U.S. patent application number 16/036595 was filed with the patent office on 2018-11-08 for inhalable pharmaceutical compositions.
The applicant listed for this patent is iCeutica Pty Ltd.. Invention is credited to H. William Bosch, Matthew Callahan, Felix Meiser, Marck Norret, Adrian Russell.
Application Number | 20180318170 16/036595 |
Document ID | / |
Family ID | 48628732 |
Filed Date | 2018-11-08 |
United States Patent
Application |
20180318170 |
Kind Code |
A1 |
Bosch; H. William ; et
al. |
November 8, 2018 |
Inhalable Pharmaceutical Compositions
Abstract
Methods for making inhalable composite particles comprising a
pharmaceutically-active agent, the method comprising: a) providing
composite particles comprising a millable grinding matrix and a
solid pharmaceutically-active agent, wherein the
pharmaceutically-active agent has an median particle size on a
volume average basis between 50 nm and 3 .mu.m; and b) milling the
composite particles in a mill without milling bodies for a time
period sufficient to produce inhalable composite particles having a
mass median aerodynamic diameter between 1 .mu.m and 20 .mu.m are
described.
Inventors: |
Bosch; H. William; (Bryn
Mawr, PA) ; Callahan; Matthew; (Philadelphia, PA)
; Meiser; Felix; (Claremont, AU) ; Norret;
Marck; (Darlington, AU) ; Russell; Adrian;
(Rivervale, AU) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
iCeutica Pty Ltd. |
Iluka |
|
AU |
|
|
Family ID: |
48628732 |
Appl. No.: |
16/036595 |
Filed: |
July 16, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13781115 |
Feb 28, 2013 |
10022303 |
|
|
16036595 |
|
|
|
|
61604435 |
Feb 28, 2012 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0075 20130101;
A61K 31/137 20130101; A61K 31/46 20130101; A61J 3/02 20130101; A61K
31/137 20130101; A61K 2300/00 20130101; A61K 31/46 20130101; A61K
2300/00 20130101 |
International
Class: |
A61J 3/02 20060101
A61J003/02; A61K 31/137 20060101 A61K031/137; A61K 31/46 20060101
A61K031/46; A61K 9/00 20060101 A61K009/00 |
Claims
1-79. (canceled)
80. An inhalable pharmaceutically-active composition comprising: a
millable grinding matrix and a solid pharmaceutically-active agent,
wherein the composite particles of the grinding matrix and the
pharmaceutically-active agent have a mass median aerodynamic
diameter of from about 1 .mu.m to about 20 .mu.m; and wherein the
pharmaceutically-active agent has a median particle size, on a
particle volume basis, of from about 50 nm to about 3 .mu.m.
81. The inhalable pharmaceutically-active composition of claim 80,
wherein the composition comprises a plurality of composite
particles comprising the millable grinding matrix and the solid
pharmaceutically-active agent.
82. The inhalable pharmaceutically-active composition of claim 80,
wherein the solid pharmaceutically-active agent has a median
particle size on a volume average basis of between 50 nm and 1
.mu.m.
83. The inhalable pharmaceutically-active composition of claim 80,
wherein the inhalable composite particles have a median particle
size on a volume average basis less than or equal to 10,000 nm.
84. The inhalable pharmaceutically-active composition of claim 80,
wherein the inhalable composite particles have a D90, determined on
a particle volume basis, of less than or equal to 15,000 nm.
85. The inhalable pharmaceutically-active composition of claim 80,
wherein the inhalable composite particles have a D90, determined on
a particle volume basis, greater than or equal to 2000 nm.
86. The inhalable pharmaceutically-active composition of claim 80,
wherein the inhalable composite particles have a volume weighted
mean (D4,3) of less than or equal to 10,000 nm.
87. The inhalable pharmaceutically-active composition of claim 80,
wherein the inhalable composite particles have a volume weighted
mean (D4,3) greater than or equal to 1000 nm.
88. The inhalable pharmaceutically-active composition of claim 80,
wherein the inhalable composite particles are capable of providing
an aerosol with a mass median aerodynamic diameter (MMAD) of the
inhalable composite particles between 1 .mu.m and 10 .mu.m when
delivered from a dry powder inhaler.
89. The inhalable pharmaceutically-active composition of claim 80,
wherein the inhalable composite particles are capable of providing
an aerosol with a fine particle fraction (FPF) of emitted dose of
the pharmaceutically active agent of greater than or equal to about
10% when delivered from a dry powder inhaler.
90. The inhalable pharmaceutically-active composition of claim 80,
wherein the inhalable composite particles are capable of providing
an aerosol with a relative standard deviation (RSD) of the fine
particle fraction FPF of emitted dose of the pharmaceutically
active agent of less than or equal to about 10%.
91. The inhalable pharmaceutically-active composition of claim 80,
wherein the inhalable composite particles are capable of providing
an aerosol with a fine particle fraction (FPF) of total recovered
dose of the pharmaceutically active agent of greater than or equal
to about 30% when delivered from a dry powder inhaler.
92. The inhalable pharmaceutically-active composition of claim 80,
wherein the inhalable composite particles when delivered from a dry
powder inhaler are capable of providing an aerosol with a mass
median aerodynamic diameter (MMAD) of the inhalable composite
particles from about 1 .mu.m to about 10 .mu.m and a FPF of the
pharmaceutically active agent of at least about 10%.
93. The inhalable pharmaceutically-active composition of claim 80,
wherein the inhalable composite particles are capable of providing
an aerosol with an emitted dose (ED) of greater than or equal to
about 70% when delivered from a dry powder inhaler.
94. The inhalable pharmaceutically-active composition of claim 80,
wherein the composite particles are capable of providing an aerosol
with an relative standard deviation (RSD) of less than or equal to
about 10% when determined on at least three samples delivered from
a dry powder inhaler.
95. The inhalable pharmaceutically-active composition of claim 80,
wherein the pharmaceutically-active agent within the provided
composite particles has a median size of from about 50 nm to about
1000 nm.
96. The inhalable pharmaceutically-active composition claim 80,
wherein the provided composite particles further comprise a milling
aid.
97. The inhalable pharmaceutically-active composition of claim 80,
wherein the millable grinding matrix is crystalline.
98. The inhalable pharmaceutically-active composition of claim 80,
wherein the pharmaceutically-active agent is crystalline.
99. The inhalable pharmaceutically-active composition of claim 80,
wherein the content uniformity of the solid pharmaceutically active
agent dispersed in the composite particle varies from the average
content by a percentage less than or equal to about 5.0%.
100. The inhalable pharmaceutically-active composition of claim 80,
wherein the content uniformity of the pharmaceutically active agent
throughout the blend has a percent relative standard deviation
(RSD) less than or equal to about 5.0%.
101. The inhalable pharmaceutically-active composition of claim 80,
wherein the inhalable composite particles have a roughness by
surface area ratio greater than or equal to a ratio of about 1.1,
wherein the specific surface area is measured using nitrogen
absorption; and wherein the surface area is calculated from the
spherical equivalent size determined by dry powder laser
diffraction.
102. The inhalable pharmaceutically-active composition of claim 80,
wherein the composite particles have a roughness root mean square
(Rrms) greater than or equal to a height selected about 15 nm and
wherein the roughness root mean square (Rrms) is measured using
atomic force microscopy or white light interferometry.
103. The inhalable pharmaceutically-active composition of claim 80,
wherein the composite particles have a median of force adhesion
(F[50]) less than or equal to about 150 nN when measured by atomic
force microscopy.
104. The inhalable pharmaceutically-active composition of claim 80,
wherein the weight of composite particles when dispensed from an
automated or semi-automated filing machine deviates from the
average weight dispensed by a percentage less than or equal to
about 10%.
105. The inhalable pharmaceutically-active composition of claim 80,
wherein the RSD from the average weight is less than or equal to
about 10% when the number of samples measured is greater than or
equal to 100 samples delivered from an automated or semi-automated
filing machine.
106. The inhalable pharmaceutically-active composition of claim 80,
wherein the composite particle further comprises a second
pharmaceutically active agent, the method producing composite
particles of the millable grinding matrix having the solid
pharmaceutically active agent and the second pharmaceutically
active agent dispersed therein.
107. The inhalable pharmaceutically-active composition of claim
106, wherein the composite particles have a fine particle fraction
ratio of the first pharmaceutically active agent and second
pharmaceutically active agent less than or equal to about 1.2 when
delivered from a dry powder inhaler and analyzed with a Next
Generation Impactor (NGI) with an induction port and a
preseparator.
108. The inhalable pharmaceutically-active composition of claim
106, wherein the composite particles have a mass median aerodynamic
diameter (MMAD) uniformity ratio of less than or equal to about 1.2
when delivered from a dry powder inhaler and analyzed with a Next
Generation Impactor (NGI) with an induction port and a
preseparator, wherein the distribution of each of the first and
second pharmaceutically active agent is assayed and each is used to
calculate an mass median aerodynamic diameter (MMAD) for the
composite particle.
109. The inhalable pharmaceutically-active composition of claim 80,
wherein the composition is formulated in a unit dosage form.
110. The inhalable pharmaceutically-active composition of claim 80,
encapsulated in a gelatin capsule.
111. The inhalable pharmaceutically-active composition of any one
of claim 80, wherein the composition is suitable for use with a dry
powder inhaler.
112. A dry powder inhaler for use with the inhalable
pharmaceutically-active composition of claim 80.
Description
RELATED APPLICATION
[0001] This application is a continuation and claims priority to
U.S. application Ser. No. 13/781,115, which was filed Feb. 28,
2013, which claims priority to U.S. Provisional Application No.
61/604,435, which was filed Feb. 28, 2012.
BACKGROUND
[0002] The rationale for delivering drugs via inhalation varies
from class to class. For example, due to the nature of certain
respiratory disease states such as infection, inflammation, or
bronchoconstriction, it has been found that inhalation is the
optimal route of administration to achieve sufficiently high levels
of drug in the diseased tissue(s). In some cases, certain agents
delivered via inhalation can produce fewer systemic side effects
when inhaled, without comprising efficacy, as is the case for some
classes of respiratory therapeutics. On the other hand, drugs
intended for systemic activity may be delivered via inhalation to
take advantage of the high surface area of the lungs, providing
rapid drug absorption into the systemic circulation without first
pass metabolic effects associated with oral administration. In some
situations, delivery of an agent to the lung may be for the
convenience of either the patient or healthcare provider. There is
currently interest in the development of vaccine delivery to the
lungs, which if successful would remove the need for injections as
part of routine vaccination. Common medicaments delivered to the
lung are drugs for the treatment of asthma and chronic obstructive
pulmonary disease (COPD) where the drugs act locally in the lung
tissue to prevent or relieve symptoms such as bronchial spasm.
Another example would be the delivery of antibiotics to treat the
presence of bacterial infections of the lung.
[0003] At present there are generally three different methods used
for delivery of drugs to the lung. The first involves drug
substance dissolved or dispersed in a liquid/gas propellant such as
a chlorofluorocarbon (CFC) or hydrofluorocarbon (HFA134a). In these
systems, the drug substance and propellant are supplied in a
canister which contains a metering valve, the canister being used
in conjunction with a device referred to as a pressurized metered
dose inhaler (pMDI). At the time of administration, patients are
required to coordinate their breath inhalation with actuation of
the device. When the device is actuated, the drug substance is
aerosolized by the propellant. Pressurized metered dose inhalers
have certain disadvantanges which include (in some cases) the use
of ozone-depleting propellants (CFCs). Also, upon actuation the
drug substance particles exit the devices at high velocities due to
the pressures generated by the propellants. This causes much of the
dose to impact the patient's throat and be swallowed instead of
being delivered to the airways of the lung. Many patients also have
difficulty coordinating their breathing with actuation of the
devices. For all of the above mentioned reasons, pressurized
metered dose inhalers are less than optimal for delivery of drug
substance to the lung.
[0004] A second method of pulmonary drug delivery involves
dissolution or dispersion of the drug substance in water followed
by nebulization of the solution or suspension with a compressed air
(jet) or ultrasonic nebulizer. This approach is often preferred for
pediatric patients who are unable to coordinate their breathing
with actuation of a pressurized metered dose inhaler. Drug delivery
by nebulization suffers from the disadvantage of being very slow.
Typical commercially available nebulizers have delivery rates in
the range of ca. 0.25 to 0.50 mL/min, leading to drug
administration times of 6 to 7 minutes or longer. Nebulization
therapy is inconvenient and requires a high level of patient
compliance. For instance, all nebulizers have to be washed and
disinfected after each use. Jet nebulizers require the use of an
electrically operated air compressor, and ultrasonic nebulizers
must be connected to line voltage or require batteries for
operation. Some nebulizers which contain mesh screens are only
suitable for delivery of drug solutions and cannot be used with
suspensions. For all of these reasons, nebulizer use is generally
limited to patients who cannot coordinate their breathing with
device actuation and to hospitalized patients with breathing tubes
in place.
[0005] The third method of pulmonary drug delivery is by the
inhalation of a dry powder formulation. Drug substance is delivered
to the lungs by the patient breathing in the powder from a delivery
device positioned in the mouth. Typical dry powder formulations
consist of carrier particles of an inert ingredient such as lactose
blended with micronized pharmaceutically active agent, although
some devices are designed to deliver pure micronized drug
substance. The most important property for successful delivery of
dry powder inhaled therapeutics is the aerodynamic size of the
aerosolized drug particles. Aerodynamic size is a measure of how
drug particles behave in an air stream and depends on a variety of
factors including the geometric particle size, shape, and density.
Aerodynamic size also depends on how readily the particles in a
powder can be be separated or deaggregated from each other when
aerosolized. Thus, small particles which are strongly aggregated
may behave like much larger particles when aerosolized. The
aerodynamic size determines how far into the lung the particles may
penetrate. In general the smaller the particle size, the deeper the
particles penetrate into the lung. Inhaled particles smaller than
about 1 .mu.m in diameter often do not deposit in the lung but are
exhaled back out of the lung. For drugs intended for systemic
absorption, deep penetration into the alveolar region of the lung
is necessary and particles having an MMAD of 0.5 to 5 (or 1 to 3)
.mu.m are generally desirable. For treating COPD, asthma and other
diseases of the respiratory tract, topical delivery to upper
airways is the aim. Particles with a size of 3 to 5 .mu.m are
generally preferred for this purpose because they tend to deposit
in the conducting airways of the lung. Most raw drug substance is
considerably larger than 1 to 5 .mu.m in diameter, therefore the
current methods of making formulations for inhalation requires air
jet micronization of the drug substance. Micronization is an
effective method of reducing drug particle size, but it tends to
impart high levels of electrostatic charge on the particles which
causes them to adhere to each other, to carrier particles in the
formulation, and to surfaces of dry powder inhaler devices. As a
result, the delivery efficiency of conventional dry powder
formulations can be relatively low, and in some cases as little as
one third of the aerosolized material may be able to reach the
patient's respiratory tract.
[0006] There are several other critical parameters for successfully
delivering therapeutic or pharmaceutical agents by dry powder
inhalation. One important parameter is the aerodynamic diameter of
the particles, which is a measure of how the particles behave when
dispersed in an air stream. In cases where the formulation contains
excipients in addition to active agent particles, adequate content
uniformity of the powder is another important attribute for
accurate delivery of dose. Another critical parameter for inhaled
dry powder formulations is the flowability of the powder. The
powder in the device used by the patient needs to flow well, so
that a full and consistent dose of the powder formulation leaves
the device. A further critical parameter for inhaled dry powder
formulations is the efficiency of dose delivery, a measure of which
is the fine particle fraction (FPF). Thus, the FPF provides an in
vitro measure of the efficiency of the device/formulation in
delivering the active to the lung.
[0007] Despite advances in methods of preparing dry powder
formulations, there remains a need for particles with the
appropriate properties, such as size, uniformity, flowability, and
FPF, for enhanced delivery of therapeutics to the lung.
Furthermore, methods are needed which can be readily utilized
without limitations imposed by the solubility of the therapeutic
agent and are cost-effective to manufacture. These needs and other
needs are satisfied by the present invention.
SUMMARY
[0008] Described herein is a method for making inhalable composite
particles comprising a pharmaceutically-active agent, the method
comprising: a) providing composite particles comprising a millable
grinding matrix and a solid pharmaceutically-active agent, wherein
the pharmaceutically-active agent has an median particle size on a
volume average basis between 50 nm and 3 .mu.m; and b) milling the
composite particles in a mill without milling bodies for a time
period sufficient to produce inhalable composite particles having a
mass median aerodynamic diameter between 1 .mu.m and 20 .mu.m.
[0009] In various aspects: inhalable composite particles comprise a
solid pharmaceutically-active agent having a median particle on a
volume average basis between 50 nm and 3 .mu.m; the inhalable
composite particles have a median particle size on a volume average
size less than or equal to 10,000 nm; the inhalable composite
particles have a D90, determined on a particle volume basis, less
than or equal to 15,000 nm; the inhalable composite particles have
a D90, determined on a particle volume basis, greater than or equal
to 2000 nm; the inhalable composite particles have a volume
weighted mean (D4,3) less than or equal to 10,000 nm; the inhalable
composite particles have a volume weighted mean (D4,3) greater than
or equal to 1000 nm; the inhalable composite particles are capable
of providing an aerosol with a mass median aerodynamic diameter
(MMAD) of the inhalable composite particles between 1 .mu.m and 10
.mu.m when delivered from a dry powder inhaler; the inhalable
composite particles are capable of providing an aerosol with a fine
particle fraction (FPF) of emitted dose of the pharmaceutically
active agent of greater than or equal to about 10% when delivered
from a dry powder inhaler; the inhalable composite particles are
capable of providing an aerosol with a related standard deviation
(RSD) of the FPF of emitted dose of the pharmaceutically active
agent of less than or equal to about 10%; the inhalable composite
particles are capable of providing an aerosol with a fine particle
fraction (FPF) of total recovered dose of the pharmaceutically
active agent of greater than or equal to about 30% when delivered
from a dry powder inhaler; the inhalable composite particles when
delivered from a dry powder inhaler are capable of providing an
aerosol with a mass median aerodynamic diameter (MMAD) of the
inhalable composite particles from about 1 .mu.m to about 10 .mu.m
and a FPF of the pharmaceutically active agent of at least about
10%.
[0010] In various aspects: the inhalable composite particles are
capable of providing an aerosol with a mass median aerodynamic
diameter (MMAD) of the inhalable composite particles between 1
.mu.m and 7 .mu.m when delivered from a dry powder inhaler; the
inhalable composite particles are capable of providing an aerosol
with a mass median aerodynamic diameter (MMAD) of the inhalable
composite particles between 1.5 .mu.m and 5 .mu.m when delivered
from a dry powder inhaler; the inhalable composite particles are
capable of providing an aerosol with a mass median aerodynamic
diameter (MMAD) of the inhalable composite particles is between 2
.mu.m and 5 .mu.m when delivered from a dry powder inhaler; the
inhalable composite particles are capable of providing an aerosol
with a mass median aerodynamic diameter (MMAD) of the inhalable
composite particles is between 2 .mu.m and 4 .mu.m when delivered
from a dry powder inhaler; the inhalable composite particles are
capable of providing an aerosol with an emitted dose (ED) of
greater than or equal to about 70% when delivered from a dry powder
inhaler; the composite particles are capable of providing an
aerosol with an related standard deviation (RSD) of less than or
equal to about 10% when determined on at least three samples
delivered from a dry powder inhaler; the pharmaceutically-active
agent within the provided composite particles has a median size of
from about 50 nm to about 1000 nm.
[0011] In various aspects, the provided composite particles further
comprise a milling aid; the millable grinding matrix is
crystalline; the pharmaceutically-active agent is crystalline; the
content uniformity of the solid pharmaceutically active agent
dispersed in the composite particle varies from the average content
by a percentage less than or equal to about 5.0%; the content
uniformity of the pharmaceutically active agent throughout the
blend has a percent relative standard deviation (RSD) less than or
equal to about 5.0%; the inhalable composite particles have a
roughness by surface area ratio greater than or equal to a ratio of
about 1.1 (wherein the specific surface area is measured using
nitrogen absorption and wherein the surface area is calculated from
the spherical equivalent size determined by dry powder laser
diffraction).
[0012] In various aspects: the composite particles have a Rrms
greater than or equal to a height selected about 15 nm and wherein
the Rrms is measured using atomic force microscopy; the composite
particles have a Rrms greater than or equal to a height selected
from about 15 nm and when the Rrms is measured using white light
interferometry; the composite particles have a median of force
adhesion (F[50]) less than or equal to about 150 nN when measured
by atomic force microscopy; the weight of composite particles when
dispensed from an automated or semi-automated filing machine
deviates from the average weight dispensed by a percentage less
than or equal to about 10%; the RSD from the average weight is less
than or equal to about 10% when the number of samples measured is
greater than or equal to 100 samples delivered from an automated or
semi-automated filing machine; the step of providing composite
particles comprises dry milling a composition comprising: a solid
pharmaceutically active agent and a millable grinding matrix in a
mill comprising a plurality of milling bodies for a time period
sufficient to produce composite particles comprising grinding
matrix and solid pharmaceutically active agent; the dry milling
comprises milling in a mill with a plurality of milling bodies; the
mill without milling bodies is selected from a cutter mill,
end-runner mill, roller mill, hammer mill, fluid energy mill, pin
mill, impact mill, mechanofusion mill, beater mill, jet mill and
air jet mill.
[0013] In various aspects, the millable grinding matrix comprises
one or more materials selected from an organic acid, organic base,
polyol, peptide, protein, fat, fatty acid, amino acid (aspartic
acid, glutamic acid, leucine, L-leucine, isoleucine, lysine,
valine, methionine, phenylalanine, glycine, arginine, aspartic
acid, glutamic acid, cysteine, alanine, serine, phenylalanine,
lysine, N-acetyl-L-cysteine, or a pharmaceutically acceptable salt,
solvate, hydrate, or polymorph thereof), carbohydrate (e.g.,
mannitol, sorbitol, xylitol, maltitol, lactitol, erythritol,
arabitol, ribitol, glucose, fructose, mannose, galactose, lactose,
sucrose, raffinose, ribitol, maltose, sorbose, cellobiose, sorbose,
trehalose, maltodextrins, dextrans, inulin,
1-O-alpha-D-glucopyranosyl-D-mannitol (Isomalt)), or a
pharmaceutically acceptable solvate, hydrate, or polymorph thereof,
phospholipid, triglyceride, detergent, polymer, or a
pharmaceutically acceptable salt, solvate, hydrate, or polymorph
thereof.
[0014] In various aspects: the millable grinding matrix comprises
lactose monohydrate and optionally one or more material selected
from sodium chloride, anhydrous lactose, mannitol, glucose,
sucrose, trehalose, sorbitol, 1-O-alpha-D-glucopyranosyl-D-mannitol
(Isomalt), xylitol, maltitol, lactitol, erythritol, arabitol,
ribitol, fructose, mannose, galactose, raffinose, ribitol, maltose,
sorbose, cellobiose, sorbose, inulin, sodium citrate, sodium
ascorbate. lecithin, soy lecithin, dipalmitoyl phosphatidylcholine,
phosphatidylglycerol, dipalmitoyl phosphatidyl ethanolamine,
dipalmitoyl phosphatidylinositol, phospatidylcholines,
phosphatidylethanolamine, phosphatidylglycerols,
phosphatidylinositol, phosphatidylserine, sodium lauryl sulphate,
magnesium lauryl sulphate; PEG 6000, PEG 3000 Tween 80, Poloxamer
188, leucine, L-leucine, isoleucine, lysine, valine, methionine,
phenylalanine, glycine, arginine, aspartic acid, glutamic acid,
cysteine, alanine, and serine.
[0015] In various aspects: the composite particle further comprises
a second pharmaceutically active agent, the method producing
composite particles of the matrix having the solid pharmaceutically
active agent and the second pharmaceutically active agent dispersed
therein; the composite particles have a fine particle fraction
ratio of the first pharmaceutically active agent and second
pharmaceutically active agent less than or equal to about 1.2 when
delivered from a dry powder inhaler and analyzed with a NGI with an
induction port and a preseparator; the composite particles have a
MMAD uniformity ratio of less than or equal to about 1.2 when
delivered from a dry powder inhaler and analyzed with a NGI with an
induction port and a preseparator, wherein the distribution of each
of the first and second pharmaceutically active agent is assayed
and each is used to calculate an MMAD for the composite
particle.
[0016] Also described is an inhalable composition of
pharmaceutically-active composite particles produced by any of the
methods described above.
[0017] Also described is an inhalable pharmaceutically-active
composition comprising: a plurality of composite particles
comprising a millable grinding matrix and a solid
pharmaceutically-active agent, wherein the composite particles of
the grinding matrix and the pharmaceutically-active agent have a
mass median aerodynamic diameter of from about 1 .mu.m to about 20
.mu.m; and wherein the pharmaceutically-active agent within the
composite particles has an average particle size of from about 50
nm to about 3 .mu.m.
