type of active particles used and the
required dose. The carrier particles may be present in an amount of
at least about 50%, more preferably at least about 70%, more
preferably at least about 80%, advantageously at least about 90%
and most preferably at least about 95%, based on the combined
weight of the composite active particles and the carrier
particles.
[0121] A 3-component system including carrier particles, such as
the one described above, would be expected to work well in a
passive device. The presence of the carrier particles makes the
powder easier to extract from the blister, capsule or other storage
means. The powder extraction tends to pose more of a problem in
passive devices, as they do not create as turbulent an air flow
through the blister upon actuation as active devices. This means
that it can be difficult to entrain all of the powder in the air
flow. The powder entrainment in a passive device is made easier
where the powder includes carrier particles as this will mean that
the powder is less cohesive and exhibits better flowability,
compared with a powder consisting entirely of smaller particles,
for example all having a diameter of less than 10 .mu.m.
[0122] Where carrier particles and the composite active particles
made according to the present invention are mixed, the active
particles should readily release from the surface of the carrier
particles upon actuation of the dispensing device by virtue of the
additive material on the surface of the active particles. This
release may be further improved where the carrier particles also
have additive material applied to their surfaces. This application
can be achieved by simple gentle blending or co-milling, for
example as described in WO 97/03649.
[0123] However, the combination of large carrier particles and fine
active particles has its disadvantages. It can only be effectively
used with a relatively low (usually only up to 5%) drug content. As
greater proportions of fine particles are used, more and more of
the fine particles fail to become attached to the large carrier
particles and segregation of the powder formulation becomes a
problem. This, in turn, can lead to unpredictable and inconsistent
dosing. The powder also becomes more cohesive and difficult to
handle.
[0124] Furthermore, the size of the carrier particles used in a dry
powder formulation can be influential on segregation.
[0125] Segregation can be a catastrophic problem in powder handling
during manufacture and the filling of devices or device components
(such as capsules or blisters) from which the powder is to be
dispensed. Segregation tends to occur where ordered mixes cannot be
made sufficiently stable. Ordered mixes occur where there is a
significant disparity in powder particle size. Ordered mixes become
unstable and prone to segregation when the relative level of the
fine component increases beyond the quantity which can adhere to
the larger component surface, and so becomes loose and tends to
separate from the main blend. When this happens, the instability is
actually exacerbated by the addition of anti-adherents/glidants
such as FCAs.
[0126] In the case of dry powder formulations of micron-sized drug,
and typical 60 to 150 .mu.m sized carrier, this instability tends
to occur once drug content exceeds a few percent, the exact amount
is dependant on the drug. However, it has been found that a carrier
with a particle size of <30 .mu.m tends not to exhibit this
instability. This is thought to be due to the fine carrier
particles having relatively higher surface area compared to the
coarse carrier particles, and the similarity between the size of
the active particles and the carrier particles. Such fine carrier
particles are not often used, mainly because of their poor flow
characteristics, as discussed above.
[0127] According to another embodiment of the present invention,
the 3-component system comprises the composite active particles
made according to the present invention, together with fine
excipient particles. Such excipient particles have a particle size
of 30 .mu.m or less, preferably 20 .mu.m or less and more
preferably 10 i.im or less. The excipient particles advantageously
have a particle size of 30 to 5 .mu.m.
[0128] One would expect such a powder formulation, made up of only
fine particles with a particle size of less than 10 .mu.m, to
suffer from the cohesion and flowability problems observed with
formulations comprising just fine active particles. The active
particles do not coat the fine excipient particles, as they do the
large carrier particles, because of the different forces existing
between fine particles and fine and large particles.
[0129] However, where the powder formulation comprises composite
active particles according to the present invention and fine
excipient particles, it has been surprisingly found that such
formulations are efficiently dispensed by an active device. It has
been found that the potentially poor flow characteristics or
.cndot. handleability of powders comprising only particles with a
size of less than 10 .mu.m are not significant when the powder is
dispensed using an active inhaler device.
[0130] As mentioned above, the active device causes turbulence
within the blister, capsule or other powder storage means. This
means that even powders with fine excipient particles can be
extracted. Furthermore, the presence of the composite active
particles means that the agglomerates formed from the fine
particles are not so stable that they are not broken up upon
actuation of the inhaler device. Thus, it has been surprisingly
found that compositions comprising the composite active particles
of the present invention and fine particles of an inert excipient
material, such as lactose, can be efficiently dispensed using an
active inhaler device.
[0131] In another embodiment of the present invention, the fine
excipient particles added to the composite active particles are
themselves co-jet milled with additive material. The co-jet milling
of the active particles with additive material and of the excipient
particles with additive material can occur separately or together,
and by similar or different forms of co-milling. For example, the
active particles may be co-jet milled, the excipient particles may
be co-processed by a compressive form of milling such as
mechanofusion or similar processes, or visa versa. The quantities
and nature of additives may be different for active and excipient.
This may be the case where the two groups of particles have
different sizes and hence relative surface areas.
[0132] Co-jet milling the fine excipient particles with the
additive material results in coating of the additive material on
the surfaces of the excipient particles. This coating can further
reduce the cohesiveness of the 3-component system and can further
enhance deagglomeration upon actuation of the inhaler device.
[0133] Generally, flow of compositions comprising fine carrier
particles is poor unless they are pelletised (e.g. as is done in
the AstraZeneca product OXIS (registered trade mark). However,
using the processes of the present invention, fine lactoses (e.g.
Sorbolac 400 with a particle size of 1 to 15 .mu.m) have been
produced which flow sufficiently well for use in DPIs with >5%
drug, and up to approximately 30% and possibly 50% cohesive
micronised drug. It should be noted that these beneficial
properties are achieved without the need to resort to
pelletisation, which has its own disadvantages of being difficult
to do and generally decreasing FPFs.
[0134] Thus, the co-milling of the fine excipient particles and
additive material in accordance with the present invention allows
one to produce blends of active and excipient materials with a much
greater range of active agent content than is possible using
conventional carrier particles (i.e. >5%). The resultant dry
powder formulations also benefit from improved aerosolisation.
[0135] In the present invention, different grinding and injection
pressures may be used in order to produce particles with different
coating characteristics. The invention also includes embodiments
where different grinding and injection pressures are combined, to
produce composite particles with desired properties, that is, to
engineer the particles.
[0136] Co-jet milling may be carried out at grinding pressures
between 0.1 and 12 bar. Varying the pressure allows one to control
the degree of particle size reduction. At pressures in the region
of 0.1-3 bar, more preferably 0.5-2 bar and most preferably 1-2
bar, the co-jet milling will primarily result in blending of the
active and additive particles, so that the additive material coats
the active particles. On the other hand, at 3-12 bar, and
preferably 5-12 bar, the co-jet milling will additionally lead to
particle size reduction.
[0137] In one embodiment, the jet milling is carried out at a
grinding pressure of between 0.1 and 3 bar, to achieve blending of
the active and additive particles. As discussed below in greater
detail, when the co-jet milling of the present invention is carried
out at such relatively low pressures, the resultant particles have
been shown to perform well when dispensed using passive devices. It
is speculated that this is because the particles are larger than
those produced by co-jet milling at higher pressures and these
relatively larger particles are more easily extracted from the
blister, capsule or other storage means in the passive device, due
to less cohesion and better flowability. Whilst such relatively
large particles are easily extracted from the blister or capsule in
an active device, they may result in throat deposition.
