U.S. patent application number 14/279185 was filed with the patent office on 2014-11-06 for method for the production of commercial nanoparticle and microparticle powders.
This patent application is currently assigned to ICEUTICA PTY LTD.. The applicant listed for this patent is ICEUTICA PTY LTD.. Invention is credited to H William BOSCH, Aaron DODD, Felix MEISER, Marck NORRET, Adrian RUSSELL.
Application Number | 20140326812 14/279185 |
Document ID | / |
Family ID | 43010606 |
Filed Date | 2014-11-06 |
United States Patent
Application |
20140326812 |
Kind Code |
A1 |
DODD; Aaron ; et
al. |
November 6, 2014 |
Method for the Production of Commercial Nanoparticle and
Microparticle Powders
Abstract
The present invention relates to methods for producing
nanoparticle and microparticle powders of a biologically active
material which have improved powder handling properties making the
powders suitable for commercial use using dry milling processes as
well as compositions comprising such materials, medicaments
produced using said biologically active materials in particulate
form and/or compositions, and to methods of treatment of an animal,
including man, using a therapeutically effective amount of said
biologically active materials administered by way of said
medicaments.
Inventors: |
DODD; Aaron; (Centennial
Park, AU) ; MEISER; Felix; (Mount Claremont, AU)
; NORRET; Marck; (Darlington, AU) ; RUSSELL;
Adrian; (Rivervale, AU) ; BOSCH; H William;
(Bryn Mawr, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ICEUTICA PTY LTD. |
Philadelphia |
PA |
US |
|
|
Assignee: |
ICEUTICA PTY LTD.
Philadelphia
PA
|
Family ID: |
43010606 |
Appl. No.: |
14/279185 |
Filed: |
May 15, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13265933 |
Mar 9, 2012 |
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PCT/AU2010/000467 |
Apr 23, 2010 |
|
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14279185 |
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61172300 |
Apr 24, 2009 |
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Current U.S.
Class: |
241/30 |
Current CPC
Class: |
A01N 47/36 20130101;
A61K 31/18 20130101; A61K 31/192 20130101; A61K 31/404 20130101;
A01N 55/02 20130101; A01N 25/10 20130101; A61K 9/1617 20130101;
A61K 9/0075 20130101; A61J 3/02 20130101; A61P 11/00 20180101; A01N
57/20 20130101; A23P 10/30 20160801; A61K 31/122 20130101; A61K
31/53 20130101; A61K 31/565 20130101; A61K 9/146 20130101; A61K
38/13 20130101; A61P 43/00 20180101; A23P 10/20 20160801; A61K
31/57 20130101; A23V 2002/00 20130101; A61K 31/405 20130101; A01N
25/34 20130101; A61K 31/137 20130101; B02C 17/20 20130101; A61K
31/497 20130101; A61K 9/1682 20130101; A61K 31/421 20130101; A01N
25/12 20130101; A61K 9/1623 20130101; A61K 31/4709 20130101; A61P
29/00 20180101; A61K 9/1652 20130101; A61K 31/198 20130101; A61K
31/415 20130101; A23L 33/10 20160801; A61K 9/1635 20130101; A61K
31/196 20130101; A61K 31/496 20130101; B02C 19/0056 20130101; A61K
31/5415 20130101; A01N 37/38 20130101; A61K 9/145 20130101; A61K
33/04 20130101; A01N 25/12 20130101; A01N 39/04 20130101; A01N
47/14 20130101; A01N 47/36 20130101; A01N 57/12 20130101; A01N
59/02 20130101; A01N 25/34 20130101; A01N 39/04 20130101; A01N
47/14 20130101; A01N 47/36 20130101; A01N 57/12 20130101; A01N
59/02 20130101 |
Class at
Publication: |
241/30 |
International
Class: |
B02C 19/00 20060101
B02C019/00 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 24, 2009 |
AU |
2009901747 |
Claims
1. A method for producing nanoparticle and/or microparticle
biologically active material with powder handling characteristics
superior to powders made by conventional size reduction processes,
wherein the said method comprises the steps of: dry milling a solid
biologically active material and a millable grinding matrix in a
mill comprising a plurality of milling bodies, for a time period
sufficient to produce particles of the biologically active material
dispersed in an at least partially milled grinding material.
2-47. (canceled)
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 13/265,933, filed on Mar. 9, 2012, which is a U.S. national
stage under 35 USC .sctn.371 of International Application Number
PCT/AU2010/000467, filed on 23 Apr. 2010, which claims priority to
AU Application No. 2009901747, filed on 24 Apr. 2009 and U.S.
Application No. 61/172,300, filed on 24 Apr. 2009, the entire
contents of which applications is hereby incorporated by
reference.
FIELD OF THE INVENTION
[0002] The present invention relates to methods for producing
nanoparticle and microparticle powders of a biologically active
material using dry milling processes, as well as compositions
comprising such materials, medicaments produced using said
biologically active materials in particulate form and/or
compositions, and to methods of treatment of an animal, including
man, using a therapeutically effective amount of said biologically
active materials administered by way of said medicaments.
Compositions of the present invention have unexpectedly improved
powder handling properties relative to compositions made by
conventional techniques, making them advantageous for use in
commercial applications.
BACKGROUND
[0003] Poor bioavailability is a significant problem encountered in
the development of compositions in the therapeutic, cosmetic,
agricultural and food industries, particularly those materials
containing a biologically active material that is poorly soluble in
water at physiological pH. An active material's bioavailability is
the degree to which the active material becomes available to the
target tissue in the body or other medium after systemic
administration through, for example, oral or intravenous means.
Many factors affect bioavailability, including the form of dosage
and the solubility and dissolution rate of the active material.
[0004] In therapeutic applications, poorly and slowly water-soluble
materials tend to be eliminated from the gastrointestinal tract
before being absorbed into the circulation. In addition, poorly
soluble active agents tend to be disfavored or even unsafe for
intravenous administration due to the risk of particles of agent
blocking blood flow through capillaries.
[0005] It is known that the rate of dissolution of a particulate
drug will increase with increasing surface area. One way of
increasing surface area is decreasing particle size. Consequently,
methods of making finely divided or sized drugs have been studied
with a view to controlling the size and size range of drug
particles for pharmaceutical compositions.
[0006] For example, dry milling techniques have been used to reduce
particle size and hence influence drug absorption. However, in
conventional dry milling the limit of fineness is reached generally
in the region of about 100 microns (100,000 nm), at which point
material cakes on the milling chamber and prevents any further
diminution of particle size. Alternatively, wet grinding may be
employed to reduce particle size, but flocculation restricts the
lower particle size limit to approximately 10 microns (10,000 nm).
The wet milling process, however, is prone to contamination,
thereby leading to a bias in the pharmaceutical art against wet
milling. Another alternative milling technique, commercial airjet
milling, has provided particles ranging in average size from as low
as about 1 to about 50 microns (1,000-50,000 nm).
[0007] There are several approaches currently used to formulate
poorly soluble active agents. One approach is to prepare the active
agent as a soluble salt. Where this approach cannot be employed,
alternate (usually physical) approaches are employed to improve the
solubility of the active agent. Alternate approaches generally
subject the active agent to physical conditions that change the
agent's physical and or chemical properties to improve its
solubility. These include process technologies such as
micronization, modification of crystal or polymorphic structure,
development of oil based solutions, use of co-solvents, surface
stabilizers or complexing agents, micro-emulsions, super-critical
fluid and production of solid dispersions or solutions. More than
one of these processes may be used in combination to improve
formulation of a particular therapeutic material. Many of these
approaches commonly convert a drug into an amorphous state, which
generally leads to a higher dissolution rate. However, formulation
approaches that result in the production of amorphous material are
not common in commercial formulations due to concerns relating to
stability and the potential for material to re-crystallize.
[0008] These techniques for preparing such pharmaceutical
compositions tend to be complex. By way of example, a principal
technical difficulty encountered with emulsion polymerization is
the removal of contaminants, such as unreacted monomers or
initiators (which may have undesirable levels of toxicity), at the
end of the manufacturing process.
[0009] Another method of providing reduced particle size is the
formation of pharmaceutical drug microcapsules, which techniques
include micronizing, polymerisation and co-dispersion. However,
these techniques suffer from a number of disadvantages including at
least the inability to produce sufficiently small particles such as
those obtained by milling, and the presence of co-solvents and/or
contaminants such as toxic monomers which are difficult to remove,
leading to expensive manufacturing processes.
[0010] Over the last decade, intense scientific investigation has
been carried out to improve the solubility of active agents by
converting the agents to ultra fine powders by methods such as
milling and grinding. These techniques may be used to increase the
dissolution rate of a particulate solid by increasing the overall
surface area and decreasing the mean particle size. U.S. Pat. No.
6,634,576 discloses examples of wet-milling a solid substrate, such
as a pharmaceutically active compound, to produce a "synergetic
co-mixture".
[0011] International Patent Application PCT/AU2005/001977
(Nanoparticle Composition(s) and Method for Synthesis Thereof)
describes, inter alia, a method comprising the step of contacting a
precursor compound with a co-reactant under mechanochemical
synthesis conditions wherein a solid-state chemical reaction
between the precursor compound and the co-reactant produces
therapeutically active nanoparticles dispersed in a carrier matrix.
Mechanochemical synthesis, as discussed in International Patent
Application PCT/AU2005/001977, refers to the use of mechanical
energy to activate, initiate or promote a chemical reaction, a
crystal structure transformation or a phase change in a material or
a mixture of materials, for example by agitating a reaction mixture
in the presence of a milling media to transfer mechanical energy to
the reaction mixture, and includes without limitation
"mechanochemical activation", "mechanochemical processing",
"reactive milling", and related processes.
[0012] International Patent Application PCT/AU2007/000910 (Methods
for the preparation of biologically active compounds in
nanoparticulate form) describes, inter alia, a method for dry
milling raloxifene with lactose and NaCl which produced
nanoparticulate raloxifene without significant aggregation
problems.
[0013] Critical to the successful commercialization of such
technology is the ability to easily and cheaply process the
materials into final formulations such as tablets or hard gelatin
capsules. Many of the technologies discussed above require the
particles to be produced in a liquid suspension such that expensive
and complicated further processing is needed to make common dry
formulations such as tablets.
[0014] Some technologies such as micronization do produce material
in a dry form, but the particles have inherently high cohesiveness
and high static charge. This leads to poor product flow and high
aggregation properties. The product fails to flow smoothly into
containers (such as capsules) and aggregates significantly when
poured. It also adheres significantly to process equipment and
containers, thus resulting in a significant loss of product. One
solution adopted by the prior art is to bind the material to a
carrier product or to dissolve the material in a solution to
improve product handling, but these steps add to the overall
expense of any process.
[0015] Fukami et al (Fukami et al. A nanoparticle processing in
solid state dramatically increases the cell membrane permeation of
a cholesterol lowering drug, Probucol. Mol. Pharmaceutics, accepted
Apr. 1, 2009) describe a process for manufacturing nanoparticles of
probucol which has a number of limitations. Firstly, the
nanoparticles produced by the Fukami process are sticky and
difficult to handle. Secondly, to overcome this problem the
particles had to be dispersed in water and spray coated onto a
carrier particle. The spray coating process, which uses significant
amounts of energy, is expensive and adds to the overall cost of the
manufacturing.
[0016] The present invention provides methods for overcoming the
problems identified by the prior art by providing a milling process
that produces nanoparticles or microparticles of a biologically
active material with powder handling characteristics superior to
powders made by conventional size reduction processes.
[0017] One limitation of many of the prior art processes is that
they are not suitable for commercial scale.
[0018] The present invention provides methods for overcoming the
problems identified by the prior art by providing a milling process
that produces small particles easily and economically even at high
volume commercial scale.
[0019] One example of a therapeutic area where this technology
could be applied in is the area of acute pain management. Many pain
medications such as meloxicam (marketed as Mobic.RTM. by
pharmaceutical company Boehringer Ingelheim) provides pain relief
for chronic pain, but must be taken on a daily basis to maintain an
effective therapeutic level.
[0020] Meloxicam is a poorly water soluble drug which is only
slowly absorbed by the body (Tmax is 4-5 hours), so a method such
as the present invention which provides for improved dissolution,
will likely provide much faster absorption resulting in a more
rapid onset of the therapeutic effect. Meloxicam also has a long
half life (15-20 hours) that means it only need be taken once a
day. By using a method such as the present invention, which
provides faster absorption, a drug such as meloxicam, could be
transformed from a chronic pain drug to an acute pain drug. For
meloxicam this would provide a medication that could provide
therapeutic relief for acute pain, with the advantage of sustained
pain relief over 24 hours.
[0021] Meloxicam also has sub-optimal bioavailability at 89% for an
oral capsule, compared with an IV dosage form. A component of this
sub optimal bioavailability is also likely due to the poor water
solubility of this drug. If the low solubility does contribute to
this sub optimal bioavailability, the improvement of the
dissolution of this drug with a method such as the present
invention could provide scope to produce a dosage form with a lower
active dose whilst still providing the effective therapeutic
dose.
[0022] Although the background to the present invention is
discussed in the context of improving the powder handling
characteristics of biologically active materials that are poorly or
slowly water soluble, the applications of the methods of the
present invention are not limited to such, as is evident from the
following description of the invention.
[0023] Further, although the background to the present invention is
largely discussed in the context of improving the powder handling
characteristics of therapeutic or pharmaceutical compounds, the
applications of the methods of the present invention are clearly
not limited to such. For example, as is evident from the following
description, applications of the methods of the present invention
include but are not limited to: nutraceutical and nutritional
compounds, complementary medicinal compounds, veterinary
therapeutic applications and agricultural chemical applications,
such as pesticide, fungicide or herbicide.
[0024] Furthermore an application of the current invention would be
to materials which contain a biologically active compound such as,
but not limited to a therapeutic or pharmaceutical compound, a
nutraceutical or nutrient, a complementary medicinal product such
as active components in plant or other naturally occurring
material, a veterinary therapeutic compound or an agricultural
compound such as a pesticide, fungicide or herbicide. Specific
examples would be the spice turmeric that contains the active
compound curcumin, or flax seed that contains the nutrient ALA an
omega 3 fatty acid. As these specific examples indicate this
invention could be applied to, but not limited to, a range of
natural products such as seeds, cocoa and cocoa solids, coffee,
herbs, spices, other plant materials or food materials that contain
a biologically active compound. The application of this invention
to these types of materials would enable greater availability of
the active compound in the materials when used in the relevant
application. For example where material subject to this invention
is orally ingested the active would be more bioavailable.
SUMMARY OF THE INVENTION
[0025] In one aspect, the present invention is directed to the
unexpected discovery of a dry milling process for producing small
particles of a material, wherein the powders made by the dry
milling process of the present invention have powder handling
characteristics that are superior to those of powders made by
conventional size reduction processes. In a preferred form of the
invention, the material is a biologically active material. In one
surprising aspect this can be done at commercial scale. In one
surprising aspect the particle size produced by the process is
equal to or less than 10,000 nm. In one surprising aspect the
particle size produced by the process is equal to or less than
5,000 nm. In one surprising aspect the particle size produced by
the process is equal to or less than 2000 nm. In another surprising
aspect the particle size produced by the process is equal to or
less than 1000 nm. In another surprising aspect the crystallinity
of the active material is unchanged or not substantially
changed.
[0026] Thus in a first aspect, the invention comprises a method for
producing nanoparticle and/or microparticle biologically active
material with powder handling characteristics superior to powders
made by conventional size reduction processes wherein the said
method comprises the steps of dry milling a solid biologically
active material and a millable grinding matrix in a mill comprising
a plurality of milling bodies, for a time period sufficient to
produce particles of the biologically active material dispersed in
an at least partially milled grinding material. Preferably the
biologically active material has a particle size less than 10,000
nm
[0027] Preferably, the powder handling characteristics of the
biologically active material produced by this invention are
superior to the powder handling characteristics of a biologically
active material with the same, similar or larger particle size
manufactured using a conventional process. Preferably, the
biologically active material subject to this invention has superior
product flow characteristic compared to the product flow
characteristic of a biologically active material with the same,
similar or larger particle size manufactured using a conventional
process. Preferably, the biologically active material subject to
this invention has a lower static charge compared to the static
charge of a biologically active material with the same, similar or
larger particle size manufactured using a conventional process.
Preferably, the biologically active material subject to this
invention has a lower cohesiveness profile compared to the
cohesiveness profile of a biologically active material with the
same, similar or larger particle size manufactured using a
conventional process. Preferably, the biologically active material
subject to this invention has a lower propensity for aggregation
compared to the propensity for aggregation of a biologically active
material with the same, similar or larger particle size
manufactured using a conventional process. Preferably, the
biologically active material subject to this invention has a lower
propensity for adherence to other materials compared to the
propensity for adherence of a biologically active material with the
same, similar or larger particle size manufactured using a
conventional process. Preferably, the biologically active material
subject to this invention has increased uniformity compared to a
biologically active material with the same, similar or larger
particle size manufactured using a conventional process.
Preferably, the biologically active material subject to this
invention has reduced levels of dust compared to a biologically
active material with the same, similar or larger particle size
manufactured using a conventional process. Preferably, the
biologically active material subject to this invention has improved
rheology compared to a biologically active material with the same,
similar or larger particle size manufactured using a conventional
process. Preferably, the biologically active material subject to
this invention has reduced segregation compared to a biologically
active material with the same, similar or larger particle size
manufactured using a conventional process. Preferably, the
biologically active material subject to this invention has
increased bulk density or tapped bulk density compared to a
biologically active material with the same, similar or larger
particle size manufactured using a conventional process.
Preferably, the biologically active material subject to this
invention has superior powder flow as defined by the Hausner ratio
or Carr's index compared to a biologically active material with the
same, similar or larger particle size manufactured using a
conventional process. Preferably, the biologically active material
subject to this invention has lower compressibility compared to a
biologically active material with the same, similar or larger
particle size manufactured using a conventional process.