[0018] In various aspects of this inhalable composition: the
inhalable composite particles comprise a solid
pharmaceutically-active agent having a median particle on a volume
average basis between 50 nm and 3 .mu.m; the inhalable composite
particles have a median particle size on a volume average size less
than or equal to 10,000 nm; the inhalable composite particles have
a D90, determined on a particle volume basis, less than or equal to
15,000 nm; the inhalable composite particles have a D90, determined
on a particle volume basis, greater than or equal to 2000 nm; the
inhalable composite particles have a volume weighted mean (D4,3)
less than or equal to 10,000 nm; the inhalable composite particles
have a volume weighted mean (D4,3) greater than or equal to 1000
nm; the inhalable composite particles are capable of providing an
aerosol with a mass median aerodynamic diameter (MMAD) of the
inhalable composite particles between 1 .mu.m and 10 .mu.m when
delivered from a dry powder inhaler; the inhalable composite
particles are capable of providing an aerosol with a fine particle
fraction (FPF) of emitted dose of the pharmaceutically active agent
of greater than or equal to about 10% when delivered from a dry
powder inhaler; the inhalable composite particles are capable of
providing an aerosol with a related standard deviation (RSD) of the
FPF of emitted dose of the pharmaceutically active agent of less
than or equal to about 10%; the inhalable composite particles are
capable of providing an aerosol with a fine particle fraction (FPF)
of total recovered dose of the pharmaceutically active agent of
greater than or equal to about 30% when delivered from a dry powder
inhaler; the inhalable composite particles when delivered from a
dry powder inhaler are capable of providing an aerosol with a mass
median aerodynamic diameter (MMAD) of the inhalable composite
particles from about 1 .mu.m to about 10 .mu.m and a FPF of the
pharmaceutically active agent of at least about 10%; the inhalable
composite particles are capable of providing an aerosol with a mass
median aerodynamic diameter (MMAD) of the inhalable composite
particles between 1 .mu.m and 7 .mu.m when delivered from a dry
powder inhaler; the inhalable composite particles are capable of
providing an aerosol with a mass median aerodynamic diameter (MMAD)
of the inhalable composite particles between 1.5 .mu.m and 5 .mu.m
when delivered from a dry powder inhaler; the inhalable composite
particles are capable of providing an aerosol with a mass median
aerodynamic diameter (MMAD) of the inhalable composite particles is
between 2 .mu.m and 5 .mu.m when delivered from a dry powder
inhaler; the inhalable composite particles are capable of providing
an aerosol with a mass median aerodynamic diameter (MMAD) of the
inhalable composite particles is between 2 .mu.m and 4 .mu.m when
delivered from a dry powder inhaler; the inhalable composite
particles are capable of providing an aerosol with an emitted dose
(ED) of greater than or equal to about 70% when delivered from a
dry powder inhaler; the composite particles are capable of
providing an aerosol with an related standard deviation (RSD) of
less than or equal to about 10% when determined on at least three
samples delivered from a dry powder inhaler; the
pharmaceutically-active agent within the provided composite
particles has a median size of from about 50 nm to about 1000 nm;
the provided composite particles further comprise a milling aid;
the millable grinding matrix is crystalline; the
pharmaceutically-active agent is crystalline; the content
uniformity of the solid pharmaceutically active agent dispersed in
the composite particle varies from the average content by a
percentage less than or equal to about 5.0%; the content uniformity
of the pharmaceutically active agent throughout the blend has a
percent relative standard deviation (RSD) less than or equal to
about 5.0%; the inhalable composite particles have a roughness by
surface area ratio greater than or equal to a ratio of about 1.1
(wherein the specific surface area is measured using nitrogen
absorption wherein the surface area is calculated from the
spherical equivalent size determined by dry powder laser
diffraction); the composite particles have a Rrms greater than or
equal to a height selected about 15 nm and wherein the Rrms is
measured using atomic force microscopy; the composite particles
have a Rrms greater than or equal to a height selected from about
15 nm and when the Rrms is measured using white light
interferometry; the composite particles have a median of force
adhesion (F[50]) less than or equal to about 150 nN when measured
by atomic force microscopy; the weight of composite particles when
dispensed from an automated or semi-automated filing machine
deviates from the average weight dispensed by a percentage less
than or equal to about 10%; the RSD from the average weight is less
than or equal to about 10% when the number of samples measured is
greater than or equal to 100 samples delivered from an automated or
semi-automated filing machine; the composite particle further
comprises a second pharmaceutically active agent, the method
producing composite particles of the matrix having the solid
pharmaceutically active agent and the second pharmaceutically
active agent dispersed therein; the composite particles have a fine
particle fraction ratio of the first pharmaceutically active agent
and second pharmaceutically active agent less than or equal to
about 1.2 when delivered from a dry powder inhaler and analyzed
with a NGI with an induction port and a preseparator; the composite
particles have a MMAD uniformity ratio of less than or equal to
about 1.2 when delivered from a dry powder inhaler and analyzed
with a NGI with an induction port and a preseparator, wherein the
distribution of each of the first and second pharmaceutically
active agent is assayed and each is used to calculate an MMAD for
the composite particle.
[0019] Also described is any of the forgoing pharmaceutical
compositions formulated in a unit dosage form. In various aspects:
the pharmaceutical composition comprises a gelatin capsule, the
composition is suitable for use in a dry powder inhaler.
[0020] Also described is a dry powder inhaler comprising the
pharmaceutical composition described above.
[0021] FIG. 1 shows representative SEM data of batch 4J
(10,000.times. magnification).
[0022] FIG. 2 shows representative SEM data of batch 4J
(100,000.times. magnification).
[0023] All publications mentioned herein are incorporated herein by
reference to disclose and describe the methods and/or materials in
connection with which the publications are cited. The publications
discussed herein are provided solely for their disclosure prior to
the filing date of the present application. Nothing herein is to be
construed as an admission that the present invention is not
entitled to antedate such publication by virtue of prior invention.
Further, the dates of publication provided herein can be different
from the actual publication dates, which can require independent
confirmation.
[0024] Specific abbreviations used herein are as follows: "AFM" is
an abbreviation for atomic force microscropy; "CI" is an
abbreviation for Anderson Cascade Impactor; "MSLI" is an
abbreviation for a Multi-Stage Liquid Impinger; and, "NGI" is an
abbreviation for Next Generation Impactor.
[0025] As used in the specification and the appended claims, the
singular forms "a," "an" and "the" include plural referents unless
the context clearly dictates otherwise. Thus, for example,
reference to "a functional group," "an alkyl," or "a residue"
includes mixtures of two or more such functional groups, alkyls, or
residues, and the like.
[0026] Ranges can be expressed herein as from "about" one
particular value, and/or to "about" another particular value. When
such a range is expressed, a further aspect includes from the one
particular value and/or to the other particular value. Similarly,
when values are expressed as approximations, by use of the
antecedent "about," it will be understood that the particular value
forms a further aspect. It will be further understood that the
endpoints of each of the ranges are significant both in relation to
the other endpoint, and independently of the other endpoint. It is
also understood that there are a number of values disclosed herein,
and that each value is also herein disclosed as "about" that
particular value in addition to the value itself. For example, if
the value "10" is disclosed, then "about 10" is also disclosed. It
is also understood that each unit between two particular units are
also disclosed. For example, if 10 and 15 are disclosed, then 11,
12, 13, and 14 are also disclosed.
[0027] References in the specification and concluding claims to
parts by weight of a particular element or component in a
composition, denotes the weight relationship between the element or
component and any other elements or components in the composition
or article for which a part by weight is expressed. Thus, in a
compound containing 2 parts by weight of component X and 5 parts by
weight component Y, X and Y are present at a weight ratio of 2:5,
and are present in such ratio regardless of whether additional
components are contained in the compound. A weight percent (wt. %)
of a component, unless specifically stated to the contrary, is
based on the total weight of the formulation or composition in
which the component is included.
[0028] As used herein, the terms "administering" and
"administration" refer to providing a pharmaceutical preparation to
a subject by inhalation or nasal administration. Administration can
be continuous or intermittent. In various aspects, a preparation
can be administered therapeutically; that is, administered to treat
an existing disease or condition. In further various aspects, a
preparation can be administered prophylactically; that is,
administered for prevention of a disease or condition.
[0029] As used herein, the term "blend" is refers to the resultant
mixture of a pharmaceutically active agent and excipient particles
combined together in a process that has the effect or intended
effect of distributing the active and excipient particles in a
uniform distribution throughout the final powder blend. In this
definition the term excipient and matrix are interchangeable. An
ensemble of composite particles as produced by the disclosed
methods is one example of a blend. Typically, a blend is made using
simple blending processes that do not involve granulation, but may
involve a milling step.
[0030] As used herein, the term "carrier excipient" refers to a
pharmaceutical excipient suitable for use in an orally inhaled
formulation that may be combined with an inhalable composite
particle to produce a formulation for therapeutic use.
[0031] As used herein, the term "carrier matrix" refers to all
material that has been milled in with the pharmaceutically active
agent and is now combined into a composite particle with
nanoparticles of pharmaceutically active agent.
[0032] As used herein, the term "chemically-inert" refers to
materials, e.g., milling bodies, that do not react chemically with
the pharmaceutically active agent or the millable grinding
matrix.
[0033] As used herein, the term "co-crystal" means a physical
association of two or more molecules which owe their stability
through non-covalent interaction. One or more components of this
molecular complex provide a stable framework in the crystalline
lattice. In certain instances, the guest molecules are incorporated
in the crystalline lattice as anhydrates or solvates, see e.g.,
"Crystal Engineering of the Composition of Pharmaceutical Phases.
Do Pharmaceutical Co-crystals Represent a New Path to Improved
Medicines?" Almarasson, O., et al., The Royal Society of Chemistry,
(2004), 1889-1896. Examples of co-crystals include
p-toluenesulfonic acid and benzenesulfonic acid.
[0034] As used herein, the term "composite particle" refers to a
particle comprising particles of a pharmaceutically active agent
and particles of a millable grinding matrix (milled or partially
milled) combined into a larger particle. In some case, the
particles of pharmaceutically active agent and the particles of
millable grinding matrix are dispersed in the composite particle.
The composite particle can comprise particles of more than one
pharmaceutically active agent or more than one millable grinding
matrix. The composite particle can further comprise additional
materials such as a milling aid. The particles of pharmaceutically
active agent can be nanoparticles and/or microparticles, but are
typically nanoparticles. The particles of millable grinding matrix
can also be nanoparticles and/or microparticles.
[0035] As used herein, the term "content uniformity" refers to
uniformity with which a pharmaceutically active agent is
distributed throughout a blend. A blend with superior content
uniformity will have the same concentration of pharmaceutically
active agent in many samples taken from different places (e.g.,
top, middle and bottom) in a blend. Typically content uniformity is
measured by assaying the sample by HPLC, or similar technique, to
determine the concentration of active in a sample. Typically
content uniformity is expressed as the percent (%) deviation of the
many samples from the known concentration of the whole blend. In
bulk powder samples, content uniformity may be measured from three
or more samples. If the powder is filled into packaging such as a
hard capsule or foil blister pack, then a number of packages will
be assayed (typically 10 randomly chosen from a larger number) to
determine the content uniformity. In the case where packages such
as a capsule are assayed to determine the content uniformity of the
powder, the assays should be corrected for the total weight of
powder in each package. One common measure for content uniformity,
is the percent deviation of each sample from average concentration
or the known concentration of the whole blend. A specification then
would be that no sample has a deviation greater than a certain
percent. The second common measure is the relative standard
deviation (RSD) of the sample assays from the average (either the
average of the samples of the known concentration of the bulk
powder).
[0036] As used herein, unless the context requires otherwise, the
term "dry mill" or variations, such as "dry milling", refer to
milling in at least the substantial absence of liquids. If liquids
are present, they are present in such amounts that the contents of
the mill retain the characteristics of a dry powder. In some cases
dry milling takes place in the complete absence of liquid.
[0037] As used herein, the term "dry powder laser diffraction"
refers to a laser diffraction measurement where compressed air is
use to disperse a dry powder into an airstream that is passed
through the measurement zone.
[0038] As used herein, the term "particle size" can refer to
measurements made on individual particles or distributions of
particles. The terms "particle size distribution," "average
particle size," "median particle size," and "mean particle size"
refer to the characterization of populations of particles which
individually are not all of the same size, and are typically
expressed in units of length (for example, nanometers or
micrometers). These parameters can be measured by a variety of
techniques including dynamic light scattering, static light
scattering, laser diffraction, sedimentation, time of flight, or
other methods known to those skilled in the art. Particle size
distributions can also be quantified by a size that corresponds to
a certain percentile of the distribution (D.sub.x), wherein a
certain percentage (x) of the population (on a volume, not weight
basis) is smaller than the defined size. For example, a
distribution having a D.sub.90 value of 500 nm means that 90% of
the distribution (on a volume basis) has a size that is less than
500 nm. As used herein, the terms "D.sub.50" and "median particle
size" are used interchangeably. The terms "average particle size"
and "mean particle size" are used interchangeably and can be
calculated from size distributions by methods known to those
skilled in the art. Mean particle size can also be represented by
the term "D.sub.(4,3)" which refers to a method of calculating the
mean of a distribution of particles.
[0039] As used herein, the term "effective aerodynamic size" refers
to the characterization of a distribution of particles when
measured in an air stream. The effective aerodynamic particle size
may be represented in terms of a median, mean, average, or size
corresponding to a specified percentile as determined by an
aerodynamic measuring technique known to those skilled in the
art.
[0040] As used herein, the terms "emitted dose" and "ED" are
interchangeable, and refer to the fraction of the total dose
available in the device delivered by an inhaler device. It is often
expressed as a percentage.
[0041] As used herein, the terms "fine particle fraction" and "FPF"
are interchangeable, and refer to the fraction of pharmaceutically
active agent that has an aerodynamic diameter less than about 4-6
.mu.m. Unless otherwise indicated, as used herein, FPF is
determined using a NGI with induction port and preseparator. Other
methods known to one skilled in the art to determine FPF include
using a Multi-Stage Liquid Impinger (MSLI) with induction port or
an Anderson Cascade Impactor (CI) with induction port and
preseparator. FPF is expressed as a fraction of total dose, and
typically it is expressed as a percentage of the total dose less
than about 4-6 micron. Unless otherwise stated the FPF is the
fraction relative to the emitted dose. Another definition is the
FPF relative to the total recovered dose (TRD), and when this
intended, it is indicated as FPF (TRD). The total recovered dose is
the sum of emitted dose and the dose remaining in the device/dose
packaging. It should be noted the disclosed composite particles
comprise pharmaceutically active agent that is uniformly aggregated
into the composite particles, thus the FPF is also an indicator of
the fraction of composites with an aerodynamic diameter less than
about 4-6 micron.
[0042] As used herein, the term "flowable" refers to a powder
having physical characteristics rendering it suitable for further
processing using typical equipment used for the manufacture of
pharmaceutical compositions and formulations.
[0043] As used herein, the term "FPF uniformity ratio" refers to
the ratio of two FPF values determined from the assay of two
separate pharmaceutically active agents present in a single
composite particle composition. The ratio is calculated by dividing
the larger FPF with the smaller one. It should be noted that it
only has meaning where there are two or more actives contained
within a composite composition. If the FPF uniformity ratio is near
1 it is an indication that the two pharmaceutically active agents
have a highly uniform distribution throughout the composite
composition.
[0044] As used herein, the term "geometric standard deviation" or
"GSD" are used interchangeable, and refers to the aerodynamice
particle size distribution, and calculated as follows:
GSD=(d.sub.84/d.sub.16).sup.1/2. Unless otherwise indicated, as
used herein, GSD is determined using a NGI with induction port and
preseparator. Other methods known to one skilled in the art to
determine GSD include using a MSLI with induction port or an CI
with induction port and preseparator. As noted above for the
definition of FPF, the disclosed composite particles comprise
pharmaceutically active agent that is uniformly aggregated into the
composite particles, thus although the GSD is determined from an
assay of the active material it is a measurement of the aerodynamic
size distribution of the composite particles.
[0045] As used herein, the phrase "identified to be in need of
treatment for a disorder," or the like, refers to selection of a
subject based upon need for treatment of the disorder. For example,
a subject can be identified as having a need for treatment of a
disorder (e.g., a respiratory disorder) based upon an earlier
diagnosis by a person of skill and thereafter subjected to
treatment for the disorder. It is contemplated that the
identification can, in one aspect, be performed by a person
different from the person making the diagnosis. It is also
contemplated, in a further aspect, that the administration can be
performed by one who subsequently performed the administration.
[0046] As used herein, the phrase "inhalable composite" refers to a
powder comprising composite particles that have the correct
aerodynamic diameter to be orally inhaled into the lungs of a
subject. The subject can be a human.
[0047] As used herein, the term "inhibit" refers to processes that
includes prohibiting, preventing, restraining, and lowering,
stopping, or reversing progression or severity, and such action on
a resultant clinical or medical symptoms.
[0048] As used herein, the term "median force of adhesion" or
"F[50]" both refer to the the median force of adhesion between
inhalable composite particles as measured by atomic force
microscopy (AFM) where the median is taken from a large number
(greater than 1000) of adhesion force measurements. Specifically,
as used herein, F[50] is measured by atomic force microscopy using
the methods as set forth by Adi et al. [European Journal of
Pharmaceutical Sciences, 35 (2008) 12-18].
[0049] As used herein, the terms "mass median aerodynamic diameter"
and "MMAD" are interchangeable, and refer to the the aerodynamic
diameter at which 50% of the particles by mass are larger and 50%
are smaller. MMAD can be determined using a Next Generation
Impactor (NGI) with induction port and preseparator. Other methods
known to one skilled in the art to determine MMAD include using a
Multi Stage Liquid Impinger (MSLI) with induction port or a Cascade
Impactor (CI) with induction port and preseparator. MMAD can also
be determined using time-of-flight measurements known to those
skilled in the art. As noted above for the definition of FPF, the
disclosed composite particles comprise pharmaceutically active
agent that is uniformly aggregated into the composite particles,
thus although the MMAD is determined from an assay of the active
material it is a measurement of the aerodynamic size of the
composite particles. MMAD is equivalent to the aerodynamic D50
value on a volume basis after correction for particle density.
[0050] As used herein, the term "MMAD uniformity ratio" refers to
the ratio of two MMAD values determined from the assay of two
separate pharmaceutically active agents present in a single
composite particle composition. The ratio is calculated by dividing
the larger MMAD with the smaller one. It should be noted that it
only has meaning where there are two or more actives contained
within a composite composition. If the MMAD uniformity ratio is
near 1, then it is an indication that the two pharmaceutically
active agents have a highly uniform distribution throughout the
composite composition.
[0051] As used herein, the term "millable" refers to a millable
grinding matrix that reduces in particle size under the dry milling
conditions of the method of the invention.
[0052] As used herein, the term "millable grinding matrix" refers
any inert substance that a pharmaceutically active agent can be or
is combined with and milled to provide composite particles. The
terms "co-grinding matrix" and "matrix" are interchangeable with
"grinding matrix".
[0053] As used herein, the term "nanoparticle" refers to a particle
having a size of about 1000 nm or less.
[0054] As used herein, the term "passive laser diffraction" refers
to the process of measuring the size of a dry powder by using laser
diffraction wherein the dry powder is dispered into an airstream
that is pulled out of an inhalation device and through the
measurement zone. The airflow pulled through the device is one that
is within the normal range for human inhalation. Airflows would
typically be, but not limited to a range of 20-100 liters/minute.
Thus, the dry powder is mechanically dispersed by air being drawn
out of the inhalation device and not by the particle size
instrument.
[0055] As used herein, the term "pharmaceutically active agent"
refers to any agent that when administered to a subject, has a
therapeutic effect, a diagnostic effect, elicits a desired
biological, and/or pharmacological effect. The term can be used
interchangeably herein with "active", "active compound", and
"biologically active". The pharmaceutically active agent can be
used in the treatment, cure, prevention, or diagnosis of disease or
used to otherwise enhance physical or mental well-being. As used
herein, the term "roughness by surface area" refers to the ratio of
the specific surface area (SSA) of the composite as measured by BET
isotherm and the surface area calculated from laser diffraction
particle size measurements of the composite wherein the laser
diffraction measurement is by dry powder laser diffraction. The
Roughness by Surface Area is a measure of the roughness of a
particle, i.e., if the ratio of actual SSA to calculated surface
area is high then the surface is rougher.
[0056] As used herein, the terms "roughness--root mean squared" and
"Rrms" both refer to the square root of the mean squared where the
mean squared is the sum of the square of the height (taken from the
zero reference plane) divided by the number of data points.
Specifically, as used herein, Rrms is measured by atomic force
microscopy or scanning white light interferometry according to the
methods set forth by Adi et al. [Langmuir, 24 (2008)
11307-11312].
[0057] As used herein, the term "segregation" refers to the
stratification of the particle size distribution of a powder or
blend. It can be caused by any physical process, but typically it
occurs when a powder or blend undergoes flow or other movement.
Examples of processes that can introduce segregation are, but not
limited to, transport, blending and flow in a hopper or other
processing equipment. A powder or blend in an unsegregated state
will have an even distribution of particle sizes throughout the
whole powder or blend such that any sample taken from any part of
the bag or container holding the powder (such as top, middle,
bottom) will give the same particle size distribution. In a powder
that has undergone segregation some parts of the powder will have
more large particles that other parts and some parts will have more
small particles than other parts of the powder. In a powder with
segregation samples taken from a variety of positions in the bag or
container holding the powder (such as top, middle, bottom) will
typically show some difference in the particle size distribution.
In some cases, for testing of powder segregation, a method of
forced segregation may be used in order to assess any changes to
content uniformity after segregation. An example of forced
segregation is to place the powder in a tube and rotate the tube at
a slight angle for a long period such that large and small
particles will separate.
[0058] Compounds described herein comprise atoms in both their
natural isotopic abundance and in non-natural abundance. The
disclosed compounds can be isotopically-labelled or
isotopically-substituted compounds identical to those described,
but for the fact that one or more atoms are replaced by an atom
having an atomic mass or mass number different from the atomic mass
or mass number typically found in nature. Examples of isotopes that
can be incorporated into compounds of the invention include
isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,
fluorine and chlorine, such as .sup.2H, .sup.3H, .sup.13C,
.sup.14C, .sup.15N, .sup.18O, .sup.17O, .sup.35S, .sup.18F and
.sup.36Cl, respectively. Compounds further comprise prodrugs
thereof, and pharmaceutically acceptable salts of said compounds or
of said prodrugs which contain the aforementioned isotopes and/or
other isotopes of other atoms are within the scope of this
invention. Certain isotopically-labelled compounds of the present
invention, for example those into which radioactive isotopes such
as .sup.3H and .sup.14C are incorporated, are useful in drug and/or
substrate tissue distribution assays. Tritiated, i.e., .sup.3H, and
carbon-14, i.e., .sup.14C, isotopes are particularly preferred for
their ease of preparation and detectability. Further, substitution
with heavier isotopes such as deuterium, i.e., .sup.2H, can afford
certain therapeutic advantages resulting from greater metabolic
stability, for example increased in vivo half-life or reduced
dosage requirements and, hence, may be preferred in some
circumstances. Isotopically labelled compounds of the present
invention and prodrugs thereof can generally be prepared by
carrying out the procedures below, by substituting a readily
available isotopically labelled reagent for a non-isotopically
labelled reagent.
[0059] The compounds described in the invention can be present as a
solvate. In some cases, the solvent used to prepare the solvate is
an aqueous solution, and the solvate is then often referred to as a
hydrate. The compounds can be present as a hydrate, which can be
obtained, for example, by crystallization from a solvent or from
aqueous solution. In this connection, one, two, three or any
arbitrary number of solvate or water molecules can combine with the
compounds according to the invention to form solvates and hydrates.
Unless stated to the contrary, the invention includes all such
possible solvates.
[0060] It is known that chemical substances form solids which are
present in different states of order which are termed polymorphic
forms or modifications. The different modifications of a
polymorphic substance can differ greatly in their physical
properties. The compounds according to the invention can be present
in different polymorphic forms, with it being possible for
particular modifications to be metastable. Unless stated to the
contrary, the invention includes all such possible polymorphic
forms.
[0061] Other definitions for selected terms used herein may be
found within the detailed description of the invention and apply
throughout. Unless otherwise defined, all other scientific and
technical terms used herein have the same meaning as commonly
understood to one of ordinary skill in the art to which the
invention belongs.
A. PREPARATION OF COMPOSITE PARTICLES
[0062] 1. Composite Particles
[0063] In one aspect, the invention relates to composite particles
comprising a millable grinding matrix and a pharmaceutically active
agent. In a further aspect, the composite particles can further
comprise a milling aid.
[0064] Without wishing to be bound by a particular theory, it is
believed that the disclosed methods, at least in some cases,
provide composite particles wherein the active particles are
uniformly distributed or substantially uniformly distributed
throughout the composite particles, so that each composite particle
contains the same proportion of pharmaceutically active agent and
millable grinding matrix. Thus, if segregation were to occur, the
blend would retain superior content uniformity. In contrast, a
conventional blend made with active particles smaller than the
excipient particles would have poor content uniformity if the blend
were to segregate.
[0065] Again, without wishing to be bound by a particular theory,
it is believed that the pharmaceutically active agent is, at least
in some cases, incorporated into a composite particle such that the
majority of the exposed surface of the composite particle is the
matrix material. As such the composite generally has the properties
of the matrix material. As many active materials are cohesive in
nature, this lowers interparticle interactions. In the case where
the weight percent of pharmaceutically active agent is very low,
the composite particle is composed almost entirely of the matrix
material. In this case the influence of the active on particle
particle interactions is almost completely eliminated. Thus, the
formulation has only one type, or predominantly one type, of
particle interaction. In conventional formulations, there are
multiple particle-particle interactions which complicate the
development of suitable formulations and the ability to use
pharmaceutically active agents as desired.
[0066] A further benefit of the nature of composite particles
provided by the disclosed methods is that if a carrier excipient is
required in order to make a formulation suitable for therapeutic
use, then a matrix such as lactose can be used in the dry milling
step together with lactose as the carrier excipient. Thus, the
particle particle interactions are simplified as they are with like
materials.
[0067] Without wishing to be bound by a particular theory, it is
believed that another beneficial property of the disclosed
composite particles, at least in some cases, is improved powder
flow, possibly arising from relative surface roughness that reduces
surface contact and reduces cohesivity.
[0068] 2. Method of Making an Inhalable Pharmaceutically-Active
Composition
[0069] Described herein is a method for making inhalable composite
particles comprising a pharmaceutically-active agent, the method
comprising: [0070] a) providing composite particles comprising a
millable grinding matrix and a solid pharmaceutically-active agent,
wherein the pharmaceutically-active agent has an median particle
size on a volume average basis between 50 nm and 3 .mu.m; and
[0071] b) milling the composite particles in a mill without milling
bodies for a time period sufficient to produce inhalable composite
particles having a mass median aerodynamic diameter between 1 .mu.m
and 20 .mu.m.