[0138] In another embodiment, the jet milling is carried out at a
grinding pressure of between 3 and 12 bar, to achieve a reduction
of the sizes of the active and additive particles. The co-jet
milling at these relatively high pressures can produce extremely
small composite active particles having an MMAD of between 3 and
0.5 .mu.m. These fine particle sizes are excellent for deep lung
deposition, but they really need to be dispensed using an active
inhaler device, as the powder formulations comprising such fine
particles are actually rather "sticky". As discussed below, this
stickiness may not pose a problem for active devices and is
actually thought to be advantageous as it can slow the extraction
of the powder so that the composite active particles travel more
slowly in the powder plume generated by the device, thereby
reducing throat deposition.
[0139] Tests were carried out whereby pre-micronised lactose (as a
drug model) was co-jet milled in an MC50 Hosakawa Micron with 5%
magnesium stearate. At 2 bar milling pressure, the resultant
material had a d(50) of approximately 3 .mu.m, whilst milling the
same mixture at around 7 bar resulted in material with a d(50) of
about 1 .mu.m. Thus, when operating with a jet milling pressure of
0.1-3 bar little milling, that it is particle size reduction, is
seen. From 3-12 bar milling pressure, increasing milling is seen,
with the particle size reduction increasing with the increasing
pressure. This means that the milling pressure may be selected
according to the desired particle size in the resultant mixture. In
one embodiment, the step of jet milling is carried out at an inlet
pressure between 0.1 and 3 bar. Alternatively, the step of jet
milling is carried out at an inlet pressure of between 3 and 12
bar.
[0140] As indicated above, co-jet milling at lower pressures
produces powders which perform well in passive devices whilst
powders milled at higher pressures perform better in active
devices, such as Aspirair (trade mark).
[0141] The co-jet milling processes according to the present
invention can also be carried out in two or more stages, to combine
the beneficial effects of the milling at different pressures and/or
different types of milling or blending processes. The use of
multiple steps allows one to tailor the properties of the co-jet
milled particles to suit a particular inhaler device, a particular
drug and/or to target particular parts of the lung.
[0142] In one embodiment, the milling process is a two-step process
comprising first jet-milling the drug on its own at high grinding
pressure to obtain the very small particle sizes possible using
this type of milling. Next, the milled drug is co-jet milled with
an additive material. Preferably, this second step is carried out
at a lower grinding pressure, so that the effect is the coating of
the small active particles with the additive material.
[0143] The additive material may also be milled on its own prior to
the co-milling step. This milling may be conducted in a jet mill, a
ball mill, a high pressure homogeniser or alternative known
ultrafine milling methods. The particles of additive material are
preferably in a form with 90% of the particles by mass of
diameter<10 .mu.m, more preferably <5 .mu.m, more preferably
<2 .mu.m, more preferably <1 .mu.m and most preferably
<0.5 .mu.m.
[0144] This two-step process produces better results than simply
co-jet milling the active material and additive material at a high
grinding pressure. Experimental results discussed below show that
the two-step process results in smaller particles and less throat
deposition than simple co-jet milling of the materials at a high
grinding pressure.
[0145] In another embodiment of the present invention, the
particles produced using the two-step process discussed above
subsequently undergo mechanofusion or an equivalent compressive
process. This final mechanofusion step is thought to "polish" the
composite active particles, further rubbing the additive material
into the particles. This allows one to enjoy the beneficial
properties afforded to particles by mechanofusion, in combination
with the very small particles sizes made possible by the co-jet
milling.
[0146] The reduction in particle size may be increased by carrying
out the co-jet milling at lower temperatures. Whilst the co-jet
milling process may be carried out at temperatures between
-20.degree. C. and 40.degree. C., the particles will tend to be
more brittle at lower temperatures, and they therefore fracture
more readily so that the milled particles tend to be even smaller.
Therefore, in another embodiment, the jet milling is carried out at
temperatures below room temperature, preferably at a temperature
below 10.degree. C., more preferably at a temperature below
0.degree. C.
[0147] Preferably, all of the particles are of a similar size
distribution. That is, substantially all of the particles are
within the size range of about 0 to about 5 .mu.m, of about 0 to
about 20 .mu.m, of about 0 to 10 .mu.m, of about 0 to 5 .mu.m or of
about 0 to 2 .mu.m.
[0148] In accordance with a second aspect of the present invention,
a pharmaceutical dry powder composition for pulmonary inhalation is
provided, comprising composite active particles made by a method
according to the first aspect of the invention.
[0149] The MMAD of the composite active particles is preferably not
more than 10 .mu.m, and advantageously it is not more than 5 .mu.m,
more preferably not more than 3 .mu.m, even more preferably not
more than 2 .mu.m, more preferably not more than 1.8 .mu.m more
preferably not more than 1.5 .mu.m, even more preferably not more
than 1.2 .mu.m and most preferably not more than 1 .mu.m.
[0150] Accordingly, advantageously at least 90% by weight of the
composite active particles have a diameter of not more than 10
.mu.m, advantageously not more than 5 .mu.m, preferably not more
than 3 .mu.m, even more preferably not more than 2.5 .mu.m, even
more preferably not more than 2 .mu.m and more preferably not more
than 1.5 .mu.m, or even not more than 1.0 .mu.m.
[0151] It is an aim of the present invention to optimise the powder
properties, so that the FPF and FPD are improved compared to those
obtained using known powder formulations, regardless of the type of
device used to dispense the composition of the invention.
[0152] It is a particular aim of the present invention to provide a
dry powder formulation which has an FPF of at least 40%.
Preferably, the FPF(ED) will be between 60 and 99%, more preferably
between 70 and 99%, more preferably between 80 and 99% and even
more preferably between 90 and 99%. Furthermore, it is desirable
for the FPF(MD) to be at least 40%. Preferably, the FPF(MD) will be
between 40 and 99%, more preferably between 50 and 99%, more
preferably between 60 and 99%, and more preferably between 70 and
99% and even more preferably between 80 and 99%.
[0153] In a preferred embodiment of the present invention the
resultant dry powder formulation has a reproducible FPF(ED) of at
least 70%. Preferably, the FPF(ED) will be at least 80%, more
preferably the FPF(ED) will be at least 85%, and most preferably
the FPF(ED) will be at least 90%.
[0154] In a further preferred embodiment, the dry powder
formulation has a reproducible FPF(MD) of at least 60%. Preferably,
the FPF(MD) will be at least 70%, more preferably the FPF(MD) will
be at least 80%, and most preferably the FPF(MD) will be at least
85%.
[0155] As illustrated by the experimental results set out below, it
has been surprisingly found that co-milling active particles with
additive particles using jet milling results in composite active
particles having significantly better FPF and FPD than those
produced by co-milling using mechanofusion, when the powders are
dispensed using the active inhaler device Aspirair (trade
mark).
[0156] This unexpected improvement in the FPF and FPD of the powder
formulations prepared is thought to be due to the following
factors. Firstly, the milling process results in very small
particles. Secondly, there appears to be only partial coverage of
the particles with the force control agent and this means that some
of the particle cohesion is retained, affording better powder
handleability despite the very small particle sizes.