Preferably, the biologically active material subject to this
invention has increased permiability compared to a biologically
active material with the same, similar or larger particle size
manufactured using a conventional process. Preferably, the
biologically active material subject to this invention has a higher
minium ignition energy compared to a biologically active material
with the same, similar or larger particle size manufactured using a
conventional process. Preferably, the biologically active material
subject to this invention has higher hopper flow rates compared to
a biologically active material with the same, similar or larger
particle size manufactured using a conventional process.
Preferably, the biologically active material subject to this
invention has smaller critical orifice diameter compared to a
biologically active material with the same, similar or larger
particle size manufactured using a conventional process.
Preferably, the biologically active material subject to this
invention has smaller angle of repose compared to a biologically
active material with the same, similar or larger particle size
manufactured using a conventional process. Preferably, the
biologically active material subject to this invention has smaller
dynamic angle of repose compared to a biologically active material
with the same, similar or larger particle size manufactured using a
conventional process.
[0028] In a second aspect, the invention comprises a method for
producing a blend containing nanoparticle and/or microparticles of
biologically active material with powder handling characteristics
superior to a blend made by conventional methods, wherein the said
method comprises the steps of dry milling a solid biologically
active material and a millable grinding matrix in a mill comprising
a plurality of milling bodies, for a time period sufficient to
produce particles of the biologically active material dispersed in
an at least partially milled grinding material. In one embodiment,
the blend has a median particle size, determined on a particle
volume basis, equal or greater than a size selected from the group
consisting of: 20,000 nm, 15,000 nm, 10,000 nm, 8000 nm, 6000 nm,
5000 nm, 4000 nm, 3000 nm and 2000 nm. In another embodiment, the
blend has a median particle size, determined on a particle volume
basis equal or less than 50 micron. In another embodiment, the
blend has a volume weighted mean (D4,3) equal or greater than a
size selected from the group consisting of: 40,000 nm, 30,000 nm,
20,000 nm, 15,000 nm, 10,000 nm, 8000 nm, 6000 nm and 5000 nm. In
another embodiment, the blend has a volume weighted mean (D4,3)
equal or less than 70 micron. In another embodiment, the percentage
of particles in the blend, on a particle volume basis, is selected
from the group consisting of: greater than 2 micron (%>2 micron)
is selected from the group 50%, 60%, 70%, 80%, 85%, 90% and 95%;
greater than 10 micron (%>10 micron) is selected from the group
10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90% and 95%; equal to
or less than 20 micron (%<20 micron) is selected from the group
10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% and 100%.
[0029] In another preferred embodiment, the average particle size
of the biologically active material, determined on a particle
number basis, is equal to or less than a size selected from the
group consisting of, 10,000 nm, 8000 nm, 6000 nm, 5000 nm, 4000 nm,
3000 nm, 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. Preferably, the
average particle size is equal to or greater than 25 nm.
[0030] In another preferred embodiment, the particles of the
biologically active material have a median particle size,
determined on a particle volume basis, equal or less than a size
selected from the group consisting of 20,000 nm, 15,000 nm, 10,000
nm, 8000 nm, 6000 nm, 5000 nm, 4000 nm, 3000 nm, 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. Preferably, the median particle size of the
biologically active material is equal to or greater than 25 nm.
Preferably, the percentage of particles, on a particle volume
basis, is selected from the group consisting of: 50%, 60%, 70%,
80%, 90%, 95% and 100% less than 20,000 nm (%<20,000 nm).
Preferably, the percentage of particles, on a particle volume
basis, is selected from the group consisting of: 50%, 60%, 70%,
80%, 90%, 95% and 100% less than 10,000 nm (%<10,000 nm).
Preferably, the percentage of particles, on a particle volume
basis, is selected from the group consisting of: 50%, 60%, 70%,
80%, 90%, 95% and 100% less than 5000 nm (%<5000 nm).
Preferably, the percentage of particles, on a particle volume
basis, is selected from the group consisting of: 50%, 60%, 70%,
80%, 90%, 95% and 100% less than 2000 nm (%<2000 nm).
Preferably, the percentage of particles, on a particle volume
basis, is selected from the group consisting of: 50%, 60%, 70%,
80%, 90%, 95% and 100% less than 1000 nm (%<1000 nm).
Preferably, the percentage of particles, on a particle volume
basis, is selected from the group consisting of: 0%, 10%, 20%, 30%,
40%, 50%, 60%, 70%, 80%, 90%, 95% and 100% less than 500 nm
(%<500 nm). Preferably, the percentage of particles, on a
particle volume basis, is selected from the group consisting of:
0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% and 100% less
than 300 nm (%<300 nm). Preferably, the percentage of particles,
on a particle volume basis, is selected from the group consisting
of: 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% and 100%
less than 200 nm (%<200 nm). Preferably, the Dx of the particle
size distribution, as measured on a particle volume basis, is
selected from the group consisting of less than or equal to 10,000
nm, 5000 nm, 3000 nm, 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 90.
[0031] In another preferred embodiment, the crystallinity profile
of the biologically active material is selected from the group
consisting of: at least 50% of the biologically active material is
crystalline, at least 60% of the biologically active material is
crystalline, at least 70% of the biologically active material is
crystalline, at least 75% of the biologically active material is
crystalline, at least 85% of the biologically active material is
crystalline, at least 90% of the biologically active material is
crystalline, at least 95% of the biologically active material is
crystalline and at least 98% of the biologically active material is
crystalline. More preferably, the crystallinity profile of the
biologically active material is substantially equal to the
crystallinity profile of the biologically active material before
the material was subjected to the method as described herein.
[0032] In another preferred embodiment, the amorphous content of
the biologically active material is selected from the group
consisting of: less than 50% of the biologically active material is
amorphous, less than 40% of the biologically active material is
amorphous, less than 30% of the biologically active material is
amorphous, less than 25% of the biologically active material is
amorphous, less than 15% of the biologically active material is
amorphous, less than 10% of the biologically active material is
amorphous, less than 5% of the biologically active material is
amorphous and less than 2% of the biologically active material is
amorphous. Preferably, the biologically active material has no
significant increase in amorphous content after subjecting the
material to the method as described herein.
[0033] In another preferred embodiment, the milling time period is
a range selected from the group consisting of: 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.
[0034] In another preferred embodiment, the milling medium is
selected from the group consisting of: ceramics, glasses, polymers,
ferromagnetics and metals. Preferably, the milling medium is steel
balls having a diameter selected from the group consisting of:
between 1 and 20 mm, between 2 and 15 mm and between 3 and 10 mm.
In another preferred embodiment, the milling medium is zirconium
oxide balls having a diameter selected from the group consisting
of: between 1 and 20 mm, between 2 and 15 mm and between 3 and 10
mm. Preferably, the dry milling apparatus is a mill selected from
the group consisting of: 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, roller mills and crusher mills. Preferably,
the milling medium within the milling apparatus is mechanically
agitated by 1, 2 or 3 rotating shafts. Preferably, the method is
configured to produce the biologically active material in a
continuous fashion.
[0035] Preferably, the total combined amount of biologically active
material and grinding matrix in the mill at any given time is equal
to or greater than a mass selected from the group consisting of:
200 grams, 500 grams, 1 kg, 2 kg, 5 kg, 10 kg, 20 kg, 30 kg, 50 kg,
75 kg, 100 kg, 150 kg, 200 kg. Preferably, the total combined
amount of biologically active material and grinding matrix is less
than 2000 kg.
[0036] In another preferred embodiment, the biologically active
material is selected from the group consisting of: fungicides,
pesticides, herbicides, seed treatments, cosmeceuticals, cosmetics,
complementary medicines, natural products, vitamins, nutrients,
nutraceuticals, pharmaceutical actives, biologics, amino acids,
proteins, peptides, nucleotides, nucleic acids, additives, foods
and food ingredients and analogs, homologs and first order
derivatives thereof. Preferably, the biologically active material
is selected from the group consisting of: anti-obesity drugs,
central nervous system stimulants, carotenoids, corticosteroids,
elastase inhibitors, anti-fungals, oncology therapies,
anti-emetics, analgesics, cardiovascular agents, anti-inflammatory
agents, such as NSAIDs and COX-2 inhibitors, anthelmintics,
anti-arrhythmic agents, antibiotics (including penicillins),
anticoagulants, antidepressants, antidiabetic agents,
antiepileptics, antihistamines, antihypertensive agents,
antimuscarinic agents, antimycobacterial agents, antineoplastic
agents, immunosuppressants, antithyroid agents, antiviral agents,
anxiolytics, sedatives (hypnotics and neuroleptics), astringents,
alpha-adrenergic receptor blocking agents, beta-adrenoceptor
blocking agents, blood products and substitutes, cardiac inotropic
agents, contrast media, cough suppressants (expectorants and
mucolytics), diagnostic agents, diagnostic imaging agents,
diuretics, dopaminergics (anti-parkinsonian agents), haemostatics,
immunological agents, lipid regulating agents, muscle relaxants,
parasympathomimetics, parathyroid calcitonin and biphosphonates,
prostaglandins, radio-pharmaceuticals, sex hormones (including
steroids), anti-allergic agents, stimulants and anoretics,
sympathomimetics, thyroid agents, vasodilators, and xanthines.
Preferably, the biologically active material is selected from the
group consisting of: indomethacin, diclofenac, naproxen, meloxicam,
metaxalone, cyclosporin A, progesterone and estradiol or any salt
or derivative thereof.
[0037] In another preferred embodiment, the grinding matrix is a
single material or is a mixture of two or more materials in any
proportion. Preferably, the single material or a mixture of two or
more materials is selected from the group consisting of: mannitol,
sorbitol, Isomalt, xylitol, maltitol, lactitol, erythritol,
arabitol, ribitol, glucose, fructose, mannose, galactose, anhydrous
lactose, lactose monohydrate, sucrose, maltose, trehalose,
maltodextrins, dextrin, Inulin, dextrates, polydextrose, starch,
wheat flour, corn flour, rice flour, rice starch, tapioca flour,
tapioca starch, potato flour, potato starch, other flours and
starches, milk powder, skim milk powders, other milk solids and
dreviatives, soy flour, soy meal or other soy products, cellulose,
microcystalline cellulose, microcystalline cellulose based co
blended materials, pregelatinized (or partially) starch, HPMC, CMC,
HPC, citric acid, tartaric acid, malic acid, maleic acid fumaric
acid, ascorbic acid, succinic acid, sodium citrate, sodium
tartrate, sodium malate, sodium ascorbate, potassium citrate,
potassium tartrate, potassium malate, potassium ascorbate, sodium
carbonate, potassium carbonate, magnesium carbonate, sodium
bicarbonate, potassium bicarbonate and calcium carbonate. dibasic
calcium phosphate, tribasic calcium phosphate, sodium sulfate,
sodium chloride, sodium metabisulphite, sodium thiosulfate,
ammonium chloride, Glauber's salt, ammonium carbonate, sodium
bisulfate, magnesium sulfate, potash alum, potassium chloride,
sodium hydrogen sulfate, sodium hydroxide, crystalline hydroxides,
hydrogen carbonates, ammonium chloride, methylamine hydrochloride,
ammonium bromide, silica, thermal silica, alumina, titanium
dioxide, talc, chalk, mica, kaolin, bentonite, hectorite, magnesium
trisilicate, clay based materials or aluminium silicates, sodium
lauryl sulfate, sodium stearyl sulfate, sodium cetyl sulfate,
sodium cetostearyl sulfate, sodium docusate, sodium deoxycholate,
N-lauroylsarcosine sodium salt, glyceryl monostearate, glycerol
distearate glyceryl palmitostearate, glyceryl behenate, glyceryl
caprylate, glyceryl oleate, benzalkonium chloride, CTAB, CTAC,
Cetrimide, cetylpyridinium chloride, cetylpyridinium bromide,
benzethonium chloride, PEG 40 stearate, PEG 100 stearate, poloxamer
188, 338, poloxamer 407 polyoxyl 2 stearyl ether, polyoxyl 100
stearyl ether, polyoxyl 20 stearyl ether, polyoxyl 10 stearyl
ether, polyoxyl 20 cetyl ether, polysorbate 20, polysorbate 40,
polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80,
polyoxyl 35 castor oil, polyoxyl 40 castor oil, polyoxyl 60 castor
oil, polyoxyl 100 castor oil, polyoxyl 200 castor oil, polyoxyl 40
hydrogenated castor oil, polyoxyl 60 hydrogenated castor oil,
polyoxyl 100 hydrogenated castor oil, polyoxyl 200 hydrogenated
castor oil, cetostearyl alcohol, macrogel 15 hydroxystearate,
sorbitan monopalmitate, sorbitan monostearate, sorbitan trioleate,
Sucrose Palmitate, Sucrose Stearate, Sucrose Distearate, Sucrose
laurate, Glycocholic acid, sodium Glycholate, Cholic Acid, Soidum
Cholate, Sodium Deoxycholate, Deoxycholic acid, Sodium
taurocholate, taurocholic acid, Sodium taurodeoxycholate,
taurodeoxycholic acid, soy lecithin, phosphatidylcholine,
phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol,
PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, alkyl naphthalene
sulfonate condensate/Lignosulfonate blend, Calcium Dodecylbenzene
Sulfonate, Sodium Dodecylbenzene Sulfonate, Diisopropyl
naphthaenesulphonate, erythritol distearate, Naphthalene Sulfonate
Formaldehyde Condensate, nonylphenol ethoxylate (poe-30),
Tristyrylphenol Ethoxylate, Polyoxyethylene (15) tallowalkylamines,
sodium alkyl naphthalene sulfonate, sodium alkyl naphthalene
sulfonate condensate, sodium alkylbenzene sulfonate, sodium
isopropyl naphthalene sulfonate, Sodium Methyl Naphthalene
Formaldehyde Sulfonate, sodium n-butyl naphthalene sulfonate,
tridecyl alcohol ethoxylate (poe-18), Triethanolamine isodecanol
phosphate ester, Triethanolamine tristyrylphosphate ester,
Tristyrylphenol Ethoxylate Sulfate,
Bis(2-hydroxyethyl)tallowalkylamines. Preferably, the concentration
of the single (or first) material is selected from the group
consisting of: 5-99% w/w, 10-95% w/w, 15-85% w/w, of 20-80% w/w,
25-75% w/w, 30-60% w/w, 40-50% w/w. Preferably, the concentration
of the second or subsequent material is selected from the group
consisting of: 5-50% w/w, 5-40% w/w, 5-30% w/w, of 5-20% w/w,
10-40% w/w, 10-30% w/w, 10-20% w/w, 20-40% w/w, or 20-30% w/w or if
the second or subsequent material is a surfactant or water soluble
polymer the concentration is selected from 0.1-10% w/w, 0.1-5% w/w,
0.1-2.5% w/w, of 0.1-2% w/w, 0.1-1%, 0.5-5% w/w, 0.5-3% w/w, 0.5-2%
w/w, 0.5-1.5%, 0.5-1% w/w, of 0.75-1.25% w/w, 0.75-1% and 1%
w/w.