[0072] In a further aspect, milling in a mill without milling
bodies (in step b) is milling in a mill selected from a cutter
mill, end-runner mill, roller mill, hammer mill, fluid energy mill,
pin mill, impact mill, mechanofusion mill, beater mill, jet mill
and air jet mill. In a still further aspect, milling in a mill
without milling bodies is milling in an air jet mill. In a yet
further aspect, the composite particles after air jet milling have
an effective aerodynamic size from about 2 .quadrature.m to about 7
.mu.m.
[0073] In a further aspect, the step of providing composite
particles (step a) comprises the step of dry milling a mixture of:
a solid pharmaceutically active agent, and a millable grinding
matrix, in a mill comprising a plurality of milling bodies for a
time period sufficient to produce composite particles of the
grinding matrix having the solid pharmaceutically active agent with
an effective aerodynamic size from about 1 .mu.m to about 20 .mu.m
(e.g, 2 to 18, 4 to 16, 6 to 20, 8 to 20 .mu.m). In a yet further
aspect, dry milling is milling in a mill with a plurality of
milling bodies. In a still further aspect, the composite particles
produced by dry milling have an effective aerodynamic size from
about 5 .mu.m to about 15 .mu.m. In an even further aspect, the
composite particles produced by dry milling have an effective
aerodynamic size from about 10 .mu.m to about 20 .mu.m. In a still
further aspect, the mixture that is dry milled further comprises a
milling aid. In a yet further aspect, the mixture that is dry
milled further comprises one or more milling aids. In a still
further aspect, the mixture that is dry milled further comprises
one or more pharmaceutically active agents.
[0074] In a further aspect, the method of making an inhalable
pharmaceutically-active composition comprises the steps of: (a) dry
milling a solid pharmaceutically active agent and a millable
grinding matrix in a mill comprising a plurality of milling bodies,
for a time period sufficient to produce nanoparticles of the
pharmaceutically active agent dispersed in an at least partially
milled grinding material; and, (b) milling the blend produced in
step (a) in a mill without milling media to produce an inhalable
composite particle comprising a pharmaceutically active agent and
millable grinding matrix. In an even further aspect, the particles
of pharmaceutically active agent dispered in the composite particle
are nanoparticles. In a yet further aspect, the mill used in the
second step is an air jet mill. In a still further aspect, the
pharmaceutically active agent has a median particle size less than
or equal to about 1000 nm of a volume basis. In an even further
aspect, the pharmaceutically active agent has a median particle
size less than or equal to about 500 nm on a volume basis (e.g., a
median size less than 400, 300, or 200 nm or has a D.sub.50 is
between 1000 and 500, between 600 and 300, between 500 and 200. In
a still further aspect, the composite particle comprising a
pharmaceutically active agent and millable grinding matrix have a
composite particle size of less than or equal to about 10 .mu.m. In
a still further aspect, the composite particle comprising a
pharmaceutically active agent and millable grinding matrix have a
composite particle size of less than or equal to about 5 .mu.m.
[0075] 3. Dry Milling
[0076] a. Milling Mixture
[0077] In one aspect, the invention relates to a method comprising
dry milling a mixture comprising a solid pharmaceutically active
agent and a millable grinding matrix. In a further aspect, the
mixture further comprises one or more milling aids. In a still
further aspect, a mixture further comprises a facilitating agent,
wherein the facilitating agent is added to the mixture at a time
prior to completion of the dry milling step.
[0078] In a further aspect, the millable grinding matrix is a
single material or is a mixture of two or more materials in any
proportion. In a still further aspect, the concentration of the
single (or first) material is selected from 5-99.9%, 10-95%,
15-85%, 20-80%, 25-75%, 30-60%, and 40-50%, wherein the percent is
given as a weight percent (w/w). In a yet further aspect, the
concentration of the second or subsequent material is selected from
5-50%, 5-40%, 5-30%, 5-20%, 10-40%, 10-30%, 10-20%, 20-40%, and
20-30%, wherein the percent is given as a weight percent (w/w). In
a yet further aspect, if the second or subsequent material, when
present, is a surfactant, polymer, a lubricant or glidant the
concentration is selected from 0.1-10%, 0.1-5%, 0.1-2.5%, 0.1-2%,
0.1-1%, 0.5-5%, 0.5-3%, 0.5-2%, 0.5-1.5%, 0.5-1%, 0.75-1.25%,
0.75-1% and 1%, wherein the percent is given as a weight percent
(w/w).
[0079] In a further aspect, the milling aid, when present, is in a
concentration selected from 0.1-10%, 0.1-5%, 0.1-2.5%. 0.1-2%,
0.1-1%, 0.5-5%, 0.5-3%, 0.5-2%, 0.5-1.5%, 0.5-1%, 0.75-1.25%,
0.75-1%, and 1%, wherein the percent is given as a weight percent
(w/w).
[0080] b. Milling Apparatus
[0081] In one aspect, the dry milling apparatus is a mill
comprising a plurality of milling bodies. In a further aspect, the
mill comprising a plurality of milling bodies is selected from a
ball mill, sand mill, bead mill, pearl mills, basket mill,
planetary mill, vibratory action ball mill, multi-axial
shaker/mixer, stirred ball mill, horizontal small media mill, and
multi-ring pulverizing mill. In a yet further aspect, the mill
comprising a plurality of milling bodies is selected from an
attritor mill, nutating mill, tower mill, planetary mill, vibratory
mill and gravity-dependent-type ball mill. In a still further
aspect, the mill comprising a plurality of milling bodies is a ball
mill. In a yet further aspect, the milling media within the milling
apparatus is mechanically agitated by 1, 2 or 3 rotating shafts. In
a still further aspect, the dry milling operation is configured to
produce the nanoparticles of pharmaceutically active agent in a
continuous fashion.
[0082] In a further aspect, the dry milling is carried out in a
mill selected from attritor mills (horizontal or vertical),
nutating mills, tower mills, pearl mills, planetary mills,
vibratory mills, eccentric vibratory mills, gravity-dependent-type
ball mills, rod mills, and crusher mills.
[0083] c. Processing Time
[0084] In one aspect, dry milling has a milling time period in the
range selected from between 10 minutes and 2 hours, between 10
minutes and 90 minutes, between 10 minutes and 1 hour, between 10
minutes and 45 minutes, between 10 minutes and 30 minutes, between
5 minutes and 30 minutes, between 5 minutes and 20 minutes, between
2 minutes and 10 minutes, between 2 minutes and 5 minutes, between
1 minutes and 20 minutes, between 1 minute and 10 minutes, and
between 1 minute and 5 minutes.
[0085] In a further aspect, dry milling of the pharmaceutically
active agent and the millable grinding matrix is for the shortest
time necessary to form the composite particle comprising the
pharmaceutically active agent and the millable grinding matrix. In
a still further aspect, dry milling of the pharmaceutically active
agent and the millable grinding matrix is for a time such that
contamination from the media mill and/or the plurality of milling
bodies is minimized. The time varies greatly, depending on the
pharmaceutically active agent and the millable grinding matrix, and
may range from as short as one minute to several hours. In a still
further aspect, dry milling times in excess of two hours can lead
to degradation of the pharmaceutically active agent and an
increased level of undesirable contaminants.
[0086] In a further aspect the total milling times are adjusted for
the type and size of milling apparatus as well as the milling
media, the weight ratio of the pharmaceutically active agent and
millable grinding matrix mixture to the plurality of milling
bodies, the chemical and physical properties of the
pharmaceutically active agent and grinding matrix, and other
parameters that can be optimized empirically by one skilled in the
art.
[0087] d. Milling Bodies
[0088] In one aspect, the dry mill with a plurality of milling
bodies uses milling media fabricated from a material selected from
ceramics, glasses, polymers, ferromagnetics and metals. In a
further aspect, the milling media is steel balls having a diameter
selected from between 1 and 20 mm, between 2 and 15 mm and between
3 and 10 mm. In a yet further aspect, the milling medium is
zirconium oxide balls having a diameter selected from between 1 and
20 mm, between 2 and 15 mm and between 3 and 10 mm. In an even
further aspect, the milling bodies are steel balls having a
diameter selected from about between 1 and 20 mm. In a still
further aspect, the milling bodies have a density of about 1 to
about 15 g/cm.sup.3. In a yet further aspect, the milling bodies
have a density of about preferably from about 1 to about 8
g/cm.sup.3.
[0089] In a further aspect, the milling bodies are chemically inert
and rigid. In a still further aspect, the milling bodies are
essentially resistant to fracture and erosion in the milling
process. In a yet further aspect, the milling bodies are provided
in the form of bodies which can have any of a variety of smooth,
regular shapes, flat or curved surfaces, and lacking sharp or
raised edges. For example, suitable milling bodies can be in the
form of bodies having ellipsoidal, ovoid, spherical or right
cylindrical shapes. In an even further aspect, the milling bodies
are provided in the form of one or more of beads, balls, spheres,
rods, right cylinders, drums or radius-end right cylinders (i.e.,
right cylinders having hemispherical bases with the same radius as
the cylinder).
[0090] The milling bodies can comprise various substances such as
ceramic, glass, metal or polymeric compositions, in a particulate
form. Suitable metal milling bodies are typically spherical and
generally have good hardness (i.e., RHC 60-70), roundness, high
wear resistance, and narrow size distribution and can include. In a
further aspect, metal materials can be selected from type AISI52100
chrome steel, type 316 or 440C stainless steel or type AISI1065
high carbon steel. Suitable ceramic milling bodies, for example,
can be selected from a wide array of ceramics desirably having
sufficient hardness and resistance to fracture to enable them to
avoid being chipped or crushed during milling and also having
sufficiently high density. In a further aspect, ceramic materials
can be selected from steatite, aluminum oxide, zirconium oxide,
zirconia-silica, yttria-stabilized zirconium oxide,
magnesia-stabilized zirconium oxide, silicon nitride, silicon
carbide, cobalt-stabilized tungsten carbide, and the like, as well
as mixtures thereof. In a further aspect, glass milling bodies are
spherical (e.g., beads), have a narrow size distribution, are
durable, and include, for example, lead-free soda lime glass and
borosilicate glass. In a still further aspect, polymeric milling
media are substantially spherical and can be selected from a wide
array of polymeric resins having sufficient hardness and friability
to enable them to avoid being chipped or crushed during milling,
abrasion-resistance to minimize attrition resulting in
contamination of the product, and freedom from impurities such as
metals, solvents, and residual monomers. In a yet further aspect,
polymeric resins can be selected from crosslinked polystyrenes,
such as polystyrene crosslinked with divinylbenzene, styrene
copolymers, polyacrylates such as polymethylmethacrylate,
polycarbonates, polyacetals, vinyl chloride polymers and
copolymers, polyurethanes, polyamides, high density polyethylenes,
polypropylenes, and the like. The use of polymeric milling media to
grind materials down to a very small particle size (as opposed to
mechanochemical synthesis) is disclosed, for example, in U.S. Pat.
Nos. 5,478,705 and 5,500,331. In a further aspect, polymeric resins
have densities ranging from about 0.8 to about 3.0 g/cm.sup.3.
Alternatively, the milling media can be composite particles
comprising dense core particles having a polymeric resin adhered
thereon. Core particles can be selected from substances known to be
useful as milling media, for example, glass, alumina, zirconia
silica, zirconium oxide, stainless steel, and the like. In a
further aspect, core substances have densities greater than about
2.5 g/cm.sup.3. In a still further aspect, the milling media are
formed from a ferromagnetic substance, thereby facilitating removal
of contaminants arising from wear of the milling media by the use
of magnetic separation techniques.
[0091] Each type of milling body has its own advantages. For
example, metals have the highest specific gravities, which increase
grinding efficiency due to increased impact energy. Metal costs
range from low to high, but metal contamination of final product
can be an issue. Glasses are advantageous from the standpoint of
low cost and the availability of small bead sizes as low as 0.004
mm. However, the specific gravity of glasses is lower than other
media and significantly more milling time is required. Finally,
ceramics are advantageous from the standpoint of low wear and
contamination, ease of cleaning, and high hardness.
[0092] e. Milling Conditions
[0093] In one aspect, the total combined amount of pharmaceutically
active agent and millable grinding matrix in the mill at any given
time is greater than or equal to a mass selected from about 200 g,
500 g, 1 kg, 2 kg, 5 kg, 10 kg, 20 kg, 30 kg, 50 kg, 75 kg, 100 kg,
150 kg, and 200 kg. In a further aspect, the total combined amount
of pharmaceutically active agent and grinding matrix in the mill at
any given time is less than about 2000 kg.
[0094] 4. Milling in a Mill without Milling Bodies
[0095] In one aspect, the invention relates to a milling step
comprising milling in a mill without milling bodies. In a further
aspect, composite particles are provided and milling is carried out
on the composite particles in a mill without milling bodies. In a
yet further aspect, composite particles have been prepared by dry
milling in a first step, and the composite particles are further
milled in a second step in a mill a without milling bodies. In a
still further aspect, the mill without milling bodies is selected
from cutter mills, end-runner mills, roller mills, hammer mills,
fluid energy mills, impact mill, mechanofusion mill, beater mill,
jet mill and air jet mills.
[0096] In a further aspect, the the sub-particles of
pharmaceutically-active agent within the composite particles, after
milling in a mill without milling bodies, have an average particle
size of from about 50 nm to about 3 .mu.m.
[0097] In a further aspect, the composite particles after milling
in a mill without milling bodies have a median particle size less
than or equal to about 10,000 nm. In a still further aspect, the
composite particles after milling in a mill without milling bodies
have a D90, determined on a particle volume basis, less than or
equal to about 15,000 nm. In a yet further aspect, the composite
particles after milling in a mill without milling bodies have a
D90, determined on a particle volume basis, greater than or equal
to about 2000 nm. In an even further aspect, the composite
particles after milling in a mill without milling bodies have a
volume weighted mean (D4,3) less than or equal to about 10,000 nm.
In a yet further aspect, the composite particles after milling in a
mill without milling bodies have a volume weighted mean (D4,3)
greater than or equal to about 1000 nm.
[0098] In a further aspect, the mill without milling bodies is an
air jet mill. In a still further aspect, the air jet mill is a size
selected from 2 inch, 4 inch, 8 inch, 10 inch, 15 inch, 20 inch, 30
inch and 42 inch. In a yet further aspect, the air pressure in the
air jet mill is selected from 1 bar, 2 bar, 3 bar, 4 bar, 5 bar, 6
bar, 7 bar, 8 bar, 9 bar and 10 bar. In an even further aspect, the
powder feed rate into the air jet mill is selected from 0.5 kg/hr,
1.0 kg/hr, 5 kg/hr, 10 kg/hr, 15 kg/hr, 20 kg/hr, 35 kg/hr, 50
kg/hr, 75 kg/hr, 100 kg/hr, 150 kg/hr, 200 kg/hr, 500 kg/hr and
1000 kg/hr.
[0099] In a further aspect, a facilitating agent is added to the
composite particles produced at the end of milling in a mill
without milling bodies, and then further processed in another
milling device such as a mechanofusion mill, cyclomixing device, or
impact mill. The impact mill for the further processing is selected
from a ball mill and a jet mill. Alternatively, in a further
aspect, the further processing is carried out a high pressure
homogenizer. In a still further aspect, the further processing is
carried out using a combination of two or more of mechanofusion
mill, cyclomixing device, impact mill, or high pressure
homogenizer.
B. MATERIALS USED IN PREPARATION OF COMPOSITE PARTICLES
[0100] 1. Millable Grinding Matrix
[0101] In one aspect, the invention relates to a millable grinding
matrix used in the preparation of a composite particle comprising a
pharmaceutically active agent and the millable grinding matrix. In
a further aspect, the millable grinding matrix is of a comparable
particle size to the pharmaceutically active agent. In a still
further aspect, the particle size of the millable grinding matrix
is substantially reduced but not as small as the pharmaceutically
active agent material. In a yet further aspect, the millable
grinding matrix is selected from the group consisting of: a
material considered to be Generally Regarded as Safe (GRAS) for
inhaled pharmaceutical products or a material considered acceptable
for use in a veterinary formulation. In an even further aspect,
millable grinding matrix can be either an inorganic or organic
substance.
[0102] In a further aspect, the millable grinding matrix comprises
one or more materials selected from an organic acid, organic base,
sugar, polyol, peptide, protein, fat, fatty acid, amino acid,
carbohydrate, phospholipid, triglyceride, detergent, polymer, or a
pharmaceutically acceptable salt, solvate, hydrate, or polymorph
thereof. In a still further aspect, the millable grinding matrix is
sodium chloride.
[0103] In a further aspect, the millable grinding matrix is a
carbohydrate selected from mannitol, sorbitol, xylitol, maltitol,
lactitol, erythritol, arabitol, ribitol, glucose, fructose,
mannose, galactose, lactose, sucrose, raffinose, ribitol, maltose,
sorbose, cellobiose, sorbose, trehalose, maltodextrins, dextrans,
inulin, 1-O-alpha-D-glucopyranosyl-D-mannitol (Isomalt), or a
pharmaceutically acceptable solvate, hydrate, or polymorph
thereof.
[0104] In a further aspect, the millable grinding matrix is an
amino acid selected from aspartic acid, glutamic acid, leucine,
isoleucine, lysine, valine, methionine, phenylalanine, glycine,
arginine, aspartic acid, glutamic acid, cysteine, alanine, serine,
phenylalanine, lysine, wherein the amino acid can be either the D
configuration, the L configuration or the DL configuration as
appropriate to the end use. N-acetyl-L-cysteine, or a
pharmaceutically acceptable salt, solvate, hydrate, or polymorph
thereof.
[0105] In a further aspect, the millable grinding matrix is a
phospholipid selected from dipalmitoyl phosphatidylcholine,
phosphatidylglycerol, dipalmitoyl phosphatidyl ethanolamine,
dipalmitoyl phosphatidylinositol, phospatidylcholines,
phosphatidylethanolamine, phosphatidylglycerol,
phosphatidylinositol, phosphatidylserine, or a pharmaceutically
acceptable solvate, hydrate, or polymorph thereof.
[0106] In a further aspect, the millable grinding matrix is a fatty
acid selected from palmitic acid, stearic acid, erucic acid,
behenic acid, lauric acid, or a pharmaceutically acceptable salt,
solvate, hydrate, or polymorph thereof. In a yet further aspect,
the fatty acid is a salt selected from sodium stearyl fumarate,
sodium stearyl lactylate, zinc stearate, magnesium stearate,
calcium stearate, sodium stearate, lithium stearate, sodium lauryl
sulphate, magnesium lauryl sulphate, or a pharmaceutically
acceptable solvate, hydrate, or polymorph thereof.
[0107] In a further aspect, the millable grinding matrix is a salt
of an organic acid selected from sodium gluconate, magnesium
gluconate, sodium citrate, sodium ascorbate. In a still further
aspect, the millable grinding matrix is human serum albumin. In a
yet further aspect, the millable grinding matrix is a fat selected
from lecithin and soy lecithin. In an even further aspect, the
millable grinding matrix is selected from Dynsan 118, Cutina HR,
gelatine, hypromellose, polyethylene glycol, PEG 6000, PEG 3000,
PEGS, Tween 80, and Poloxamer 188.
[0108] In a further aspect, the millable grinding matrix comprises
lactose monohydrate and optionally one or more material selected
from sodium chloride, anhydrous lactose, mannitol, glucose,
sucrose, trehalose, sorbitol, 1-O-alpha-D-glucopyranosyl-D-mannitol
(Isomalt), xylitol, maltitol, lactitol, erythritol, arabitol,
ribitol, fructose, mannose, galactose, raffinose, ribitol, maltose,
sorbose, cellobiose, sorbose, inulin, sodium citrate, sodium
ascorbate, lecithin, soy lecithin, dipalmitoyl phosphatidylcholine,
phosphatidylglycerol, dipalmitoyl phosphatidyl ethanolamine,
dipalmitoyl phosphatidylinositol, phospatidylcholines,
phosphatidylethanolamine, phosphatidylglycerols,
phosphatidylinositol, phosphatidylserine, sodium lauryl sulphate,
magnesium lauryl sulphate, PEG 6000, PEG 3000 Tween 80, Poloxamer
188, leucine, isoleucine, lysine, valine, methionine,
phenylalanine, glycine, arginine, aspartic acid, glutamic acid,
cysteine, alanine, and serine, wherein the amino acid can be the D
configuration, the L configuration, or the DL configuration as
appropriate to the desired appalication.
[0109] In a further aspect, the millable grinding matrix comprises
lactose anhydrous and optionally one or more material selected from
sodium chloride, lactose monohydrate, mannitol, glucose, sucrose,
trehalose, sorbitol, 1-O-alpha-D-glucopyranosyl-D-mannitol
(Isomalt), xylitol, maltitol, lactitol, erythritol, arabitol,
ribitol, fructose, mannose, galactose, raffinose, ribitol, maltose,
sorbose, cellobiose, sorbose, inulin, sodium citrate, sodium
ascorbate, lecithin, soy lecithin, dipalmitoyl phosphatidylcholine,
phosphatidylglycerol, dipalmitoyl phosphatidyl ethanolamine,
dipalmitoyl phosphatidylinositol, phospatidylcholines,
phosphatidylethanolamine, phosphatidylglycerols,
phosphatidylinositol, phosphatidylserine, sodium lauryl sulphate,
magnesium lauryl sulphate, PEG 6000, PEG 3000 Tween 80, Poloxamer
188, leucine, isoleucine, lysine, valine, methionine,
phenylalanine, glycine, arginine, aspartic acid, glutamic acid,
cysteine, alanine, and serine, wherein the amino acid can be the D
configuration, the L configuration, or the DL configuration as
appropriate to the desired appalication.
[0110] In a further aspect, the millable grinding matrix comprises
mannitol and optionally one or more material selected from sodium
chloride, lactose monohydrate, lactose anhydrous, glucose, sucrose,
trehalose, sorbitol, 1-O-alpha-D-glucopyranosyl-D-mannitol
(Isomalt), xylitol, maltitol, lactitol, erythritol, arabitol,
ribitol, fructose, mannose, galactose, raffinose, ribitol, maltose,
sorbose, cellobiose, sorbose, inulin, sodium citrate, sodium
ascorbate. lecithin, soy lecithin, dipalmitoyl phosphatidylcholine,
phosphatidylglycerol, dipalmitoyl phosphatidyl ethanolamine,
dipalmitoyl phosphatidylinositol, phospatidylcholines,
phosphatidylethanolamine, phosphatidylglycerols,
phosphatidylinositol, phosphatidylserine, sodium lauryl sulphate,
magnesium lauryl sulphate; PEG 6000, PEG 3000 Tween 80, Poloxamer
188, leucine, isoleucine, lysine, valine, methionine,
phenylalanine, glycine, arginine, aspartic acid, glutamic acid,
cysteine, alanine, and serine, wherein the amino acid can be the D
configuration, the L configuration, or the DL configuration as
appropriate to the desired appalication.
[0111] In a further aspect, the millable grinding matrix comprises
sucrose and optionally one or more material selected from sodium
chloride, lactose monohydrate, lactose anhydrous, mannitol,
glucose, trehalose, sorbitol, 1-O-alpha-D-glucopyranosyl-D-mannitol
(Isomalt), xylitol, maltitol, lactitol, erythritol, arabitol,
ribitol, fructose, mannose, galactose, raffinose, ribitol, maltose,
sorbose, cellobiose, sorbose, inulin, sodium citrate, sodium
ascorbate, lecithin, soy lecithin, dipalmitoyl phosphatidylcholine,
phosphatidylglycerol, dipalmitoyl phosphatidyl ethanolamine,
dipalmitoyl phosphatidylinositol, phospatidylcholines,
phosphatidylethanolamine, phosphatidylglycerols,
phosphatidylinositol, phosphatidylserine, sodium lauryl sulphate,
magnesium lauryl sulphate, PEG 6000, PEG 3000 Tween 80, Poloxamer
188, leucine, isoleucine, lysine, valine, methionine,
phenylalanine, glycine, arginine, aspartic acid, glutamic acid,
cysteine, alanine, and serine, wherein the amino acid can be the D
configuration, the L configuration, or the DL configuration as
appropriate to the desired appalication.
[0112] In a further aspect, the millable grinding matrix comprises
glucose and optionally one or more material selected from sodium
chloride, lactose monohydrate, lactose anhydrouse, mannitol,
sucrose, trehalose, sorbitol, 1-O-alpha-D-glucopyranosyl-D-mannitol
(Isomalt), xylitol, maltitol, lactitol, erythritol, arabitol,
ribitol, fructose, mannose, galactose, raffinose, ribitol, maltose,
sorbose, cellobiose, sorbose, inulin, sodium citrate, sodium
ascorbate, lecithin, soy lecithin, dipalmitoyl phosphatidylcholine,
phosphatidylglycerol, dipalmitoyl phosphatidyl ethanolamine,
dipalmitoyl phosphatidylinositol, phospatidylcholines,
phosphatidylethanolamine, phosphatidylglycerols,
phosphatidylinositol, phosphatidylserine, sodium lauryl sulphate,
magnesium lauryl sulphate, PEG 6000, PEG 3000 Tween 80, Poloxamer
188, leucine, isoleucine, lysine, valine, methionine,
phenylalanine, glycine, arginine, aspartic acid, glutamic acid,
cysteine, alanine, and serine, wherein the amino acid can be the D
configuration, the L configuration, or the DL configuration as
appropriate to the desired appalication.