[0157] Co-jet milling has surprisingly been found to be capable of
significantly reducing the median primary particle size of active
particles (for example, from 3 or 2 .mu.m to 1 .mu.m), while also
allowing good aerosolisation from a delivery device. This further
reduction in primary particle size is considered to be advantageous
for delivery of systemically targeted molecules to the deep lung.
The benefit here is to co-jet mill active particles with additive
particles in order to reduce primary particle size while still
achieving a reduction in the level of powder cohesion and adhesion
by coating the particles for additive material.
[0158] Test Methods
[0159] All materials were evaluated in the Next Generation Impactor
(NGI). Details of the test are provided in each case.
[0160] Formulations were processed using:
[0161] 1) The Hosokawa Micron MechanoFusion AMS Mini system. This
system was operated with a novel rotor, providing a 1mm compression
gap; and
[0162] 2) The Hosokawa Micron AS50 spiral jet mill.
[0163] The in-vitro testing was performed using an Aspirair (trade
mark) device, which is an active inhaler device.
[0164] The formulations were composed of one or more of the
following constituents:
[0165] Magnesium stearate (standard grade)
[0166] L-Leucine (Ajinomoto) and jet milled by Micron
Technologies
[0167] Sorbolac 400 lactose
[0168] Micronised clobozam
[0169] Micronised apomorphine hydrochloride
[0170] Micronised lactose
[0171] Re-condensed Leucine (Aerocine)
[0172] Comparison of Co-Jet Milled and Mechanofused Formulations
(Clobozam)
[0173] The following is a comparison of 2-component systems
comprising co-jet milled or mechanofused active particles and
additive material.
[0174] 1.01 g of micronised clobozam was weighed out, and then
gently pressed through a 300 .mu.m metal sieve, using the rounded
face of a metal spatula. This formulation was recorded as "3A".
[0175] 9.37 g of micronised clobozam was then combined with 0.50 g
of micronised L-leucine in the MechanoFusion system. The material
was processed at a setting of 20% power for 5 minutes, followed by
a setting of 80% power for 10 minutes. This material was recorded
as "4A". After blending, this powder was then gently pushed through
a 300 .mu.m metal sieve with a spatula. This material was recorded
as "4B".
[0176] 9.57 g of micronised clobozam was then combined with 0.50 g
of magnesium stearate in the MechanoFusion system. The material was
processed at a setting of 20% power for 5 minutes, followed by a
setting of 80% power for 10 minutes. This material was recorded as
"5A". After blending, this powder was rested overnight, and then
was gently pushed through a 300 .mu.m metal sieve with a spatula.
This material was recorded as "5B".
[0177] 9.5 g of micronised clobozam was then combined with 0.50 g
of micronised L-leucine in the MechanoFusion system. The material
was processed at a relatively low speed setting of 20% power for 5
minutes. This process was intended only to produce a good mix of
the components. This material was recorded as "6A".
[0178] 6.09 g of "6A" fed at approximately 1 g per minute into an
AS50 spiral jet mill, set with an injector pressure of about 7 bar
and a grinding pressure of about 5 bar. The resulting material was
recovered and recorded as "6B".
[0179] After milling, this powder was rested overnight, and then
was gently pushed through a 300 .mu.m metal sieve with a spatula.
This material was recorded as "6C".
[0180] 9.5 g of micronised clobozam was then combined with 0.50 g
of magnesium stearate in the MechanoFusion system. The material was
processed at a setting of 20% power for 5 minutes. This material
was recorded as "7A".
[0181] 6.00 g of "7A" was fed at approximately 1 g per minute into
the AS50 spiral jet mill, set with an injector pressure of about 7
bar and a grinding pressure of about 5 bar. The resulting material
was recovered and recorded as "7B".
[0182] After milling, this powder was gently pushed through a 300
.mu.m metal sieve with a spatula. This material was recorded as
"7C".
[0183] A batch of re-condensed leucine (also referred to as
"Aerocine") was produced by subliming to vapour a sample of leucine
in a tube furnace, and re-condensing as a very finely dispersed
powder as the vapour cooled. This batch was identified as "8A".
[0184] 9.5 g of micronised clobozam was then combined with 0.50 g
of Aerocine, in the MechanoFusion system. The material was
processed at a setting of 20% power for 5 minutes, followed by a
setting of 80% power for 10 minutes. This material was recorded as
"8B". After blending, this powder was rested overnight, and then
was gently pushed through a 300 .mu.m metal sieve with a spatula.
This material was recorded as "8C".
[0185] 9.5 g of micronised clobozam was combined with 0.50 g of
Aerocine in the MechanoFusion system. The material was processed at
a setting of 20% power for 5 minutes. 7.00 g of this powder was
then fed into the AS50 spiral jet mill, set with an injector
pressure of about 7 bar and a grinding pressure of about 5 bar. The
resulting material was recovered and recorded as "9A".
[0186] After milling, this powder was gently pushed through a 300
.mu.m metal sieve with a spatula. This material was recorded as
"9B".
[0187] A number of foil blisters were filled with approximately 2
mg of the following clobozam formulations:
[0188] 3A--no milling & no additive material
[0189] 4B--leucine & mechanofused
[0190] 5B--magnesium stearate & mechanofused
[0191] 6C--leucine & co-jet milled
[0192] 7C--magnesium stearate & co-jet milled
[0193] 8C--Aerocine & co-jet milled
[0194] 9B--Aerocine & mechanofused.
[0195] These formulations were then fired from an Aspirair device
into an NGI at a flow rate of 60 l/m. The Aspirair was operated
under 2 conditions for each formulation: with a reservoir of 15 ml
of air at 1.5 bar or with a reservoir of 30 ml of air at 0.5
bar.
[0196] Full details of the results are attached. The impactor test
results are summarised in Tables 1, 2 and 3 below.