[0038] Preferably, the grinding matrix is selected from the group
consisting of: [0039] (a) lactose monohydrate or lactose
monohydrate combined with at least one material selected from the
group consisting of: xylitol; lactose anhydrous; microcrystalline
cellulose; sucrose; glucose; sodium chloride; talc; kaolin; calcium
carbonate; malic acid; trisodium citrate dihydrate; D,L-Malic acid;
sodium pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76;
sodium n-lauroyl sacrosine; lecithin; docusate sodium;
polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl
sulfate or other alkyl sulfate surfactants with a chain length
between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and
polyethylene glycol 40 stearate, sodium lauryl sulfate and
polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG
3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate
and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl
sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407,
sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and
Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl
naphthalene sulfonate condensate/Lignosulfonate blend; Calcium
Dodecylbenzene Sulfonate (Branched); Diisopropyl
naphthalenesulphonate; erythritol distearate; linear and branched
dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde
Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters,
Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15)
tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl
naphthalene sulfonate condensate; sodium alkylbenzene sulfonate;
sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene;
Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene
sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine
isodecanol phosphate ester; Triethanolamine tristyrylphosphate
ester; Tristyrylphenol Ethoxylate Sulfate;
Bis(2-hydroxyethyl)tallowalkylamines. [0040] (b) lactose anhydrous
or lactose anhydrous combined with at least one material selected
from the group consisting of: lactose monohydrate; xylitol;
microcrystalline cellulose; sucrose; glucose; sodium chloride;
talc; kaolin; calcium carbonate; malic acid; trisodium citrate
dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl
sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin;
docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica;
sodium lauryl sulfate or other alkyl sulfate surfactants with a
chain length between C5 to C18; polyvinyl pyrrolidone; sodium
lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl
sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate
and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl
sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium
lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer
407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate
and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188,
alkyl naphthalene sulfonate condensate/Lignosulfonate blend;
Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl
naphthalenesulphonate; erythritol distearate; linear and branched
dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde
Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters,
Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15)
tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl
naphthalene sulfonate condensate; sodium alkylbenzene sulfonate;
sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene;
Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene
sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine
isodecanol phosphate ester; Triethanolamine tristyrylphosphate
ester; Tristyrylphenol Ethoxylate Sulfate;
Bis(2-hydroxyethyl)tallowalkylamines. [0041] (c) mannitol or
mannitol combined with at least one material selected from the
group consisting of: lactose monohydrate; xylitol; lactose
anhydrous; microcrystalline cellulose; sucrose; glucose; sodium
chloride; talc; kaolin; calcium carbonate; malic acid; trisodium
citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium
octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine;
lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed
silica; sodium lauryl sulfate or other alkyl sulfate surfactants
with a chain length between C5 to C18; polyvinyl pyrrolidone;
sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium
lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl
sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium
lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000,
sodium lauryl sulfate and Brij700, sodium lauryl sulfate and
Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium
lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338,
Poloxamer 188, alkyl naphthalene sulfonate
condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate
(Branched); Diisopropyl naphthalenesulphonate; erythritol
distearate; linear and branched dodecylbenzene sulfonic acids;
Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol
ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate,
Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl
naphthalene sulfonate; sodium alkyl naphthalene sulfonate
condensate; sodium alkylbenzene sulfonate; sodium isopropyl
naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde
Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl
alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate
ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol
Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines. [0042]
(d) Sucrose or sucrose combined with at least one material selected
from the group consisting of: lactose monohydrate; lactose
anhydrous; mannitol; microcrystalline cellulose; glucose; sodium
chloride; talc; kaolin; calcium carbonate; malic acid; tartaric
acid; trisodium citrate dihydrate; D,L-Malic acid; sodium pentane
sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium
n-lauroyl sacrosine; lecithin; docusate sodium;
polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl
sulfate or other alkyl sulfate surfactants with a chain length
between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and
polyethylene glycol 40 stearate, sodium lauryl sulfate and
polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG
3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate
and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl
sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407,
sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and
Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl
naphthalene sulfonate condensate/Lignosulfonate blend; Calcium
Dodecylbenzene Sulfonate (Branched); Diisopropyl
naphthalenesulphonate; erythritol distearate; linear and branched
dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde
Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters,
Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15)
tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl
naphthalene sulfonate condensate; sodium alkylbenzene sulfonate;
sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene;
Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene
sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine
isodecanol phosphate ester; Triethanolamine tristyrylphosphate
ester; Tristyrylphenol Ethoxylate Sulfate;
Bis(2-hydroxyethyl)tallowalkylamines. [0043] (e) Glucose or glucose
combined with at least one material selected from the group
consisting of: lactose monohydrate; lactose anhydrous; mannitol;
microcrystalline cellulose; sucrose; sodium chloride; talc; kaolin;
calcium carbonate; malic acid; tartaric acid; trisodium citrate
dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium octadecyl
sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin;
docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica;
sodium lauryl sulfate or other alkyl sulfate surfactants with a
chain length between C5 to C18; polyvinyl pyrrolidone; sodium
lauryl sulfate and polyethylene glycol 40 stearate, sodium lauryl
sulfate and polyethylene glycol 100 stearate, sodium lauryl sulfate
and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium lauryl
sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium
lauryl sulfate and Brij700, sodium lauryl sulfate and Poloxamer
407, sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate
and Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188,
alkyl naphthalene sulfonate condensate/Lignosulfonate blend;
Calcium Dodecylbenzene Sulfonate (Branched); Diisopropyl
naphthalenesulphonate; erythritol distearate; linear and branched
dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde
Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters,
Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15)
tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl
naphthalene sulfonate condensate; sodium alkylbenzene sulfonate;
sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene;
Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene
sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine
isodecanol phosphate ester; Triethanolamine tristyrylphosphate
ester; Tristyrylphenol Ethoxylate Sulfate;
Bis(2-hydroxyethyl)tallowalkylamines. [0044] (f) Sodium chloride or
sodium chloride combined with at least one material selected from
the group consisting of: lactose monohydrate; lactose anhydrous;
mannitol; microcrystalline cellulose; sucrose; glucose; talc;
kaolin; calcium carbonate; malic acid; tartaric acid; trisodium
citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium
octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine;
lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed
silica; sodium lauryl sulfate or other alkyl sulfate surfactants
with a chain length between C5 to C18; polyvinyl pyrrolidone;
sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium
lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl
sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium
lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000,
sodium lauryl sulfate and Brij700, sodium lauryl sulfate and
Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium
lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338,
Poloxamer 188, alkyl naphthalene sulfonate
condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate
(Branched); Diisopropyl naphthalenesulphonate; erythritol
distearate; linear and branched dodecylbenzene sulfonic acids;
Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol
ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate,
Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl
naphthalene sulfonate; sodium alkyl naphthalene sulfonate
condensate; sodium alkylbenzene sulfonate; sodium isopropyl
naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde
Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl
alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate
ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol
Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines. [0045]
(g) xylitol or xylitol combined with at least one material selected
from the group consisting of: lactose monohydrate; lactose
anhydrous; mannitol; microcrystalline cellulose; sucrose; glucose;
sodium chloride; talc; kaolin; calcium carbonate; malic acid;
tartaric acid; trisodium citrate dihydrate; D,L-Malic acid; sodium
pentane sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium
n-lauroyl sacrosine; lecithin; docusate sodium;
polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl
sulfate or other alkyl sulfate surfactants with a chain length
between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and
polyethylene glycol 40 stearate, sodium lauryl sulfate and
polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG
3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate
and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl
sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407,
sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and
Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl
naphthalene sulfonate condensate/Lignosulfonate blend; Calcium
Dodecylbenzene Sulfonate (Branched); Diisopropyl
naphthalenesulphonate; erythritol distearate; linear and branched
dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde
Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters,
Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15)
tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl
naphthalene sulfonate condensate; sodium alkylbenzene sulfonate;
sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene;
Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene
sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine
isodecanol phosphate ester; Triethanolamine tristyrylphosphate
ester; Tristyrylphenol Ethoxylate Sulfate;
Bis(2-hydroxyethyl)tallowalkylamines. [0046] (h) Tartaric acid or
tartaric acid combined with at least one material selected from the
group consisting of: lactose monohydrate; lactose anhydrous;
mannitol; microcrystalline cellulose; sucrose; glucose; sodium
chloride; talc; kaolin; calcium carbonate; malic acid; trisodium
citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium
octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine;
lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed
silica; sodium lauryl sulfate or other alkyl sulfate surfactants
with a chain length between C5 to C18; polyvinyl pyrrolidone;
sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium
lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl
sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium
lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000,
sodium lauryl sulfate and Brij700, sodium lauryl sulfate and
Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium
lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338,
Poloxamer 188, alkyl naphthalene sulfonate
condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate
(Branched); Diisopropyl naphthalenesulphonate; erythritol
distearate; linear and branched dodecylbenzene sulfonic acids;
Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol
ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate,
Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl
naphthalene sulfonate; sodium alkyl naphthalene sulfonate
condensate; sodium alkylbenzene sulfonate; sodium isopropyl
naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde
Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl
alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate
ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol
Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.
[0047] (i) microcrystalline cellulose or microcrystalline cellulose
combined with at least one material selected from the group
consisting of: lactose monohydrate; xylitol; lactose anhydrous;
mannitol; sucrose; glucose; sodium chloride; talc; kaolin; calcium
carbonate; malic acid; tartaric acid; trisodium citrate dihydrate;
D,L-Malic acid; sodium pentane sulfate; sodium octadecyl sulfate;
Brij700; Brij76; sodium n-lauroyl sacrosine; lecithin; docusate
sodium; polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium
lauryl sulfate or other alkyl sulfate surfactants with a chain
length between C5 to C18; polyvinyl pyrrolidone; sodium lauryl
sulfate and polyethylene glycol 40 stearate, sodium lauryl sulfate
and polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG
3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate
and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl
sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407,
sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and
Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl
naphthalene sulfonate condensate/Lignosulfonate blend; Calcium
Dodecylbenzene Sulfonate (Branched); Diisopropyl
naphthalenesulphonate; erythritol distearate; linear and branched
dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde
Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters,
Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15)
tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl
naphthalene sulfonate condensate; sodium alkylbenzene sulfonate;
sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene;
Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene
sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine
isodecanol phosphate ester; Triethanolamine tristyrylphosphate
ester; Tristyrylphenol Ethoxylate Sulfate;
Bis(2-hydroxyethyl)tallowalkylamines. [0048] (j) Kaolin combined
with at least one material selected from the group consisting of:
lactose monohydrate; xylitol; lactose anhydrous; mannitol;
microcrystalline cellulose; sucrose; glucose; sodium chloride;
talc; kaolin; calcium carbonate; malic acid; tartaric acid;
trisodium citrate dihydrate; D,L-Malic acid; sodium pentane
sulfate; sodium octadecyl sulfate; Brij700; Brij76; sodium
n-lauroyl sacrosine; lecithin; docusate sodium;
polyoxyl-40-stearate; Aerosil R972 fumed silica; sodium lauryl
sulfate or other alkyl sulfate surfactants with a chain length
between C5 to C18; polyvinyl pyrrolidone; sodium lauryl sulfate and
polyethylene glycol 40 stearate, sodium lauryl sulfate and
polyethylene glycol 100 stearate, sodium lauryl sulfate and PEG
3000, sodium lauryl sulphate and PEG 6000, sodium lauryl sulphate
and PEG 8000, sodium lauryl sulphate and PEG 10000, sodium lauryl
sulfate and Brij700, sodium lauryl sulfate and Poloxamer 407,
sodium lauryl sulfate and Poloxamer 338, sodium lauryl sulfate and
Poloxamer 188; Poloxamer 407, Poloxamer 338, Poloxamer 188, alkyl
naphthalene sulfonate condensate/Lignosulfonate blend; Calcium
Dodecylbenzene Sulfonate (Branched); Diisopropyl
naphthalenesulphonate; erythritol distearate; linear and branched
dodecylbenzene sulfonic acids; Naphthalene Sulfonate Formaldehyde
Condensate; nonylphenol ethoxylate, POE-30; Phosphate Esters,
Tristyrylphenol Ethoxylate, Free Acid; Polyoxyethylene (15)
tallowalkylamines; sodium alkyl naphthalene sulfonate; sodium alkyl
naphthalene sulfonate condensate; sodium alkylbenzene sulfonate;
sodium isopropyl naphthalene sulfonate; Sodium Methyl Naphthalene;
Formaldehyde Sulfonate; sodium salt of n-butyl naphthalene
sulfonate; tridecyl alcohol ethoxylate, POE-18; Triethanolamine
isodecanol phosphate ester; Triethanolamine tristyrylphosphate
ester; Tristyrylphenol Ethoxylate Sulfate;
Bis(2-hydroxyethyl)tallowalkylamines. [0049] (k) Talc combined with
at least one material selected from the group consisting of:
lactose monohydrate; xylitol; lactose anhydrous; mannitol;
microcrystalline cellulose; sucrose; glucose; sodium chloride;
kaolin; calcium carbonate; malic acid; tartaric acid; trisodium
citrate dihydrate; D,L-Malic acid; sodium pentane sulfate; sodium
octadecyl sulfate; Brij700; Brij76; sodium n-lauroyl sacrosine;
lecithin; docusate sodium; polyoxyl-40-stearate; Aerosil R972 fumed
silica; sodium lauryl sulfate or other alkyl sulfate surfactants
with a chain length between C5 to C18; polyvinyl pyrrolidone;
sodium lauryl sulfate and polyethylene glycol 40 stearate, sodium
lauryl sulfate and polyethylene glycol 100 stearate, sodium lauryl
sulfate and PEG 3000, sodium lauryl sulphate and PEG 6000, sodium
lauryl sulphate and PEG 8000, sodium lauryl sulphate and PEG 10000,
sodium lauryl sulfate and Brij700, sodium lauryl sulfate and
Poloxamer 407, sodium lauryl sulfate and Poloxamer 338, sodium
lauryl sulfate and Poloxamer 188; Poloxamer 407, Poloxamer 338,
Poloxamer 188, alkyl naphthalene sulfonate
condensate/Lignosulfonate blend; Calcium Dodecylbenzene Sulfonate
(Branched); Diisopropyl naphthalenesulphonate; erythritol
distearate; linear and branched dodecylbenzene sulfonic acids;
Naphthalene Sulfonate Formaldehyde Condensate; nonylphenol
ethoxylate, POE-30; Phosphate Esters, Tristyrylphenol Ethoxylate,
Free Acid; Polyoxyethylene (15) tallowalkylamines; sodium alkyl
naphthalene sulfonate; sodium alkyl naphthalene sulfonate
condensate; sodium alkylbenzene sulfonate; sodium isopropyl
naphthalene sulfonate; Sodium Methyl Naphthalene; Formaldehyde
Sulfonate; sodium salt of n-butyl naphthalene sulfonate; tridecyl
alcohol ethoxylate, POE-18; Triethanolamine isodecanol phosphate
ester; Triethanolamine tristyrylphosphate ester; Tristyrylphenol
Ethoxylate Sulfate; Bis(2-hydroxyethyl)tallowalkylamines.
[0050] Preferably, the grinding matrix is selected from the group
consisting of: a material considered to be Generally Regarded as
Safe (GRAS) for pharmaceutical products; a material considered
acceptable for use in an agricultural formulation; and a material
considered acceptable for use in a veterinary formulation.
[0051] In another preferred embodiment, a milling aid or
combination of milling aids is used. Preferably, the milling aid is
selected from the group consisting of: colloidal silica, a
surfactant, a polymer, a stearic acid and derivatives thereof.
Preferably, the surfactant is selected from the group consisting
of: polyoxyethylene alkyl ethers, polyoxyethylene stearates,
polyethylene glycols (PEG), poloxamers, poloxamines, sarcosine
based surfactants, polysorbates, aliphatic alcohols, alkyl and aryl
sulfates, alkyl and aryl polyether sulfonates and other sulfate
surfactants, trimethyl ammonium based surfactants, lecithin and
other phospholipids, bile salts, polyoxyethylene castor oil
derivatives, polyoxyethylene sorbitan fatty acid esters, Sorbitan
fatty acid esters, Sucrose fatty acid esters, alkyl
glucopyranosides, alkyl maltopyranosides, glycerol fatty acid
esters, Alkyl Benzene Sulphonic Acids, Alkyl Ether Carboxylic
Acids, Alkyl and aryl Phosphate esters, Alkyl and aryl Sulphate
esters, Alkyl and aryl Sulphonic acids, Alkyl Phenol Phosphates
esters, Alkyl Phenol Sulphates esters, Alkyl and Aryl Phosphates,
Alkyl Polysaccharides, Alkylamine Ethoxylates, Alkyl-Naphthalene
Sulphonates formaldehyde condensates, Sulfosuccinates,
lignosulfonates, Ceto-Oleyl Alcohol Ethoxylates, Condensed
Naphthalene Sulphonates, Dialkyl and Alkyl Naphthalene Sulphonates,
Di-alkyl Sulphosuccinates, Ethoxylated nonylphenols, Ethylene
Glycol Esters, Fatty Alcohol Alkoxylates, Hydrogenated
tallowalkylamines, Mono-alkyl Sulphosuccinamates, Nonyl Phenol
Ethoxylates, Sodium Oleyl N-methyl Taurate, Tallowalkylamines,
linear and branched dodecylbenzene sulfonic acids
[0052] Preferably, the surfactant is selected from the group
consisting of: sodium lauryl sulfate, sodium stearyl sulfate,
sodium cetyl sulfate, sodium cetostearyl sulfate, sodium docusate,
sodium deoxycholate, N-lauroylsarcosine sodium salt, glyceryl
monostearate, glycerol distearate glyceryl palmitostearate,
glyceryl behenate, glyceryl caprylate, glyceryl oleate,
benzalkonium chloride, CTAB, CTAC, Cetrimide, cetylpyridinium
chloride, cetylpyridinium bromide, benzethonium chloride, PEG 40
stearate, PEG 100 stearate, poloxamer 188, poloxamer 407, poloxamer
338, polyoxyl 2 stearyl ether, polyoxyl 100 stearyl ether, polyoxyl
20 stearyl ether, polyoxyl 10 stearyl ether, polyoxyl 20 cetyl
ether, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate
61, polysorbate 65, polysorbate 80, polyoxyl 35 castor oil,
polyoxyl 40 castor oil, polyoxyl 60 castor oil, polyoxyl 100 castor
oil, polyoxyl 200 castor oil, polyoxyl 40 hydrogenated castor oil,
polyoxyl 60 hydrogenated castor oil, polyoxyl 100 hydrogenated
castor oil, polyoxyl 200 hydrogenated castor oil, cetostearyl
alcohol, macrogel 15 hydroxystearate, sorbitan monopalmitate,
sorbitan monostearate, sorbitan trioleate, Sucrose Palmitate,
Sucrose Stearate, Sucrose Distearate, Sucrose laurate, Glycocholic
acid, sodium Glycholate, Cholic Acid, Soidum Cholate, Sodium
Deoxycholate, Deoxycholic acid, Sodium taurocholate, taurocholic
acid, Sodium taurodeoxycholate, taurodeoxycholic acid, soy
lecithin, phosphatidylcholine, phosphatidylethanolamine,
phosphatidylserine, phosphatidylinositol, PEG4000, PEG6000,
PEG8000, PEG10000, PEG20000, alkyl naphthalene sulfonate
condensate/Lignosulfonate blend, Calcium Dodecylbenzene Sulfonate,
Sodium Dodecylbenzene Sulfonate, Diisopropyl naphthaenesulphonate,
erythritol distearate, Naphthalene Sulfonate Formaldehyde
Condensate, nonylphenol ethoxylate (poe-30), Tristyrylphenol
Ethoxylate, Polyoxyethylene (15) tallowalkylamines, sodium alkyl
naphthalene sulfonate, sodium alkyl naphthalene sulfonate
condensate, sodium alkylbenzene sulfonate, sodium isopropyl
naphthalene sulfonate, Sodium Methyl Naphthalene Formaldehyde
Sulfonate, sodium n-butyl naphthalene sulfonate, tridecyl alcohol
ethoxylate (poe-18), Triethanolamine isodecanol phosphate ester,
Triethanolamine tristyrylphosphate ester, Tristyrylphenol
Ethoxylate Sulfate, Bis(2-hydroxyethyl)tallowalkylamines.
[0053] Preferably the polymer is selected from the list of:
polyvinylpyrrolidones (PVP), polyvinylalcohol, Acrylic acid based
polymers and copolymers of acrylic acid
[0054] Preferably, the milling aid has a concentration selected
from the group consisting of: 0.1-10% w/w, 0.1-5% w/w, 0.1-2.5%
w/w, of 0.1-2% w/w, 0.1-1%, 0.5-5% w/w, 0.5-3% w/w, 0.5-2% w/w,
0.5-1.5%, 0.5-1% w/w, of 0.75-1.25% w/w, 0.75-1% and 1% w/w.