[0113] In a further aspect, the millable grinding matrix comprises
sodium chloride and optionally one or more material selected from
lactose anhydrous, lactose monohydrate, mannitol, glucose, sucrose,
trehalose, sorbitol, 1-O-alpha-D-glucopyranosyl-D-mannitol
(Isomalt), xylitol, maltitol, lactitol, erythritol, arabitol,
ribitol, fructose, mannose, galactose, raffinose, ribitol, maltose,
sorbose, cellobiose, sorbose, inulin, sodium citrate, sodium
ascorbate, lecithin, soy lecithin, dipalmitoyl phosphatidylcholine,
phosphatidylglycerol, dipalmitoyl phosphatidyl ethanolamine,
dipalmitoyl phosphatidylinositol, phospatidylcholines,
phosphatidylethanolamine, phosphatidylglycerols,
phosphatidylinositol, phosphatidylserine, sodium lauryl sulphate,
magnesium lauryl sulphate, PEG 6000, PEG 3000 Tween 80, Poloxamer
188, leucine, isoleucine, lysine, valine, methionine,
phenylalanine, glycine, arginine, aspartic acid, glutamic acid,
cysteine, alanine, and serine, wherein the amino acid can be the D
configuration, the L configuration, or the DL configuration as
appropriate to the desired appalication.
[0114] In a further aspect, the millable grinding matrix comprises
trehalose and optionally one or more material selected from sodium
chloride, lactose anhydrous, lactose monohydrate, mannitol,
glucose, sucrose, sorbitol, 1-O-alpha-D-glucopyranosyl-D-mannitol
(Isomalt), xylitol, maltitol, lactitol, erythritol, arabitol,
ribitol, fructose, mannose, galactose, raffinose, ribitol, maltose,
sorbose, cellobiose, sorbose, inulin, sodium citrate, sodium
ascorbate, lecithin, soy lecithin, dipalmitoyl phosphatidylcholine,
phosphatidylglycerol, dipalmitoyl phosphatidyl ethanolamine,
dipalmitoyl phosphatidylinositol, phospatidylcholines,
phosphatidylethanolamine, phosphatidylglycerols,
phosphatidylinositol, phosphatidylserine, sodium lauryl sulphate,
magnesium lauryl sulphate, PEG 6000, PEG 3000 Tween 80, Poloxamer
188, leucine, L-leucine, isoleucine, lysine, valine, methionine,
phenylalanine, glycine, arginine, aspartic acid, glutamic acid,
cysteine, alanine, and serine, wherein the amino acid can be the D
configuration, the L configuration, or the DL configuration as
appropriate to the desired appalication.
[0115] In a further aspect, the millable grinding matrix is a
single material or is a mixture of two or more materials in any
proportion. In a still further aspect, the material is selected
from sodium chloride, mannitol, sorbitol, Isomalt, xylitol,
maltitol, lactitol, erythritol, arabitol, ribitol, glucose,
fructose, mannose, galactose, anhydrous lactose, lactose
monohydrate, sucrose, raffinose, ribitol, maltose, sorbose,
cellobiose, sorbose, trehalose, Inulin, Isomalt other sugars or
polyols, aspartic acid, glutamic acid, sodium gluconate,
maltodextrins, dextrans, magnesium gluconate, peptides and proteins
such as human serum albumin, organic salts such as sodium citrate
and sodium ascorbate lecithin, soy lecithin, dipalmitoyl
phosphatidylcholine, phosphatidylglycerol, dipalmitoyl phosphatidyl
ethanolamine, dipalmitoyl phosphatidylinositol,
phospatidylcholines, phosphatidylethanolamine,
phosphatidylglycerols, phosphatidylinositol, phosphatidylserine or
other phospholipids; stearic acid and derivatives or salts thereof
such as sodium stearyl fumarate, sodium stearyl lactylate, zinc
stearate, magnesium stearate, calcium stearate, sodium stearate,
lithium stearate; solid state fatty acids such as, palmitic acid,
stearic acid, erucic acid, behenic acid, or derivatives therof,
including esters and salts; lauric acid and its salts, for example,
sodium lauryl sulphate, magnesium lauryl sulphate; triglycerides
such as Dynsan 118 and Cutina HR; gelatine, hypromellose; PEG 6000,
PEG 3000 or other PEGS; Tween 80, Poloxamer 188; amino acids, such
as aspartic acid, glutamic acid, leucine, L-leucine, isoleucine,
lysine, valine, methionine, phenylalanine, glycine, arginine,
aspartic acid, glutamic acid, cysteine, alanine, serine, phenyl
alanine lysine, N-acetyl-L-cysteine, wherein the amino acid can be
the D configuration, the L configuration, or the DL configuration
as appropriate to the desired appalication, and derivatives, salts,
solvates, hydrates, and polymorphs thereof; and, peptides and
polypeptides having molecular weight from 0.25 to 1000 kDa.
[0116] In one aspect, the millable grinding matrix is selected
from: lactose (e.g., lactose monohydrate), mannitol, glucose,
sucrose, and xylitol.
[0117] In a further aspect, the grinding matrix is harder than
pharmaceutically active agent, and is thus capable of reducing the
particle size of the active material under dry milling conditions.
Without wishing to be bound by particular theory, under the
disclosed dry milling conditions it is believed that the millable
grinding matrix affords the advantage of the smaller particles of
grinding matrix produced under the dry milling conditions enabling
greater interaction with the pharmaceutically active agent. It is
also believed, without wishing to be bound by a particular theory,
that the physical degradation (including but not limited to
particle size reduction) of the millable grinding matrix affords
the advantage of acting as a more effective diluent than grinding
matrix of a larger particle size.
[0118] In a further aspect, the quantity of the grinding matrix
relative to the quantity of pharmaceutically active agent, and the
extent of physical degradation of the grinding matrix, is
sufficient to inhibit re-agglomeration of the particles of the
active material. In a still further aspect, the quantity of the
grinding matrix relative to the quantity of pharmaceutically active
agent, and the extent of physical degradation of the grinding
matrix, is sufficient to inhibit re-agglomeration of the particles
of the active material in nanoparticulate form. In a further
aspect, the grinding matrix is not generally selected to be
chemically reactive with the pharmaceutically active agent under
the disclosed milling conditions, excepting for example, where the
matrix is deliberately chosen to undergo a mechanico-chemical
reaction, e.g., the conversion of a free base or acid to a salt or
vice versa. Without wishing to be bound by a particular theory, the
grinding matrix the grinding matrix will physically degrade under
the disclosed dry milling conditions to facilitate the formation
and retention of particulates of the pharmaceutically active agent
with reduced particle size. The precise extent of degradation
required will depend on certain properties of the grinding matrix
and the pharmaceutically active agent, the ratio of
pharmaceutically active agent to grinding matrix, and the particle
size distribution of the particles comprising the pharmaceutically
active agent.
[0119] The physical properties of the grinding matrix necessary to
achieve the requisite degradation are dependent on the precise
milling conditions. For example, a harder grinding matrix may
degrade to a sufficient extent provided it is subjected to more
vigorous dry milling conditions. Physical properties of the
grinding matrix relevant to the extent that the agent will degrade
under dry milling conditions include hardness, friability, as
measured by indicia such as hardness, fracture toughness and
brittleness index. A low hardness (typically a Mohs Hardness less
than 7) of the pharmaceutically active agent is desirable to ensure
fracture of the particles during processing, so that composite
microstructures develop during milling. Preferably, the hardness is
less than 3, as determined using the Mohs Hardness scale.
[0120] In a further aspect, the grinding matrix is of low
abrasivity. Without wishing to be bound by a particular theory, low
abrasivity is desirable to minimize contamination of the mixture of
the pharmaceutically active agent in the grinding matrix by the
milling bodies and/or the milling chamber of the media mill. An
indirect indication of the abrasivity can be obtained by measuring
the level of milling-based contaminants.
[0121] In a further aspect, the millable grinding matrix has a low
tendency to agglomerate during dry milling. While it is difficult
to objectively quantify the tendency to agglomerate during milling,
it is possible to obtain a subjective measure by observing the
level of "caking" of the grinding matrix on the milling bodies and
the milling chamber of the media mill as dry milling
progresses.
[0122] 2. Milling Aid
[0123] In one aspect, the invention relates to the use of a milling
aid in the disclosed methods to prepare the composite particles
comprising a pharmaceutically active agent and a millable grinding
matrix. In a further aspect, the composite particle further
comprises a milling aid. In a yet further aspect, a milling aid or
combination of milling aids is used in the dry milling step. In a
further aspect, the milling aid is added to mixture of
pharmaceutically active agent and millable grinding matrix at a
time prior to the completion of the dry milling step. In a yet
further aspect, the milling aid is added at a time prior to the
completion of milling in a mill without milling bodies.
[0124] In a further aspect, the milling aid is selected from
surfactants, polymers, phospholipids, fatty acids or derivatives,
stearic acid and derivatives thereof, and amino acids or
derivatives.
[0125] In a further aspect, the milling aid is selected from
lecithin, soy lecithin, dipalmitoyl phosphatidylcholine,
phosphatidylglycerol, dipalmitoyl phosphatidyl ethanolamine,
dipalmitoyl phosphatidylinositol, phospatidylcholines,
phosphatidylethanolamine, phosphatidylglycerols,
phosphatidylinositol, phosphatidylserine sodium stearyl fumarate,
sodium stearyl lactylate, zinc stearate, magnesium stearate,
calcium stearate, sodium stearate, lithium stearate, palmitic acid,
stearic acid, erucic acid, behenic acid, sodium lauryl sulphate,
magnesium lauryl sulphate; Dynsan 118, Cutina HR, aspartic acid,
gelatine, glutamic acid, hypromellose, PEG 6000, PEG 3000, Tween
80, Poloxamer 188, leucine, L-leucine, isoleucine, lysine, valine,
methionine, phenylalanine, glycine, arginine, aspartic acid,
glutamic acid, cysteine, alanine, serine, phenyl alanine lysine and
N-acetyl-L-cysteine.
[0126] In a further aspect, the milling aid is selected from
lecithin, soy lecithin, dipalmitoyl phosphatidylcholine,
phosphatidylglycerol, dipalmitoyl phosphatidyl ethanolamine,
dipalmitoyl phosphatidylinositol, phospatidylcholines,
phosphatidylethanolamine, phosphatidylglycerols,
phosphatidylinositol, phosphatidylserine or other phospholipids,
sodium stearyl fumarate, sodium stearyl lactylate, zinc stearate,
magnesium stearate, calcium stearate, sodium stearate, lithium
stearate. solid state fatty acids such as, palmitic acid, stearic
acid, erucic acid, behenic acid, or derivatives (such as esters and
salts) thereof, lauric acid and its salts, for example, sodium
lauryl sulphate, magnesium lauryl sulphate; triglycerides such as
Dynsan 118 and Cutina HR, aspartic acid, gelatine, glutamic acid,
hypromellose, PEG 6000, PEG 3000 or other PEGS, Tween 80, Poloxamer
188, amino acids, such as leucine, isoleucine, lysine, valine,
methionine, phenylalanine, glycine, arginine, aspartic acid,
glutamic acid, cysteine, alanine, serine, phenyl alanine lysine,
and derivatives, wherein the amino acid can be the D configuration,
the L configuration, or the DL configuration as appropriate to the
desired appalication, thereof, N-acetyl-L-cysteine, and peptides
and polypeptides having molecular weight from 0.25 to 1000 kDa.
[0127] In one aspect the milling aid is selected from: lecithin,
phospholipids, polyvinylpyrrolidone, polyoxyethylene sorbate
esters, polysorbate 80, polysorbate 20.
[0128] In one aspect the millable grinding matrix is is selected
from: lactose (e.g., lactose monohydrate), mannitol, glucose,
sucrose, and xylitol.
[0129] In one aspect the millable grinding matrix is is selected
from: lactose (e.g., lactose monohydrate), mannitol, glucose,
sucrose, and xylitol and the milling aid is selected from:
lecithin, phospholipids, polyvinylpyrrolidone, polyoxyethylene
sorbate esters, polysorbate 80, polysorbate 20.
[0130] 3. Facilitating Aid
[0131] In a further aspect, the facilitating agent is selected from
one or more of lecithin; soy lecithin, dipalmitoyl
phosphatidylcholine, phosphatidylglycerol, dipalmitoyl phosphatidyl
ethanolamine, dipalmitoyl phosphatidylinositol, phospatidylcholine,
phosphatidylethanolamine, phosphatidylglycerol,
phosphatidylinositol, phosphatidylserine, phospholipid, sodium
stearyl fumarate, sodium stearyl lactylate, zinc stearate,
magnesium stearate, calcium stearate, sodium stearate, and lithium
stearate.
[0132] In a further aspect, the facilitating agent is selected from
a solid state fatty acids. In yet further aspect, the solid state
fatty acid is selected from palmitic acid, stearic acid, erucic
acid, and behenic acid, or derivatives thereof such as esters and
salts. In a still further aspect, the facilitating agent is
selected from lauric acid and a lauric acid salt. In an even
further aspect, the lauric acid salt is selected from sodium lauryl
sulphate and magnesium lauryl sulphate. In a still further aspect,
the facilitating agent is a triglyceride. In a yet further aspect,
the triglyceride is selected from Dynsan 118 and Cutina HR.
[0133] In a further aspect, the facilitating agent is an amino
acid. In yet further aspect, the amino acid is selected from
aspartic acid, glutamic acid, leucine, isoleucine, lysine, valine,
methionine, phenylalanine, glycine, arginine, aspartic acid,
glutamic acid, cysteine, alanine, serine, N-acetyl-cysteine,
phenylalanine, lysine, or pharmaceutically acceptable derivatives,
salts, solvates, hydrates, and polymorphs thereof.
[0134] In a further aspect, the facilitating agent is selected from
peptides and polypeptides having molecular weight from 0.25 to 1000
KDa. In a yet further aspct, the facilitating agent is selected
from gelatine, hypromellose, PEG 6000, PEG 3000 or other PEGS,
Tween 80, and Poloxamer 188.
[0135] 4. Pharmaceutically Active Agent
[0136] In one aspect, the invention relates to a pharmaceutically
active agent selected from vitamins, pharmaceutical actives,
biologics, amino acids, proteins, peptides, polypeptides,
nucleotides, oligonucleotides, vaccines, monoclonal antibodies,
nucleic acids, or a pharmaceutically acceptable salt, derivative,
solvate, hydrate, or polymorph thereof. In a further aspect,
pharmaceutically active agent is agent used in the treatment of a
disorder in an animal. In a still further aspect, the
pharmaceutically active agent is used in the treatment of a
disorder in human.
[0137] In a further aspect, the pharmaceutically active agent is an
organic compound. In a still further aspect, the pharmaceutically
active agent is a material for which one of skill in the art
desires to deliver to the lung by oral inhalation. In a yet further
aspect, the pharmaceutically active agent can also be a material
for which one of skill in the art desires improved dissolution
properties. Examples of pharmaceutically active agents are provided
below (Additional Embodiments).
C. NANOPARTICLES OF PHARMACEUTICALLY ACTIVE AGENT
[0138] 1. Methods for Determining Particle Size of the
Pharmaceutically Active Agent
[0139] There are a wide range of techniques that can be utilized to
characterize the particle size distribution of a material. The
technique that is choosen to characterize a material will depend on
the size of the material to be analysed, the information required
and the nature of the material to be sized. If the particles to be
measured are less than 1 .mu.m, it will be difficult to use any
aerodynamic or dry powder measurement system. Instead other common
ensemble methods must be used. As the active particles in this
invention are typically less than 1 .mu.m such techniques are
required. Amongst these various methods, two types of measurements
are most commonly used. Photon correlation spectroscopy (PCS), also
known as `dynamic light scattering` (DLS) is commonly used to
measure particles with a size less than 10 micron. Typically this
measurement yields an equivalent hydrodynamic radius often
expressed as the average size of a number distribution. The other
common particle size measurement is laser diffraction, which is
commonly used to measure particle size from 100 nm to 2000 .mu.m.
This technique calculates a volume distribution of equivalent
spherical particles that can be expressed using descriptors such as
the median particle size or the percent of particles under a given
size.
[0140] Those skilled in the art also understand that almost all
these techniques do not physically measure the actually particle
size, as one might measure something with a ruler, but measure a
physical phenomena which is interpreted to indicate a particle
size. As part of the interpretation process some assumptions need
to be made to enable mathematical calculations to be made. These
assumptions deliver results such as an equivalent spherical
particle size, or a hydrodynamic radius.
[0141] Those skilled in the art recognize that different
characterization techniques such as photon correlation spectroscopy
and laser diffraction measure different properties of a particle
ensemble. As a result multiple techniques will give multiple
answers to the question, "what is the particle size." In theory,
one could convert and compare the various parameters each technique
measures, however, for real world particle systems this is not
practical. As a result the particle size used to describe this
invention can be given as two different sets of values that each
relate to these two common measurement techniques, such that
measurements could be made with either technique and then evaluated
against the description of this invention.
[0142] For measurements made using a photo correlation spectroscopy
instrument, or an equivalent method known in the art, the term
"number average particle size" is defined as the average particle
diameter as determined on a number basis.
[0143] For measurements made using a laser diffraction instrument,
or an equivalent method known in the art, the term "median particle
size" is defined as the median particle diameter as determined on
an equivalent spherical particle volume basis. Where the term
median is used, it is understood to describe the particle size that
divides the population in half such that 50% of the population is
greater than or less than this size. The median particle size is
often written as D50, D(0.50) or D[0.5] or similar. As used herein
D50, D(0.50) or D[0.5] or similar shall be taken to mean `median
particle size`.
[0144] The term "Dx of the particle size distribution" refers to
the xth percentile of the distribution on a particle volume basis;
thus, D90 refers to the 90th percentile, D95 refers to the 95th
percentile, and so forth. Taking D90 as an example this can often
be written as, D(0.90) or D[0.9] or similar. With respect to the
median particle size and Dx an upper case D or lowercase d are
interchangeable and have the same meaning. Another way to
quantitate a particle size distribution is the volume weighted mean
(D4,3). D4,3 is defined as sum of the diameters to the power 4
divided by the sum of the diameters cubed.
[0145] Another commonly used way of describing a particle size
distribution measured by laser diffraction, or an equivalent method
known in the art, is to describe what % of a distribution is under
or over a nominated size. The term "percentage less than" also
written as "%<" is defined as the percentage, by volume, of a
particle size distribution under a nominated size--for example the
%<1000 nm. The term "percentage greater than" also written as
"%>" is defined as the percentage, by volume, of a particle size
distribution over a nominated size--for example the %>1000
nm.
[0146] The particle size used to describe this invention should be
taken to mean the particle size as measured at or shortly before
the time of use. For example, the particle size is measured 2
months after the material is subject to the milling method of this
invention. In a preferred form, the particle size is measured at a
time selected from the group consisting of: 1 day after milling, 2
days after milling, 5 days after milling, 1 month after milling, 2
months after milling, 3 months after milling, 4 months after
milling, 5 months after milling, 6 months after milling, 1 year
after milling, 2 years after milling, 5 years after milling.
[0147] For many of the materials subject to the methods of this
invention the particle size can be easily measured. Where the
active material has poor water solubility and the matrix it is
milled in has good water solubility the powder can simply be
dispersed in an aqueous solvent. In this scenario the matrix
dissolves leaving the active material dispersed in the solvent.
This suspension can then be measured by techniques such as PCS or
laser diffraction.
[0148] Suitable methods to measure an accurate particle size where
the active material has substantive aqueous solubility or the
matrix has low solubility in a water based dispersant, are outlined
below.
[0149] In the circumstance where insoluble matrix such as
microcrystalline cellulose prevents the measurement of the active
material, separation techniques such as filtration or
centrifugation could be used to separate the insoluble matrix from
the active material particles. Other ancillary techniques would
also be required to determine if any active material was removed by
the separation technique, so that this could be taken into
account.
[0150] In the case where the active material is too soluble in
water, other solvents could be evaluated for the measurement of
particle size. Where a solvent could be found that active material
is poorly soluble in, but is a good solvent for the matrix, a
measurement would be relatively straight forward. If such a solvent
is difficult to find, another approach would be to measure the
ensemble of matrix and active material in a solvent (such as
iso-octane) which both are insoluble in. Then the powder would be
measured in another solvent where the active material is soluble,
but the matrix is not. Thus with a measurement of the matrix
particle size and a measurement of the size of the matrix and
active material together, an understanding of the active material
particle size can be obtained. Another approach to measuring
actives particles with moderate to high aqueous solubility, is to
measure the size in a saturated solution of the active
material.
[0151] In some circumstances image analysis could be used to obtain
information about the particle size distribution of the active
material. Suitable image measurement techniques might include
transmission electron microscopy (TEM), scanning electron
microscopy (SEM), optical microscopy and confocal microscopy. In
addition to these standard techniques some additional technique
would be required to be used in parallel to differentiate the
active material and matrix particles. Depending on the chemical
makeup of the materials involved possible techniques could be
elemental analysis, Raman spectroscopy, FTIR spectroscopy or
fluorescence spectroscopy.
[0152] In some other cases nanoparticles of pharmaceutically active
agents are formed, but have small amounts of agglomeration or
bridging present. Thus when they are analyzed by an ensemble
technique such as laser diffraction they appear to be much larger
particles. As those skilled in the pharmaceutical arts would
understand, the key to such materials is not what size an
instrument may indicate, but product performance. So, if the
particles are indeed nano sized in dimension and have high surface
area that is available, then they will perform as nanoparticles in
vivo.
[0153] In this invention, the key aspect required of the
pharmaceutically active agent is that it is small enough to be
uniformly distributed throughout the composite material, even after
the composite particle size has been reduced to an inhalable size.
So where ensemble particle size methods such as laser diffraction
cannot be used, other techniques and numerics will be required to
characterize the material. Some examples of these methods are, but
not limited to:
1. Image analysis of SEM micrographs of the composites; 2. SEM or
TEM microscopy combined with elemental or spectrographic analysis;
3. SEM or TEM microscopy optinally combined with elemental or
spectrographic analysis on slices of composite particles prepared
in a resin; 4. AFM analysis combined with Raman microscopy; 5.
Image analysis of SEM microgrpahs of the active materials after the
matrix material has been washed out; and, 6. Specific surface area
(SSA) measurements of the active material after the matrix material
has been washed out. From the SSA an equivalent sphereical diameter
could be calculated or the SSA itself could be used as a
quantitative descriptor. There would be a requirement to dry the
active material after washing out the matrix. It is important to
preserve the high surface area during the washing and drying
process. One possible way to do this would be to spray dry the
active material.
[0154] 2. Pharmaceutically Active Agent Particle Size
[0155] In one aspect, the invention relates to a composite particle
comprising a millable grinding matrix and a pharmaceutically active
agent wherein the pharmaceutically active is a particle dispersed
in the composite particle. In a further aspect, the sub-particles
of pharmaceutically active agent within the composite particles are
nanoparticles. In a still further aspect, sub-particles of
pharmaceutically active agent within the composite particles
produced by the disclosed methods have particle size of less than
or equal to 1000 nm. In a yet further aspect, sub-particles of
pharmaceutically active agent within the composite particles
produced by the disclosed methods have particle size of less than
or equal to 500 nm. In an even further aspect, the sub-particles of
pharmaceutically-active agent are crystalline. In a further aspect,
the sub-particles of pharmaceutically-active agent within the
composite particles have an average particle size of from about 50
nm to about 1000 nm.
[0156] In a further aspect, the sub-particles of the
pharmaceutically active agent within the composite particles have a
median particle size, determined on a particle volume basis, less
than or equal to a size selected from about 1000 nm, 900 nm, 800
nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm, 200 nm and 100 nm. In a
yet further aspect, the median particle size of the
pharmaceutically active agent is greater than or equal to about 25
nm.
[0157] In a further aspect, the percentage of particles of the
pharmaceutically active agent, on a particle volume basis, is
selected from 50%, 60%, 70%, 80%, 90%, 95% and 100%, wherein the
percentage represents the fraction less than about 1000 nm, 800,
600, 400 or 200 nm or between 1000 and 500 nm, 900 and 400 nm, 800
and 300 nm. In a still further aspect, the percentage of particles
of the pharmaceutically active agent, on a particle volume basis,
is selected from 50%, 60%, 70%, 80%, 90%, 95% and 100%, wherein the
percentage represents volume basis is less than about 500 nm. In a
yet further aspect, the percentage of particles of the
pharmaceutically active agent, on a particle volume basis, is
selected from 50%, 60%, 70%, 80%, 90%, 95% and 100%, wherein the
percentage represents the fraction less than about 300 nm. In an
even further aspect, the percentage of particles of the
pharmaceutically active agent, on a particle volume basis, is
selected from 50%, 60%, 70%, 80%, 90%, 95% and 100%, wherein the
percentage represents the fraction less than about 200 nm.
[0158] In a further aspect, the Dx (e.g., D.sub.50) of the particle
size distribution of the pharmaceutically active agent, as measured
on a particle volume basis, is selected from 2000 nm, 1900 nm, 1800
nm, 1700 nm, 1600 nm, 1500 nm, 1400 nm, 1300 nm, 1200 nm, 1100 nm,
1000 nm, 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400 nm, 300 nm,
200 nm, and 100 nm; wherein x is greater than or equal to about
90.
[0159] 3. Dissolution Profile
[0160] The disclosed methods result in the pharmaceutically active
agent having an improved dissolution profile. An improved
dissolution can provide improved bioavailability of the
pharmaceutically active agent in vivo. In one aspect, the improved
dissolution profile is observed in vitro. In a further aspect, the
improved dissolution profile is observed in vivo by the observation
of an improved bioavailability profile. Standard methods for
determining the dissolution profile of a material in vitro are
available in the art. A suitable method to determine an improved
dissolution profile in vitro can include determining the
concentration of the sample material in a solution over a period of
time and comparing the results from the sample material to a
control sample. An observation that peak solution concentration for
the sample material was achieved in less time than the control
sample can indicate that the sample material has an improved
dissolution profile if results meet statistical significance.
[0161] Typically, all of the formulation is placed into the
dissolution apparatus for testing when measuring a typical
dissolution profile. Such a procedure is used when assessing the
dissolution profile of an oral formulation. In the case of an oral
medication this is appropriate, as all of the active in the
formulation is taken into the gastro-intestinal tract, where it has
an opportunity to be absorbed by the body. In contrast, not all of
the active particles of an inhaled formulation can effectively
reach the lung, where the active material can be either act locally
or be absorbed systemically. In order to make a more precise
estimation of what an in vivo dissolution profile may be from an in
vitro measurement, the formulation must first be separated into
those components that will reach the lung and those that will not.