TABLE-US-00001 TABLE 1 FPD (mg) Formulation MD (mg) ED (mg) (<5
.mu.m) MMAD 3A 2.04 1.12 0.88 2.91 0.5 bar 30 ml 3A 1.92 1.74 1.23
2.86 1.5 bar 15 ml 4B 1.84 1.48 0.82 3.84 0.5 bar 30 ml 4B 1.80
1.56 0.81 3.32 1.5 bar 15 ml 5B 1.84 1.53 1.17 2.34 0.5 bar 30 ml
5B 1.85 1.55 1.12 2.22 1.5 bar 15 ml 6C 1.93 1.80 1.67 2.11 0.5 bar
30 ml 1.86 1.73 1.62 2.11 6C 1.97 1.86 1.67 2.07 1.5 bar 15 ml 6C
1.74 1.65 1.46 2.03 1.5 bar 15 ml (silicon coated plates) 7C 2.06
1.99 1.87 1.97 0.5 bar 30 ml 7C 1.89 1.78 1.63 1.79 1.5 bar 15 ml
8C 1.82 1.73 1.62 2.02 0.5 bar 30 ml 8C 1.81 1.74 1.57 2.01 1.5 bar
15 ml 9B 1.88 1.73 1.04 3.48 0.5 bar 30 ml 9B 1.80 1.64 0.94 3.12
1.5 bar 15 ml
TABLE-US-00002 TABLE 2 FPF FPF FPF FPF FPF (MD) (ED) (ED) (ED) (ED)
% % % % % Formulation (<5 .mu.m) (<5 .mu.m) (<3 .mu.m)
(<2 .mu.m) (<1 .mu.m) 3A 43 78 49 32 17 0.5 bar 30 ml 3A 64
71 45 24 6 1.5 bar 15 ml 4B 45 55 28 15 7 0.5 bar 30 ml 4B 45 52 30
18 9 1.5 bar 15 ml 5B 64 77 54 42 30 0.5 bar 30 ml 5B 61 72 52 38
25 1.5 bar 15 ml 6C 87 93 77 44 8 0.5 bar 30 ml 87 94 76 44 9 6C 85
90 73 44 10 1.5 bar 15 ml 6C 84 89 74 45 8 1.5 bar 15 ml (silicon
coated plates) 7C 91 94 79 50 14 0.5 bar 30 ml 7C 86 92 82 56 16
1.5 bar 15 ml 8C 89 93 79 48 12 0.5 bar 30 ml 8C 87 90 76 46 9 1.5
bar 15 ml 9B 55 60 34 24 15 0.5 bar 30 ml 9B 52 57 34 24 15 1.5 bar
15 ml
TABLE-US-00003 TABLE 3 Formulation *recovery *throat *blister
*device 3A 102% 3% 1% 43% 0.5 bar 30 ml 3A 96% 15% 1% 8% 1.5 bar 15
ml 4B 97% 15% 7% 12% 0.5 bar 30 ml 4B 95% 27% 6% 8% 1.5 bar 15 ml
5B 97% 7% 13% 4% 0.5 bar 30 ml 5B 98% 14% 12% 4% 1.5 bar 15 ml 6C
97% 2% 1% 6% 0.5 bar 30 ml 101% 3% 1% 5% 6C 104% 6% 3% 3% 1.5 bar
15 ml 6C 91% 8% 1% 4% 1.5 bar 15 ml (silicon coated plates) 7C 110%
2% 1% 3% 0.5 bar 30 ml 7C 99% 6% 2% 3% 1.5 bar 15 ml 8C 99% 3% 1%
4% 0.5 bar 30 ml 8C 95% 6% 1% 3% 1.5 bar 15 ml 9B 96% 16% 2% 7% 0.5
bar 30 ml 9B 95% 26% 4% 5% 1.5 bar 15 ml
[0197] From these results it can be seen that the co-jet milled
formulations exhibited exceptional FPFs when dispensed from an
active dry powder inhaler device. The FPFs observed were
significantly better that those of the mechanofused formulations
and those formulations which did not include an additive material.
This improvement would appear to be largely due to reduced throat
deposition, which was less than 8% for the co-jet milled
formulations, compared to 15% for the pure drug and up to 27% for
the mechanofused formulations.
[0198] The reproducibility of the FPFs obtained was also tested.
Through life dose uniformity for the primary candidate, 6C, the
preparation of which is described above, was tested by firing 30
doses, with the emitted doses collected by DUSA. Through life dose
uniformity results are presented in the graph of FIG. 8.
[0199] The mean ED was 1965 .mu.g, with an RSD (relative standard
deviation) of 2.8%. This material consequently demonstrated
excellent through life dose reproducibility.
[0200] The particle size distributions of these powdered materials
indicate both the level of size reduction obtained by the
co-milling, and the level of dispersion efficiency at varied
pressures. The d(50) and d(97) plots provide a further indication
of this dispersibility of the powders as a function of
pressure.
[0201] Formulation 5B exhibited much the best dispersion.
[0202] This set of dispersibility tests shows that the MechanoFused
powders disperse more easily at lower pressures than the original
drug, and that magnesium stearate gives the best dispersion within
these, followed by Aerocine and leucine. The co-jet milled powders
do not appear to disperse any more easily in this test than the
original drug, however the primary particle sizes (d(50)) are
reduced.
[0203] Comparison of Co-Jet Milled and Mechanofused Formulations
(Apomorphine)
[0204] In order to establish the effect of co-jet milling on
different active agents, apomorphine hydrochloride formulations
with fine carrier particles (i.e. a 3-component system) were
prepared and tested.
[0205] 19.0 g of Sorbolac 400 lactose and 1.0 g of micronised
L-leucine were combined in the MechanoFusion system. The material
was processed at a setting of 20% power for 5 minutes, followed by
a setting of 80% power for 10 minutes. This material was recovered
and recorded as "2A".
[0206] 15.0 g of apomorphine hydrochloride and 0.75 g of micronised
L-leucine were combined in the MechanoFusion system. The material
was processed at a setting of 20% power for 5 minutes, followed by
a setting of 80% power for 10 minutes. This material was recovered
and recorded as "2B".
[0207] 2.1 g "2B` plus 0.4 g micronised leucine were blended by
hand in a mortar and pestle for 2 minutes. 2.5 g micronised lactose
was added and blended for a further 2 minutes. 5 g micronised
lactose was added and blended for another 2 minutes. This mixture
was then processed in the AS50 Spiral jet mill using an inlet
pressure of 7 bar and a grinding pressure of 5 bar, feed rate 5
ml/min. This powder was gently pushed through a 3001.im metal sieve
with a spatula. This material was recorded as "10A".
[0208] 1.5 g "10A" was combined with 0.20 g micronised L-leucine
and 3.75 g of Sorbolac 400 lactose by hand in a mortar with a
spatula for 10 minutes. This powder was gently pushed through a 300
.mu.m metal sieve with a spatula. This material was recorded as
"10B".
[0209] 9 g micronised apomorphine HCl plus 1 g micronised leucine
were placed in the MechanoFusion system and processed at 20% (1000
rpm) for 5 minutes. This initial blend was then processed in the
AS50 Spiral jet mill using an inlet pressure of 7 bar and a
grinding pressure of 5 bar, feed rate 5 ml/min This material was
recorded as "11A".
[0210] After blending, this powder was rested overnight, and then
was gently passed through a 300 .mu.m metal sieve by shaking. This
material was recorded as "11B".
[0211] 2 g micronised apomorphine HCl plus 0.5 g micronised leucine
were blended by hand in mortar and pestle for 2 minutes. 2.5 g
micronised lactose was added and blended for a further 2 minutes.
Then 5 g micronised lactose was added and blended for another 2
minutes. This mixture was then processed in the AS50 Spiral jet
mill using an inlet pressure of 7 bar and a grinding pressure of 5
bar, feed rate 5 ml/min. This powder was gently pushed through a
300 .mu.m metal sieve with a spatula. This material was recorded as
"12A".
[0212] 16.5 g of Sorbolac 400 and 0.85 g of micronised leucine were
placed in the MechanoFusion system and processed at 20% (1000 rpm)
for 5 minutes then at 80% (4000 rpm) for 10 minutes. This material
was recorded as "13A".
[0213] 0.5 g micronised apomorphine HCl plus 2.0 g "13A" were
blended by hand in a mortar with a spatula for 10 minutes. This
powder was gently pushed through a 300 .mu.m metal sieve with a
spatula. This material was recorded as "13B".