[0055] In another preferred embodiment of the invention, a
facilitating agent is used or combination of facilitating agents is
used. Preferably, the facilitating agent is selected from the group
consisting of: surfactants, polymers, binding agents, filling
agents, lubricating agents, sweeteners, flavouring agents,
preservatives, buffers, wetting agents, disintegrants, effervescent
agents, agents that may form part of a medicament, including a
solid dosage form or a dry powder inhalation formulation and other
material required for specific drug delivery. Preferably, the
facilitating agent is added during dry milling. Preferably, the
facilitating agent is added to the dry milling at a time selected
from the group consisting of: with 1-5% of the total milling time
remaining, with 1-10% of the total milling time remaining, with
1-20% of the total milling time remaining, with 1-30% of the total
milling time remaining, with 2-5% of the total milling time
remaining, with 2-10% of the total milling time remaining, with
5-20% of the total milling time remaining and with 5-20% of the
total milling time remaining. Preferably, the disintegrant is
selected from the group consisting of: crosslinked PVP, cross
linked carmellose and sodium starch glycolate. Preferably, the
facilitating agent is added to the milled biologically active
material and grinding matrix and further processed in a
mechanofusion process. Mechanofusion milling causes mechanical
energy to be applied to powders or mixtures of particles in the
micrometre and nanometre range.
[0056] The reasons for including facilitating agents include, but
are not limited to providing better dispersibility, control of
agglomeration, the release or retention of the active particles
from the delivery matrix. Examples of facilitating agents include,
but are not limited to crosslinked PVP (crospovidone), cross linked
carmellose (croscarmellose), sodium starch glycolate, Povidone
(PVP), Povidone K12, Povidone K17, Povidone K25, Povidone K29/32
and Povidone K30, stearic acid, magnesium stearate, calcium
stearate, sodium stearyl fumarate, sodium stearyl lactylate, zinc
stearate, sodium stearate or lithium stearate, other solid state
fatty acids such as oleic acid, lauric acid, palmitic acid, erucic
acid, behenic acid, or derivatives (such as esters and salts),
Amino acids such as leucine, isoleucine, lysine, valine,
methionine, phenylalanine, aspartame or acesulfame K. In a
preferred aspect of manufacturing this formulation the facilitating
agent is added to the milled mixture of biologically active
material and co-grinding matrix and further processed in another
milling device such as Mechnofusion, Cyclomixing, or impact milling
such as ball milling, jet milling, or milling using a high pressure
homogeniser, or combinations thereof. In a highly preferred aspect
the facilitating agent is added to the milling of the mixture of
biologically active material and co-grinding matrix as some time
before the end of the milling process.
[0057] In another preferred embodiment, indomethacin is milled with
lactose monohydrate and alkyl sulfates. Preferably indomethacin is
milled with lactose monohydrate and sodium lauryl sulfate.
Preferably indomethacin is milled with lactose monohydrate and
sodium octadecyl sulfate. In another preferred embodiment,
Indomethacin is milled with lactose monohydrate, alkyl sulfates and
another surfactant or polymers. Preferably indomethacin is milled
with lactose monohydrate, sodium lauryl sulfate and polyether
sulfates. Preferably indomethacin is milled with lactose
monohydrate, sodium lauryl sulfate and polyethylene glycol 40
stearate. Preferably indomethacin is milled with lactose
monohydrate, sodium lauryl sulfate and polyethylene glycol 100
stearate. Preferably indomethacin is milled with lactose
monohydrate, sodium lauryl sulfate and a poloxamer. Preferably
indomethacin is milled with lactose monohydrate, sodium lauryl
sulfate and poloxamer 407. Preferably indomethacin is milled with
lactose monohydrate, sodium lauryl sulfate and poloxamer 338.
Preferably indomethacin is milled with lactose monohydrate, sodium
lauryl sulfate and poloxamer 188. Preferably indomethacin is milled
with lactose monohydrate, sodium lauryl sulfate and a solid
polyethylene glycol. Preferably indomethacin is milled with lactose
monohydrate, sodium lauryl sulfate and polyethylene glycol 6000.
Preferably indomethacin is milled with lactose monohydrate, sodium
lauryl sulfate and polyethylene glycol 3000. In another preferred
embodiment, Indomethacin is milled with lactose monohydrate and
polyether sulfates. Preferably indomethacin is milled with lactose
monohydrate and polyethylene glycol 40 stearate. Preferably
indomethacin is milled with lactose monohydrate and polyethylene
glycol 100 stearate In another preferred embodiment indomethacin is
milled with lactose monohydrate and polyvinyl-pyrrolidine.
Preferably indomethacin is milled with lactose monohydrate and
polyvinyl-pyrrolidone with an approximate molecular weight of
30,000-40,000. In another preferred embodiment, indomethacin is
milled with lactose monohydrate and alkyl sulfonates. Preferably
indomethacin is milled with lactose monohydrate and docusate
sodium. In another preferred embodiment, indomethacin is milled
with lactose monohydrate and a surfactant. Preferably indomethacin
is milled with lactose monohydrate and lecithin. Preferably
indomethacin is milled with lactose monohydrate and sodium
n-lauroyl sarcosine. Preferably indomethacin is milled with lactose
monohydrate and polyoxyethylene alkyl ether surfactants. Preferably
indomethacin is milled with lactose monohydrate and PEG 6000. In
another preferred formulation indomethacin is milled with lactose
monohydrate and silica. Preferably indomethacin is milled with
lactose monohydrate and Aerosil R972 fumed silica. In another
preferred embodiment, indomethacin is milled with with lactose
monohydrate, tartaric acid and sodium lauryl sulfate. In another
preferred embodiment, indomethacin is milled with lactose
monohydrate, sodium bicarbonate and sodium lauryl sulfate. In
another preferred embodiment, indomethacin is milled with lactose
monohydrate, potassium bicarbonate and sodium lauryl sulfate. In
another preferred embodiment, indomethacin is milled with mannitol
and alkyl sulfates. Preferably indomethacin is milled with mannitol
and sodium lauryl sulfate. Preferably indomethacin is milled with
mannitol and sodium octadecyl sulfate. In another preferred
embodiment, Indomethacin is milled with mannitol, alkyl sulfates
and another surfactant or polymers. Preferably indomethacin is
milled with mannitol, sodium lauryl sulfate and polyether sulfates.
Preferably indomethacin is milled with mannitol, sodium lauryl
sulfate and polyethylene glycol 40 stearate. Preferably
indomethacin is milled with mannitol, sodium lauryl sulfate and
polyethylene glycol 100 stearate. Preferably indomethacin is milled
with mannitol, sodium lauryl sulfate and a poloxamer. Preferably
indomethacin is milled with mannitol, sodium lauryl sulfate and
poloxamer 407. Preferably indomethacin is milled with mannitol,
sodium lauryl sulfate and poloxamer 338. Preferably indomethacin is
milled with mannitol, sodium lauryl sulfate and poloxamer 188.
Preferably indomethacin is milled with mannitol, sodium lauryl
sulfate and a solid polyethylene glycol. Preferably indomethacin is
milled with mannitol, sodium lauryl sulfate and polyethylene glycol
6000. Preferably indomethacin is milled with mannitol, sodium
lauryl sulfate and polyethylene glycol 3000. In another preferred
embodiment, Indomethacin is milled with mannitol and polyether
sulfates. Preferably indomethacin is milled with mannitol and
polyethylene glycol 40 stearate. Preferably indomethacin is milled
with mannitol and polyethylene glycol 100 stearate In another
preferred embodiment indomethacin is milled with mannitol and
polyvinyl-pyrrolidine. Preferably indomethacin is milled with
mannitol and polyvinyl-pyrrolidone with an approximate molecular
weight of 30,000-40,000. In another preferred embodiment,
indomethacin is milled with mannitol and alkyl sulfonates.
Preferably indomethacin is milled with mannitol and docusate
sodium. In another preferred embodiment, indomethacin is milled
with mannitol and a surfactant. Preferably indomethacin is milled
with mannitol and lecithin. Preferably indomethacin is milled with
mannitol and sodium n-lauroyl sarcosine. Preferably indomethacin is
milled with mannitol and polyoxyethylene alkyl ether surfactants.
Preferably indomethacin is milled with mannitol and PEG 6000. In
another preferred formulation indomethacin is milled with mannitol
and silica. Preferably indomethacin is milled with mannitol and
Aerosil R972 fumed silica. In another preferred embodiment,
indomethacin is milled with mannitol, tartaric acid and sodium
lauryl sulfate. In another preferred embodiment, indomethacin is
milled with mannitol, sodium bicarbonate and sodium lauryl sulfate.
In another preferred embodiment, indomethacin is milled with
mannitol, potassium bicarbonate and sodium lauryl sulfate.
[0058] In another preferred embodiment, naproxen is milled with
lactose monohydrate and alkyl sulfates. Preferably naproxen is
milled with lactose monohydrate and sodium lauryl sulfate.
Preferably naproxen is milled with lactose monohydrate and sodium
octadecyl sulfate. In another preferred embodiment, Naproxen is
milled with lactose monohydrate, alkyl sulfates and another
surfactant or polymers. Preferably naproxen is milled with lactose
monohydrate, sodium lauryl sulfate and polyether sulfates.
Preferably naproxen is milled with lactose monohydrate, sodium
lauryl sulfate and polyethylene glycol 40 stearate. Preferably
naproxen is milled with lactose monohydrate, sodium lauryl sulfate
and polyethylene glycol 100 stearate. Preferably naproxen is milled
with lactose monohydrate, sodium lauryl sulfate and a poloxamer.
Preferably naproxen is milled with lactose monohydrate, sodium
lauryl sulfate and poloxamer 407. Preferably naproxen is milled
with lactose monohydrate, sodium lauryl sulfate and poloxamer 338.
Preferably naproxen is milled with lactose monohydrate, sodium
lauryl sulfate and poloxamer 188. Preferably naproxen is milled
with lactose monohydrate, sodium lauryl sulfate and a solid
polyethylene glycol. Preferably naproxen is milled with lactose
monohydrate, sodium lauryl sulfate and polyethylene glycol 6000.
Preferably naproxen is milled with lactose monohydrate, sodium
lauryl sulfate and polyethylene glycol 3000. In another preferred
embodiment, Naproxen is milled with lactose monohydrate and
polyether sulfates. Preferably naproxen is milled with lactose
monohydrate and polyethylene glycol 40 stearate. Preferably
naproxen is milled with lactose monohydrate and polyethylene glycol
100 stearate In another preferred embodiment naproxen is milled
with lactose monohydrate and polyvinyl-pyrrolidine. Preferably
naproxen is milled with lactose monohydrate and
polyvinyl-pyrrolidone with an approximate molecular weight of
30,000-40,000. In another preferred embodiment, naproxen is milled
with lactose monohydrate and alkyl sulfonates. Preferably naproxen
is milled with lactose monohydrate and docusate sodium. In another
preferred embodiment, naproxen is milled with lactose monohydrate
and a surfactant. Preferably naproxen is milled with lactose
monohydrate and lecithin. Preferably naproxen is milled with
lactose monohydrate and sodium n-lauroyl sarcosine. Preferably
naproxen is milled with lactose monohydrate and polyoxyethylene
alkyl ether surfactants. Preferably naproxen is milled with lactose
monohydrate and PEG 6000. In another preferred formulation naproxen
is milled with lactose monohydrate and silica. Preferably naproxen
is milled with lactose monohydrate and Aerosil R972 fumed silica.
In another preferred embodiment, naproxen is milled with lactose
monohydrate, tartaric acid and sodium lauryl sulfate. In another
preferred embodiment, naproxen is milled with lactose monohydrate,
sodium bicarbonate and sodium lauryl sulfate. In another preferred
embodiment, naproxen is milled with lactose monohydrate, potassium
bicarbonate and sodium lauryl sulfate. In another preferred
embodiment, naproxen is milled with mannitol and alkyl sulfates.
Preferably naproxen is milled with mannitol and sodium lauryl
sulfate. Preferably naproxen is milled with mannitol and sodium
octadecyl sulfate. In another preferred embodiment, Naproxen is
milled with mannitol, alkyl sulfates and another surfactant or
polymers. Preferably naproxen is milled with mannitol, sodium
lauryl sulfate and polyether sulfates. Preferably naproxen is
milled with mannitol, sodium lauryl sulfate and polyethylene glycol
40 stearate. Preferably naproxen is milled with mannitol, sodium
lauryl sulfate and polyethylene glycol 100 stearate. Preferably
naproxen is milled with mannitol, sodium lauryl sulfate and a
poloxamer. Preferably naproxen is milled with mannitol, sodium
lauryl sulfate and poloxamer 407. Preferably naproxen is milled
with mannitol, sodium lauryl sulfate and poloxamer 338. Preferably
naproxen is milled with mannitol, sodium lauryl sulfate and
poloxamer 188. Preferably naproxen is milled with mannitol, sodium
lauryl sulfate and a solid polyethylene glycol. Preferably naproxen
is milled with mannitol, sodium lauryl sulfate and polyethylene
glycol 6000. Preferably naproxen is milled with mannitol, sodium
lauryl sulfate and polyethylene glycol 3000. In another preferred
embodiment, Naproxen is milled with mannitol and polyether
sulfates. Preferably naproxen is milled with mannitol and
polyethylene glycol 40 stearate. Preferably naproxen is milled with
mannitol and polyethylene glycol 100 stearate In another preferred
embodiment naproxen is milled with mannitol and
polyvinyl-pyrrolidine. Preferably naproxen is milled with mannitol
and polyvinyl-pyrrolidone with an approximate molecular weight of
30,000-40,000. In another preferred embodiment, naproxen is milled
with mannitol and alkyl sulfonates. Preferably naproxen is milled
with mannitol and docusate sodium. In another preferred embodiment,
naproxen is milled with mannitol and a surfactant. Preferably
naproxen is milled with mannitol and lecithin. Preferably naproxen
is milled with mannitol and sodium n-lauroyl sarcosine. Preferably
naproxen is milled with mannitol and polyoxyethylene alkyl ether
surfactants. Preferably naproxen is milled with mannitol and PEG
6000. In another preferred formulation naproxen is milled with
mannitol and silica. Preferably naproxen is milled with mannitol
and Aerosil R972 fumed silica. In another preferred embodiment,
naproxen is milled with mannitol, tartaric acid and sodium lauryl
sulfate. In another preferred embodiment, naproxen is milled with
mannitol, sodium bicarbonate and sodium lauryl sulfate. In another
preferred embodiment, naproxen is milled with mannitol, potassium
bicarbonate and sodium lauryl sulfate.
[0059] In another preferred embodiment, diclofenac is milled with
lactose monohydrate and alkyl sulfates. Preferably diclofenac is
milled with lactose monohydrate and sodium lauryl sulfate.
Preferably diclofenac is milled with lactose monohydrate and sodium
octadecyl sulfate. In another preferred embodiment, Diclofenac is
milled with lactose monohydrate, alkyl sulfates and another
surfactant or polymers. Preferably diclofenac is milled with
lactose monohydrate, sodium lauryl sulfate and polyether sulfates.
Preferably diclofenac is milled with lactose monohydrate, sodium
lauryl sulfate and polyethylene glycol 40 stearate. Preferably
diclofenac is milled with lactose monohydrate, sodium lauryl
sulfate and polyethylene glycol 100 stearate. Preferably diclofenac
is milled with lactose monohydrate, sodium lauryl sulfate and a
poloxamer. Preferably diclofenac is milled with lactose
monohydrate, sodium lauryl sulfate and poloxamer 407. Preferably
diclofenac is milled with lactose monohydrate, sodium lauryl
sulfate and poloxamer 338. Preferably diclofenac is milled with
lactose monohydrate, sodium lauryl sulfate and poloxamer 188.
Preferably diclofenac is milled with lactose monohydrate, sodium
lauryl sulfate and a solid polyethylene glycol. Preferably
diclofenac is milled with lactose monohydrate, sodium lauryl
sulfate and polyethylene glycol 6000. Preferably diclofenac is
milled with lactose monohydrate, sodium lauryl sulfate and
polyethylene glycol 3000. In another preferred embodiment,
Diclofenac is milled with lactose monohydrate and polyether
sulfates. Preferably diclofenac is milled with lactose monohydrate
and polyethylene glycol 40 stearate. Preferably diclofenac is
milled with lactose monohydrate and polyethylene glycol 100
stearate In another preferred embodiment diclofenac is milled with
lactose monohydrate and polyvinyl-pyrrolidine. Preferably
diclofenac is milled with lactose monohydrate and
polyvinyl-pyrrolidone with an approximate molecular weight of
30,000-40,000. In another preferred embodiment, diclofenac is
milled with lactose monohydrate and alkyl sulfonates. Preferably
diclofenac is milled with lactose monohydrate and docusate sodium.
In another preferred embodiment, diclofenac is milled with lactose
monohydrate and a surfactant. Preferably diclofenac is milled with
lactose monohydrate and lecithin. Preferably diclofenac is milled
with lactose monohydrate and sodium n-lauroyl sarcosine. Preferably
diclofenac is milled with lactose monohydrate and polyoxyethylene
alkyl ether surfactants. Preferably diclofenac is milled with
lactose monohydrate and PEG 6000. In another preferred formulation
diclofenac is milled with lactose monohydrate and silica.