Only those components that are likely to reach the lung should be
assessed. Son et al. [Dissolution Technologies, 17(2), 6-13
(2010)], herebye incorporated by reference, have demonstrated such
a method. By actuating an inhaled formulation through a NGI device
fitted with extra filters they were able to collect the fraction of
particles that had a MMAD suitable for deposition in the lung. This
fraction of the particles was then tested in a standard dissolution
apparatus.
[0162] In a further aspect, the dissolution profile of the
disclosed composite particles, inhalable composites, or inhalable
compositions can be determined as described above and compared to a
conventional inhalable composition. A conventional formulation is
defined as an inhaled formulation that has been made using jet
milled active and a carrier excipient such as lactose.
[0163] Standard methods for determining the improved dissolution
profile of a material in vivo are available in the art. A suitable
method to determine an improved dissolution profile in a human may
be after delivering the dose to measure the rate of active material
absorption by measuring the plasma concentration of the sample
compound over a period of time and comparing the results from the
sample compound to a control. An observation that peak plasma
concentration for the sample compound was achieved in less time
than the control would indicate (assuming it is statistically
significant) that the sample compound has improved bioavailability
and an improved dissolution profile. Preferably, the improved
dissolution profile is observed in a dissolution medium that is
similar to fluids found in the lung, when it is observed in vitro.
Suitable methods for quantifying the concentration of a compound in
an in vitro sample or an in vivo sample are widely available in the
art. Suitable methods could include the use of spectroscopy or
radioisotope labeling.
D. COMPOSITE PARTICLE CHARACTERISTICS
[0164] 1. Particle Size of the Composite Particle
[0165] a. Methods for Determining
[0166] One measurement that can be used to characterise the
particle size of the composites is the aerodynamic particle size.
As used herein aerodynamic particle size refers to a volume or mass
particle size measurement which is based on the aerodynamic
characteristics of the particles being measured. It is known to
those skilled in the art that the aerodynamic diameter D(a) of an
individual particle is related to its density (p) and Stokes
diameter D(s) according to the equation: D(a)=D(s)(.phi..sup.1/2.
The Stokes diameter of a particle is the diameter of a sphere which
has the same terminal settling velocity as the particle being
measured. Thus, the aerodynamic size of a particle is a measure of
how it behaves when aerosolized. Aerodynamic particle size can be
measured with commercially available instruments such as the
Aerosizer LD or Model 3321 Aerodynamic Particle Sizer.RTM. (TSI
Incorporated, Shoreview, Minn. 55126 USA) or similar instruments
known to those skilled in the art.
[0167] Another measurement that can be used to determine the size
of the composites is laser diffraction. These measurements can be
broadly divided into wet methods and dry methods. Wet methods use a
solvent such as iso-octane or isopar G which will not dissolve the
matrix and for almost all pharmaceutical actives will not dissolve
the active either. The composites are first dispersed in the
solvent, sometimes with dispersion aids such as lecithin, and then
measured using a standard wet laser diffraction measurement cell.
Laser diffraction instruments to conduct these measurements are
well known in the art, some examples of which are Malvern
Mastersizers, Sympatec and Microtrac. Dry powder laser diffraction
measurements use the same principle as wet methods only in this
case an air stream is used to disperse and carry the particles
through the laser beam. Examples of measurement instruments that do
this are the Scirocco measurement cell for use with a Malvern
Mastersizer, a Turbotrac dispersion unit with a Microtrac
instrument or a RODOS dispersion unit used with a Sympatec laser
diffraction instrument. In these measurement instruments,
compressed air is used to disperse the powder so that the primary
particle size of the composite can be measured.
[0168] Another approach to dry powder laser diffraction
measurements is to use passive dispersion method. When these
measurements are performed there is no dispersion cell in the
instrument inself. Instead, the powder is packaged into an
inhalation device that is attached to the measurement instrument. A
defined airflow is then pulled through the instrument causing the
powder to exit the device (after any dispersion the device may
impart) and pass through the laser beam. The airflows used in
passive laser diffraction are typically in the range of 20-100
L/min. Airflows in this range are used as they mimic the airflows
during human inhalation. That is, pulling air through the device
and dispersing the powder in a similar way to that which occurs
when a patient uses the device, means the powder properties are
also similar to what will happen during patient use. In this way a
particle size distribution of the powder dispersed is obtained that
is similar to that which is inhaled by a patient. Laser diffraction
instruments to conduct passive laser diffraction measurements are
well known in the art, some examples of which are the Malvern
Spraytec or a Sympatec instrument with an INHALER module.
[0169] All three laser diffraction techniques, wet, dry powder and
passive, measure the same physical property: a diffraction pattern
created by the ensemble of particles within the measurement zone.
The instrument then calculates a particle size distribution (by
volume or mass) of equivalent spherical particle size. The particle
size distributions would typically be characterised by the median
particle size (D[50]), the volume weighted mean (D[4,3]) or the
90.sup.th percentile (D[90]).
[0170] Another approach to the measurement of aerodynamic particle
size is to use devices that measure aerodynamic particle size
directly, by means of flow through different sized gratings.
Examples of such devices are impactors and impingers where
particles will be retained at multiple stages depending on their
aereodynamic size. Particles smaller that any given stage will
continue to further stages until a stage is reached where the size
is larger than the cutoff. An assay can then be used to establish
mass balances across a series of stages with different size cutoffs
to establish the particle size distribution. Typically the assay is
of the active material present in the formulation. In a
conventional inhalation formulation the active particles are
discrete particles so the assay and subsequent particle size
distribution is of the actives particles from a formulation that
have made their way into the testing device. In contrast, the
disclosed composite particles have the pharmaceutically active
agent particles uniformly distributed throughout the composite
particles so in effect they are a marker probe that enables the
mass distribution of the composite particle throughout the impactor
or impinger stages to be determined. Thus the aerodynamic particle
size distribution calculated is effectively of the composite
particles in the formulation. Examples of impactors and impingers
are the CI, MSLI and the NGI.
[0171] It is important to note that these measurement devices do
not measure the aerodynamic particle size of the entire ensemble of
particles (such as happens in a time of flight instrument such as
the Aeroszier LD or Model 3321 Aerodynamic Particle Sizer.RTM.).
This is because before the powder enters the impactor/impinger it
must first travel through an induction port (often referred to as a
throat) and in some devices a preseparator which will both remove
some of the powder from the airstream. By design the induction port
and preseparator remove larger particles from a distribution. This
means the measurement does not report the size distribution of the
entire powder sample, but rather the aerodynamic particle size of
the material which passes through the induction port and
preseparator. These impactors/impingers are designed this way in
order to mimic what happens when a dry powder formulation is orally
inhaled. In the oral inhalation process large particles will have
larger momentum and will hit the back of the throat while those
particles in the correct size range will flow down into the lungs.
For this reason, measurements from impactors/impingers provide the
best in vitro indication of in vivo performance.
[0172] It is still necessary and important to know and measure the
particle size distribution of the whole powder as this provides
knowledge of the potential for the powder formulation once coupled
with an inhalation device. Measurements such as laser diffraction
and time of flight measurements are easier and are therefore useful
in providing tools for optimization and fast quality control
analysis. From this information provided by the mass distribution
across the various stages of an impactor/impinger the following can
be determined: a Mass Median Aerodynamic Diameter (MMAD), a
geometric standard deviation (GSD) and the FPF. These parameters
are described in greater detail below.
[0173] b. Composite Particle Characteristics
[0174] In one aspect, the invention relates to composite particles
comprising millable grinding matrix and a pharmaceutically active
agent with appropriate particle size properties. In a further
aspect, the disclosed composite particles of a millable grinding
matrix and a pharmaceutically active agent have a median particle
size of about 1 to about 20 .mu.m. In a yet further aspect, the
disclosed composite particles comprising millable grinding matrix
and a pharmaceutically active agent have a median particle size
less than or equal to about 10 .mu.m. In a still further aspect,
the disclosed composite particles comprising millable grinding
matrix and a pharmaceutically active agent have a median particle
size less than or equal to about 5 .mu.m. In an even further
aspect, the disclosed composite particles comprising millable
grinding matrix and a pharmaceutically active agent have a median
particle size less than or equal to about 4 .mu.m. In a yet further
aspect, the disclosed composite particles comprising millable
grinding matrix and a pharmaceutically active agent have a particle
size less than or equal to about 3 .mu.m.
[0175] In a further aspect, the composite particles have a median
particle size less than or equal to about 10,000 nm. In a still
further aspect, the composite particles have a D90, determined on a
particle volume basis, less than or equal to about 15,000 nm. In a
yet further aspect, the composite particles have a D90, determined
on a particle volume basis, greater than or equal to about 2000 nm.
In an even further aspect, the composite particles have a volume
weighted mean (D4,3) less than or equal to about 10,000 nm. In a
still further aspect, the composite particles have a volume
weighted mean (D4,3) greater than or equal to about 1000 nm.
[0176] In a further aspect, the composite particles comprising
millable grinding matrix and a pharmaceutically active agent have a
median particle size, determined on a particle volume basis, less
than or equal to a size selected from 10,000 nm, 8000 nm, 6000 nm,
5000 nm, 4500 nm, 4000 nm, 3500 nm, 32500 nm, 3000 nm, 2900 nm,
2800 nm, 2700 nm, 2600 nm, 2500 nm, 2400 nm, 2300 nm, 2200 nm, 2100
nm, 2000 nm, 1900 nm, 1800 nm, 1700 nm, 1600 nm and 1500 nm. In a
yet further aspect, the composite particles comprising millable
grinding matrix and a pharmaceutically active agent have a median
particle size is greater than or equal to 1000 nm. In a yet further
aspect, the median particle size is measured by dry powder laser
diffraction, passive dry powder laser diffraction or wet laser
diffraction. In an even further aspect, the median particle size is
measured by passive laser diffraction.
[0177] In a further aspect, the composite particles comprising
millable grinding matrix and a pharmaceutically active agent have a
volume weighted mean (D4,3) less than or equal to a size selected
from 10,000 nm, 8000 nm, 6000 nm, 5000 nm, 4500 nm, 4000 nm, 3500
nm, 3250 nm, 3000 nm, 2900 nm, 2800 nm, 2700 nm, 2600 nm, 2500 nm,
2400 nm, 2300 nm, 2200 nm, 2100 nm, 2000 nm, 1900 nm, 1800 nm, 1700
nm, 1600 nm and 1500 nm. In a yet further aspect, the composite
particles comprising millable grinding matrix and a
pharmaceutically active agent have a volume weighted mean (D4,3)
greater than or equal to about 1000 nm. In an even further aspect,
the (D4,3) is measured by dry powder laser diffraction, passive dry
powder laser diffraction or wet laser diffraction. In an even
further aspect, the (D4,3) is measured by passive laser
diffraction.
[0178] In a further aspect, the composite particles comprising
millable grinding matrix and a pharmaceutically active agent have a
D90, determined on a particle volume basis, less than or equal to a
size selected from 15,000 nm, 12,000 nm, 11,000 nm, 10,000 nm, 9000
nm, 8000 nm, 7000 nm, 6000 nm, 5000 nm, 4000 nm and 3000 nm. In a
yet further aspect, the composite particles comprising millable
grinding matrix and a pharmaceutically active agent have a D90 is
greater than or equal to about 2000 nm. In a still further aspect,
the D90 is measured by dry powder laser diffraction, passive dry
powder laser diffraction or wet laser diffraction. In a still
further aspect, the D90 is measured by pass laser diffraction.
[0179] In a further aspect, the composite particles comprising
millable grinding matrix and a pharmaceutically active agent have a
mean particle size less than or equal to a size selected from
15,000 nm, 12,000 nm, 11,000 nm, 10,000 nm, 9000 nm, 8000 nm, 7000
nm, 6000 nm, 5000 nm, 4000 nm and 3000 nm. In a yet further aspect,
the composite particles comprising millable grinding matrix and a
pharmaceutically active agent have mean particle size greater than
or equal to about 1000 nm. In a still further aspect, the mean
particle size is measured by a time-of-flight instrument.
[0180] 2. Content Uniformity
[0181] a. Methods for Determining
[0182] Content uniformity in the present context is a measure of
how evenly the pharmaceutically active agent(s) are distributed
throughout a blend. Content uniformity is vital for accurate
delivery of the pharmaceutically active agent to the lungs in a dry
powder formulation. However, in some current commercial
formulations as little as 0.02 mg of pharmaceutically active agent
in 5 mg dose of powder is delivered to the lungs from an inhalation
device. For optimal therapeutic and clinical value, content
uniformity in powder for inhalation must be very accurate and
highly repeatable.
[0183] Typically content uniformity is measured by assaying a
number of samples by HPLC or similar technique to determine the
concentration of pharmaceutically active agent in each sample. In
bulk powder samples, content uniformity can be measured from three
or more samples. If the powder is filled into packaging such as a
hard capsule or foil blister pack then an appropriate number of
packages will be assayed to determine the content uniformity (e.g.,
typically 10 randomly chosen from a larger number). In the case
where packages such as a capsule are assayed to determine the
content uniformity of the material, the assays should be corrected
for the total weight of powder in each package. One common measure
for content uniformity is the percent deviation of each sample from
the average concentration or known concentration of the blend
(e.g., batch or lot). For quality control, a content uniformity
specification would provide that no sample has a deviation greater
than a defined percentage. The second common measure is the RSD of
the sample assays from the average (e.g., RSD from the average of
the samples analyzed, or alternatively, the RSD from the known or
nominal concentration of the bulk material).
[0184] The term "segregation" refers to the stratification of the
particle size distribution of a material such as a powder or blend.
It can be caused by any physical process, but typically it occurs
when a powder or blend undergoes flow or other movement, e.g.,
during shipment, handling, storage, and blending and flow in a
hopper or other processing equipment. A powder or blend in an
unsegregated state will have an even distribution of particle sizes
throughout the whole powder or blend such that any sample taken
from any part of the bag or container holding the powder (such as
top, middle, bottom) will give the same particle size distribution.
In a powder that has undergone segregation some parts of the powder
will have more large particles that other parts and some parts will
have more small particles than other parts of the powder. In a
powder with segregation samples taken from a variety of positions
in the bag or container holding the powder (such as top, middle,
bottom) will typically show some difference in the particle size
distribution. For testing a powder's properties, forced segregation
may be used in order to assess any changes to content uniformity
after segregation. An example of forced segregation would be to
place the powder in a tube and rotate the tube at a slight angle
for a long period such that large and small particles will
separate.
[0185] b. Composite Particle Characteristics
[0186] In one aspect, the invention relates to composite particles
comprising millable grinding matrix and a pharmaceutically active
agent with appropriate content uniformity properties. In a further
aspect, the content uniformity of the solid pharmaceutically active
agent dispersed in the composite particle varies from the average
content by a percentage less than or equal to about 5.0%. In a yet
further aspect, the content uniformity of the pharmaceutically
active agent throughout the blend varies from the average content
by a percentage less than or equal to a percentage selected from
0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.75%, 1.0%, 1.5%, 2.0%, 3.0%, 4.0%
and 5.0%. In a still further aspect, the content uniformity after
segregation of the pharmaceutically active agent throughout the
blend varies from the average content by a percentage less than or
equal to a percentage selected from 0.1%, 0.2%, 0.3%, 0.4%, 0.5%,
0.75%, 1.0%, 1.5%, 2.0%, 3.0%, 4.0% and 5.0%. In a yet further
aspect, the content uniformity of the pharmaceutically active agent
throughout the blend has a RSD less than or equal to a percentage
selected from 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.75%, 1.0%, 1.5%,
2.0%, 3.0%, 4.0% and 5.0%. In a still further aspect, the content
uniformity of the pharmaceutically active agent throughout the
blend has a percent relative standard deviation (RSD) less than or
equal to about 5.0%. In an even further aspect, the content
uniformity after segregation of the pharmaceutically active agent
throughout the blend has a RSD less than or equal to a percentage
selected from 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.75%, 1.0%, 1.5%,
2.0%, 3.0%, 4.0% and 5.0%.
[0187] 3. Surface Roughness
[0188] a. Methods for Determining
[0189] The shape, texture and roughness of individual particles and
their distribution for an assembly of particles is an important
particle property that affects several critical properties of
particles used inhalation compositions, including flowability,
cohesiveness, and dissolution properties. In one aspect, the
surface roughness can be characterized by parameters such as
Roughness by Surface Area (RSA), Roughness--root mean square
(Rrms), and median force of adhesion (F[50]). The meaning and use
of these terms is described above. Briefly, RSA can be determined
by measurement of the specific surface area (SSA) using nitrogen
absorption, with the BET isotherm and the surface area calculated
from the spherical equivalent size determined by laser diffraction.
In a further aspect, the laser diffraction method used is powder
laser diffraction. Both Rrms and F[50] can be measured using atomic
force microscopy per the methodology set forth by Adi, et al.
(Langmuir, 2008, 34:11307-11312 and Pharm. Sci., 2008, 35:12-18,
respectively). Rrms can also be measured using scanning white light
interferometry as described by Adi et al. (Langmuir, ibid).
[0190] b. Composite Particle Characteristics
[0191] In one aspect, the invention relates to composite particles
comprising millable grinding matrix and a pharmaceutically active
agent with appropriate surface roughness properties. In a further
aspect, the composite particles have a roughness by surface area
ratio greater than or equal to a ratio of about 1.1; wherein the
specific surface area is measured using nitrogen absorption; and,
wherein the surface area is calculated from the spherical
equivalent size determined by dry powder laser diffraction. In a
still further aspect, the composite particles have a Rrms greater
than or equal to a height selected about 15 nm and wherein the Rrms
is measured using atomic force microscopy. In a yet further aspect,
the composite particles have a Rrms greater than or equal to a
height selected from about 15 nm and wherein the Rrma is measured
using white light interferometry. In an even further aspect, the
composite particles have a median of force adhesion (F[50]) less
than or equal to about 150 nN when measure by atomic force
microscopy.
[0192] In a further aspect, the composite particles comprising
millable grinding matrix and a pharmaceutically active agent have a
Rrms greater than or equal to a height selected from 15 nm, 30 nm,
50 nm, 75 nm, 100 nm, 125 nm, 150 nm, 175 nm, 200 nm, 225 nm, 250
nm, 275 nm, 300 nm, 325 nm, 350 nm, 375 nm and 400 nm. In a yet
further aspect, the composite particles comprising millable
grinding matrix and a pharmaceutically active agent have a
roughness by surface area ratio greater than or equal to a ratio
selected from 1.1, 1.2, 1.3, 1.4, 1.5, 1.75, 2.0, 2.25, 2.5, 2.75,
3.0, 3.25, 3.5, 3.75, 4, 4.5 and 5.0. In a still further aspect,
the composite particles comprising millable grinding matrix and a
pharmaceutically active agent have a F[50] less than or equal to a
force selected from 150 nN, 125 nN, 100 nN, 80 nN, 70 nN, 60 nN, 50
nN, 40 nN, 30 nN, 25 nN, 20 nN, 15 nN, 10 nN and 5 nN.
[0193] 4. Cohesivity and Powder Flow
[0194] a. Methods for Determining
[0195] In order to produce a commercially viable dry powder
formulation, the powder flow must be suitable for accurate and
precise delivery of small amount of powder. The amount of powder
typically delivered in an inhaled dry powder inhaler is typically
in the range of about 1 to about 20 mg. For formulations with high
loadings this amount can be higher, e.g., about 20 to about 200 mg.
The powder comprising the pharmaceutically active agent and carrier
excipients must have flow properties that enable accurate and
precise delivery of a fixed amount of powder. Depending upon the
type of device used to deliver the powder the method used to
measure this accuracy and precision will differ. If the powder is
delivered in a reservoir style device the device itself will be
used to deliver an aliquot amount of powder for each inhalation. In
other devices some sort of packaging is used to pre-fill a single
dose into an appropriate container for actuation in the device.
Examples of such packaging are hard gelatine capsules, hard HMPC
capsules, foil blister strips or foil blister rings. Filling of
such packaging is carried out using an automated or semi automated
dispenser to fill the capsules or foil blisters. The accuracy and
precision that such a dispenser can deliver a given dose of powder
is a measure of the powder flow, i.e., good powder flow results in
better accuracy and repeatability. In contrast, poor powder flow
results in variability in the amount of powder delivered to the
capsule or foil blister. The variability of powder dispensed from
an automated or semi automated filling machine could be quantified
in a number of ways. For example, the weight of several samples
dispensed into packaging can be determined, and then the percentage
that each sample weight varies from the average weight delivered is
calculated. Alternatively, the variability of powder dispensed can
be determined from measuring the weight of several samples
dispensed into packaging and calculate the variation in weight in
terms of the RSD of a number of samples from the average weight
delivered.
[0196] b. Composite Particle Characteristics
[0197] In one aspect, the invention relates to composite particles
comprising millable grinding matrix and a pharmaceutically active
agent with appropriate properties of cohesivity and powder flow. In
a further aspect, the weight of composite particles when dispensed
from an automated or semi-automated filling machine deviates from
the average weight dispensed by a percentage less than or equal to
about 10%. In a still further aspect, the relative standard
deviation (RSD) from the average weight is less than or equal to
about 10% when the number of samples measured is greater than or
equal to 50 samples delivered from an automated or
semi-automated.
[0198] In a further aspect, the weight dispensed from an automated
filling machine of a powder comprising composite particles deviates
from the average weight dispensed by a percentage less than or
equal to a percentage selected from 0.1%, 0.2%, 0.3%, 0.4%, 0.5%,
0.75%, 1.0%, 1.5%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%
and 10.0%, wherein the composite particles comprise a millable
grinding matrix and a pharmaceutically active agent. In a still
further aspect, for such testing the target weight of a powder
comprising composite particles to be dispensed is selected from 1
mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 75
mg, 100 mg, 150 mg and 200 mg. In a yet further aspect, for such
testing the number of dispensed samples to be weighed is selected
from 3, 5, 10, 15, 20, 25, 30, 50, and 100. In an even further
aspect, a semi-automated filling machine is used to dispense the
powder instead of an automated filling machine.
[0199] In a further aspect, the weight dispensed from an automated
filling machine of a powder comprising composite particles has a
RSD from the average weight dispensed is a percentage less than or
equal to a percentage selected from 0.1%, 0.2%, 0.3%, 0.4%, 0.5%,
0.75%, 1.0%, 1.5%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%
and 10.0%, wherein the composite particles comprise a millable
grinding matrix and a pharmaceutically active agent. In a still
further aspect, for such testing the target weight of a powder
comprising composite particles to be dispensed is selected from 1
mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 40 mg, 50 mg, 75
mg, 100 mg, 150 mg and 200 mg. For such a test the number of
dispensed samples to be weighed is selected from the group
consisting of: 3, 5, 10, 15, 20, 25, 30, 50, 100. In a yet further
aspect, for such testing the number of dispensed samples to be
weighed is selected from 3, 5, 10, 15, 20, 25, 30, 50, and 100. In
an even further aspect, a semi-automated filling machine is used to
dispense the powder instead of an automated filling machine.
[0200] 5. Stability
[0201] a. Methods for Determining
[0202] A critical characteristic of a dry powder inhalation
formulation, is the stability of the formulation performance over
time during storage. Typically, parameters such as as the emitted
dose (ED), FPF and MMAD are determined as a function of time. These
parameters need to be relatively stable over a reasonable period of
time commensurate with typical cycles of manufacture, storage,
sales, and end-user use. If not, the formulation is unlikely to be
commercially viable. The period during which these parameters
remain within acceptable norms of use is typically referred to as
the shelf life. Conventional inhaled formulations often have
stability problems which are often thought to arise from changes in
the particle-particle interactions in the formulation. Without
wishing to be bound by a particular theory, the disclosed composite
particles are believed to simplify the the range and nature of
particle-particle interactions, and thus it is to be expected that
the disclosed compositions comprising the composite particles will
have improved stability properties compared to conventional
formulations with the same amount of active and excipient.
Stability studies are typically carried out by placing samples of
the material in environmental chambers with specified temperature
and humidity conditions. At designated times, samples are removed
and assayed for the given property or parameter of interest. For
the disclosed composite particles, the samples would be assayed for
ED, FPF, MMAD or any of the other parameters described herein. A
typical study would involve analysis of samples 1, 3, 7, 14, 21,
and 28 days; and, 2, 3, 4, 6, 9, 12, 18 and 24 months.
[0203] b. Composite Particle Characteristics
[0204] In one aspect, the invention relates to composite particles
comprising millable grinding matrix and a pharmaceutically active
agent with appropriate stability properties. In a further aspect,
the stability of the composite particles comprising millable
grinding matrix and a pharmaceutically active agent is measured
after storage at conditions selected 25.degree. C., 30.degree. C.,
35.degree. C., 40.degree. C., 25.degree. C./60% relative humidity,
30.degree. C./65% relative humidity and 40.degree. C./75% relative
humidity. In a still further aspect, the stability of the composite
particles comprising millable grinding matrix and a
pharmaceutically active agent is measured after storage for a
period of time selected from 1 month, 3 months, 6 months, 9 months,
12 months, 18 months and 2 years. In a yet further aspect, the
stability of the composite particles comprising millable grinding
matrix and a pharmaceutically active agent is measured by
determining the value of a specific property at the beginning of
storage and the percentage change from the property at the
beginning of storage at a later time less than or equal to a
percentage selected from 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.75%, 1.0%,
1.5%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, 10.0%, 12.5%,
15%, 17.5% and 20%. In an even further aspect, the specific
property determined for stability is selected from ED, MMAD, FPF,
and particle size.