[0214] A number of foil blisters were filled with approximately 2
mg of the following formulations:
[0215] 10A--20% apomorphine HCl, 5% l-leucine, 75% micronised
lactose (co-jet milled)
[0216] 10C--26.2% apomorphine HCl, 5% l-leucine, 68.7% sorbolac
(geometric)
[0217] 11B--95% apomorphine HCl, 5% l-leucine (co-jet milled)
[0218] 12A--20% apomorphine HCl, 5% leucine, 75% micronised lactose
(all co-jet milled)
[0219] 13B--20% apomorphine HCl, 5% l-leucine, 75% Sorbolac 400
(leucine & Sorbolac mechanofused)
[0220] These were then fired from an Aspirair device into an NGI at
a flow rate of 60 l/m. The Aspirair was operated with a reservoir
of 15 ml at 1.5 bar. Each in vitro test was conducted once to
screen, and then the selected candidates were repeated. Further
candidates were also repeated in ACI at 60 l/m.
TABLE-US-00004 TABLE 4 FPD (.mu.g) Formulation MD (.mu.g) ED
(.mu.g) (<5 .mu.m) MMAD 10A 384 356 329 1.78 13B 359 327 200
1.54 (1793) (1635) (1000) 10C 523 492 374 1.63 11B 1891 1680 1614
1.36 1882 1622 1551 1.44 1941 1669 1601 1.49 Ave. 1905 1657 1589
1.43 SD 32 31 33 0.07 RSD 1.7 1.9 2.1 4.6 11B 1895 1559 1514 1.58
1895 1549 1485 1.62 1923 1565 1504 1.62 ACI Ave. 1904 1558 1501
1.61 SD 16 8 15 0.02 RSD 1 1 1 1 12A 414 387 363 1.63 410 387 363
1.66 406 378 355 1.68 Ave. 410 384 360 1.66 SD 4 5 5 0.03 RSD 1 1 1
2 Total ave. 2050 1920 1800 12A 395 365 341 1.80 411 385 360 1.85
400 370 349 1.84 ACI Ave. 402 373 350 1.83 SD 8 10 10 0.04 RSD 2 3
3 2 Total ave. 2011 1866 1750
TABLE-US-00005 TABLE 5 Formulation FPF FPF FPF FPF FPF 2 mg, 1.5
bar (MD) (ED) (ED) (ED) (ED) 15 ml reservoir % % % % % 60 l/min
(<5 .mu.m) (<5 .mu.m) (<3 .mu.m) (<2 .mu.m) (<1
.mu.m) 10A 86 93 87 60 13 13B 56 61 52 42 19 10C 72 76 67 51 16 11B
85 96 95 81 24 82 96 93 77 22 82 96 92 74 20 Ave. 83 96 93 77 22 SD
0 1.5 3.5 2 RSD 0 1.6 4.5 9.1 11B 80 97 94 74 14 78 96 93 70 14 78
96 94 72 12 ACI Ave. 79 96 94 72 13 SD 1 1 2 1 RSD 1 1 3 9 12A 88
94 89 68 13 89 94 89 66 12 87 94 88 64 12 Ave. 88 94 89 66 12 SD 0
1 2 1 RSD 0 1 3 5 12A 86 94 85 57 9 88 93 84 55 8 87 94 85 56 8 ACI
Ave. 87 94 85 56 8 SD 1 1 1 1 RSD 1 1 2 7
TABLE-US-00006 TABLE 6 Formulation 2 mg, 1.5 bar 15 ml reservoir 60
l/min Recovery Throat Blister Device 10A 96% 5% 0.3% 7% 13B 94% 29%
3% 6% 10C 100% 16% 2% 4% 11B 101% 2% 0.6% 10% 99% 2% 0.2% 14% 102%
2% 0.3% 14% Ave. 101% 2% 0.4% 13% SD 1.5 0 0.2 2.3 RSD 1.5 0 57 18
11B 100% 1% 0.5% 17% 100% 2% 0.1% 18% 101% 2% 0.4% 18% ACI Ave.
100% 2% 0.3% 18% SD 1 1 0.2 1 RSD 1 35 62 3 12A 109% 4% 0.3% 6%
108% 4% 0.2% 6% 107% 4% 0.02% 7% Ave. 108 4% 0.2 6% SD 1 0 0.1 1
RSD 1 0 82 9 12A 104% 3% 0.4% 7% 108% 4% 0.2% 6% 105% 2% 0.4% 7%
ACI Ave. 106% 3% 0.3 7% SD 2 1 0.1 1 RSD 2 33 35 9
[0221] The co-jet milled formulations once again exhibited
exceptional FPFs when it is dispensed using an active dry powder
inhaler device. The improvement appears to be largely due to
reduced throat deposition which was less than 5%, compared to
between 16 and 29% for the mechanofused formulations. "12A" was
produced as a repeat of "10A", but excluding the mechanofused
pre-blend (to show it was not required).
[0222] The reproducibility of the FPFs obtained with the
formulation 12A, the preparation of which is described above, was
tested.
[0223] A number of foil blisters were filled with approximately 2
mg of formulation 12A. Through life dose uniformity was tested by
firing 30 doses, with the emitted doses collected by DUSA. Through
life dose uniformity results are presented in the graph in FIG.
2.
[0224] The mean ED was 389 .mu.g, with an RSD of 6.1% and the
through life delivery of this drug-lactose formulation was very
good.
[0225] In order to investigate the cause of the unexpected
differences between the co-jet milled formulations and those
prepared by mechanofusion, formulations "11B", "10A" and "2C" were
fired from an Aspirair and plume and vortex behaviour recorded on
digital video. The images were studied in light of the above
differences in throat deposition.
[0226] Video of plume behaviour indicated a difference between the
co-jet milled formulations and mechanofused formulations.
Mechanofused formulations showed a highly concentrated fast moving
bolus at the front of the air jet. Most powder appeared to have
been emitted after approximately 40 ms. Co-jet milled formulations
showed a greater spread of the plume. The plume front moves at a
similar velocity, but the front is less concentrated, appears to
slow more quickly and powder is emitted for considerably longer
(i.e. >200 ms).
[0227] Video of the vortex showed that the mechanofused powders
enter the vortex within 10 ms, whereas co-jet milled formulations
take at least 30 ms. Similarly the mechanofused powders appeared
quicker to leave the vortex, with the co-jet milled materials
forming a more prolonged fogging of the vortex. The behaviour
observed for co-jet milled materials was described as an increased
tendency to stick, but then scour from the inside of the
vortex.
[0228] Particle size distributions of the raw materials and
selected formulations were determined by Malvern particle sizer,
via the Scirroco dry powder disperser. The data are summarised in
the graphs shown in FIGS. 3 to 10.
[0229] FIG. 3 shows the particle size distribution of the raw
material micronised lactose.
[0230] FIG. 4 shows the particle size distribution of the raw
material apomorphine.
[0231] FIG. 5 shows the particle size distribution of the raw
material clobozam.
[0232] FIG. 6 shows the particle size distribution of the clobozam
formulation comprising 95% clobozam and 5% mechanofused magnesium
stearate.
[0233] FIG. 7 shows the particle size distribution of the clobozam
formulation comprising 95% clobozam and 5% co-jet milled
Aerocine.
[0234] FIG. 8 shows the particle size distribution of the clobozam
formulation comprising 95% clobozam and 5% co-jet milled
leucine.
[0235] FIG. 9 shows the particle size distribution of the
apomorphine formulation comprising 75% lactose, 20% apomorphine and
5% co-jet milled leucine.
[0236] Finally, FIG. 10 also shows the particle size distribution
of the apomorphine formulation comprising 75% lactose, 20%
apomorphine and 5% co-jet milled leucine.