Preferably diclofenac is milled with lactose monohydrate and
Aerosil R972 fumed silica. In another preferred embodiment,
diclofenac is milled with lactose monohydrate, tartaric acid and
sodium lauryl sulfate. In another preferred embodiment, diclofenac
is milled with lactose monohydrate, sodium bicarbonate and sodium
lauryl sulfate. In another preferred embodiment, diclofenac is
milled with lactose monohydrate, potassium bicarbonate and sodium
lauryl sulfate. In another preferred embodiment, diclofenac is
milled with mannitol and alkyl sulfates. Preferably diclofenac is
milled with mannitol and sodium lauryl sulfate. Preferably
diclofenac is milled with mannitol and sodium octadecyl sulfate. In
another preferred embodiment, Diclofenac is milled with mannitol,
alkyl sulfates and another surfactant or polymers. Preferably
diclofenac is milled with mannitol, sodium lauryl sulfate and
polyether sulfates. Preferably diclofenac is milled with mannitol,
sodium lauryl sulfate and polyethylene glycol 40 stearate.
Preferably diclofenac is milled with mannitol, sodium lauryl
sulfate and polyethylene glycol 100 stearate. Preferably diclofenac
is milled with mannitol, sodium lauryl sulfate and a poloxamer.
Preferably diclofenac is milled with mannitol, sodium lauryl
sulfate and poloxamer 407. Preferably diclofenac is milled with
mannitol, sodium lauryl sulfate and poloxamer 338. Preferably
diclofenac is milled with mannitol, sodium lauryl sulfate and
poloxamer 188. Preferably diclofenac is milled with mannitol,
sodium lauryl sulfate and a solid polyethylene glycol. Preferably
diclofenac is milled with mannitol, sodium lauryl sulfate and
polyethylene glycol 6000. Preferably diclofenac is milled with
mannitol, sodium lauryl sulfate and polyethylene glycol 3000. In
another preferred embodiment, Diclofenac is milled with mannitol
and polyether sulfates. Preferably diclofenac is milled with
mannitol and polyethylene glycol 40 stearate Preferably diclofenac
is milled with mannitol and polyethylene glycol 100 stearate In
another preferred embodiment diclofenac is milled with mannitol and
polyvinyl-pyrrolidine. Preferably diclofenac is milled with
mannitol and polyvinyl-pyrrolidone with an approximate molecular
weight of 30,000-40,000. In another preferred embodiment,
diclofenac is milled with mannitol and alkyl sulfonates. Preferably
diclofenac is milled with mannitol and docusate sodium. In another
preferred embodiment, diclofenac is milled with mannitol and a
surfactant. Preferably diclofenac is milled with mannitol and
lecithin. Preferably diclofenac is milled with mannitol and sodium
n-lauroyl sarcosine. Preferably diclofenac is milled with mannitol
and polyoxyethylene alkyl ether surfactants. Preferably diclofenac
is milled with mannitol and PEG 6000. In another preferred
formulation diclofenac is milled with mannitol and silica.
Preferably diclofenac is milled with mannitol and Aerosil R972
fumed silica. In another preferred embodiment, diclofenac is milled
with mannitol, tartaric acid and sodium lauryl sulfate. In another
preferred embodiment, diclofenac is milled with mannitol, sodium
bicarbonate and sodium lauryl sulfate. In another preferred
embodiment, diclofenac is milled with mannitol, potassium
bicarbonate and sodium lauryl sulfate.
[0060] In another preferred embodiment, meloxicam is milled with
lactose monohydrate and alkyl sulfates. Preferably meloxicam is
milled with lactose monohydrate and sodium lauryl sulfate.
Preferably meloxicam is milled with lactose monohydrate and sodium
octadecyl sulfate. In another preferred embodiment, Meloxicam is
milled with lactose monohydrate, alkyl sulfates and another
surfactant or polymers. Preferably meloxicam is milled with lactose
monohydrate, sodium lauryl sulfate and polyether sulfates.
Preferably meloxicam is milled with lactose monohydrate, sodium
lauryl sulfate and polyethylene glycol 40 stearate. Preferably
meloxicam is milled with lactose monohydrate, sodium lauryl sulfate
and polyethylene glycol 100 stearate. Preferably meloxicam is
milled with lactose monohydrate, sodium lauryl sulfate and a
poloxamer. Preferably meloxicam is milled with lactose monohydrate,
sodium lauryl sulfate and poloxamer 407. Preferably meloxicam is
milled with lactose monohydrate, sodium lauryl sulfate and
poloxamer 338. Preferably meloxicam is milled with lactose
monohydrate, sodium lauryl sulfate and poloxamer 188. Preferably
meloxicam is milled with lactose monohydrate, sodium lauryl sulfate
and a solidpolyethylene glycol. Preferably meloxicam is milled with
lactose monohydrate, sodium lauryl sulfate and polyethylene glycol
6000. Preferably meloxicam is milled with lactose monohydrate,
sodium lauryl sulfate and polyethylene glycol 3000. In another
preferred embodiment, Meloxicam is milled with lactose monohydrate
and polyether sulfates. Preferably meloxicam is milled with lactose
monohydrate and polyethylene glycol 40 stearate. Preferably
meloxicam is milled with lactose monohydrate and polyethylene
glycol 100 stearate In another preferred embodiment meloxicam is
milled with lactose monohydrate and polyvinyl-pyrrolidine.
Preferably meloxicam is milled with lactose monohydrate and
polyvinyl-pyrrolidone with an approximate molecular weight of
30,000-40,000. In another preferred embodiment, meloxicam is milled
with lactose monohydrate and alkyl sulfonates. Preferably meloxicam
is milled with lactose monohydrate and docusate sodium. In another
preferred embodiment, meloxicam is milled with lactose monohydrate
and a surfactant. Preferably meloxicam is milled with lactose
monohydrate and lecithin. Preferably meloxicam is milled with
lactose monohydrate and sodium n-lauroyl sarcosine. Preferably
meloxicam is milled with lactose monohydrate and polyoxyethylene
alkyl ether surfactants. Preferably meloxicam is milled with
lactose monohydrate and PEG 6000. In another preferred formulation
meloxicam is milled with lactose monohydrate and silica. Preferably
meloxicam is milled with lactose monohydrate and Aerosil R972 fumed
silica. In another preferred embodiment, meloxicam is milled with
lactose monohydrate, tartaric acid and sodium lauryl sulfate. In
another preferred embodiment, meloxicam is milled with lactose
monohydrate, sodium bicarbonate and sodium lauryl sulfate. In
another preferred embodiment, meloxicam is milled with lactose
monohydrate, potassium bicarbonate and sodium lauryl sulfate. In
another preferred embodiment, meloxicam is milled with mannitol and
alkyl sulfates. Preferably meloxicam is milled with mannitol and
sodium lauryl sulfate. Preferably meloxicam is milled with mannitol
and sodium octadecyl sulfate. In another preferred embodiment,
Meloxicam is milled with mannitol, alkyl sulfates and another
surfactant or polymers. Preferably meloxicam is milled with
mannitol, sodium lauryl sulfate and polyether sulfates. Preferably
meloxicam is milled with mannitol, sodium lauryl sulfate and
polyethylene glycol 40 stearate. Preferably meloxicam is milled
with mannitol, sodium lauryl sulfate and polyethylene glycol 100
stearate. Preferably meloxicam is milled with mannitol, sodium
lauryl sulfate and a poloxamer. Preferably meloxicam is milled with
mannitol, sodium lauryl sulfate and poloxamer 407. Preferably
meloxicam is milled with mannitol, sodium lauryl sulfate and
poloxamer 338. Preferably meloxicam is milled with mannitol, sodium
lauryl sulfate and poloxamer 188. Preferably meloxicam is milled
with mannitol, sodium lauryl sulfate and a solid polyethylene
glycol. Preferably meloxicam is milled with mannitol, sodium lauryl
sulfate and polyethylene glycol 6000. Preferably meloxicam is
milled with mannitol, sodium lauryl sulfate and polyethylene glycol
3000. In another preferred embodiment, Meloxicam is milled with
mannitol and polyether sulfates. Preferably meloxicam is milled
with mannitol and polyethylene glycol 40 stearate. Preferably
meloxicam is milled with mannitol and polyethylene glycol 100
stearate In another preferred embodiment meloxicam is milled with
mannitol and polyvinyl-pyrrolidine. Preferably meloxicam is milled
with mannitol and polyvinyl-pyrrolidone with an approximate
molecular weight of 30,000-40,000. In another preferred embodiment,
meloxicam is milled with mannitol and alkyl sulfonates. Preferably
meloxicam is milled with mannitol and docusate sodium. In another
preferred embodiment, meloxicam is milled with mannitol and a
surfactant. Preferably meloxicam is milled with mannitol and
lecithin. Preferably meloxicam is milled with mannitol and sodium
n-lauroyl sarcosine. Preferably meloxicam is milled with mannitol
and polyoxyethylene alkyl ether surfactants. Preferably meloxicam
is milled with mannitol and PEG 6000. In another preferred
formulation meloxicam is milled with mannitol and silica.
Preferably meloxicam is milled with mannitol and Aerosil R972 fumed
silica. In another preferred embodiment, meloxicam is milled with
mannitol, tartaric acid and sodium lauryl sulfate. In another
preferred embodiment, meloxicam is milled with mannitol, sodium
bicarbonate and sodium lauryl sulfate. In another preferred
embodiment, meloxicam is milled with mannitol, potassium
bicarbonate and sodium lauryl sulfate.
[0061] In another preferred embodiment, metaxalone is milled with
lactose monohydrate and alkyl sulfates. Preferably metaxalone is
milled with lactose monohydrate and sodium lauryl sulfate.
Preferably metaxalone is milled with lactose monohydrate and sodium
octadecyl sulfate. In another preferred embodiment, Metaxalone is
milled with lactose monohydrate, alkyl sulfates and another
surfactant or polymers. Preferably metaxalone is milled with
lactose monohydrate, sodium lauryl sulfate and polyether sulfates.
Preferably metaxalone is milled with lactose monohydrate, sodium
lauryl sulfate and polyethylene glycol 40 stearate. Preferably
metaxalone is milled with lactose monohydrate, sodium lauryl
sulfate and polyethylene glycol 100 stearate. Preferably metaxalone
is milled with lactose monohydrate, sodium lauryl sulfate and a
poloxamer. Preferably metaxalone is milled with lactose
monohydrate, sodium lauryl sulfate and poloxamer 407. Preferably
metaxalone is milled with lactose monohydrate, sodium lauryl
sulfate and poloxamer 338. Preferably metaxalone is milled with
lactose monohydrate, sodium lauryl sulfate and poloxamer 188.
Preferably metaxalone is milled with lactose monohydrate, sodium
lauryl sulfate and a solid polyethylene glycol. Preferably
metaxalone is milled with lactose monohydrate, sodium lauryl
sulfate and polyethylene glycol 6000. Preferably metaxalone is
milled with lactose monohydrate, sodium lauryl sulfate and
polyethylene glycol 3000. In another preferred embodiment,
Metaxalone is milled with lactose monohydrate and polyether
sulfates. Preferably metaxalone is milled with lactose monohydrate
and polyethylene glycol 40 stearate. Preferably metaxalone is
milled with lactose monohydrate and polyethylene glycol 100
stearate. In another preferred embodiment metaxalone is milled with
lactose monohydrate and polyvinyl-pyrrolidine. Preferably
metaxalone is milled with lactose monohydrate and
polyvinyl-pyrrolidone with an approximate molecular weight of
30,000-40,000. In another preferred embodiment, metaxalone is
milled with lactose monohydrate and alkyl sulfonates. Preferably
metaxalone is milled with lactose monohydrate and docusate sodium.
In another preferred embodiment, metaxalone is milled with lactose
monohydrate and a surfactant. Preferably metaxalone is milled with
lactose monohydrate and lecithin. Preferably metaxalone is milled
with lactose monohydrate and sodium n-lauroyl sarcosine. Preferably
metaxalone is milled with lactose monohydrate and polyoxyethylene
alkyl ether surfactants. Preferably metaxalone is milled with
lactose monohydrate and PEG 6000. In another preferred formulation
metaxalone is milled with lactose monohydrate and silica.
Preferably metaxalone is milled with lactose monohydrate and
Aerosil R972 fumed silica. In another preferred embodiment,
metaxalone is milled with lactose monohydrate, tartaric acid and
sodium lauryl sulfate. In another preferred embodiment, metaxalone
is milled with lactose monohydrate, sodium bicarbonate and sodium
lauryl sulfate. In another preferred embodiment, metaxalone is
milled with lactose monohydrate, sodium bicarbonate, poloxamer 407
and sodium lauryl sulfate. In another preferred embodiment,
metaxalone is milled with lactose monohydrate, potassium
bicarbonate and sodium lauryl sulfate. In another preferred
embodiment, metaxalone is milled with lactose monohydrate,
potassium bicarbonate, poloxamer 407 and sodium lauryl sulfate.
[0062] In another preferred embodiment, metaxalone is milled with
mannitol and alkyl sulfates. Preferably metaxalone is milled with
mannitol and sodium lauryl sulfate. Preferably metaxalone is milled
with mannitol and sodium octadecyl sulfate. In another preferred
embodiment, Metaxalone is milled with mannitol, alkyl sulfates and
another surfactant or polymers. Preferably metaxalone is milled
with mannitol, sodium lauryl sulfate and polyether sulfates.
Preferably metaxalone is milled with mannitol, sodium lauryl
sulfate and polyethylene glycol 40 stearate. Preferably metaxalone
is milled with mannitol, sodium lauryl sulfate and polyethylene
glycol 100 stearate. Preferably metaxalone is milled with mannitol,
sodium lauryl sulfate and a poloxamer. Preferably metaxalone is
milled with mannitol, sodium lauryl sulfate and poloxamer 407.
Preferably metaxalone is milled with mannitol, sodium lauryl
sulfate and poloxamer 338. Preferably metaxalone is milled with
mannitol, sodium lauryl sulfate and poloxamer 188. Preferably
metaxalone is milled with mannitol, sodium lauryl sulfate and a
solid polyethylene glycol. Preferably metaxalone is milled with
mannitol, sodium lauryl sulfate and polyethylene glycol 6000.
Preferably metaxalone is milled with mannitol, sodium lauryl
sulfate and polyethylene glycol 3000. In another preferred
embodiment, Metaxalone is milled with mannitol and polyether
sulfates. Preferably metaxalone is milled with mannitol and
polyethylene glycol 40 stearate Preferably metaxalone is milled
with mannitol and polyethylene glycol 100 stearate In another
preferred embodiment metaxalone is milled with mannitol and
polyvinyl-pyrrolidine. Preferably metaxalone is milled with
mannitol and polyvinyl-pyrrolidone with an approximate molecular
weight of 30,000-40,000. In another preferred embodiment,
metaxalone is milled with mannitol and alkyl sulfonates. Preferably
metaxalone is milled with mannitol and docusate sodium. In another
preferred embodiment, metaxalone is milled with mannitol and a
surfactant. Preferably metaxalone is milled with mannitol and
lecithin. Preferably metaxalone is milled with mannitol and sodium
n-lauroyl sarcosine. Preferably metaxalone is milled with mannitol
and polyoxyethylene alkyl ether surfactants. Preferably metaxalone
is milled with mannitol and PEG 6000. In another preferred
formulation metaxalone is milled with mannitol and silica.
Preferably metaxalone is milled with mannitol and Aerosil R972
fumed silica. In another preferred embodiment, metaxalone is milled
with mannitol, tartaric acid and sodium lauryl sulfate. In another
preferred embodiment, metaxalone is milled with mannitol, sodium
bicarbonate and sodium lauryl sulfate. In another preferred
embodiment, metaxalone is milled with mannitol, potassium
bicarbonate and sodium lauryl sulfate. In another preferred
embodiment, metaxalone is milled with mannitol, sodium bicarbonate
and sodium lauryl sulphate and Polxamer 407. In another preferred
embodiment, metaxalone is milled with mannitol, potassium
bicarbonate and sodium lauryl sulphate and Polxamer 407.
[0063] In another preferred embodiment, the particles have a volume
weighted mean (D4,3), determined on a particle volume basis, equal
or greater than a size selected from the group consisting of: 5000
nm, 10,000 nm, 15,000 nm, 20,000 nm, 25,000 nm, 35,000 nm, 40,000
nm and 50,000 nm.
[0064] In another preferred embodiment, the powder handling
characteristic is a characteristic selected from the group
consisting of: flow property, static charge, aggregation property,
content uniformity, content uniformity after segregation, adherence
property, cohesivity, dust level, powder rheology, segregation
property, bulk density, tapped bulk density, powder flow, angle of
repose, compressibility, permeability and minimum ignition
property. In another preferred embodiment, the content uniformity
and/or content uniformity after segregation of the biologically
active material throughout the blend varies from the average
content by a percentage less than or equal to a percentage selected
from the group consisting of: 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 another preferred
embodiment the static property is selected from the group
consisting of: less than 10 nC/g, less than 5 nC/g, less than 3
nC/g, less than 2 nC/g, less than 1.5 nC/g, less than 1.25 nC/g,
less than 1 nC/g less than 0.75 nC/g, less than 0.5 nC/g, less than
0.25 nC/g and less than 0.1 nC/g. In another preferred embodiment,
the biologically active material and/or blend containing
biologically active material has a lower propensity for adherence
to other materials such as but not limited to stainless steel,
glass, plastic, polyethylene and polypropylene compared to the
propensity for adherence of a biologically active material and/or
blend with the same, similar or larger biologically active material
particle size manufactured using a conventional process.
[0065] In a third aspect the invention comprises a biologically
active material produced by the method described herein and
composition comprising the biologically active material as
described herein. Preferably, the average particle size of the
biologically active material, determined on a particle number
basis, is equal to or less than a size selected from the group
10,000 nm, 8000 nm, 6000 nm, 5000 nm, 4000 nm, 3000 nm, 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. Preferably, the average particle
size of the biologically active material is equal to or greater
than 25 nm. Preferably, the particles of the biologically active
material have a median particle size, determined on a particle
volume basis, equal or less than a size selected from the group
consisting of: 20,000 nm, 15,000 nm, 10,000 nm, 8000 nm, 6000 nm,
5000 nm, 4000 nm, 3000 nm, 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.