[0205] 6. Aerodynamic Properties (ED, FPF, GSD, and MMAD)
[0206] a. Methods for Determining
[0207] Delivery of a dose of powder from a dry powder inhalation
device is less than perfect. A number of parameters are used to
described the amount of powder in the device is delivered (or
anticipated to be delivered) to the lungs. The FPF is defined as
the fraction of pharmaceutically active agent that has an
aerodynamic diameter less than about 4 to about 6 .mu.m. The MMAD
is defined as the aerodynamic diameter at which 50% of the
particles by mass are larger and 50% are smaller. Another parameter
useful in discussing these particular properties is the geometric
standard deviation (GSD), which is a measure of the spread of an
aerodynamic particle size distribution. It is typically calculated
using the formula: GSD=(d84/d16).sup.1/2. For the parameters ED,
FPF, GSD and MMAD, the values are dependent upon the device used to
carryout the measurements. For example, ED, FPF, GSD, and MMAD can
be determined using a MSLI with induction port, an CI with
induction port and preseparator, or a NGI with induction port and
preseparator.
[0208] In one aspect, the invention relates to composite particles
wherein the parameters of ED, FPF, GSD and MMAD are determined
using a NGI with induction port and preseparator. In a still
further aspect, the composite particle parameters of ED, FPF, GSD
and MMAD are determined using a device selected from a MSLI with
induction port, an CI with induction port and preseparator, or a
NGI with induction port and preseparator. It should be noted, for
the disclosed composite particles, the pharmaceutically active
agent is uniformly aggregated into the composite particles, thus
the ED, FPF, GSD and MMAD for the pharmaceutically active agent is
also an indicator of these properties for the composite
particles.
[0209] ED provides an indication of the delivery of a drug
formulation from a suitable inhaler device after a firing or
dispersion event. More specifically, for dry powder formulations,
the ED is a measure of the percentage of powder which is drawn out
of a unit dose package and which exits the mouthpiece of an inhaler
device. The ED is defined as the fraction of the total dose
available in the device delivered by an inhaler device. The ED is
experimentally determined by placing a dose of dry powder,
typically in unit dose form, into a suitable dry powder inhaler
which is then actuated, dispersing the powder. The total amount of
powder found to have left the device is then measured and compared
to the nominal dose. This measurement can be done when
impactor/impinger testing is performed on the powder. The
consistency of the ED is important, thus several doses should be
measured and the consistency between the doses calculated. One way
to measure this is as a RSD from the average emitted dose, which is
typically given as a percent RSD (% RSD).
[0210] The FPF is one of the most important predictors of in vivo
performance for a dry powder formulation and device combination. As
described above, FPF is the fraction relative to the emitted dose
unless otherwise specified, wherein the ED is defined as the
fraction of the total dose available in the device delivered by an
inhaler device, and it is often expressed as a percentage of the
total dose. In some cases, the FPF relative to the total recovered
dose (TRD) is specified and is indicated as "FPF(TRD)." The total
recovered dose is the sum of emitted dose and the dose remaining in
the device and/or dose packaging. Additional parameters of interest
which are specific to composite particles comprising two or more
pharmaceutically active agents are the MMAD uniformity ratio and
FPF uniformity ratio. Both of these are defined and discussed
above.
[0211] b. Composite Particle Characteristics
[0212] In one aspect, the invention relates to composite particles
comprising millable grinding matrix and a pharmaceutically active
agent with appropriate aerodynamic properties. In a still further
aspect, the composite particles are capable of providing an aerosol
with a FPF of emitted dose of the pharmaceutically active agent of
greater than or equal to about 10% when delivered from a dry powder
inhaler and analyzed with a NGI with an induction port and a
preseparator. In a yet further aspect, the composite particles are
capable of providing an aerosol with a related standard deviation
(RSD) of the FPF of emitted dose of the pharmaceutically active
agent of less than or equal to about 10% when delivered from a dry
powder inhaler and analyzed with a NGI with an induction port and a
preseparator. In an even further aspect, the composite particles
are capable of providing an aerosol with a FPF of total recovered
dose of the pharmaceutically active agent of greater than or equal
to about 30% when delivered from a dry powder inhaler and analyzed
with a NGI with an induction port and a preseparator.
[0213] In a further aspect, the composite particles are capable of
providing an aerosol with a mass median aerodynamic diameter (MMAD)
of the composite particles from about 1 .mu.m to about 10 .mu.m
when delivered from a dry powder inhaler and analyzed with a NGI
with an induction port and a preseparator. In a yet further aspect,
the mass median aerodynamic diameter (MMAD) is from about 1 .mu.m
to about 7 .mu.m. In a still further aspect, the MMAD is from about
1.5 .mu.m to about 5 .mu.m. In an even further aspect, the MMAD is
from about 2 .mu.m to about 5 .mu.m. In a still further aspect, the
MMAD is from about 2 .mu.m to about 4 .mu.m.
[0214] In a further aspect, the composite particles when delivered
from a dry powder inhaler and analyzed with a NGI are capable of
providing an aerosol with a mass median aerodynamic diameter (MMAD)
of the composite particles from about 1 .mu.m to about 10 .mu.m and
a FPF of the pharmaceutically active agent of at least about 10%.
In a still further aspect, the composite particles are capable of
providing an aerosol with an ED of greater than or equal to about
70% when delivered from a dry powder inhaler and analyzed with a
NGI with an induction port and a preseparator. In a yet further
aspect, the composite particles are capable of providing an aerosol
with an emitted dose with a RSD of less than or equal to about 10%
when determined on at least three samples delivered from a dry
powder inhaler and analyzed with a NGI with an induction port and a
preseparator.
[0215] In a further aspect, the composite particles comprising
millable grinding matrix and a pharmaceutically active agent have
the ED, FPF, GSD MMAD measured using a MSLI with induction port, an
CI with induction port and preseparator, or a NGI with induction
port and preseparator. In a yet further aspect, the composite
particles comprising millable grinding matrix and a
pharmaceutically active agent have the ED, FPF, GSD MMAD measured
using a NGI with a USP induction port and preseparator.
[0216] In a further aspect, the composite particles comprising a
millable grinding matrix and a pharmaceutically active agent have
an ED greater than or equal to a percentage selected from 70%, 75%,
80%, 85%, 87.5%, 90%, 92.5%, 95%, 96%, 97%, 98% and 99%. In a yet
further aspect, the composite particles comprising millable
grinding matrix and a pharmaceutically active agent have a % RSD of
three or more measurements of the ED less than or equal to a
percentage selected from 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.75%, 1.0%,
1.5%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0% and 10.0%. In
a still further aspect, the ED determined for the pharmaceutically
active agent is same or about the same ED for the composite
particles. In an even further aspect, the pharmaceutically active
agent is uniformly aggregated in the disclosed composite particles,
thus the ED determined for the pharmaceutically active agent also
an indicator of the ED for composite particles.
[0217] In a further aspect, the composite particles comprising a
millable grinding matrix and a pharmaceutically active agent have
an FPF with an MMAD less than or equal to a size selected from the
group consisting of: 4.0 .mu.m, 4.1 .mu.m, 4.2 .mu.m, 4.3 .mu.m,
4.4 .mu.m, 4.5 .mu.m, 4.6 .mu.m, 4.7 .mu.m, 4.8 .mu.m, 4.9 .mu.m,
5.0 .mu.m, 5.1 .mu.m, 5.2 .mu.m, 5.3 .mu.m, 5.4 .mu.m, 5.5 .mu.m,
5.6 .mu.m, 5.7 .mu.m, 5.8 .mu.m, 5.9 .mu.m and 6.0 .mu.m. In a yet
further aspect, the composite particles comprising millable
grinding matrix and a pharmaceutically active agent have an FPF
greater than or equal to a percentage selected from 10%, 20%, 30%,
35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% and 90%. In a
still further aspect, the composite particles comprising a millable
grinding matrix and a pharmaceutically active agent have an FPF
(TRD) greater than or equal to a percentage selected from 10%, 20%,
30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85% and 90%.
In an even further aspect, the composite particles comprising
millable grinding matrix and a pharmaceutically active agent have a
% RSD of three or more measurements of the FPF or FPF (TRD) less
than or equal to a percentage selected from 0.1%, 0.2%, 0.3%, 0.4%,
0.5%, 0.75%, 1.0%, 1.5%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%,
9.0% and 10.0%. In one aspect the FPF is about 50%-60% and the MMAD
is 2 to 4 .mu.m (e.g., 2.2 to 3.8 .mu.m, 2.4 to 3.6 .mu.m, 2.4 to
3.4 .mu.m, 2.5 to 3.1 .mu.m or 2.6 to 3.0 .mu.m. In a still further
aspect, the FPF or FPF (TRD) determined for the pharmaceutically
active agent is same or about the same FPF or FPF (TRD) for the
composite particles. In an even further aspect, the
pharmaceutically active agent is uniformly aggregated in the
disclosed composite particles, thus the FPF or FPF (TRD) determined
for the pharmaceutically active agent also an indicator of the FPF
or FPF (TRD) for composite particles.
[0218] In a further aspect, the composite particles comprising a
millable grinding matrix and a pharmaceutically active agent have
an MMAD less than or equal to a size selected from about 10,000 nm,
8000 nm, 6000 nm, 5000 nm, 4500 nm, 4000 nm, 3500 nm, 3250 nm, 3000
nm, 2900 nm, 2800 nm, 2700 nm, 2600 nm, 2500 nm, 2400 nm, 2300 nm,
2200 nm, 2100 nm, 2000 nm, 1900 nm, 1800 nm, 1700 nm, 1600 nm and
1500 nm. In a still further aspect, the composite particles
comprising a millable grinding matrix and a pharmaceutically active
agent have an MMAD greater than about 1,000 nm.
[0219] In a further aspect, the composite particles comprising a
millable grinding matrix and a pharmaceutically active agent have a
GSD equal or less than the ratio selected from the group consisting
of: 4, 3.5, 3, 2.9, 2.8, 2.7, 2.6, 2.5, 2.4, 2.3, 2.2, 2.1, 2.0,
1.9, 1.8 and 1.7.
[0220] In a further aspect, the composite particles have a fine
particle fraction ratio of the first pharmaceutically active agent
and second pharmaceutically active agent less than or equal to
about 1.2 when delivered from a dry powder inhaler and analyzed
with a NGI with an induction port and a preseparator.
[0221] In a further aspect, the composite particles have a MMAD
uniformity ratio of less than or equal to about 1.2 when delivered
from a dry powder inhaler and analyzed with a NGI with an induction
port and a preseparator, wherein the distribution of each of the
first and second pharmaceutically active agent is assayed and each
is used to calculate an MMAD for the composite particle.
[0222] In a further aspect, the composite particles comprising a
millable grinding matrix and at least two pharmaceutically active
agents have a FPF uniformity ratio less than or equal to ratio
selected from about 1.002, 1.005, 1.0075, 1.01, 1.0125, 1.015,
1.0175, 1.02, 1.03, 1.04, 1.05, 1.075, 1.02, 1.05, 1.075, 1.1,
1.125, 1.15 and 1.2. In a yet further aspect, the composite
particles comprising a millable grinding matrix and at least two
pharmaceutically active agents have a MMAD uniformity ratio less
than or equal to a ratio selected from about 1.002, 1.005, 1.0075,
1.01, 1.0125, 1.015, 1.0175, 1.02, 1.03, 1.04, 1.05, 1.075, 1.02,
1.05, 1.075, 1.1, 1.125, 1.15 and 1.2.
E. INHALABLE COMPOSITION
[0223] In one aspect, the invention relates to an inhalable
composition of pharmaceutically-active composite particles produced
by a method comprising the steps of: (a) providing composite
particles of a millable grinding matrix and a solid
pharmaceutically-active agent, wherein the pharmaceutically-active
agent within the composite particles has an average particle size
of from about 50 nm to about 3 .mu.m; and, (b) milling in a mill
without milling bodies the composite particles for a time period
sufficient to produce composite particles of the grinding matrix
and the solid pharmaceutically-active agent for a time period
sufficient to produce composite particles of the grinding matrix
and the pharmaceutically-active agent with an effective aerodynamic
particle size of from about 1 .mu.m to about 20 .mu.m.
[0224] In a further aspect, the invention relates to an inhalable
pharmaceutically-active composition comprising: a plurality of
composite particles of a millable grinding matrix and a solid
pharmaceutically-active agent, wherein the composite particles of
the grinding matrix and the pharmaceutically-active agent have an
effective aerodynamic particle size of from about 1 .mu.m to about
20 .mu.m; and, wherein the pharmaceutically-active agent within the
composite particles has an average particle size of from about 50
nm to about 3 .mu.m.
F. MEDICAMENTS
[0225] 1. Manufacture of Medicaments
[0226] In one aspect, the invention relates the manufacture of a
medicament comprising the disclosed composite particles comprising
a pharmaceutically active agent and a millable grinding matrix. In
a further aspect, the medicament can further comprise one or more
of each of a pharmaceutically acceptable carrier, milling aid,
facilitating agent, pharmaceutically acceptable excipients, or
other agents commonly used in the preparation of pharmaceutically
acceptable inhaled compositions.
[0227] In a further aspect, the medicament can be formulated into a
suitable device for administration by oral inhalation. Actual
dosage levels of the pharmaceutically active agent in the
medicament of the invention may be varied in accordance with the
nature of the pharmaceutically active agent material. In a yet
further aspect, the dosage level is varied due to differences in
the therapeutically effective amount when medicament comprises the
disclosed composite particles. In a still further aspect, the
medicament comprising the disclosed composite particles has an
improved efficacy and a lower dose is required for a
therapeutically effective amount.
[0228] In a further aspect, a disclosed composite particle can be
combined into a medicament with another pharmaceutically active
agent material, or even the same pharmaceutically active agent
material. In a still further aspect, the medicament can have
different release characteristics--early release from the
pharmaceutically active agent material, and later release from a
larger average size pharmaceutically active agent material.
[0229] a. Facilitating Agent
[0230] In a further aspect, the facilitating agent is selected from
one or more of lecithin; soy lecithin, dipalmitoyl
phosphatidylcholine, phosphatidylglycerol, dipalmitoyl phosphatidyl
ethanolamine, dipalmitoyl phosphatidylinositol, phospatidylcholine,
phosphatidylethanolamine, phosphatidylglycerol,
phosphatidylinositol, phosphatidylserine, phospholipid, sodium
stearyl fumarate, sodium stearyl lactylate, zinc stearate,
magnesium stearate, calcium stearate, sodium stearate, and lithium
stearate.
[0231] In a further aspect, the facilitating agent is selected from
a solid state fatty acids. In yet further aspect, the solid state
fatty acid is selected from palmitic acid, stearic acid, erucic
acid, and behenic acid, or derivatives thereof such as esters and
salts. In a still further aspect, the facilitating agent is
selected from lauric acid and a lauric acid salt. In an even
further aspect, the lauric acid salt is selected from sodium lauryl
sulphate and magnesium lauryl sulphate. In a still further aspect,
the facilitating agent is a triglyceride. In a yet further aspect,
the triglyceride is selected from Dynsan 118 and Cutina HR.
[0232] In a further aspect, the facilitating agent is an amino
acid. In yet further aspect, the amino acid is selected from
aspartic acid, glutamic acid, leucine, isoleucine, lysine, valine,
methionine, phenylalanine, glycine, arginine, aspartic acid,
glutamic acid, cysteine, alanine, serine, N-acetyl-cysteine,
phenylalanine, lysine, or pharmaceutically acceptable derivatives,
salts, solvates, hydrates, and polymorphs thereof.
[0233] In a further aspect, the facilitating agent is selected from
peptides and polypeptides having molecular weight from 0.25 to 1000
KDa. In a yet further aspct, the facilitating agent is selected
from gelatine, hypromellose, PEG 6000, PEG 3000 or other PEGS,
Tween 80, and Poloxamer 188.
[0234] b. Carrier Excipient
[0235] In a further aspect, the carrier excipient is selected from
mannitol, sorbitol, Isomalt, xylitol, maltitol, lactitol,
erythritol, arabitol, ribitol, glucose, fructose, mannose,
galactose, anhydrous lactose, lactose monohydrate, sucrose,
raffinose, ribitol, maltose, sorbose, cellobiose, sorbose,
trehalose, inulin, and Isomalt. In a yet further aspect, the
carrier excipient is a sugar or a polyol. In a still further
aspect, the carrier excipient is lactose or mannitol. In an even
further aspect, the carrier excipient is lactose monohydrate.
[0236] In a further aspect, the diameter of the carrier excipient
particles is between about 50 .mu.m and about 1000 .mu.m. In a
still further aspect, the diameter of the carrier excipient
particles is between about 60 .mu.m and about 250 .mu.m. In a yet
further aspect, the diameter of the carrier excipient particles is
between about 90 .mu.m and 250 .mu.m.
[0237] 2. Uses of Medicaments
[0238] Therapeutic uses of the disclosed composite particles,
inhalable composites, and medicaments comprising the disclosed
composite particles include pain relief, anti-inflammatory,
anti-infective, migraine, asthma, COPD and other disorders that
require the pharmaceutically active agent to be administered with a
high bioavailability. In a further aspect, the pharmaceutically
active agent has optimal effect when delivered locally to the lung.
Alternatively, there are therapeutic uses wherein optimal clinical
benefit is achieved with rapid bioavailability of a
pharmaceutically active agent, e.g., relief of pain. In a still
further aspect, the medicament comprising the disclosed composite
particles is used to treat a pain disorder. In a yet further
aspect, the pain disorder is selected from neuropathic,
nociceptive, acute, chronic, and disease-specific path (e.g., pain
associated with osteoarthritis or fibromyalgia). In a further
aspect, analgesics, such as cyclooxgenase inhibitors, e.g., aspirin
or NSAIDs, may be prepared as medicaments according to the present
invention.
[0239] In a further aspect, medicaments comprising the disclosed
composite particles can also be used for treatment of eye
disorders. That is, the pharmaceutically active agent can be
formulated for administration on the eye as an aqueous suspension
in physiological saline, or a gel. In a still further aspect, the
pharmaceutically active agent can be prepared in a powder form for
administration via the nose for rapid central nervous system
penetration.
[0240] In a further aspect, medicaments comprising the disclosed
composite particles can be used for the treatment of cardiovascular
disease. In a yet further aspect, the cardiovascular disease
treated is angina pectoris. In a still further aspect, the
pharmaceutically active agent is molsidomine. The clinical benefit
and side effect profile of molsidomine can be improved by delivery
to the lungs. Without wishing to be bound by a particular theory,
such improvement can be attributed to enhanced bioavailability.
[0241] In a further aspect, medicaments comprising the disclosed
composite particles can be used to treat treatment of hair loss,
sexual dysfunction, or dermal treatment of psoriasis.
G. METHOD OF TREATING A PATIENT
[0242] 1. Treating a Patient
[0243] In one aspect, the invention relates to a method of treating
a patient having a need for treatment of a disorder, the method
comprising the step of administering by inhalation an effective
amount of an inhalable pharmaceutically-active composition
comprising: a plurality of composite particles of a millable
grinding matrix and a solid pharmaceutically-active agent, wherein
the composite particles have an effective aerodynamic particle size
of from about 1 .mu.m to about 20 .mu.m; and, wherein the
pharmaceutically-active agent within the composite particles has an
average particle size of from about 50 nm to about 3 .mu.m.
[0244] In a further aspect, the treatment is preventing. In a still
further aspect, the patient has been diagnosed with the disorder
prior to administration.
[0245] In a further aspect, the disorder that is treated is
selected from chronic obstructive pulmonary disease, acute asthma,
chronic asthma, severe asthma, allergic asthma, acute respiratory
distress syndrome, infant respiratory distress syndrome, revesible
airways disease, and cystic fibrosis.
[0246] In a further aspect, the disorder that is treated is an
infection. In a yet further aspect, the infection is selected from
bacterial, fungal, and viral. In a still further aspect, the
infection is a bacterial infection. In an even further aspect, the
infection is a viral infection. In a still further aspect, the
infection is a fungal infection.
[0247] In a further aspect, the disorder that is treated is a pain
disorder. In a yet further aspect, the pain disorder is selected
from neuropathic, nociceptive, acute, chronic, and disease-specific
path (e.g., pain associated with osteoarthritis or
fibromyalgia).
[0248] In a further aspect, the disorder that is treated is
selected from cystic fibrosis, tuberculosis, pneumonia, severe
acute respiratory syndrome, infection, pulmonary embolus,
tuberculosis, pulmonary arterial hypertension, pulmonary edema, and
pneumocystis pneumonia. In a still further aspect, the disorder
that is treated is selected from eye disorders, hair loss, sexual
dysfunction, and cardiovascular disease. In a yet further aspect,
the cardiovascular disease is angina pectoris.
[0249] 2. Inhaled Delivery
[0250] Dry powder formulations of active pharmaceutical ingredients
(including blends of active and excipients) for oral inhalation are
important tools for the delivery of medications. Common uses have
been in the delivery of pharmaceutical agents that act locally,
e.g., asthma medications delivered to the lungs. This delivery
route is also becoming more important for systemic delivery. Two of
the critical parameters for inhaled dry powder formulations are
particle size and the flowability of the powder. The powder in the
device used by the patient needs to flow well so that a full and
consistent dose of the powder formulation leaves the device. If the
powder flow is poor, powder may remain behind in the device or
stick to the device as it is dispensed. The particle size of the
powder is then critical to ensure that the powder (and active
material) is (are) delivered to the required absorption zone.
[0251] One common measure of particle size used to characterize dry
powder formulations is the Mass Median Aerodynamic Diameter (MMAD).
As described above, MMAD the aerodynamic diameter at which 50% of
the particles by mass are larger and 50% are smaller. Methods of
measuring aerodynamic particle size are described above, including
the Anderson Cascade Impactor or the New Generation Impactor.
Alternatively, particle size measures such as the median particle
size measured by a laser diffraction dry powder analysis are also
useful. However, MMAD is the preferred measurement for an inhaled
formulation as it better approximates the aerodynamic properties of
the lungs. In a further aspect, an inhaled formulation has an MMAD
less than about 10 .mu.m. In a still further aspect, an inhaled
formulation has an MMAD less than about 5 .mu.m. In a yet further
aspect, an inhaled formulation has a median particle size is
preferably less than about 10 .mu.m, wherein the dry powder sizing
is determined by laser diffraction.
[0252] 3. Packaging and Devices
[0253] In order to deliver a powder to the lungs by oral inhalation
the powder must be packaged into a suitable device. The device must
be suitable to aerosolise the powder during the inhalation process.
In a further aspect, the device allows for a dose, packaged into
individual packing, to be inserted into the device prior to
delivery. In a yet further aspect, the device has a reservoir for
delivering multiple doses. In a still further aspect, a device that
has two or more individual doses of powder packaged into individual
packing and assembled or inserted into the device allowing a device
to deliver multiple doses. Suitable devices can be reusable or
disposable.
[0254] In a further aspect, the device is selected from the group
consisting of: 3M Conix.TM. 1 DPI (3M), 3M Conix.TM. 2 DPI (3M),
3M.TM. Taper DPI (3M), Acu-Breathe (Respirics), Aspirair (Vectura),
Cricket.TM. inhaler (Mannkind), Dreamboat.TM. (Mannkind), Duohaler
(Vectura), Easyhaler.RTM. (Orion), Flowcaps.RTM. (Hovione),
Genuair.RTM. (Almirall Sofotec), Gen-X.RTM. (Cambridge
Consultants), GyroHaler (Vectura), Manta Multi Dose (Manta), Manta
Single Dose (Manta), MicroDose DPI (MicroDose Therapeutx), Next.TM.
(Chiesi Farmaceutici), Novolizer.RTM. (Meda/Almirall Sofotec),
Prohaler.TM. (Valois), SkyeHaler.TM. (Skye Pharma), Smartinhaler
(Nexus6), Solis.TM. (Oriel Therapeutics/Sandoz), Sun DPI (Sun
pharmaceuticals/Cambridge Consultants), TAIFUN.RTM. (Akela
Pharma/Focus Inhalation), Twin Caps.TM. (Hovione), Twincer.TM.
(Groningen University), Xcaps (Hovione), Spinhaler (Aventis),
Rotahaler (GlaxoSmithKline), Inhalator (Boehringer-Ingeheim),
Cyclohaler (Pharmachemie), Handihaler (Boehringer-Ingeheim),
Aerolizer (Novartis), FlowCaps (Hovione), TwinCaps (Hovione),
Turbohaler (Astra Zeneca), Diskhaler (GlaxoSmithKline),
Diskus/Accuhaler (GlaxoSmithKline), Aerohaler
(Boehringer-Ingeheim), Easyhaler (Orion Pharma), Ultrahaler
(Aventis), Pulvinal (Chiesi), Novolizer (ASTA), MAGhaler
(Boehringer-Ingeheim), Taifun (LAB Pharma), Eclipse (Aventis),
Clickhaler (Innoveta Biomed), Asmanex Twisthaler (Schering-Plough
Corporation), Airmax (Norton Healthcare), CRC-749 (Pfizer),
Omnihaler (Innoveta Biomeds Ltd), Actispire (Britania), DirectHaler
(Direct-Haler), JAGO (SkyPharma), Airmax (Norton Healthcare),
Turbospin (PH & T), AIR (Alkermes), Cyclovent (Pharmachemie),
Dispohaler (AC Pharma). Microhaler (Harris Pharmaceutical),
Technohaler (Innoveta Biomed Ltd), Spiros (Dura), Bulkhaler (Asta
Medica), Miat-Haler (MiatSpA), Monodose Inhaler (MiatSpA),
Acu-Breath (Respirics), Swinghaler.RTM. (Otsuka Pharmaceutical Co.
Ltd), Pfeiffer (Pfeiffer GmbH), Certihaler (Novartis Pharma/Skye
Pharma), Otsuka DPI/breath actuated (Otsuka Pharmaceutical Co.
Ltd), Flexihaler (Astra Zeneca) and devices that are the same but
have different names or are made by different companies, and
devices that are similar or are generic copies of these
devices.