[0237] Where clobozam is co-jet milled with an additive material, a
significant drop in particle size is observed. This is not seen for
the clobozam mechanofused formulation here.
[0238] With the apomorphine-lactose co-milled materials, the size
distribution is low (d(50) 1.8 to 1.6), when compared to the
particle size distribution of the micronised lactose which
comprises 75% of the composition. However, size reduction is not
detectable with respect to pure apomorphine, although it should be
noted that this comprises only 20% of the powder composition.
[0239] In vitro data confirm that, surprisingly, mechanofusion of
active particles increased the throat deposition substantially.
Mechanofusion has previously been associated with improvement in
dispersibility from a passive device, and reduced throat
deposition. In this case, mechanofusion with magnesium stearate
gives slightly lower throat deposition than mechanofusion with
leucine.
[0240] The throat deposition appears especially high for
mechanofused formulations containing leucine. It is speculated that
this could be due to an agglomerating affect during mechanofusion
specific to leucine and not magnesium stearate, or an electrostatic
effect specific to leucine.
[0241] However, surprisingly co-jet milling produces materials
which, in comparison, give very low throat deposition, low device
deposition and excellent dispersion from an active device. This
co-jet milling also produces a significant further size reduction,
for example, d(50) changes from about 2.6 .mu.m to about 1 .mu.m
for clobozam. When these factors are combined, a remarkable
aerosolisation performance is obtained from the in-vitro tests.
FPF(ED) are 90 to 96%. This excellent performance was obtained for
leucine, Aerocine and magnesium stearate, and for 3 different
formulations, including 2 different active agents, with or without
lactose diluent.
[0242] The consequence of this is the achievement of a very low
oropharangeal deposition to the patient, typically of approximately
5%. Given that both throat and upper airway deposition
(corresponding to impactor throat and upper impactor stages) is
reduced to a minimum, this will also result in a minimised
tasteable component, and minimised fraction delivered to the GI
tract. This corresponds to a 4-fold reduction in comparison to
formulations without additive material.
[0243] It was noted that the co-jet milled materials were highly
agglomerated in appearance, in contrast to the mechanofused blends,
which appeared as more free flowing powders.
[0244] Studies suggest that the difference between the performance
of the co-jet milled and mechanofused compositions is most apparent
when the formulations are dispensed using an active device, such as
Aspirair. Video of plume behaviour provided some indication of the
reason for differences between the co-jet milled formulations and
mechanofused formulations. Mechanofused formulations showed a short
fast bolus, whereas co-jet milled formulations showed a more drawn
out plume. The "enhanced" flow properties of the mechanofused
powders appear to explain their worse Aspirair performance. A
degree of powder hold-up within the device appears to be
beneficial, allowing a less dense and extended plume to occur.
[0245] These video observations suggest the throat deposition
difference is related to the powder lifetime within the vortex,
with a longer lifetime giving reduced throat deposition. Lower
aerosol concentration at the plume front, lower momentum of aerosol
plume (with lower cloud density and smaller particle size) and
greater opportunity to be de-agglomerated are possible contributors
to this improvement. Also, there is also more material in the
later, slower part of the plume. Furthermore, lower powder density
in the cyclone appears to lead to better dispersion.
[0246] It is speculated that the fact that the powder formulations
are difficult to extract from the blister actually enhances their
delivery characteristics. It slows the extraction of the powder and
so the active particles are travelling slower when they are
expelled from the dispensing device. This means that the active
particles do not travel at the front of the plume of powder created
when the device is actuated and this means that the active
particles are significantly less likely to impact on the throat of
the user. Rather, the active particles are thought to be further
back in the plume, which allows them to be inhaled and administered
to the lung. Naturally, too much blister retention will be
undesirable, as it will result in active agent remaining in the
device after actuation.
[0247] In general, the co-milling of active particles with additive
particles has yielded reduced device/blister retention compared to
formulations prepared without additive particles. Mechanofusion was
shown to give significantly greater blister retention than co-jet
milling. The worst blister retention was seen for mechanofused
clobozam with magnesium stearate (13%). This appears related to the
dusting nature of such formulations. The mechanofused powders
spread and flow more easily, which facilitates higher degrees of
contact with the surfaces in bulk powder contact. The co-milled
powders however are heavily agglomerated, so contact with surfaces
is much reduced, and dust residues are also much less. The device
retention also appears greater for mechanofused than co-jet milled
powders for clobozam. However, the device retention of apomorphine
HCl co-jet milled with leucine appears notably high, at 13%. Device
and blister retention does not appear substantially different
between the 0.5 and 1.5 bar tests, except for the case of the
unaltered pure clobozam, where device retention approaches 50% for
the 0.5 bar test.
[0248] The tendency of a powder formulation to stick in the blister
can be overcome in active devices, where a significant amount of
turbulence is created within the blister when the device is
actuated. However, this is not the case in a passive device.
Therefore, the tendency of a formulation to stick in the blister
will have a detrimental effect on the performance of a powder
administered using a passive device. That said, as the active
particles in the powder dispensed by a passive device are generally
not moving as quickly as they would if dispensed by an active
device, the problem of throat deposition (usually a result of the
active particles travelling at the front of the powder plume) is
not so great. Thus, it is clear that the properties of the active
particles need to be tailored to the type of device used to
dispense the powder.
[0249] Tests were carried out to compare the FPF achieved when the
co-jet milled compositions are dispensed using passive and active
devices. The experiments used a lactose model fired into a TSI. The
results were as follows:
TABLE-US-00007 TABLE 7 FPF (MD) % FPF (MD) % Formulation FPF (ED) %
(Cyclohaler) (Aspirair) Micronised lactose 32 18 -- With 5%
magnesium stearate 35 32 27 (MgSt) in a conventional blender 5%
MgSt jet-milled at 2 bar 68 53 62 5% MgSt jet-milled at 7 bar 52 39
72 5% MgSt mechanofused 69 57 49
[0250] This shows that jet milled material which has been co-jet
milled at low pressure is better in passive devices whilst high
pressure jet milled materials perform better in active devices such
as Aspirair.
[0251] Co-Jet Milled Clomipramine Hydrochloride Formulations in
Aspirair
[0252] Clomipramine hydrochloride was obtained in powdered form.
Force control agents leucine and magnesium stearate were used.
[0253] Twelve formulations were produced from the original powder,
using the Hosokawa AS50 jet mill. Either the pure drug was passed
through the mill or a blend of drug with 5% w/w of a force control
agent added. The mill was used with a range of parameters.
Primarily, these were injector air pressure, grinding air pressure
and powder feed rate.
[0254] Formulation 14: The pure clomipramine hydrochloride was
passed through the microniser three times, each time with an
injector air pressure of 8 bar, grinding air pressure of 1.5 bar
and powder feed rate of .about.1 g/min. Malvern (dry powder)
particle size measurement gave a d(50) of 1.2 .mu.m.
[0255] Formulation 15: Formulation 14 was pre-blended in a pestle
with a spatula with 5% micronised l-leucine. This blend was further
micronised with an injector air pressure of 8 bar, grinding air
pressure of 1.5 bar and powder feed rate of .about.1 g/min. Malvern
(dry powder) particle size measurement gave a d(50) of 1.2
.mu.m.
[0256] Formulation 16: The pure clomipramine hydrochloride was
micronised with an injector air pressure of 7 bar, grinding air
pressure of 5 bar and powder feed rate of .about.10 g/min. Malvern
(dry powder) particle size measurement gave a d(50) of 1.0
.mu.m.