Preferably, the median particle size of the biologically active
material is equal to or greater than 25 nm. Preferably, the
percentage of particles, on a particle volume basis, is selected
from the group consisting of: 50%, 60%, 70%, 80%, 90%, 95% and 100%
less than 20,000 nm (%<20,000 nm). Preferably, the percentage of
particles, on a particle volume basis, is selected from the group
consisting of: 50%, 60%, 70%, 80%, 90%, 95% and 100% less than
10,000 nm (%<10,000 nm). Preferably, the percentage of
particles, on a particle volume basis, is selected from the group
consisting of: 50%, 60%, 70%, 80%, 90%, 95% and 100% less than 5000
nm (%<5000 nm). Preferably, the percentage of particles, on a
particle volume basis, is selected from the group consisting of:
50%, 60%, 70%, 80%, 90%, 95% and 100% less than 2000 nm (%<2000
nm). Preferably, the percentage of particles, on a particle volume
basis, is selected from the group consisting of: 50%, 60%, 70%,
80%, 90%, 95% and 100% less than 1000 nm (%<1000 nm).
Preferably, the percentage of particles, on a particle volume
basis, is selected from the group consisting of: 0%, 10%, 20%, 30%,
40%, 50%, 60%, 70%, 80%, 90%, 95% and 100% less than 500 nm
(%<500 nm). Preferably, the percentage of particles, on a
particle volume basis, is selected from the group consisting of:
0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% and 100% less
than 300 nm (%<300 nm). Preferably, the percentage of particles,
on a particle volume basis, is selected from the group consisting
of: 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% and 100%
less than 200 nm (%<200 nm). Preferably, the Dx of the particle
size distribution, as measured on a particle volume basis, is
selected from the group consisting of less than or equal to 10,000
nm, 5000 nm, 3000 nm, 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 90 Preferably, the
crystallinity profile of the biologically active material is
selected from the group consisting of: at least 50% of the
biologically active material is crystalline, at least 60% of the
biologically active material is crystalline, at least 70% of the
biologically active material is crystalline, at least 75% of the
biologically active material is crystalline, at least 85% of the
biologically active material is crystalline, at least 90% of the
biologically active material is crystalline, at least 95% of the
biologically active material is crystalline and at least 98% of the
biologically active material is crystalline. Preferably, the
crystallinity profile of the biologically active material is
substantially equal to the crystallinity profile of the
biologically active material before the material was subject to the
method described herein. Preferably, the amorphous content of the
biologically active material is selected from the group consisting
of: less than 50% of the biologically active material is amorphous,
less than 40% of the biologically active material is amorphous,
less than 30% of the biologically active material is amorphous,
less than 25% of the biologically active material is amorphous,
less than 15% of the biologically active material is amorphous,
less than 10% of the biologically active material is amorphous,
less than 5% of the biologically active material is amorphous and
less than 2% of the biologically active material is amorphous.
Preferably, the biologically active material has had no significant
increase in amorphous content following subjecting the material to
the method as described herein. Preferably, the biologically active
material comprised in the composition is selected from the group
consisting of: fungicides, pesticides, herbicides, seed treatments,
cosmeceuticals, cosmetics, complementary medicines, natural
products, vitamins, nutrients, nutraceuticals, pharmaceutical
actives, biologics, amino acids, proteins, peptides, nucleotides,
nucleic acids, additives, foods and food ingredients and analogs,
homologs and first order derivatives thereof. Preferably, where the
biologically active material is a naturally occurring material or a
derivate of a naturally occuring material, such as but not limited
to, seeds, cocoa and cocoa solids, coffee, herbs, spices, other
plant materials, minerals, animal products, shells and other
skeletal material, the particles of the biologically active
material have a median particle size, determined on a particle
volume basis, equal or less than a size selected from the group
20,000, 15,000 nm, 10,000 nm, 8000 nm, 6000 nm, 5000 nm, 4000 nm
and 3000 nm. Preferably, the biologically active material is
selected from the group consisting of: anti-obesity drugs, central
nervous system stimulants, carotenoids, corticosteroids, elastase
inhibitors, anti-fungals, oncology therapies, anti-emetics,
analgesics, cardiovascular agents, anti-inflammatory agents, such
as NSAIDs and COX-2 inhibitors, anthelmintics, anti-arrhythmic
agents, antibiotics (including penicillins), anticoagulants,
antidepressants, antidiabetic agents, antiepileptics,
antihistamines, antihypertensive agents, antimuscarinic agents,
antimycobacterial agents, antineoplastic agents,
immunosuppressants, antithyroid agents, antiviral agents,
anxiolytics, sedatives (hypnotics and neuroleptics), astringents,
alpha-adrenergic receptor blocking agents, beta-adrenoceptor
blocking agents, blood products and substitutes, cardiac inotropic
agents, contrast media, cough suppressants (expectorants and
mucolytics), diagnostic agents, diagnostic imaging agents,
diuretics, dopaminergics (anti-parkinsonian agents), haemostatics,
immunological agents, lipid regulating agents, muscle relaxants,
parasympathomimetics, parathyroid calcitonin and biphosphonates,
prostaglandins, radio-pharmaceuticals, sex hormones (including
steroids), anti-allergic agents, stimulants and anoretics,
sympathomimetics, thyroid agents, vasodilators, and xanthenes.
Preferably, the biologically active material is selected from the
group consisting of: indomethacin, diclofenac, naproxen, meloxicam,
metaxalone, cyclosporin A, progesterone celecoxib, cilostazol,
ciprofloxacin, 2,4-dichlorophenoxyacetic acid, anthraquinone,
creatine monohydrate, glyphosate, halusulfuron, mancozeb,
metsulfuron, salbutamol, sulphur, tribenuran and estradiol or any
salt or derivative thereof.
[0066] Preferably, the biologically active material is selected
from the group consisting of: anti-obesity drugs, central nervous
system stimulants, carotenoids, corticosteroids, elastase
inhibitors, anti-fungals, oncology therapies, anti-emetics,
analgesics, cardiovascular agents, anti-inflammatory agents, such
as NSAIDs and COX-2 inhibitors, anthelmintics, anti-arrhythmic
agents, antibiotics (including penicillins), anticoagulants,
antidepressants, antidiabetic agents, antiepileptics. Preferably
cosmeceuticals, cosmetics, complementary medicines, natural
products, vitamins, nutrients and nutraceuticals are selected from
the group consisting of: Glycolic acids, Lactic acids, Carrageenan,
Almonds, Mahogany wood, Andrographis Paniculata, Aniseed, Anthemis
nobilis (chamomile), Apricot kernel, leaves of bearberry, leaves of
cranberry, leaves of blueberry, leaves of pear trees,
beta-carotene, black elderberry, black raspberry, black walnut
shell, blackberry, bladderwrack, bletilla striata, borage seed,
boysenberry, brazil nut, burdock root, butcher's broom extract,
calamine, calcium gluconate, calendula, carnosic acid, Cantella
asiatica, charcoal, chaste tree fruit, Chicory root extract,
chitosan, choline, cichorium intybus, clematis vitalba, coffea
Arabica, coumarin, crithmum maritimum, curcumin, coffee, cocoa,
cocoa powder, cocoa nibs, cocoa mass, cocoa liquor, cocoa products,
dogwood, Echinacea, echium lycopsis, anise, atragalus, bilberry,
bitter orange, black cohosh, cat's claw, chamomile, chasteberry,
cranberry, dandelion, Echinacea, ephedra, European elder Epilobium
angustifolium, horse chestnut, cloves, evening primrose, fennel
seed, fenugreek, feverfew, flaxseed, fumaria officinalis, garlic,
geranium, ginger, ginkgo, ginseng, goldenseal, grape seed, green
tea, guava, hawthorn, hayflower, hazelnut, helichrysum, hoodia,
horseradish, mulbe italicum, hibiscus, hierochloe odorata, hops,
horse chestnut, ilex paraguariensis, indian gooseberry, irish moss,
juniper berry, kudzu root, lady's thistle, lavender, lemongrass,
lentius edodes, licorice, longifolene, loquat, lotus seed, luffa
cylindrica, lupine, maroinberry, marjoram, meadowsweet, milk vetch
root, mimosa tenuiflora, mistletoe, mulberry, noni, kelp, oatmeal,
oregano, papaya, parsley, peony root, pomegranate, pongamia glabra
seed, pongamia pinnata, quinoa seed, red raspberry, rose hip,
rosemary, sage, saw palmetto, soy bean, szechuan peppercorn,
tephrosia purpurea, terminalia catappa, terminalia sericea, thunder
god vine, thyme, turmeric, valeriana officinalis, walnuts, white
tea leaf, yam, witch hazel, wormwood, yarrow, valerian, yohimbe,
mangosteen, sour sob, goji berry, spirulina and durian skin.
[0067] In one preferred embodiment, the invention comprises
compositions comprising the biologically active ingredient together
with a grinding matrix, a mixture of grinding matrix materials,
milling aids, mixtures of milling aids, facilitating agents and/or
mixtures of facilitating agents as described herein, in
concentrations and ratios as described herein under the methods of
the invention.
[0068] In a fourth aspect the invention comprises a pharmaceutical
composition comprising a biologically active material produced by
the method described herein and compositions described herein.
Preferably, the invention comprises pharmaceutical compositions
comprising the biologically active ingredient together with a
grinding matrix, a mixture of grinding matrix materials, milling
aids, mixtures of milling aids, facilitating agents and/or mixtures
of facilitating agents as described herein, in concentrations and
ratios as described herein under the methods of the invention.
Preferably, the average particle size of the biologically active
material, determined on a particle number basis, is equal to or
less than a size selected from the group 10,000 nm, 8000 nm, 6000
nm, 5000 nm, 4000 nm, 3000 nm, 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. Preferably, the average particle size of the biologically
active material is equal to or greater than 25 nm. Preferably, the
particles of the biologically active material have a median
particle size, determined on a particle volume basis, equal or less
than a size selected from the group 20,000 nm, 15,000 nm, 10,000
nm, 8000 nm, 6000 nm, 5000 nm, 4000 nm, 3000 nm, 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. Preferably, the median particle size of the
biologically active material is equal to or greater than 25 nm.
Preferably, the percentage of particles, on a particle volume
basis, is selected from the group consisting of: 50%, 60%, 70%,
80%, 90%, 95% and 100% less than 20,000 nm (%<20,000 nm).
Preferably, the percentage of particles, on a particle volume
basis, is selected from the group consisting of: 50%, 60%, 70%,
80%, 90%, 95% and 100% less than 10,000 nm (%<10,000 nm).
Preferably, the percentage of particles, on a particle volume
basis, is selected from the group consisting of: 50%, 60%, 70%,
80%, 90%, 95% and 100% less than 5000 nm (%<5000 nm).
Preferably, the percentage of particles, on a particle volume
basis, is selected from the group consisting of: 50%, 60%, 70%,
80%, 90%, 95% and 100% less than 2000 nm (%<2000 nm).
Preferably, the percentage of particles, on a particle volume
basis, is selected from the group consisting of: 50%, 60%, 70%,
80%, 90%, 95% and 100% less than 1000 nm (%<1000 nm).
Preferably, the percentage of particles, on a particle volume
basis, is selected from the group consisting of: 0%, 10%, 20%, 30%,
40%, 50%, 60%, 70%, 80%, 90%, 95% and 100% less than 500 nm
(%<500 nm). Preferably, the percentage of particles, on a
particle volume basis, is selected from the group consisting of:
0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% and 100% less
than 300 nm (%<300 nm). Preferably, the percentage of particles,
on a particle volume basis, is selected from the group consisting
of: 0%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% and 100%
less than 200 nm (%<200 nm). Preferably, the Dx of the particle
size distribution, as measured on a particle volume basis, is
selected from the group consisting of less than or equal to 10,000
nm, 5000 nm, 3000 nm, 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 90. Preferably, the
biologically active material is selected from the group consisting
of: fungicides, pesticides, herbicides, seed treatments,
cosmeceuticals, cosmetics, complementary medicines, natural
products, vitamins, nutrients, nutraceuticals, pharmaceutical
actives, biologics, amino acids, proteins, peptides, nucleotides,
nucleic acids, additives, foods and food ingredients and analogs,
homologs and first order derivatives thereof. Preferably, the
biologically active material is selected from the group consisting
of: anti-obesity drugs, central nervous system stimulants,
carotenoids, corticosteroids, elastase inhibitors, anti-fungals,
oncology therapies, anti-emetics, analgesics, cardiovascular
agents, anti-inflammatory agents, such as NSAIDs and COX-2
inhibitors, anthelmintics, anti-arrhythmic agents, antibiotics
(including penicillins), anticoagulants, antidepressants,
antidiabetic agents, antiepileptics, antihistamines,
antihypertensive agents, antimuscarinic agents, antimycobacterial
agents, antineoplastic agents, immunosuppressants, antithyroid
agents, antiviral agents, anxiolytics, sedatives (hypnotics and
neuroleptics), astringents, alpha-adrenergic receptor blocking
agents, beta-adrenoceptor blocking agents, blood products and
substitutes, cardiac inotropic agents, contrast media, cough
suppressants (expectorants and mucolytics), diagnostic agents,
diagnostic imaging agents, diuretics, dopaminergics
(anti-parkinsonian agents), haemostatics, immunological agents,
lipid regulating agents, muscle relaxants, parasympathomimetics,
parathyroid calcitonin and biphosphonates, prostaglandins,
radio-pharmaceuticals, sex hormones (including steroids),
anti-allergic agents, stimulants and anoretics, sympathomimetics,
thyroid agents, vasodilators, and xanthenes. Preferably, the
biologically active material is selected from the group consisting
of: indomethacin, diclofenac, naproxen, meloxicam, metaxalone,
cyclosporin A, progesterone celecoxib, cilostazol, ciprofloxacin,
2,4-dichlorophenoxyacetic acid, anthraquinone, creatine
monohydrate, glyphosate, halusulfuron, mancozeb, metsulfuron,
salbutamol, sulphur, tribenuran and estradiol or any salt or
derivative thereof. In a preferred embodiment, the composition is
adapted for delivery by inhalation, intranasal delivery and/or
pulmonary delivery.
[0069] In a fifth aspect the invention comprises a method of
treating a human in need of such treatment comprising the step of
administering to the human an effective amount of a pharmaceutical
composition as described herein. In a preferred embodiment, the
composition is administered by inhalation, intranasal delivery
and/or pulmonary delivery.
[0070] In a sixth aspect, the invention comprises the use of a
pharmaceutical composition as described herein in the manufacture
of a medicament for the treatment of a human in need of such
treatment. In a preferred embodiment, the medicament is adapted to
be administered by inhalation, intranasal delivery and/or pulmonary
delivery.
[0071] In a seventh aspect the invention comprises a method for
manufacturing a pharmaceutical composition as described herein
comprising the step of combining a therapeutically effective amount
of a biologically active material prepared by a method described
herein or a composition as described herein, together with a
pharmaceutically acceptable carrier to produce a pharmaceutically
acceptable dosage form.
[0072] In a eighth aspect the invention comprises a method for
manufacturing a veterinary product comprising the step of combining
a therapeutically effective amount of the biologically active
material prepared by a method as described herein or a composition
as described herein, together with an acceptable excipient to
produce a dosage form acceptable for veterinary use.
[0073] In an ninth aspect the invention comprises a method for
manufacturing an agricultural product comprising the step of
combining an effective amount of the biologically active material
prepared by a method described herein or a composition as described
herein. Preferably the agricultural product is combined with an
acceptable excipient to produce a formulation such as, but not
limited to a water dispersible granule, wettable granule, dry
flowable granule or soluble granule that is used to prepare a
solution for use in agricultural applications. Preferably, the
product is selected from the group consisting of: herbicides,
pesticides, seed treatments, herbicide safeners, plant growth
regulators and fungicides. The methods of the invention can be used
to increase the dissolution of the biologically active material
particles in water or other solvents, resulting in better, faster
or more complete preparation and mixing. This will result in a more
consistent product performance such as better weed, disease and
pest control and other practical benefits such as faster machinery,
tank and sprayer cleanout, less rinsate, and a reduced impact on
the environment.
[0074] In another aspect of the method of invention, the invention
provides methods to produce powders that have active particles with
a high surface area. Such powders would provide better performance
in areas such as seed treatment where dry powders are applied to
seeds as fungicides, herbicide safeners, plant growth regulators
and other treatments. The higher surface area would provide more
activity per mass of active used.
[0075] In another preferred aspect, actives such as pesticides,
fungicides and seed treatments subject to the method of invention
are formulated to produce suspensions of the actives when added to
water or other solvents. As these suspensions will have particles
of very small size and high surface area they will possess at least
three highly desirable traits. The first is that small particles
with high surface area will adhere better to surfaces such as leafs
and other foliage that the suspension is applied to. This will
result in better rain fastness and a longer period of activity. The
second aspect is that smaller particles with a higher surface area
deliver superior coverage per unit mass of active applied. For
example, if 100 particles are needed on a leaf and if the particle
diameter is reduced to one third of the former diameter by the
methods of this invention, then the dosage can be reduced to about
11% of the former dosage, resulting in lower cost, less residue on
harvested crops, and mitigation of environmental impact. In the
third aspect the smaller particles will deliver better
bioavailability. With many low solubility actives, such as
fungicides and pesticides the particles that adhere to plant
material slowly dissolve over days and weeks providing continued
protection from disease and pests. With this method of invention
able to deliver better bioavailability in many circumstances it
will be possible to reduce the amount of active that needs to be
applied. As with the second aspect such an outcome would lower
costs, minimize residues and mitigate environmental impact. In a
highly preferred aspect of the invention the powder produced in the
milling process would be subject to a process such as wet or dry
granulation that makes the powder free flowing and low in dust
content yet easily dispersible once in water or other solvent.