[0255] In a further aspect, the device is assembled with or has
inserted into it the packaging that carries the powder ready for
dispensing by the device just prior to the inhalation process. For
example, hard capsules are used as packaging. In a still further
aspect, hard capsules used as packaging are made from gelatine or
HMPC. In a yet further aspect, the capsules have a size that is
selected from the group consisting of: size 4, size 3, size 2, size
1 and size 0. In an even further aspect, the capsules are further
packaged into individual blister packs. In a still further aspect,
the blister pack is formed from aluminium foil laminates at the top
and bottom. In devices that contain multiple doses specialised
packaging is used. For example, the packaging used can contain
multiple doses is small blister packs formed from aluminium foil
laminates at the top and bottom. In some instances, it is desirable
that the blister packs are in the form of strips of individual
blisters. In a further aspect, the foil blisters are formed in a
disk or ring.
H. EXPERIMENTAL
[0256] 1. Materials
[0257] The following materials were used in the examples: active
pharmaceutical ingredients (salbutamol) were sourced from
commercial suppliers, the lactose from DMV-Fonterra, and the
lecithin (USP grade) from Spectrum chemicals. Ventolin Rotocaps
(200 .mu.g of salbutamol as salbutamol sulphate) were obtained as
commercial supplies. Unless otherwise indicated, where materials in
a composition are given as a percent it is in weight percent (%
w/w), unless otherwise indicated.
[0258] 2. General Methods
[0259] a. Attritor-Type Mill
[0260] Dry-milling experiments were performed using a 1S Union
Process attritor mill with a 1.5 gallon grinding chamber. The
grinding media consisted of 20 kg of 3/8'' stainless steel balls. A
total of 1 kg of powder was milled for each batch. The mill was
loaded through the loading port, with the grinding media added
initially, then followed by the dry powders. The milling process
was conducted with the jacket cooled to 13-16.degree. C. and the
shaft rotating at 400 rpm. Upon completion of milling, the milled
powder was discharged from the mill through the bottom discharge
port at 77 rpm.
[0261] b. Air Jet Milling:
[0262] Two air jet milligng conditions were used.
[0263] Ten inch air jet milling was performed in a 10'' Spiral Jet
Mill (Powdersize Inc) at a feed rate of 10 kg/hour. Between
500-1000 grams of powder was fed through the mill for each sample.
Four inch air jet milling was performed in a 4'' Spiral Jet Mill
(Powdersize Inc) at variable feed rates and pressures. Between
50-400 grams of powder was fed through the mill for each
sample.
[0264] c. Laser Diffraction
[0265] The particle size distribution (PSD) was determined using a
Malvern Mastersizer 2000. For wet (aqueous) measurements of the
active material a Malvern Hydro 2000S pump unit was used. For dry
particle size measurements of the composites a Scirocco 2000
measurment unit was used.
[0266] For the wet measurements the following settings were used:
Measurement Time: 12 seconds, Measurement cycles: 3. Final result
generated by averaging the 3 measurements. Samples were measured by
adding dry powder to saturated aqueous salbutamol containing
.about.0.03% PVP. Up to 2 minutes of sonication was applied within
the measurement cell before measurement. The refractive index of
the active was set to 1.56 with the absorption at 0.01.
[0267] For dry measurements a pressure of 3-3.5 bar was used for
the measurements. The refractive index of lactose was used for
analysis (1.35 with the absorption at 0.01.)
[0268] Other laser diffraction measurement of the composites were
measured with isoparG as a solvent. These were performed on a
Microtrac S3000 instrument using a 10 second run time. The
refractive index of the composite was set at 1.51 and the solvent
was 1.42.
[0269] d. Time of Flight Measurements:
[0270] Time of flight measurements were measured on a TSI Aerosizer
with an Aerodisperser set to a medium shear force and feed rate.
Deagglomeration was set to normal and pin vibration was on. The
particle size statistics are a volume distribution.
[0271] e. Aerodynamic Particle Size Distribution:
[0272] Aerodynamic Particle Size Distribution was measured on Next
Generation Pharmaceutical Impactor with stainless steel collection
cups, preseparator and a USP induction port. Testing was performed
with a total flow of 4 L with a pressure drop of 4 kPa up to a
maximum of 100 L/min. The actual flow was approximately 98-100
L/min. The commercial Ventolin Rotocaps where used as received.
Other powders (.about.20 mg) were filled into Size 3 HPMC
inhalation capsules or machine filled (.about.24.5 mg) using a
Harro Hofliger Omnidose Drumfiller (see section g for settings)
into Size 3 HPMC inhalation capsules. All capsules were tested in a
Monodose Inhaler. HPLC analysis was used to assay the active.
[0273] f. Powder Uniformity
[0274] Ten samples were taken from the bulk blend at locations
throughout the sample. These were then assayed by HPLC and
expressed as a % RSD over those 10 samples. For some batches an
assay by HPLC was also measured.
[0275] g. Automatic Powder Dispensing
[0276] A Harro Hofliger Omnidose Drumfiller was used to dose powder
to measure the accurary and precision of powder dispensing. The
dispenser was set to 35 cycles/min, a 500 mbar product vacuum, a
300 mbar dispense pressure with 2 stirrer rotations (180% speed)
and 2 shots per cavity. The powder was filled into stainless steel
thimbles for accurately weighing the mass of powder dispensed.
[0277] h. Scanning Electron Microscopy (SEM)
[0278] SEM's were measured on a Zeiss 1555 VPSEM. The powder
samples were applied to a carbon tab on the SEM stub and coated
with 3-5 nm of platinum before imaging.
[0279] 3. Production of Composite Particles with 10% Salbutamol in
Lactose Monohydrate
[0280] a. Dry-Milling of 10% Salbutamol in Lactose Monohydrate:
[0281] Four batches (labeled as 1A, B, C, and D) of 10% salbutamol
in lactose monohydrate with 1% (w/w) lecithin were dry-milled at 1
kg scale for 15 minutes. The particle size of the pharmaceutically
active agent was measured and the data are shown in Table 1. The
particle size data of the composite particle comprising salbutamol
and lactose are also shown in Table 1.
TABLE-US-00001 TABLE 1 Active particle Size (Wet (aqueous) laser
diffraction) Composite Size % < % < % < % < (Dry laser
diffraction) Batch D[50] 0.2 0.3 0.5 1.0 D[50] D[90] D[4, 3] No.
.mu.m .mu.m .mu.m .mu.m .mu.m .mu.m .mu.m .mu.m 1A 0.137 72 85 89
90 8.3 31.8 13.1 1B 0.137 80 95 96 96 8.2 30.0 12.4 1C 0.136 79 92
93 93 1D 0.129 84 98 100 100 8.8 32.3 13.4
[0282] b. Air Jet Milling
[0283] Material from batches 1A-D was air jet-milled in the ten
inch setup at four different pressures, 7.24 Bar (batch 2A), 4.83
Bar (batch 2B), 3.45 Bar (batch 2C) and 1.72 Bar (batch 2D). The
particle size of the composite particles are shown in Table 2, and
particle size was measured, as indicated, either by dry laser or
wet laser diffraction using Isopar.TM. G as a solvent. Particle
size of the pharmaceutically active agent, salbutamol, was
determined after air jet-milling for batches 2A-D using wet laser
diffraction and is shown in Table 3. The particle size of the
composite particle after air jet-milling was determined by time of
flight measurement and the data are shown in Table 4.
TABLE-US-00002 TABLE 2 Composite Size Composite Size Jet Mill Dry
laser diffraction (Wet (isoparG) laser diffraction) Batch Pressure
D[50] D[90] D[4, 3] D[50] D[90] No. (Bar) .mu.m .mu.m .mu.m .mu.m
.mu.m 2A 7.24 1.8 4.2 2.2 2.4 4.7 2B 4.83 2.2 5.3 2.6 2.9 5.6 2C
3.45 2.5 6.8 3.1 3.7 7.1 2D 1.72 3.5 9.5 4.4 4.8 10.8
TABLE-US-00003 TABLE 3 Active particle Size Jet Mill (Wet (aqueous)
laser diffraction) Batch Pressure D[50] % < % < % < % <
No. (Bar) .mu.m 0.2 .mu.m 0.3 .mu.m 0.5 .mu.m 1.0 .mu.m 2A 7.24
0.127 84 96 96 99 2B 4.83 0.128 84 97 98 99 2C 3.45 0.137 75 86 88
92 2D 1.72 0.127 83 97 98 99
TABLE-US-00004 TABLE 4 Jet Mill Composite Size - Time of Flight
Batch Pressure Mean D[90] D[4, 3] No. (Bar) (.mu.m) .mu.m .mu.m 2A
7.24 3.7 7.6 4.3 2B 4.83 6.0 12.6 7.2 2C 3.45 5.4 10.5 6.1 2D 1.72
7.7 12.8 8.4
[0284] 4. Production of Composite Particles with 1% Salbutamol in
Lactose Monohydrate
[0285] a. Dry-Milling of 1% Salbutamol in Lactose Monohydrate:
[0286] Another batch (labeled as 3A) comprising was dry-milled at
at 1 kg scale for 20 minutes with lactose monohydrate as the
millable grinding matrix and comprising 1% salbutamol and 1%
lecithin. The particle size data of the composite particle
comprising salbutamol and lactose for Batch 3A are shown in Table
5.
TABLE-US-00005 TABLE 5 Composite Size - Dry laser diffraction Batch
D[50] D[90] D[4, 3] No. .mu.m .mu.m .mu.m 3A 7.9 48.9 17.0
[0287] b. Air Jet Milling
[0288] Material from batch 3A was air jet-milled in the ten inch
setup at 4.83 Bar (batch 3B). The particle size of the composite
particles of batch 3B is shown in Table 6, and particle size was
measured, as indicated, either by dry laser or wet laser
diffraction using Isopar.TM. G as a solvent. Particle size of the
pharmaceutically active agent, salbutamol, was determined after air
jet-milling for batches 3B using wet laser diffraction. The
particle size is shown in Table 7. The particle size of the
composite particle after air jet-milling was determined by time of
flight measurement and the data are shown in Table 8.
TABLE-US-00006 TABLE 6 Composite Size Composite Size Jet Mill Dry
laser diffraction (Wet (isoparG) laser diffraction) Batch Pressure
D[50] D[90] D[4, 3] D[50] D[90] No. (Bar) .mu.m .mu.m .mu.m .mu.m
.mu.m 3B 4.83 2.4 6.1 3.0 3.5 7.0
TABLE-US-00007 TABLE 7 Active particle Size Jet Mill (Wet (aqueous)
laser diffraction) Batch Pressure D[50] % < % < % < % <
No. (Bar) .mu.m 0.2 .mu.m 0.3 .mu.m 0.5 .mu.m 1.0 .mu.m 3B 4.83
0.132 87 100 100 100
TABLE-US-00008 TABLE 8 Jet Mill Composite Size - Time of Flight
Batch Pressure Mean D[90] D[4, 3] No. (Bar) (.mu.m) .mu.m .mu.m 3B
4.83 5.2 9.3 5.8
[0289] c. Next Generation Impactor Measurements
[0290] Ventolin Rotacaps and powder from batch 3B were both
evaluated through the NGI. Three capsules were analyzed for each
sample (either Ventolin Rotocap or batch 3B, as indicated, wherein
the pharmaceutically active agent in each was salbutamol). 6 months
after the testing of batch 3B the bulk powder, which had been
stored at ambient conditions, was split into two lots. One lot was
used to handfil further capsules for NGI testing (3 capsules). The
other lot was filled into capsules using an Omindose Drumfiller.
These capsules (3 capsules tested) were tested 8 months after the
intial NGI testing of batch 3B. In Table 9 and 10 the average of
the three measurements and the relative standard deviation (RSD, %)
between the three measurements are shown. The data shown in Table 9
and 10 show the mass of salbuatmol in each of the various
components and stages of the test apparatus determined by assay for
salabutamol. The table indicates the size cutoff for each stage
(assumming a flow of 100 L/min). The total recovered dose (TRD) is
the sum of all material in the apparatus. The ED is the sum of
material found in the induction port through to the MOF (filter),
i.e. all the material except the residue in the capsule and device.
The fine particle dose (FPD) is the amount of material calculated
to be below an aerodynamic diameter of 5 .mu.m. Calculations for
FPD were carried out using the Copley Inhaler Testing Data Analysis
Software (Copley Scientific Limited, Nottingham, UK).
[0291] The data from Table 9 and 10 was then used to evaluate the
emitted dose as a percent of the TRD, the FPF, which is the
percentage of particles below 5 .mu.m, relative to either the ED
and the TRD, as well as the MMAD. This data are shown in Table 11,
which shows the emitted dose as a percent of the TRD, the FPF
relative to the ED and the TRD as indicated, and the MMAD
calculated from the NGI measurements.
TABLE-US-00009 TABLE 9 Ventolin Rotacaps Batch 3B-Initial Mass Mass
Sample (.mu.g) % RSD (.mu.g) % RSD Induction Port 33.7 13.5 34.8
4.9 Pre-separator 86.0 4.7 5.7 6.3 Stage 1 (6.1 .mu.m) 14.7 9.0
13.5 2.3 Stage 2 (3.4 .mu.m) 18.2 12.5 24.4 3.0 Stage 3 (2.2 .mu.m)
21.8 8.9 23.6 3.7 Stage 4 (1.3 .mu.m) 23.3 10.3 23.1 4.3 Stage 5
(0.7 .mu.m) 12.3 11.7 11.9 5.9 Stage 6 (0.4 .mu.m) 3.0 24.0 3.7 9.4
Stage 7 (0.2 .mu.m) 1.4 27.7 1.6 12.5 MOF 0.3 45.8 0.7 14.3
Residual in Capsule & Device 45.7 10.4 11.1 19.0 Total
recovered dose (TRD) 260.5 1.7 154.1 0.2 Emitted dose (ED) 214.7
3.4 143.0 1.5 Fine Particle Dose 74.6 6.7 81.9 4.3 (FPD) (.mu.g
< 5 .mu.m)
TABLE-US-00010 TABLE 10 Batch 3B-6 months Batch 3B-8 months Mass
Mass Sample (.mu.g) % RSD (.mu.g) % RSD Induction Port 26.8 45.3
34.3 0.2 Pre-separator 14.8 64.8 10.6 6.6 Stage 1 (6.1 .mu.m) 14.6
6.5 17.8 9.3 Stage 2 (3.4 .mu.m) 23.7 10.3 29.2 1.4 Stage 3 (2.2
.mu.m) 20.0 5.7 24.9 5.6 Stage 4 (1.3 .mu.m) 18.8 4.1 23.9 5.1
Stage 5 (0.7 .mu.m) 8.8 2.4 11.9 1.9 Stage 6 (0.4 .mu.m) 3.1 3.2
3.7 1.6 Stage 7 (0.2 .mu.m) 0.9 12.4 1.2 24.7 MOF 0.3 33.3 0.5 24.7
Residual in Capsule & Device 17.2 52.2 11.7 7.8 Total recovered
dose (TRD) 148.9 8.1 169.5 3.0 Emitted dose (ED) 131.7 2.5 157.8
2.7 Fine Particle Dose 68.1 5.6 86.3 3.2 (FPD) (.mu.g < 5
.mu.m)
TABLE-US-00011 TABLE 11 Ventolin Batch 3B- Batch 3B Batch 3B Sample
Rotacaps Initial 6 months 8 months % Emitted Dose 82.4 92.8 88.7
93.1 FPF (relative to 34.7 57.3 51.8 54.7 the the ED, %) FPF
(relative to 28.6 53.1 46.0 50.9 the the TRD, %) MMAD (.mu.m) 2.6
2.6 3.0 2.9 GSD 2.3 2.1 2.2 2.2
[0292] The data in this example shows that the formulation for oral
inhalation produced by this invention is superior to a conventional
produced formulation (Ventolin Rotacaps). The MMAD for both samples
was shown to be the same so a head to head comparison is truly
valid. The first key superiority is the emitted dose which is 10%
higher for batch 3B as little powder remains in the device after
actuation. The key superiority is the FPF where batch 3B has also
double the amount of active in the particle size range suitable for
inhalation. The data also shows that the delivery of the dose is
more consistent and uniform for batch 3B. For the ventolin sample
the percent RSD for each of the stages is at least double those
measured for batch 3B. This shows that batch 3B has a much more
consistent particle size distribution from dose to dose compared to
the ventolin sample. This is important to the patient as the exact
size of the particles will determine which part of the lung the
active is delivered to. As the bioavailability and efficacey of the
active is dependant on which part of the lung the particle settles
variability in where the active settles will lead to variability in
theurepeatic effect.
[0293] The data for batch 3B measured after 6 and 8 months also
shows little change from the initial testing which demonstrates
that the invention described herein is capable of producing
formulations with stable performance over time. The data of batch
3B at 8 months was also filled into the capsules using an automated
filling machine. So the fact that there is little change in the
aerodynamic properties also demonstrates that the powders produced
by this invention can be successfully filled using automated
equipment without determential changes to the powder
properties.
[0294] d. Powder Uniformity
[0295] The powder uniformity of batch 3B was measured and the data
is shown in Table 12. The data shows that the blend has excellent
uniformity, even at this low active loading. It should also be
noted that batch 3A was manufactured in Australia and transported
to the USA for jet milling to become batch 3B and then the sample
was transported to another facility for the uniformity tests. The
fact that the content uniformity has been retained to such a high
level is strong testament to the excellent uniformity properties of
this material.
TABLE-US-00012 TABLE 12 Sample No. 1 2 3 4 5 6 7 8 9 10 Ave RSD (%)
Batch 3B 0.84 0.82 0.83 0.82 0.82 0.82 0.83 0.82 0.82 0.82 0.82
0.71
[0296] e. Powder Flowability
[0297] A sample of batch 3B that was 6 months old was dispensed
from a Harro Hofliger Omnidose Drumfiller. A set of 60 24.5 mg
shots of powder were dispensed. The mean weight for this set was
24.53 mg. The minimum fill weight was 23.58 mg. The maximum fill
weight was 25.37 mg. The relative standard deviation (% RSD) was
1.70.
[0298] 5. Production of Composite Particles with Ipratropium
Bromide and Salbutamol Sulfate in Lactose Monohydrate
[0299] a. Dry-Milling of Ipratropium Bromide and Salbutamol Sulfate
in Lactose Monohydrate:
[0300] Four batches (labeled as 4A, B, C, and D) of various %'s of
ipratropium bromide and salbutamol sulfate in lactose monohydrate
with 1 w/w lecithin were dry-milled at 1 kg scale for 20 minutes.
The % of the two actives in each batch is shown in Table 13. The
particle size data of the composite particles comprising
ipratropium bromide, salbutamol sulfate and lactose are also shown
in Table 13.
TABLE-US-00013 TABLE 13 Composite Size Ipratropium Salbutamol (Dry
laser diffraction) Batch Bromide Sulfate D[50] D[90] D[4, 3] No. (%
(w/w)) (% (w/w)) .mu.m .mu.m .mu.m 4A 0.105 8.2 36.1 14.4 4B 0.42
7.5 23.6 10.3 4C 0.105 0.6 7.4 37.9 13.3 4D 0.42 2.4 6.2 21.5
9.4
[0301] b. Air Jet Milling
[0302] Material from each of batches 4A-D was divided into two and
air jet-milled in the four inch setup at two different conditions.
The lower energy condition was a pressure of 3.45 Bar and a
relative feed rate of 385-425, the higher energy condition was was
a pressure of 4.14-4.48 Bar and a relative feed rate of 220-275. A
relative feed rate of 220 is a target feed rate of 350 grams/hour.
The details of how each batch was milled are shown in Table 14. The
particle size of the composite particles are shown in Table 15, and
particle size was measured, as indicated, either by dry laser or
wet laser diffraction using Isopar.TM. G as a solvent.
TABLE-US-00014 TABLE 14 Input Ipratropium Salbutamol Jetmilling
Batch Batch Bromide Sulfate Pressure Feedrate No. No. (% (w/w)) (%
(w/w)) (Bar) (relative) 4E 4A 0.105 3.45 435 4F 4A 0.105 4.14 275
4G 4B 0.42 3.45 385 4H 4B 0.42 4.48 220 4I 4C 0.105 0.6 3.45 425 4J
4C 0.105 0.6 4.14 255 4K 4D 0.42 2.4 3.45 385 4L 4D 0.42 2.4 4.14
250
TABLE-US-00015 TABLE 15 Composite Size Composite Size Dry laser
diffraction (Wet laser diffraction) Batch Jet Mill D[50] D[90] D[4,
3] D[50] D[90] No. Energy .mu.m .mu.m .mu.m .mu.m .mu.m 4E low 2.9
7.4 3.5 3.8 8.1 4F high 2.3 5.8 2.8 3.2 5.5 4G low 2.4 6.9 3.1 3.8
7.8 4H high 1.8 4.5 2.2 2.4 4.0 4I low 2.6 7.1 3.3 3.9 7.9 4J high
1.9 4.6 2.3 2.4 4.0 4K low 2.3 6.1 2.9 3.6 6.7 4L high 2.0 5.3 2.5
3.0 5.0
[0303] c. Powder Uniformity
[0304] The assay of actives and the powder uniformity of batches
4E-L was measured by HPLC and the data is shown in Table 16. The
data show that the powders have the correct assays and excellent
uniformity, even at these very low active loading. It should also
be noted that these batches were dry milled in Australia and
transported to the USA for jet milling and then transported back to
Australia for assay and uniformity tests. The fact that the content
uniformity has been retained to such a high level despite this
extensive transport is strong testament to the excellent uniformity
properties of this material.
TABLE-US-00016 TABLE 16 Assay by HPLC Content Uniformity Batch Jet
Mill (% w/w) (% RSD) No. Energy IB SS IB SS 4E low 0.11 4.5 4F high
0.11 0.8 4G low 0.44 2.4 4H high 0.44 1.5 4I low 0.11 0.62 3.1 2.8
4J high 0.11 0.62 0.9 0.7 4K low 0.44 2.35 3.2 3.3 4L high 0.42
2.30 3.9 4.1
[0305] d. Scanning Electron Microscopy (SEM)
[0306] SEM images of one sample (4J) where taken and are shown in
FIGS. 1-2. FIG. 1 is shown at a magnification of 10,000.times. and
shows an overview of the composite size and shape. The image
clearly shows the particles have an irregular shape and a primary
particle size between 1-5 micron. FIG. 2 shows an images at high
magnification show that the composite particles are an agreegate of
matrix and active particles of order 200 nm or less. The figure
also shows that the composite particles have high surface rougness
on a nanometer scale.
[0307] It will be apparent to those skilled in the art that various
modifications and variations can be made in the present invention
without departing from the scope or spirit of the invention. Other
embodiments of the invention will be apparent to those skilled in
the art from consideration of the specification and practice of the
invention disclosed herein. It is intended that the specification
and examples be considered as exemplary only, with a true scope and
spirit of the invention being indicated by the following
claims.
I. OTHER EMBODIMENTS
[0308] In a further aspect, the pharmaceutically active agent is
selected from one or more of alpha 1 antitrypsin, beclomethasone,
budesonide, calcitonin, ciclesonide, ciprofloxacin, clarithromycin,
clinafloxacin, cloxacillin, colistimethate, colistin, cromolyn,
darotropium, desmopressin, dihydroergotamine, dirithromycin,
elcatonin, enokizumab, epinastine, erdosteine, ergotamine,
erythromycin, erythropoietin (EPO), etamiphylline, factor IX,
fenspiride, fentanyl, floxacillin, flunisolide, flurisolide,
flurithromycin, fluticasone, formoterol, glycopyrrolate,
guaifenesin, hydrocortisone, indacaterol, insulin, insulin tropin,
insulin-like growth factor (IGF), interferon alpha, interferon
beta, interferon gamma, ipratropium, ipratropium, lebrikizumab,
levocetirizine, levofloxacin, lomefloxacin, losmapimod, low
molecular weight heparin (LMWH), mabuterol, masilukast, mecysteine,
metaproterenol, methicillin, milveterol, mometasone, montelukast,
muscarinic acetylcholine receptor antagonist and beta 2
adrenoceptor dual agonist (MABA), olodaterol, omalizumab,
oxitropium, oxtriphylline, pirbuterol, Polymyxin B, pranlukast,
procaterol, proinsulin, pyruvate, rifampicin, salbutamol,
salmeterol, seratrodast, theophylline, tobramycin, tofimilast,
tulobuterol, vancomycin, vasopressin, vilanterol, X-ray contrast
agents, xylometazoline, zafirlukas, zileuton, or a pharmaceutically
acceptable salt, solvate, hydrate, or polymorph thereof.
[0309] In a further aspect, the pharmaceutically active agent is an
insulin. In a yet further aspect, the insulin is selected from a
recombinant insulin, insulin purified from a mammal, substituted
insulin, pro-insulin, semi-synthetic insulin, synthetic insulin, or
a pharmaceutically acceptable salt, solvate, hydrate, or polymorph
thereof. In an even further aspect, the insulin is selected from
human recombinant insulin, insulin regular, insulin aspart, insulin
aspart protamine, insulin detemir, insulin glargine, insulin
glulisine, insulin isophane, insulin lispro, or a pharmaceutically
acceptable salt, solvate, hydrate, or polymorph thereof.
[0310] In a further aspect, the pharmaceutically active agent is
selected from beclomethasone, budesonide, ciclesonide,
ciprofloxacin, colistin, dihydroergotamine, formoterol,
fluticasone, insulin, ipratropium, mometasone, Polymyxin B,
rifampicin, salbutamol, salmeterol, tobramycin, or a
pharmaceutically acceptable salt, solvate, hydrate, or polymorph
thereof.
[0311] In a further aspect, the pharmaceutically active agent is
selected from AZD1419, AZD1981, AZD3199, AZD5069, AZD5423, AZD8683,
AZD9164, AZD9668, GSK1325756, GSK159802, GSK2190915, GSK2245840,
GSK256066, GSK573719, GSK610677, GSK681323, GSK961081, GW870086,
PF184, PF3526299, PF3635659, PF3893787, PF4191834, PF4764793,
PF610355, TD4208, and TD5959.