[0257] Formulation 17: The pure clomipramine hydrochloride was
micronised with an injector air pressure of 7 bar, grinding air
pressure of 5 bar and powder feed rate of .about.10 g/min. This
micronised clomipramine hydrochloride was pre-blended in a pestle
with a spatula with 5% micronised l-leucine. This blend was then
micronised with an injector air pressure of 7 bar, grinding air
pressure of 5 bar and powder feed rate of .about.10 g/min. Malvern
(dry powder) particle size measurement gave a d(50) of 0.95
.mu.m.
[0258] Formulation 18: The pure clomipramine hydrochloride was
pre-blended in a pestle with a spatula with 5% magnesium stearate.
This blend was micronised with an injector air pressure of 7 bar,
grinding air pressure of 5 bar and powder feed rate of .about.10
g/min. Malvern (dry powder) particle size measurement gave a d(50)
of 0.95 .mu.m.
[0259] Formulation 19: The pure clomipramine hydrochloride was
micronised with an injector air pressure of 7 bar, grinding air
pressure of 1 bar and powder feed rate of .about.1 g/min. Malvern
(dry powder) particle size measurement gave a d(50) of 1.8
.mu.m.
[0260] This pre-micronised clomipramine hydrochloride was then
blended in a pestle with a spatula with 5% micronised l-leucine.
This blend was then micronised with an injector air pressure of 7
bar, grinding air pressure of 1 bar and powder feed rate of
.about.1 g/min. Malvern (dry powder) particle size measurement gave
a d(50) of 1.38 .mu.m.
[0261] Formulation 20: The pure clomipramine hydrochloride was
micronised with an injector air pressure of 7 bar, grinding air
pressure of 1 bar and powder feed rate of .about.10 g/min. Malvern
(dry powder) particle size measurement gave a d(50) of 3.5
.mu.m.
[0262] This pre-micronised clomipramine hydrochloride was then
blended in a pestle with a spatula with 5% micronised l-leucine.
This blend was then micronised with an injector air pressure of 7
bar, grinding air pressure of 1 bar and powder feed rate of
.about.10 g/min. Malvern (dry powder) particle size measurement
gave a d(50) of 2.0 .mu.m.
[0263] Formulation 21: The pure clomipramine hydrochloride was
micronised with an injector air pressure of 7 bar, grinding air
pressure of 3 bar and powder feed rate of .about.1 g/min. Malvern
(dry powder) particle size measurement gave a d(50) of 1.2
.mu.m.
[0264] This pre-micronised clomipramine hydrochloride was then
blended in a pestle with a spatula with 5% micronised l-leucine.
This blend was then micronised with an injector air pressure of 7
bar, grinding air pressure of 3 bar and powder feed rate of
.about.1 g/min. Malvern (dry powder) particle size measurement gave
a d(50) of 0.99 .mu.m.
[0265] Formulation 22 The pure clomipramine hydrochloride was
micronised with an injector air pressure of 7 bar, grinding air
pressure of 3 bar and powder feed rate of .about.10 g/min. Malvern
(dry powder) particle size measurement gave a d(50) of 1.6
.mu.m.
[0266] This pre-micronised clomipramine hydrochloride was then
blended in a pestle with a spatula with 5% micronised l-leucine.
This blend was then micronised with an injector air pressure of 7
bar, grinding air pressure of 3 bar and powder feed rate of
.about.10 g/min. Malvern (dry powder) particle size measurement
gave a d(50) of 1.1 .mu.m.
[0267] Formulation 23: The clomipramine hydrochloride was
pre-blended in a pestle with a spatula with 5% micronised
l-leucine. This blend was micronised with an injector air pressure
of 7 bar, grinding air pressure of 5 bar and powder feed rate of
.about.10 g/min. Malvern (dry powder) particle size measurement
gave a d(50) of 1.8 .mu.m.
[0268] Formulation 24: The pure clomipramine hydrochloride was
micronised with an injector air pressure of 7 bar, grinding air
pressure of 5 bar and powder feed rate of .about.10 g/min.
[0269] This pre-micronised clomipramine hydrochloride was then
blended in a pestle with a spatula with 5% magnesium stearate. This
blend was then micronised with an injector air pressure of 7 bar,
grinding air pressure of 1 bar and powder feed rate of .about.10
g/min. Malvern (dry powder) particle size measurement gave a d(50)
of 1.38 .mu.m.
[0270] Formulation 25: Formulation 24 was then processed in the
Hosokawa MechanoFusion Minikit with 1 mm compression gap for 10
minutes. Malvern (dry powder) particle size measurement gave a
d(50) of 1.39 .mu.m.
[0271] Particle Size Distributions
[0272] The Malvern particle size distributions show that
clomipramine hydrochloride micronised very readily to small
particle sizes. For example, Formulation 16 micronised to 1.0 .mu.m
with one pass at the relatively high grinding pressure of 5 bar and
the higher powder feed rate of 10 g/min.
[0273] Reducing the grinding pressure, for example to 1 bar as with
Formulation 19 interim powder, resulted in larger particles (d(50)
.about.1.8 .mu.m). Intermediate grinding pressure (3 bar) gave an
intermediate particle size distribution (d(50) .about.1.2 .mu.m as
for Formulation 21 interim powder).
[0274] Similarly, increasing powder feed rate, for example from 1
to 10 g/min, resulted in larger particles, as can be seen by
comparing d(50)s for Formulations 19 and 20.
[0275] The addition of an additive material, for example leucine as
in Formulation 23, appeared to reduce the milling efficiency.
However, this change may have been caused by the concomitant
improvement in flowability of the original drug powder leading to a
small but significant increase in the powder feed rate into the
mill. It was observed in other studies that milling efficiency was
increasingly sensitive to this powder feed rate as it increased
above 10 g/min.
[0276] It appeared possible from this series of examples to design
the milling parameters to select a particular d(50). For example, a
d(50) of .about.1.4 could be obtained either by repeated low
pressure milling and low feed rate (Formulation 19) or by a mix of
higher and lower pressure milling at a higher feed rate
(Formulation 25).
[0277] Aspirair Dispersion Performance
[0278] Approximately 2 mg of each formulation was then loaded and
sealed into a foil blister. This was then fired from an Aspirair
device into a Next Generation Impactor with air flow set at 60
l/min. The performance data are summarised in Tables 8, 9 and
10.