[0076] Preferably the biologically active material is a herbicide,
pesticide, seed treatment, herbicide safener, plant growth
regulator or fungicide selected from the group consisting of:
2-phenylphenol, 8-hydroxyquinoline sulfate, acibenzolar, allyl
alcohol, azoxystrobin, basic benomyl, benzalkonium chloride,
biphenyl, blasticidin-S, Bordeaux mixture, Boscalid, Burgundy
mixture, butylamine, Cadendazim, calcium polysulfide, Captan,
carbamate fungicides, carbendazim, carvone, chloropicrin,
chlorothalonil, ciclopirox, clotrimazole, conazole fungicides,
Copper hydroxide, copper oxychloride, copper sulfate, copper(II)
carbonate, copper(II) sulfate, cresol, cryprodinil, cuprous oxide,
cycloheximide, Cymoxanil, DBCP, dehydroacetic acid, dicarboximide
fungicides, difenoconazole, dimethomorph, diphenylamine,
disulfiram, ethoxyquin, famoxadone, fenamidone, Fludioxonil,
formaldehyde, fosetyl, Fosetyl-aluminium, furfural, griseofulvin,
hexachlorobenzene, hexachlorobutadiene, hexachlorophene,
hexaconazole, imazalil, Imidacloprid, iodomethane, Iprodione, Lime
sulfur, mancozeb, mercuric chloride, mercuric oxide, mercurous
chloride, Metalaxyl, metam, methyl bromide, methyl isothiocyanate,
metiram, natamycin, nystatin, organotin fungicides, oxythioquinox,
pencycuron, pentachlorophenol, phenylmercury acetate, potassium
thiocyanate, procymidone, propiconazole, propineb, pyraclostrobin,
pyrazole fungicides, pyridine fungicides, pyrimethanil, pyrimidine
fungicides, pyrrole fungicides, quinoline fungicides, quinone
fungicides, sodium azide, streptomycin, sulfur, Tebucanazole,
thiabendazole, thiomersal, tolnaftate, Tolylfluanid, triadimersol,
tributyltin oxide, Trifloxystrobin, triflumuron, Undecylenic acid,
urea fungicides, vinclozolin, Ziram,
3-dihydro-3-methyl-1,3-thiazol-2-ylidene-xylidene, 4-D esters, 4-DB
esters, 4-parathion methyl, Acetamiprid, aclonifen, acrinathrin,
alachlor, allethrin, alpha-cypermethrin, Aluminium phosphide,
amitraz, anilophos, azaconazole, azinphos-ethyl, azinphos-methyl,
benalaxyl, benfluralin, benfuracarb, benfuresate, bensulide,
benzoximate, benzoylprop-ethyl, betacyfluthrin, beta-cypermethrin,
bifenox, bifenthrin, binapacryl, bioallethrin, bioallethrin S,
bioresmethrin, biteranol, Brodifacoum, bromophos, bromopropylate,
bromoxynil, bromoxynil esters, bupirimate, buprofezin,
butacarboxim, butachlor, butamifos, butoxycarboxin, butralin,
butylate, calcium sulfate, cambda-cyhalothrin, carbetamide,
carboxin, chlordimeform, chlorfenvinphos, chlorflurazuron,
chlormephos, chlornitrofen, chlorobenzilate, chlorophoxim,
chloropropylate, chlorpropham, Chlorpyrifos, chlorpyrifos-methyl,
cinmethylin, clethodim, clomazone, clopyralid esters, CMPP esters,
cyanophos, cycloate, cycloprothrin, cycloxydim, cyfluthrin,
cyhalothrin, cypermethrin, cyphenothrin, cyproconazole,
deltamethrin, demeton-S-methyl, desmedipham, dichlorprop esters,
dichlorvos, diclofop-methyldiethatyl, dicofol, difenoconazole,
dimethachlor, dimethomoph, diniconazole, dinitramine, dinobuton,
dioxabenzafos, dioxacarb, disulfoton, ditalimfos, dodemorph,
dodine, edifenphos, emamectin, empenthrin, endosulfan,
EPNethiofencarb, epoxyconazole, esfenvalerate, ethalfluralin,
ethofumesate, ethoprophos, ethoxyethyl, etofenprox, etridiazole,
etrimphos, Famoxadone, fenamiphos, fenarimol, fenazaquin,
fenitrothion, fenobucarb, fenoxapropethyl, fenoxycarb,
fenpropathrin, fenpropidin, fenpropimorph, fenthiocarb, fenthion,
fenvalerate, fluazifop, fluazifop-P, fluchloralin, flucythrinate,
flufenoxim, flufenoxuron, flumetralin, fluorodifen, fluoroglycofen
ethyl, fluoroxypyr esters, flurecol butyl, flurochloralin,
flusilazole, formothion, gamma-HCH, haloxyfop, haloxyfop-methyl,
hexaflumuron, hydroprene, imibenconazole, indoxacarb, ioxynil
esters, isofenphos, isoprocarb, isopropalin, isoxathion, malathion,
maneb, MCPA esters, mecoprop-P esters, mephospholan, Metaldehyde,
methidathion, Methomyl, methoprene, methoxychlor, metolachlor,
mevinphos, monalide, myclobutanil, N-2, napropamide, nitrofen,
nuarimol, oxadiazon, oxycarboxin, oxyfluorfen, penconazole,
pendimethalin, permethrin, phenisopham, phenmedipham, phenothrin,
phenthoate, phosalone, phosfolan, phosmet, picloram esters,
pirimicarb, pirimiphos-ethyl, pirimiphos-methyl, pretilachlor,
prochloraz, profenofos, profluralin, promecarb, propachlor,
propanil, propaphos, propaquizafop, propargite, propetamphos,
pymetrozine, pyrachlofos, pyridate, pyrifenox, quinalphos,
quizalofop-P, resmethrin, Spinetoram J, Spinetoram L, Spinosad A,
Spinosad B, tau-fluvalinate, tebuconazole, Tebufenozide,
tefluthrin, temephos, terbufos, tetrachlorinphos, tetraconazole,
tetradifon, tetramethrin, Thiamethoxam, tolclofos-methyl,
tralomethrin, triadimefon, triadimenol, triazophos, triclopyr
esters, tridemorph, tridiphane, triflumizole, trifluralin,
xylylcarb, 3-dihydro-3-methyl-1,3-thiazol-2-ylidene-xylidene, 4-D
esters, 4-DB esters, 4-parathion methyl, Acetamiprid, acetochlor,
aclonifen, acrinathrin, alachlor, allethrin, alpha-cypermethrin,
Aluminium phosphide, amitraz, anilophos, azaconazole,
azinphos-ethyl, azinphos-methyl, benalaxyl, benfluralin,
benfuracarb, benfuresate, bensulide, benzoximate,
benzoylprop-ethyl, betacyfluthrin, beta-cypermethrin, bifenox,
bifenthrin, binapacryl, bioallethrin, bioallethrin S,
bioresmethrin, biteranol, Brodifacoum, bromophos, bromopropylate,
bromoxynil, bromoxynil esters, bupirimate, buprofezin,
Butacarboxim, butachlor, butamifos, butoxycarboxin, butralin,
butylate, calcium sulfate, cambda-cyhalothrin, carbetamide,
carboxin, chlordimeform, chlorfenvinphos, chlorflurazuron,
chlormephos, chlornitrofen, chlorobenzilate, chlorophoxim,
chloropropylate, chlorpropham, Chlorpyrifos, chlorpyrifos-methyl,
cinmethylin, clethodim, clomazone, clopyralid esters, CMPP esters,
cyanophos, cycloate, cycloprothrin, cycloxydim, cyfluthrin,
cyhalothrin, cypermethrin, cyphenothrin, cyproconazole,
deltamethrin, demeton-S-methyl, desmedipham, dichlorprop esters,
dichlorvos, diclofop-methyldiethatyl, dicofol, dimethachlor,
dimethomoph, diniconazole, dinitramine, dinobuton, dioxabenzafos,
dioxacarb, disulfoton, ditalimfos, dodemorph, dodine, edifenphos,
emamectin, empenthrin, endosulfan, EPNethiofencarb, epoxyconazole,
esfenvalerate, ethalfluralin, ethofumesate, ethoprophos,
ethoxyethyl, ethoxyquin, etofenprox, etridiazole, etrimphos,
fenamiphos, fenarimol, fenazaquin, fenitrothion, fenobucarb,
fenoxapropethyl, fenoxycarb, fenpropathrin, fenpropidin,
fenpropimorph, fenthiocarb, fenthion, fenvalerate, fluazifop,
fluazifop-P, fluchloralin, flucythrinate, flufenoxim, flufenoxuron,
flumetralin, fluorodifen, fluoroglycofen ethyl, fluoroxypyr esters,
flurecol butyl, flurochloralin, flusilazole, formothion, gamma-HCH,
haloxyfop, haloxyfop-methyl, hexaflumuron, hydroprene,
imibenconazole, indoxacarb, ioxynil esters, isofenphos, isoprocarb,
isopropalin, isoxathion, malathion, maneb, MCPA esters, mecoprop-P
esters, mephospholan, Metaldehyde, methidathion, Methomyl,
methoprene, methoxychlor, mevinphos, monalide, myclobutanil,
myclobutanil, N-2, napropamide, nitrofen, nuarimol, oxadiazon,
oxycarboxin, oxyfluorfen, penconazole, permethrin, phenisopham,
phenmedipham, phenothrin, phenthoate, phosalone, phosfolan,
phosmet, picloram esters, pirimicarb, pirimiphos-ethyl,
pirimiphos-methyl, pretilachlor, prochloraz, profenofos,
profluralin, promecarb, propachlor, propanil, propaphos,
propaquizafop, propargite, propetamphos, pymetrozine, pyridate,
pyrifenox, quinalphos, quizalofop-P, resmethrin, Spinetoram J,
Spinetoram L, Spinosad A, Spinosad B, tau-fluvalinate,
Tebufenozide, tefluthrin, temephos, terbufos, tetrachlorinphos,
tetraconazole, tetradifon, tetramethrin, Thiamethoxam,
tolclofos-methyl, tralomethrin, triadimenol, triazophos, triclopyr
esters, tridemorph, tridiphane, triflumizole, trifluralin,
xylylcarb and any combination thereof.
[0077] In an ninth aspect the invention comprises a method for
manufacturing of a pharmaceutical formulation comprising the step
of combining an effective amount of the biologically active
material prepared by a method described herein together with
acceptable excipients to produce a formulation that can deliver a
therapeutically effective amount of active to the pulmonary or
nasal area. Such a formulation could be, but is not limited to a
dry powder formulation for oral inhalation to the lungs or a
formulation for nasal inhalation. Preferably the method for
manufacturing such a formulation uses lactose, mannitol, sucrose,
sorbitol, xylitol or other sugars or polyols as the co-grinding
matrix together with surfactant such as, but not limited to
lecithin, DPPC (dipalmitoyl phosphatidylcholine), PG
(phosphatidylglycerol), dipalmitoyl phosphatidyl ethanolamine
(DPPE), dipalmitoyl phosphatidylinositol (DPPI) or other
phospholipid. The particle size of the material produced by the
invention disclosed herein results in the materials being readily
aerosolized and suitable for methods of delivery to a subject in
need thereof, including pulmonary and nasal delivery methods. In a
tenth aspect, the invention comprises a method for the manufacture
of a composition for industrical application, such as, but not
limited to paints, polymers or other functional coatings,
comprising the step of combining an effective amount of the active
material prepared by a method described herein together with an
acceptable excipient to produce a composition that can deliver an
active particle such as, but not limited to, a fungicide in solid
form to a coating resistant to attack by biologically agents such
as, but not limited to, a fungus or algae. Because small particles
provide a greater surface coverage of active agent per unit mass
than conventionally sized particles less active is required in the
composition. The particles generated by the invention would also
provide ascetic advantages as they can be incorporated into a
coating formulation without the appearance of having particulate
matter in the coating. Preferably the method for manufacturing such
a composition uses titanium dioxide, silica, sodium chloride or
other inorganic salts with a suitable surfactant or polymer.
Preferably the active is a fungicide selected from the list of
herbicides, pesticides, seed treatments, herbicide safeners, plant
growth regulators and fungicides described above.
[0078] In an eleventh aspect, the invention comprises a method for
the manufacture of a radio-contrast agent for use in radiological
examinations. A common example of such an agent would be barium
sulfate which is commonly used in examinations of the
gastrointestinal tract. Agents such as barium sulfate are
essentially insoluble in water and function as discrete particles
dispersed throughout the area of examination. Formulations of
active material used as radio-contrast agents as prepared by a
method described herein with other acceptable excipients could be
used to provide enhanced sensitivity and lower toxicity due to the
increased surface area provided by the particle size reduction. The
increased surface area will provide greater coverage of the tissue
to be measured providing better contrast. If the agent has toxic
side effects greater contrast per unit mass would allow for less
contrast agent to be used compared with conventional formulations.
Another advantage of preparing such a formulation using the method
described herein is the ability to administer that contrast agent
as a dry formulation thus eliminating undesirable aspects of
drinking a liquid formulation.
[0079] In a twelfth aspect, the invention comprises a method for
the manufacture of a composition for use as a food product where
the production of small particles has other functional advantages
in addition to a faster dissolution of the active. One example
would be where the active agent is cocoa or cocoa derived solids.
When cocoa is processed in the manufacture of chocolate the
particle size must be reduced below a size threshold such that the
chocolate has a smooth feel when eaten. In the same way better
flavour is thought to come from small cocoa particles. Premium
chocolate is known to have a small particle size distribution. By
combining an appropriate amount of the active material, such as
cocoa, cocoa powder, cocoa nibs, cocoa mass or cocoa liquor
prepared by a method described herein together with other food
ingredients a food product such as chocolate can be prepared. This
can be done to both enhance existing food products such as
chocolate or provide a more efficient and less costly process for
some aspects of the food product manufacture. Another aspect of
this invention is the preparation of a food product for drinking by
combining an appropriate amount of the active material, such as
cocoa, cocoa powder, cocoa nibs, cocoa mass, cocoa liquor or
coffee, prepared by the method described herein together with other
food ingredients. Materials produced using this invention, having
very small particles, could be directly used in drink products
without leaving residue in the products due to large particle size.
An example of this would be a drinking cocoa or drinking chocolate
were a cocoa material could be milled with a matrix such as but not
limited to sugar, glucose or lactose. Apart from greater release of
flavours, such a product could directly use the natural product
where conventional food products only use water soluble extracts. A
clear example of this is coffee products. Instant coffee provides a
convenient form of the product but is made by extracting flavor
from coffee beans and then processing it into a soluble powder. In
doing so some of the complex flavor of coffee is lost. In
comparison, coffee made from ground coffee beans provides an
enhanced flavor rich drink but requires greater preparation and
often uses expensive apparatuses. Some coffee styles used ground
coffee beans directly in a cup but this method leaves a thick
sludge in the bottom of the cup. Material produced by the method
described herein would overcome these limitations of the prior art.
By preparing the composition from coffee beans the full flavor can
be accessed and the small particle size produced by this invention
produces a drink where the particles are suspended in the liquid
which do not form a thick sludge. A further advantage of this
invention is that the material produced is a dry powder which can
then be easily packaged or processed further to provide a saleable
product. A further advantage of this invention is that natural
products such as coffee are encapsulated into the carrier matrix
and thus have superior powder handling properties compared to
natural products milled on there own. Materials such as coffee can
be milled in high energy mills to produce particles with small size
but the material is sticky and hard to handle. Other technologies,
such as wet milling would be more costly as further processing,
like spray drying, would be required to produce a powder. Preferred
matrices used for milling in this aspect include, but are not
limited to, lactose, sucrose, fructose, mannitol, glucose, xylitol,
milk powders, other milk solids and lethicin. In one embodiment,
the particles of biologically active material of the invention are
a size equal to or less than 20,000 nm. In one embodiment, the
particles of biologically active material of the invention are a
size equal to or less than 10,000 nm. In one embodiment, the
particles of biologically active material of the invention are a
size equal to or less than 5,000 nm.
[0080] While the method of the present invention has particular
application in the preparation of poorly water-soluble biologically
active materials, the scope of the invention is not limited
thereto. For example, the method of the present invention enables
production of highly water-soluble biologically active materials.
Such materials may exhibit advantages over conventional materials
by way of, for example, more rapid therapeutic action or lower
dose. In contrast, wet grinding techniques utilizing water (or
other comparably polar solvents) are incapable of being applied to
such materials, as the particles dissolve appreciably in the
solvent.
[0081] Other aspects and advantages of the invention will become
apparent to those skilled in the art from a review of the ensuing
description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0082] FIG. 1A. Powder charge composition and particle size
distribution of material milled in SPEX mill, examples A to S.
[0083] FIG. 1B. Powder charge composition and particle size
distribution of material milled in SPEX mill, examples T to AL.
[0084] FIG. 1C. Powder charge composition and particle size
distribution of material milled in SPEX mill, examples AM to
BE.
[0085] FIG. 1D. Powder charge composition and particle size
distribution of material milled in SPEX mill, examples BF to
BX.
[0086] FIG. 1E. Powder charge composition and particle size
distribution of material milled in SPEX mill, examples BY to
CQ.
[0087] FIG. 1F. Powder charge composition and particle size
distribution of material milled in SPEX mill, examples CR to
DJ.
[0088] FIG. 1G. Powder charge composition and particle size
distribution of material milled in SPEX mill, examples DK to
EC.
[0089] FIG. 1H. The figure shows the X-Ray diffraction patterns:
(A) after milling of Naproxen sodium in tartaric acid; (B) unmilled
Naproxen sodium and (C) unmilled Naproxen acid.
[0090] FIG. 2A. Powder charge composition and particle size
distribution of material milled in 110 mL HD01 Attritor mill,
examples A to F.
[0091] FIG. 3A. Powder charge composition and particle size
distribution of material containing a mixture of 2 matrices, milled
in SPEX mill, examples A to E.
[0092] FIG. 4A. Powder charge composition and particle size
distribution of material milled in 1 L HD01 Attritor mill, examples
A to G.
[0093] FIG. 5A. Powder charge composition and particle size
distribution of material milled in 750 mL 1S Attritor mill,
examples A to F.