[0312] In a further aspect, the composite particle further
comprises a second pharmaceutically active agent, the method
producing composite particles of the matrix having the solid
pharmaceutically active agent and the second pharmaceutically
active agent dispersed therein. In a yet further aspect, the first
and second pharmaceutically active agents are selected from
fluticasone and salmeterol; budesonide and formeterol; ciclesonide
and formeterol; beclomethasone and formeterol; fluticasone and
formeterol; mometasone and formeterol; ipratropium and salbutamol;
fluticasone and vilanterol; mometasone and formeterol; indacaterol
and mometasone; arformoterol and ciclesonide; indacaterol and
tiotropium; aclidinium and formeterol; darotropium and vilanterol;
formoterol and glycopyrrolate; GSK573719 and vilanterol
trifenatate; or a pharmaceutically acceptable salt, solvate,
hydrate, or polymorph thereof.
[0313] In a further aspect, the pharmaceutically active agent is
selected from a known class of drug. In a still further aspect, the
known class of drug is selected from 5-hydroxytryptamine (5-HT)
receptor antagonist, 5-lipoxygenase (5-LO)-activating protein
(FLAP) inhibitor, a combination of a (32 adrenergic receptor
(ADRB2) agonist and a glucocorticoid receptor (GR) agonist, a
combination of a (32 adrenergic receptor (ADRB2) agonist and a
leukotriene D4 (LTD4) receptor antagonist, a combination of a (32
adrenergic receptor (ADRB2) agonist and a Mu-Opioid receptor
antagonist and a muscarinic M1 receptor antagonist, a combination
of a (32 adrenergic receptor (ADRB2) agonist and a muscarinic M3
receptor antagonist, a combination of a (32 adrenergic receptor
(ADRB2) agonist and a muscarinic receptor antagonist, a combination
of a glucocorticoid receptor (GR) agonist and a histamine H1
receptor antagonist, a combination of a glucocorticoid receptor
(GR) agonist and a leukotriene D4 (LTD4) receptor antagonist, a
combination of a histamine H1 receptor antagonist and a leukotriene
D4 (LTD4) receptor antagonist, a combination of a human leukocyte
elastase (HLE) inhibitor and a proteinase 3 (PRTN3) inhibitor,
adenosine A1 receptor (ADORA1) antagonist, adenosine A2B receptor
(ADORA2B) antagonist, adenosine release inhibitor, adenosine
triphosphate (ATP) dephosphorylation, .alpha.-adrenergic receptor
blocking agents, analgesics, anepileptics, anthelmintics,
anti-allergic agents, antiandrogenic agents, antianxiety drugs
(anxiolytics), antiarrhythmics, anti-asthma agents,
anti-bacterials, antibiotics, antibodies, anti-cancer agents,
anti-cholinergies, anticoagulants, anti-convulsants,
anti-cytokines, antidepressants, antidiabetic agents, antiemetics,
antienteritis agents, antiepileptics, antifungals, antigens,
antihistamines, antihypertensives, anti-inflammatories,
antimalarials, antimigraine agents, antimuscarinic agents,
antimycobacterial agents, anti-narcotic antibodies,
antineoplastics, anti-obesity drugs, antioxicants, antiparasitics,
antiparkinson agents (dopamine antagnonists), anti-spasmodics,
antithrombotic agents, antithyroid agents, anti-tussives,
antivirals, anxiolytics, appetite suppressants, astringents,
.beta.1 adrenergic receptor (ADRB1) antagonist/.beta.2 adrenergic
receptor (ADRB2) antagonist, (32 adrenergic receptor (ADRB2)
agonist, .beta.-adrenoceptor blocking agents, beta-agonists,
biphosphonates, blood products and substitutes, bronchodilators,
cardiac inotropic agents, cardiovascular agents, carotenoids,
cathepsin S (CTSS) inhibitor, CC Chemokine receptor 3 (CCR3)
antagonist, chemokine (C--C motif) receptor 4 (CCR4) antagonist,
cell surface antigens and hypoglycaemic agents, central nervous
system stimulants, chemoattractant receptor-homologous molecule
expressed on TH2 Cells (CRTH2) antagonist, chloride channel Type-2
(ClC-2) Activator, C-Kit receptor tyrosine kinase (CD117)
inhibitor, cluster of differentiation 28 (CD28) receptor
antagonist, complement inhibitor, contrast media, contrast agents,
corticosteroids, cough suppressants (e.g., expectorants and
mucolytics), COX-2 inhibitors, cromones, CXC chemokine receptor 2
(CXCR2) antagonist, cytokine receptors, diagnostic imaging agents,
diuretics, dopaminergics (anti-parkinsonian agents), elastase 2
neutrophil (ELA2) inhibitor, elastase inhibitors, eoxin inhibitor,
E-selectin inhibitor, L-selectin inhibitor, P-selectin inhibitor,
glucocorticoid receptor (GR) agonist, glutathione-S-transferase
(GST) activator, growth factors, growth supplements, haemostatics,
histamine H1 receptor antagonist, histamine H4 receptor antagonist,
histamine Release inhibitor, hormonal agents including
contraceptives, hormones, human leukocyte elastase (HLE) inhibitor,
hypnotics, sedatives, hypoglycemics, immunoglobulin E (IgE)
receptor antagonist, immunoglobulins, immunomodulating agents,
immunosuppressants, infectious agents, inflammatory mediators,
inhibitor of kappa light polypeptide gene enhancer in
B-cells/kinase gamma (IKBKG), inhibitor of kappa light polypeptide
gene enhancer in B-cells/kinase beta (IKBKB) inhibitor, inhibitor
of kappa light polypeptide gene enhancer in B-cells/kinase episolon
(IKBKE) inhibitor, integrins, a4 (ITGA4) mRNA inhibitor,
interferons, interleukin 13 (IL13) inhibitor, interleukin 4
receptor (IL4R) mRNA inhibitor, interleukin-1 (IL-1) receptor
antagonist, interleukin-4 (IL-4) receptor antagonist, interleukin-5
(IL-5) receptor antagonist, interleukin-9 (IL-9) inhibitor,
interleukins, kallikrein 1 (KLK1) inhibitor, inhibitor of kappa
light polypeptide gene enhancer in B-cells/kinase beta (IKBKB)
inhibitor, leukotriene C4 (LTC4) receptor antagonist, leukotriene
C4 (LTC4) receptor antagonist/leukotriene D4 (LTD4) receptor
antagonist, leukotriene D4 (LTD4) receptor antagonist, leukotriene
D4 (LTD4) receptor antagonist/leukotriene E4 (LTE4) receptor
antagonist, leukotriene E4 (LTE4) receptor antagonist, leukotriene
receptor antagonist, leukotrienes, lipid regulating agents,
L-selectin inhibitor, lymphotoxin A (LTA) inhibitor, lymphotoxin A
(LTA) inhibitor/tumor necrosis factor-.alpha. (TNF.alpha.)
inhibitor, matrix metalloproteinase (MMP) inhibitor, matrix
metalloproteinase-12 (MMP-12) inhibitor, mucolyties, muscarinic M1
receptor antagonist, muscarinic M1 receptor antagonist/muscarinic
M3 receptor antagonist, muscarinic M3 receptor antagonist,
muscarinic receptor antagonist, muscle contractants, muscle
relaxants, myristoylated alanine-rich C-kinase substrate (MARCKS)
inhibitor, neoplastics, neuroactive agents, neurokinin NK1 receptor
antagonist, neurokinin NK1 receptor antagonist, neurokinin NK2
receptor antagonist, neurokinin NK3 receptor antagonist, neurokinin
NK2 receptor antagonist, neurokinin NK3 receptor antagonist,
non-opioid analgesic agents, NSAIDs, nuclear factor-.kappa.B
(NF-.kappa.B) inhibitor, nutritional agents and supplements,
oncology therapies, p38 alpha mitogen-activated protein (MAP)
kinase inhibitor, p38 kinase inhibitor, parasympathomimetics,
parathyroid calcitonin, peripheral chemoreceptor agonist,
phosphatidylinositol 3-Kinase (PI3K) inhibitor, phosphodiesterase 7
(PDE7) inhibitor/phosphodiesterase-4 (PDE-4) inhibitor,
phosphodiesterase-3 (PDE-3) inhibitor, phosphodiesterase-3 (PDE-3)
inhibitor/phosphodiesterase-4 (PDE-4) inhibitor,
phosphodiesterase-3 (PDE-3) inhibitor/phosphodiesterase-5 (PDE-5)
inhibitor, phosphodiesterase-4 (PDE-4) inhibitor,
phosphodiesterase-5 (PDE-5) inhibitor, phosphodiesterase-7 (PDE-7)
inhibitor, prostaglandin D2 (PGD2) receptor antagonist,
prostaglandins, protease serine 8 (PRSS8) inhibitor, protein
synthesis inhibitor, proteinase 3 (PRTN3) inhibitor, P-selectin
inhibitor, psychic energizers, radio-pharmaceuticals, respiratory
drugs, sedatives, semicarbazide-sensitive amine oxidase (SSAO)
inhibitor, sex hormones (including steroids), sirtuin 1 (SIRT1)
activator, steroids, stimulants and anoretics, superoxide dismutase
(SOD) mimetic, sympathomimetic amines, sympathomimetics,
thromboxane A2 (TXA2) receptor antagonist, thyroid agents,
Toll-like receptor 9 (TLR9) agonist, tranquilizers, transient
receptor potential cation channel subfamily A/member 1 (TRPA1)
antagonist, tumor necrosis factor-.alpha. (TNF.alpha.) inhibitor,
tumor necrosis factor super family member 4 (TNFSF4) inhibitor,
vaccines (including influenza, measles, menigitis, tuberculosis),
vasoactive agents, vasodilators, and xanthines; or a
pharmaceutically acceptable salt, derivative, solvate, hydrate, or
polymorph thereof.
[0314] In a further aspect the pharmaceutically active agent is
selected from ciprofloxacin, colistin, dihydroergotamine,
fluticasone furoate, fluticasone propionate, formoterol,
ipratropium, polymyxin B, rifampicin, salbutamol, salmeterol
xinafoate, budesonide acetonide, clarithromycin, clinafloxacin,
cloxacillin, colistimethate, dihydroergotamine tartrate,
dirithromycin, elcatonin, erythromycin, erythropoietin (EPO),
factor IX insulin, floxacillin, flurithromycin, insulin,
insulin-like growth factor(IGF), insulin tropin, interferon alpha,
interferon beta, interferon gamma, levofloxacin, lomefloxacin, low
molecular weight heparin (LMWH), methicillin, tobramycin,
vancomycin, vasopressin, beclomethasone dipropionate, budesonide,
calcitonin, desmopressin, ergotamine, fentanyl citrate,
flurisolide, insulin (including substituted insulins and
pro-insulins), mometasone furoate, salbutamol sulphate, salmeterol,
ipratropium bromide, proinsulin, semi-synthetic insulins, synthetic
insulins, x-ray contrast agents, alpha 1 antitrypsin, AZD1419,
AZD1981, AZD3199, AZD5069, AZD5423, AZD8683, AZD9164, AZD9668,
ciclesonide, cromolyn sodium, darotropium, enokizumab, epinastine
hydrochloride, erdosteine, etamiphylline hydrochloride, fenspiride
hydrochloride, flunisolide, glycopyrrolate, GSK1325756, GSK159802,
GSK2190915, GSK2245840, GSK256066, GSK573719, GSK610677, GSK681323,
GSK961081, guaifenesin, GW870086, hydrocortisone sodium succinate,
indacaterol, lebrikizumab, levocetirizine dihydrochloride,
losmapimod, MABA, mabuterol hydrochloride, masilukast, mecysteine
hydrochloride, metaproterenol sulphate, milveterol hydrochloride,
montelukast sodium, olodaterol, omalizumab, oxitropium bromide,
oxtriphylline, PF184, PF3526299, PF3635659, PF3893787, PF4191834,
PF4764793, PF610355, pirbuterol acetate, pranlukast hydrate,
procaterol hydrochloride, seratrodast, sodium pyruvate, TD4208,
TD5959, theophylline, tofimilast, tulobuterol hydrochloride,
vilanterol trifenatate, xylometazoline hydrochloride, zafirlukas,
zileuton and analogues, agonists, antagonists, inhibitors; or a
pharmaceutically acceptable salt, derivative, solvate, hydrate, or
polymorph thereof.
[0315] In a further aspect, the pharmaceutically active agent is
selected from 13-cis-retinoic acid, 5-fluorouracil,
9-nitrocamptothesin, AB1010, abatacept, acefylline piperazine,
acetylcysteine, aclidinium bromide, ACT129968, AEOL10150, AFX300,
AGNCA805, AI128, AIR645, alatrofloxacin, albendazole, albendazole
sulfoxide, albuterol sulphate, alfaxalone, alfentanil
hydrochloride, alkaline phosphatise, almitrine mesylate, alpha 1
antitrypsin, alpha 1 proteinaseinhibitor, alphaprodine
hydrochloride, alprostadil, AM103, AM803, ambroxol, AMG157, AMG761,
amifloxacin, amikacin, aminofostin, amitriptyline, amoxicillin,
AMP4R1RA, ampicillin, amylin, andazithromycin, anileridine,
anipamil, anti-CMV antibody, antiepileptics, papaveretum,
antithrombin III, AP1500, ARRY006, atenolol, ATL1102, ATL844,
AVE0675, AZD1419, AZD1981, AZD3199, AZD5069, AZD5423, AZD8683,
AZD9164, AZD9668, azelastine, azidothymidine, azithromycin,
azlocillin, AZN6553, aztreonam, bacitracin, baclofen, bambuterol,
bambuterol hydrochloride, beclobrate, beclomethasone dipropionate,
belomycin, benralizumab, benzocaine, benzodiazepines,
.beta.-carotene, .beta. endorphin, .beta. interferon, bezafibrate,
bezitramide, BI671800, bimosiamose disodium, binovum, BIO11006,
biperiden, bispecific antibody, bisphosphonates, BMS639623,
bromazepam, bromocryptine, bucindolol, budesonide, budesonide
acetonide, buflomedil, bupivacaine, buprenorphine hydrochloride,
busulfan, butorphanol tartrate, cadralazine, caffeine, calcitonin,
camptothesin, canakinumab, canceractivity, canthaxanthin,
capreomycin, captopril, carbamazepine, carbenicillin,
carbocysteine, carboprost, carfentanil citrate, carmoterol, CAT354,
cefaclor, cefadroxil, cefalexin, cefalotin, cefamandole,
cefatrizine, cefazedone, cefazolin, cefepime, cefinenoxime,
cefixime, cefluoroxime, cefmetazole, cefonicid, cefoperazone,
ceforanide, cefotaxime, cefotetan, cefoxitin, cefpodoxime,
cefprozil, cefsulodin, ceftazidime, ceftbuten, ceftizoxime,
ceftriaxone, cefuroxime, CEM315, cephacetrile, cephalexin,
cephaloglycin, cephaloridine, cephalothin, cephapirin, cephradrine,
ceredase, cerezyme, CHF5480, chlorambucil, chromoglycinic acid,
ciclesonide, ciclonicate, ciglitazone, cillin, cintredekin
besudotox, ciprofloxacin, ciramadol, clarithromycin, clenbuterol,
clenbuterol hydrochloride, clinafloxacin, clonidine, clopiogrel,
cloxacillin, cobiprostone, codeine, colistimethate, colistin,
cortexolone, corticosterone, cortisol, cortisone, CP325366, CP4166,
c-peptide, cromolyn sodium, CS003, CWF0710, cyclophosphamide,
cyclosporine A and other cyclosporins, cytarabine, dantrolene,
daptomycin, darotropium, davercin, deoxyribonuclease (Dnase),
desmopressin, desocryptin, desogestrel, dexamethasone,
dextromoramide, dextropropoxyphene, dezocine, diamorphine
hydrochloride, diazepam, diclofenac, dicloxacillin,
dideoxyadenosine, dideoxyinosine, digitoxin, digoxin,
dihydrocodeine, dihydroergotamine, dihydroergotamine tartrate,
dihydroergotoxin, diltiazem, DIMS0001, dipipanone hydrochloride,
dirithromycin, disodium pamidronate, dopamine antagonists,
doxofylline, doxorubicin, DRL2546, DW403, DX2300, econazole, EL246,
Elafin, ELB353, elcatonin, enadoline, enalapril, endothelial growth
factors, endralazine, enkephalin, enokizumab, enoxacin, EP101,
EPI12323, epinastine hydrochloride, epoprostenol, eptazocine
hydrobromide, erdosteine, ergotamine, erythromycin, erythropoietin
(EPO), estradiol, estramustine, etamiphylline hydrochloride,
ethoheptazinecitrate, ethylmorphine hydrochloride, etofibrate,
etoposide, etorphine hydrochloride, ETX9101, factorix, factor IX
insulin, factor viii, felbamate, fenbendazole, fenofibrate,
fenoterol, fenspiride hydrochloride, fentanyl citrate,
fexofenedine, FHTCT4, flecainide, fleroxacin, floxacillin,
flunarizin, flunisolide, flurazepam, flurbiprofen, flurisolide,
flurithromycin, Fluticasone furoate, fluticasone propionate,
follicle stimulating hormone (FSH), formoterol, fosfomycin,
fosmidomycin, furosemide, galampicillin, gallopamil, gamma
interferon, gatifloxacin, gentamicin, gepefrine, ghrelin, glial
growth factor (GGF), gliclazide, glipizide, glucagon-like peptide 1
(GLP-1), glucagon-like peptide thymosin alphal, glycopyrrolate,
gramicidin, granulocyte colony stimulating factor (GCSF),
granulocyte macrophage colony stimulating factor (GMCSF), GRC3886,
grepafloxacin, griseofulvin, growth colony stimulating factor,
growth hormone, growth hormone releasing hormone (GHRH),
GSK1325756, GSK159802, GSK2190915, GSK2245840, GSK256066,
GSK573719, GSK610677, GSK681323, GSK961081, guaifenesin, GW870086,
HAE1, haptoglobulin, HC030031, heparin, hepatitis B vaccine,
hetacillin, HF1020, HI164OV, HL028, HMT, HS-A1, human growth
hormone (HGH), hydralazine, hydrochlorothiazide, hydrocodone,
hydrocortisone, hydrocortisone sodium succinate, hydromorphone
hydrochloride, hydroxyzine, hyoscine, ibuprofen, ibuproxam, IC485,
IL-4 inhibitor COSMIX, IMA026, IMD1041, imipenem, IMO2134,
indacaterol, indinavir, indomethacin, INDUS82010, insulin, insulin
(including substituted insulins and pro-insulins), insulin-like
growth factor (IGF), insulin tropin, interferon alpha, interferon
beta, interferon gamma, interleukin-1, interleukin-1 receptor,
interleukin-1 receptorantagonist, interleukin-2, interleukin-3,
interleukin-4, interleukin-4R, interleukin-6, iodamide,
ipratropium, ipratropium bromide, irloxacin, josamycin, kanamycin,
keratinocyte growth factor (KGF), ketamine, ketobemidone,
ketoconazole, ketoprofen, ketotifen, ketotifen fumarate, KM278,
KPE06001, K-strophanthin, L971, labetalol, lactobacillus vaccine,
LAS100977, lebrikizumab, leucomycin, leuprolide, leutinizing
hormone releasing hormone, levocetirizine dihydrochloride,
levofloxacin, levomethadone hydrochloride, levomethadyl acetate,
levorphanol tartrate, lidocaine, lidoflazin, lignocaine, lisuride,
lisuride hydrogen maleate, LMP160, lomefloxacin, loracarbef,
lorazepam, losmapimod, lovastatin, low molecular weight heparin
(LMWH), luteinizing hormone releasing hormone (LHRH), MABA,
mabuterol hydrochloride, macrophage colony stimulating factor
(M-CSF), masilukast, MDT011, mecysteine hydrochloride, MEDI557,
mefenamic acid, melphalan, MEM1414, memantin, meptazinol
hydrochloride, meropenem, mesulergin, metaproterenol sulphate,
metergoline, methadone hydrochloride, methicillin, methotrexate,
methotrimeprazine, methyldigoxin, methylprednisolone, metipranolol,
metisoprenol, metkephamide, metolazone, metoprolol, metoprolol
tartrate, metronidazole, mexiletine, mezlocillin, mianserin,
miconazole, miconazole nitrate, midazolam, midecamycin, mideplanin,
milveterol hydrochloride, minoxidil, miocamycin, misonidazol,
MK6105, MLN6095, MMP protease inhibitor, molsidomin, montelukast,
montelukast sodium, morphine, moxalactam, moxifloxicin, nadolol,
nafazatrom, nafcillin, nafiverine, nalbuphine hydrochloride,
naproxen, natural insulins, NCX1020, nedocromil, neomycin, nerve
growth factor (NGF), nesapidil, netilmicin, nicardipine,
nicomorphine hydrochloride, nicorandil, nifedipine, niludipin,
nimodipine, nitrazepam, nitrendipine, nitrocamptothesin,
norfloxacin, NPB3, OC000459, octreotide, ofloxacin, olanzapine,
oleandomycin, olodaterol, omalizumab, opium, OPLCCL11LPM, OX2477,
OX40, OX914, oxacillin, oxazepam, oxitropium bromide, oxprenolol,
oxtriphylline, oxycodone, oxymorphone hydrochloride,
oxytetracycline, oxytropium bromide, thiazinamide chloride, PA401,
paracetamol, paramecin, parathyroid hormone (PTH), parogrelil
hydrochloride, pazufloxacin, pefloxacin, penecillin O, penicillin G
benethamine, penicillin G, penicillin V, Pentamidine, pentamidine
isethiouate, pentamorphone, pentazocine, PEP03, pethidine
hydrochloride, PF184, PF3526299, PF3635659, PF3893787, PF4191834,
PF4764793, PF610355, phenazocine hydrobromide, phenoperidine
hydrochloride, phenothiazines, phenylbutazone, phosphodiesterase
(PDE) compounds, picenadol hydrochloride, picotamide, pindolol,
piperacillin, piposulfan, pirbuterol, pirbuterol acetate,
piretanide, piribedil, piritramide, piroxicam, pirprofen, PLA950,
plasminogenici activator, POL6014, polymyxin B, pranlukast hydrate,
prednisolone, prednisone, pregnenolone, procarbacin, procaterol,
procaterol hydrochloride, progesterone, proinsulin, propafenone,
propanolol, propentofyllin, propiram furmarate, propofol,
propranolol, prulifloxacin, PS291822, PT002, PT003, PT009, PT010,
PUP1, PXS4159, PXS74, QAX028, QAX576, R7103, raloxifene,
rampolanin, RBx11082, REGN668, remifentanil hydrochloride,
reproterol, respiratory syncytial virus antibody, RG7449,
rifampicin, rifapentin, rokitamycin, roxithromycin, RPL554, RTA403,
salbutamol sulphate, salbutamol, salmeterol, salmeterol xinafoate,
SAR21609, SAR389644, SB656933, SCH527123, semi-synthetic insulins,
seratrodast, simvastatin, sitafloxacin, sobrerol, sodium pyruvate,
sodium, cromoglycate, somastotine, somatostatin, somatropin,
sparfloxacin, spiradoline mesylate, spiromycin, stilamine, STNM03,
streptomycin, sufentanil citrate, sulfinalol hydrochloride,
sulfinpyrazone, suloctidil, sulproston, suprofen, swinolide A,
synthetic insulins, TA106, talinolol, TAPI, TARGALLERG I200,
TARGALLERG I201, TARGALLERG I202, taxol, taxotere, tazanolast,
TD4208, TD5959, teicoplanin, temafloxacin, terbutaline,
testosterone, testosterone propionate, testosterone undecanoate,
tetomilast, tetracane HI, theophylline, thrombopoietin (TPO),
tiaramide hydrochloride, ticarcillin, tilidate hydrochloride,
tissue growth factors, tobramycin, tofimilast, tolmetin, tonazocine
mesylate, tosufloxacin, TPI1100, TPI2200, tramadol hydrochloride,
tranilast, trefentanil, triamcinolone acetamide, triquilar,
troleandomycin, tromantadine hydrochloride, trovafloxacin, TT32,
tulobuterol hydrochloride, tumor necrosis factor (TNF), UR5908,
UR63325, urokinase, VAK694, valium, vancomycin, vasopressin,
verapamil, vidarabine, vidarabine phosphate sodium salt, vilanterol
trifenatate, vinblastine, vinburin, vincamine, vincristine,
vindesine, vinpocetine, vitamin A, vitamin E succinate, VLA-4
inhibitors, X072NAB, X-ray contrast agents, xylometazoline
hydrochloride, zafirlukast, and zileuton including analogues,
agonists, antagonists, inhibitors; or a pharmaceutically acceptable
salt, derivative, solvate, hydrate, or polymorph thereof.
[0316] In reference to peptides and proteins, a therapeutic peptide
or protein is inclusive of synthetic, native, glycosylated,
unglycosylated, pegylated forms, and pharmaceutically active agent
fragments and analogs thereof.
[0317] A description of the above classes of pharmaceutically
active agents and a listing of individual therapeutic agents within
each class can be found in Martindale's The Extra Pharmacopoeia,
31st Edition (The Pharmaceutical Press, London, 1996), specifically
incorporated by reference. Alternative, a description and listing
of suitable pharmaceutically active agents can be found in
Physicians Desk Reference (60th Ed., pub. 2005). The disclosed
pharmaceutically active agents are either commercially available
and/or can be prepared by techniques known in the art. An
exhaustive list of drugs for which the methods of the invention are
suitable would be burdensomely long for this specification;
however, reference to the general pharmacopoeia listed above would
allow one of skill in the art to select appropriate
pharmaceutically active agents which can be used to prepare the
disclosed composite particles comprising a millable grinding matrix
and a pharmaceutically active agent. It is also expected that new
pharmaceutically active agents, including novel chemical entities
(NCE) and other therapeutic agents for which the disclosed methods
are suitable will be created or become commercially available in
the future.
* * * * *