TABLE-US-00008 TABLE 8 MD ED FPD Formulation (mg) (mg) (mg) MMAD 14
1.64 1.19 1.05 1.53 (pure drug, jet milled at 8/1.5 bar) 15 1.55
1.32 1.19 1.68 (5% leucine, jet-milled at 8/1.5 bar) 16 2.414 1.832
1.493 1.80 (pure drug, jet-milled at 7/5 bar) 17 2.120 1.624 1.474
1.52 (5% leucine, jet-milled at 7/5 bar) 18 1.737 1.519 1.390 1.44
(5% MgSt, jet-milled at 7/5 bar) 19 2.031 1.839 1.550 1.90 (5%
leucine, jet-milled at 7/1 bar) 20 1.821 1.685 1.071 2.44 (5%
leucine, jet-milled at 7/1 bar) 21 1.846 1.523 1.437 1.61 (5%
leucine, jet-milled at 7/3 bar) 22 2.213 1.940 1.733 1.72 (5%
leucine, jet-milled at 7/3 bar) 23 1.696 1.557 1.147 2.13 (5%
leucine, single pass at 7/5 bar) 24 1.743 1.542 1.274 1.82 (5%
MgSt, jet-milled at 7/5 bar & mechanofused) 25 1.677 1.570
1.351 1.72 (5% MgSt, jet-milled at 7/5 bar)
TABLE-US-00009 TABLE 9 FPF % FPF % FPF % FPF % Formulation (<5
.mu.m) (<3 .mu.m) (<2 .mu.m) (<1 .mu.m) 14 88 83 65 21
(pure drug, jet milled at 8/1.5 bar) 15 90 82 60 17 (5% leucine,
jet-milled at 8/1.5 bar) 16 82 71 51 14 (pure drug, jet-milled at
7/5 bar) 17 91 85 68 21 (5% leucine, jet-milled at 7/5 bar) 18 91
90 73 20 (5% MgSt, jet-milled at 7/5 bar) 19 84 74 48 10 (5%
leucine, jet-milled at 7/1 bar) 20 64 46 28 6 (5% leucine,
jet-milled at 7/1 bar) 21 94 88 67 14 (5% leucine, jet-milled at
7/3 bar) 22 89 80 56 14 (5% leucine, jet-milled at 7/3 bar) 23 74
57 37 9 (5% leucine, single pass at 7/5 bar) 24 83 68 47 15 (5%
MgSt, jet-milled at 7/5 bar & mechanofused) 25 86 74 53 21 (5%
MgSt, jet-milled at 7/5 bar)
TABLE-US-00010 TABLE 10 Re- covery Throat Blister Device
Formulation % % % % 14 82 8 1 26 (pure drug, jet milled at 8/1.5
bar) 15 81 7 0 15 (5% leucine, jet-milled at 8/1.5 bar) 16 121 10 3
21 (pure drug, jet-milled at 7/5 bar) 17 106 5 1 23 (5% leucine,
jet-milled at 7/5 bar) 18 91 6 0 12 (5% MgSt, jet-milled at 7/5
bar) 19 107 10.6 1.3 8.2 (5% leucine, jet-milled at 7/1 bar) 20 96
24 1.3 6.1 (5% leucine, jet-milled at 7/1 bar) 21 97 3 0.6 16.9 (5%
leucine, jet-milled at 7/3 bar) 22 116 7 0.6 16.9 (5% leucine,
jet-milled at 7/3 bar) 23 87 18 2 6 (5% leucine, single pass at 7/5
bar) 24 92 14 1 10 (5% MgSt, jet-milled at 7/5 bar &
mechanofused) 25 87 10 1 6 (5% MgSt, jet-milled at 7/5 bar)
[0279] The device retention appeared high (above 20%) where pure
drug was used, and especially increased with small particle sizes
(especially 1 .mu.m and below): for example Formulations 14 and 16
had high drug retention. Device retention was lower with use of
magnesium stearate, for example as with Formulation 18 where device
retention was 12% despite a d(50) of 0.95 .mu.m. Device retention
was also reduced below 20% when leucine was used in combination
with a particle size above 1 .mu.m, for example with Formulation
22.
[0280] Throat deposition was reduced proportionately as particle
size was reduced. High throat deposition (>20%) occurs with
particle size d(50)>2 .mu.m: e.g. Formulation 20. Throat
deposition of below 10% was seen for particle sizes below 1 .mu.m.
The reduced inertial behaviour of the smaller particles may well
contribute to this observation. However, as noted above, device
retention tended to be greater for such small particles.
[0281] It is argued that as particle size was reduced, increased
adhesiveness and cohesiveness results in increased device
retention. This adhesiveness and cohesiveness and hence device
retention can be reduced by addition of force control agents,
attached to the drug particle surface (or drug and excipient
particle surfaces, as appropriate). As argued previously for the
apomorphine and clobozam examples, and demonstrated by the video
study, in Aspirair it is believed that a level of adhesiveness and
cohesiveness is desirable to prolong lifetime in the vortex,
yielding a slower plume, but adhesiveness and cohesiveness should
not be so high as to result in high device retention. Consequently
a balance of particle size, adhesiveness and cohesiveness is
required to achieve an optimum performance in Aspirair. The
examples contained herein indicate how such a balance may be
achieved. This balance may require modifying for each particular
different material characteristic.
[0282] Single step co-milling with a force control agent appears
effective in some examples such as Formulation 18. Multiple stage
processing may be more effective, for example, where the conditions
are selected to achieve particularly desirable effects. For
example, first stage high pressure milling of pure drug may be used
to produce the required size distribution (i.e. .about.1.4 .mu.m),
and a second stage lower pressure co-milling used to mix in the
force control agent, whereby better mixing is achieved without
milling and with reduced segregation of components in the mill.
Such is shown in Formulation 25, where a combination of both
relatively low throat deposition and low device retention are
achieved.
[0283] The results of jet milling heparin with an FCA are set out
below.
TABLE-US-00011 TABLE 11 d FPD Formulation d (10) d (50) d (60) (90)
<5 .mu.m Jet milled heparin + leucine 0.85 3.4 4.2 8.8 20.4 (1x)
Jet milled heparin + leucine 0.95 3.5 4.1 7.0 37.1 (2x) Jet milled
heparin + leucine 1.1 2.8 3.3 5.5 41.0 (3x) Jet milled pure heparin
(2x) 7.0
[0284] The combination of heparin and leucine (95:5) was air jet
milled using a Hosokawa Micron AS50 mill. The material was passed
up to three times through the mill. The powder was then filled into
capsules at 20 mg, and then fired from a Monohaler into a twin
stage impinger to give a resulting FPF(MD). The powder was also
analysed by Malvern particle sizer, and the results are summarised
in the table. Pure heparin powder was air jet milled with two
passes and gave an FPF(MD) of only 7%.
[0285] The optimum amount of additive material will depend on the
chemical composition and other properties of the additive material
and upon the nature of the active material and/or excipient
material, if present. In general, the amount of additive material
in the composite active particles will be not more than 60% by
weight, based on the weight of the active material and any
excipient material. However, it is thought that for most additive
materials the amount of additive material should be in the range of
40% to 0.25%, preferably 30% to 0.5%, more preferably 20% to 2%,
based on the total weight of the additive material and the active
material being milled. In general, the amount of additive material
is at least 0.01% by weight based on the weight of the active
material.
[0286] Clearly, many different designs of jet mills exist and any
of these may be used in the present invention. For example, in
addition to the AS50 Spiral jet mill and the MC50 Hosakawa Micron
used in the experiments discussed above, one can also use other
spiral jet mills, pancake jet mills or opposed fluid bed jet mills.
The feed rate for the jet mills will depend on their size. Small
spiral jet mills might use a feed rate of, for example, 1 to 2 g
per minute, whilst industrial scale mills will have a feed rate in
the order of kilograms per hour.
[0287] The properties of the co-jet milled particles produced using
the present invention may, to an extent, be tailored or adjusted by
making changes to the jet milling apparatus. For example, the
degree of particle coating and particle size reduction may be
adjusted by changing the number of jets which are used in the
apparatus, and/or by adjusting their orientation, that is, the
angles at which they are positioned.
* * * * *