[0094] FIG. 6A. Powder charge composition and particle size
distribution of material milled in 1/2 Gallon 1S Attritor mill,
examples A to R.
[0095] FIG. 6B. Powder charge composition and particle size
distribution of material milled in 1/2 Gallon 1S Attritor mill,
examples S to AK.
[0096] FIG. 6C. Powder charge composition and particle size
distribution of material milled in 1/2 Gallon 1S Attritor mill,
examples AL to AU.
[0097] FIG. 7A. Powder charge composition and particle size
distribution of Metaxalone milled in a variety of mills, examples A
to O.
[0098] FIG. 8A. Powder charge composition and particle size
distribution of material milled in HICOM mill, examples A to P.
[0099] FIG. 9A. Powder charge composition and particle size
distribution of material milled in 11/2 Gallon 1S Attritor mill,
examples A to S.
[0100] FIG. 9B. Powder charge composition and particle size
distribution of material milled in 11/2 Gallon 1S Attritor mill,
examples T to AL.
[0101] FIG. 10A. Powder charge composition and particle size
distribution of material milled in a variety of large scale mills,
examples A to F.
[0102] FIG. 11A. Powder charge composition and particle size
distribution of food grade material milled in SPEX mill, examples A
to S.
[0103] FIG. 11B. Powder charge composition and particle size
distribution of food grade material milled in SPEX mill, examples T
to AC.
[0104] FIG. 11C. Powder charge composition and particle size
distribution of food grade material milled in SPEX mill, examples
AD to AV.
[0105] FIG. 12A. Powder charge composition and particle size
distribution of food grade material milled in 1/2 Gallon 1S
Attritor mill, examples A to F.
[0106] FIG. 12B: Photos at the end of the milling in example 12
sample B.
[0107] FIG. 13A. Powder charge composition and particle size
distribution of Naproxen Acid milled in Mannitol in a 1/2 Gallon 1S
Attritor mill, examples A to M.
[0108] FIG. 14A. Powder charge composition and particle size
distribution of Naproxen Acid milled in SPEX mill and particle size
distribution after filtration, examples A to L.
[0109] FIG. 15: Table describing the milling of various actives and
some matrices without active and the particle size of these actives
as well as the particle size of actives in a variety of other
blends made for powder handling characteristic testing.
[0110] FIG. 16: Powder adherence, angle of repose and particle size
as measured by dry powder laser diffraction of various
actives/blends from example 16
[0111] FIG. 17: Powder adherence measurements for stainless steel;
A: Example 16, M; B: Example 16, E; C Example 16, L; D: Example 16,
K.
[0112] FIG. 18: Powder adherence measurements for Polypropylene; A:
Example 16, B; B: Example 16, G; C Example 16, F; D: Example 16,
L.
[0113] FIG. 19: Powder adherence measurements for Glass; A: Example
16, G; B: Example 16, M; C Example 16, F; D: Example 16, B.
[0114] FIG. 20: Bulk and Tap bulk density data and data from powder
rheology measurements of various actives/blends from example 16
[0115] FIG. 21: SEM of Example 16 Sample S after 20 minutes milling
1,000.times.
[0116] FIG. 22 SEM of Example 16 Sample S after 20 minutes milling
6,000.times.
[0117] FIG. 23: SEM of Example 16 Sample S after 20 minutes milling
60,000.times.
[0118] FIG. 24 SEM of Example 16 Sample S after 30 minutes milling
1,000.times.
[0119] FIG. 25: SEM of Example 16 Sample S after 30 minutes milling
100,000.times.
[0120] FIG. 26: SEM of Example 16 Sample R after 20 minutes milling
1,000.times.
[0121] FIG. 27: SEM of Example 16 Sample R after 20 minutes milling
100,000.times.
[0122] FIG. 28: SEM of Example 16 Sample R after 20 minutes milling
100,000.times.
DETAILED DESCRIPTION OF THE INVENTION
[0123] General
[0124] Those skilled in the art will appreciate that the invention
described herein is susceptible to variations and modifications
other than those specifically described. It is to be understood
that the invention includes all such variations and modifications.
The invention also includes all of the steps, features,
compositions and materials referred to or indicated in the
specification, individually or collectively and any and all
combinations or any two or more of the steps or features.
[0125] The present invention is not to be limited in scope by the
specific embodiments described herein, which are intended for the
purpose of exemplification only. Functionally equivalent products,
compositions and methods are clearly within the scope of the
invention as described herein.
[0126] The invention described herein may include one or more
ranges of values (e.g. size, concentration etc). A range of values
will be understood to include all values within the range,
including the values defining the range, and values adjacent to the
range that lead to the same or substantially the same outcome as
the values immediately adjacent to that value which defines the
boundary to the range.
[0127] The entire disclosures of all publications (including
patents, patent applications, journal articles, laboratory manuals,
books, or other documents) cited herein are hereby incorporated by
reference. Inclusion does not constitute an admission is made that
any of the references constitute prior art or are part of the
common general knowledge of those working in the field to which
this invention relates.
[0128] Throughout this specification, unless the context requires
otherwise, the word "comprise" or variations, such as "comprises"
or "comprising" will be understood to imply the inclusion of a
stated integer, or group of integers, but not the exclusion of any
other integers or group of integers. It is also noted that in this
disclosure, and particularly in the claims and/or paragraphs, terms
such as "comprises", "comprised", "comprising" and the like can
have the meaning attributed to it in US Patent law; e.g., they can
mean "includes", "included", "including", and the like.
[0129] "Therapeutically effective amount" as used herein with
respect to methods of treatment and in particular drug dosage,
shall mean that dosage that provides the specific pharmacological
response for which the drug is administered in a significant number
of subjects in need of such treatment. It is emphasized that
"therapeutically effective amount," administered to a particular
subject in a particular instance will not always be effective in
treating the diseases described herein, even though such dosage is
deemed a "therapeutically effective amount" by those skilled in the
art. It is to be further understood that drug dosages are, in
particular instances, measured as oral dosages, or with reference
to drug levels as measured in blood.
[0130] The term "inhibit" is defined to include its generally
accepted meaning which includes prohibiting, preventing,
restraining, and lowering, stopping, or reversing progression or
severity, and such action on a resultant symptom. As such the
present invention includes both medical therapeutic and
prophylactic administration, as appropriate.
[0131] The term "biologically active material" is defined to mean a
biologically active compound or a substance which comprises a
biologically active compound. In this definition, a compound is
generally taken to mean a distinct chemical entity where a chemical
formula or formulas can be used to describe the substance. Such
compounds would generally, but not necessarily be identified in the
literature by a unique classification system such as a CAS number.
Some compounds may be more complex and have a mixed chemical
structure. For such compounds they may only have an empirical
formula or be qualitatively identified. A compound would generally
be a pure material, although it would be expected that up to 10%,
20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% of the substance could be
other impurities and the like. Examples of biologically active
compounds are, but not limited to, fungicides, pesticides,
herbicides, seed treatments, cosmeceuticals, cosmetics,
complementary medicines, natural products, vitamins, nutrients,
nutraceuticals, pharmaceutical actives, biologics, amino acids,
proteins, peptides, nucleotides, nucleic acids, additives, foods
and food ingredients and analogs, homologs and first order
derivatives thereof. A substance that contains a biologically
active compound is any substance which has as one of its components
a biologically active compound. Examples of substances containing
biologically active compounds are, but not limited to,
pharmaceutical formulations and products, cosmetic formulations and
products, industrial formulations and products, agricultural
formulations and products, foods, seeds, cocoa and cocoa solids,
coffee, herbs, spices, other plant materials, minerals, animal
products, shells and other skeletal material.
[0132] Any of the terms, "biological(ly) active", "active", "active
material" shall have the same meaning as biologically active
material.
[0133] The term "grinding matrix" is defined as any inert substance
that a biologically active material can or is combined with and
milled. The terms "co-grinding matrix" and "matrix" are
interchangeable with "grinding matrix".
[0134] The term "of the same, similar or larger particle size" is
defined as where the median (by volume) particle size of an active
material produced by a conventional manufacturing process is the
same, with a median size +/-20%; similar, with a median size +/-5
micron; or larger, where the median size is greater than the
particle size of an active material produced by the process
described herein but is less than or equal to 20 micron.
[0135] The term "conventional process" is defined as another
(different to the one described herein) dry manufacturing process
where a biologically active material is subject to particle size
reduction. Examples of such processes are, but are not limited to,
conventional ball milling (where no matrix is present or the active
material is greater than 80% w/w), pin mills, air jet mills or
other fluid energy mills
[0136] The term "nanoparticle" is defined as having a median
diameter (by volume) of 1000 nm or less.
[0137] The term "microparticle" is defined as having a median
diameter (by volume) of 1000 nm to 20,000 nm inclusive
[0138] The term "composite particle" is defined as the combination
of nanopaticle and/or microparticles of a biologically active
material together with the particles of the grinding matrix (milled
or partially milled) into a larger particle.
[0139] The term "blend" is defined as the resultant mixture of a
biologically active material 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 invention described herein
is one example of a blend. Preferably a blend is made using simple
blending processes that do not involve granulation but may involve
a milling step.
[0140] The term "content uniformity" is defined as the measure of
how evenly an active material is distributed throughout a blend. A
blend with superior content uniformity will have the same
concentration of active in many samples taken from different places
(eg: 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 % deviation of the
many samples from the known concentration of the whole blend.
[0141] The term "segregation" is 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.
[0142] Blends and Composite Particles
[0143] A conventional approach to reducing the size (in a dry
process) of active particles is fluid energy milling. An example of
this is airjet milling (also known as micronisation). This
technique and other similar milling techniques typically reduced
the particle size to between 2 and 10 micron. The powder that
results from air milling typically has poor powder handling
characteristics. This powder is often cohesive, has poor flow
properties, has high static charge and low bulk density. In order
to process this micronized active material into a product such as,
but not limited to, a solid oral dose or inhaled powder, it must
first be processed into a suitable blend with other excipients. The
creation of a blend is not a trivial process with the poor handling
properties of a micronized material making any process difficult.
The creation of the blend has many benefits such as diluting the
active to lower doses, bulking the active up to make dosage forms
of a practical size and the creation of a powder with superior flow
properties making it easier to handle in subsequent manufacturing
processes, such as granulation or tabletting.
[0144] To create a blend with improved powder handling properties,
excipients with a particle size significantly larger than the
micronized active could be used. However, this approach has the
disadvantage of potential segregation during the blending or
subsequent process. If the segregation of such a blend occurs, the
content uniformity will be poor which is highly undesirable in
pharmaceutical manufacturing. If excipients with a particle size
similar to the micronized active are used, then segregation is less
likely but the powder handling properties of the material would be
poor. In practice a compromise is usually undertaken whereby an
intermediate sized excipient is used. In this case, careful
blending and processing can maintain acceptable content uniformity
and the powder handling properties are improved enough to
facilitate further processing such as wet or dry granulation.
[0145] If a high level of content uniformity is required an
alternative approach would be to process the excipient and active
in an airjet mill together. This process would create a blend where
the excipient and active have almost identical particle size thus
preventing segregation. However this material would have poor
powder handling properties and would require careful handling in
subsequent processes. This material would likely need to be wet or
dry granulated.
[0146] In a surprising and unexpected discovery, the invention
described herein overcomes both of these problems. Even more
surprising is that the invention overcomes these problems even when
the active particles produced in the milling process are
significantly smaller than active particles produced in
conventional milling process such as air jet milling. One skilled
in the art would expect that if 2 .mu.m particles have poor powder
handling properties then 200 nm particles would have significantly
poorer powder handling properties.
[0147] It is thought that the process described herein overcomes
both the issue of poor powder handling and poor content uniformity
by the simultaneous production of active nanoparticles and/or
microparticle, the blending of these with the grinding matrix
(excipients) and the formation of composite particles of the active
particles and matrix particles. In this way, powder with three
clear benefits is produced in a "one pot" process. Firstly, active
nanoparticles and/or microparticle are made, secondly, the particle
size of the blend produced is large enough to give superior powder
handling properties compared to conventional methods and, thirdly,
the formation of the composite particles deliveries robust content
uniformity.
[0148] It is thought that during the process described herein the
active particles are uniformly distributed throughout the composite
particles so that each composite particle contains the same
proportion of active and excipient. This means that even 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.
[0149] Those skilled in the art recognise that it is beneficial to
measure the particle size distribution of a powder or blend of
powders because this information can be used to predict the powder
handling properties. Methods use to determine the particle size of
powders are well known in the art. Some common methods include
laser diffraction measurements of a stream of the powder dispersed
in air. Laser diffraction measurements can also be made in solvents
where the solvent does not dissolve any of the powder or particles
in the powder. The same methods can be used to determine the size
distribution of a powder blend or, in the case of the invention
herein, the composite particles. In the case of this invention, the
particle size distribution of the composite and the blend are the
same thing. In the case where a solvent based measurement is used
to characterise the composite particles, care must be taken to
ensure that the solvent does not break up the composite as this
will not give a true indication of the composite behaviour as a dry
powder. For this reason it is preferable to measure the particle
size distribution of the composites using a dry powder method such
as air dispersion coupled with laser diffraction.
[0150] Preferably, the blend particles have a median particle size,
determined on a particle volume basis, equal or greater than a size
selected from the group consisting of: 2000 nm, 3000 nm, 4000 nm,
5000 nm, 6000 nm, 8000 nm, 10,000 nm, 15,000 nm, 20,000 nm.
Preferably, the median particle size is equal to or less than 50
micron.
[0151] Preferably, the blend particles have a volume weighted mean
(D4,3) equal or greater than a size selected from the group
consisting of: 5000 nm, 10,000 nm, 15,000 nm, 20,000 nm, 25,000 nm,
35,000 nm, 40,000 nm Preferably, the median particle size is equal
to or less than 70 micron.
[0152] Preferably, the percentage of particles in the blend, on a
particle volume basis, is selected from the group consisting of:
greater than 2 micron (%>2 micron) is selected from the group
50%, 60%, 70%, 80%, 85%, 90% and 95%; greater than 10 micron
(%>10 micron) is selected from the group 10%, 20%, 30%, 40%,
50%, 60%, 70%, 80%, 85%, 90% and 95%; equal to or less than 20
micron (%<20 micron) is selected from the group 10%, 20%, 30%,
40%, 50%, 60%, 70%, 80%, 90%, 95% and 100%
[0153] Powder Handling Characteristics
[0154] The expression "powder handling characteristics" refers to,
but is not limited to, at least one of the product's flow
properties; static charge, aggregation properties, cohesive
properties, uniformity properties, content uniformty, content
uniformity after segregation, dust levels, powder rheology,
segregation properties, bulk density, powder flow, compressibility,
permeability and/or ignition properties. The process described
herein to mill biologically active material and generate reduced
particle size wherein the powders and/or blends made by the process
of the present invention have powder handling properties that are
superior to those of powders made by a conventional process
delivering the same, similar or larger particle size of the
biologically active material when the product: is stored in vials,
bags, containers or other closures; is dispensed; is blended; is
granulated (wet or dry); is packaged or filled and processed and/or
transported during other manufacturing steps.
[0155] In one preferred embodiment, the powder handling
characteristics of the biologically active material subject to this
invention is an improvement over the powder handling
characteristics of a biologically active material of the same,
similar or larger particle size manufactured using a conventional
process. Preferably, the biologically active material subject to
this invention has superior powder flow properties compared to the
powder flow properties of a biologically active material with the
same, similar or larger particle size manufactured using a
conventional process. This is a particular advantage during
processing of the material. Preferably, the biologically active
material subject to this invention has a lower static charge
compared to the static charge of a biologically active material
with the same, similar or larger particle size manufactured using a
conventional process. Preferably the static charge of the product
is selected from the group consisting of: less than 10 nC/g, less
than 5 nC/g, less than 3 nC/g, less than 2 nC/g, less than 1.5
nC/g, less than 1.25 nC/g, less than 1 nC/g less than 0.75 nC/g,
less than 0.5 nC/g, less than 0.25 nC/g or less than 0.1 nC/g.
Preferably, the biologically active material subject to this
invention has a lower cohesiveness profile compared to the
cohesiveness profile of a biologically active material with the
same, similar or larger particle size manufactured using a
conventional process. Preferably the specific energy (were a lower
value indicates less cohesiveness), as measured by powder rheology,
of the product is selected from the group consisting of: less than
12 mJ/g, less than 10 mJ/g, less than 9 mJ/g, less than 8 mJ/g,
less than 7 mJ/g, less than 6 mJ/g, less than 5 mJ/g less than 4
mJ/g or less than 3 mJ/g. Preferably, the biologically active
material subject to this invention has a lower propensity for
aggregation compared to the propensity for aggregation of a
biologically active material with the same, similar or larger
particle size manufactured using a conventional process.
Preferably, the biologically active material subject to this
invention has a lower propensity for adherence to other materials
such as but not limited to stainless steel, glass, plastic,
polyethylene and polypropylene compared to the propensity for
adherence of a biologically active material with the same, similar
or larger particle size manufactured using a conventional
process.
[0156] Preferably, the biologically active material subject to this
invention has increased uniformity compared to a biologically
active material with the same, similar or larger particle size
manufactured using a conventional process. Preferably the
biological active material maintains its superior uniformity
despite numerous process steps and modifications to the material.
Preferably, the biological active material maintains its superior
uniformity despite some level of segregation. For example, even if
the biological material particles of varying size segregate, a
uniform amount of active is maintained in the particles. Preferably
the content uniformity of the biologically active material
throughout the blend (even after segregation) varies from the
average content by a percentage less than or equal to a percentage
selected from the group consisting of: 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%.
[0157] Preferably, the composite particles made by the methods of
the invention comprises both biologically active material and
matrix material and these composite particles have increased
uniformity compared to matter made by conventional processes. This
has advantages in the preparation of pharmaceuticals whereby the
composite particles made by the methods of the invention is ready
to use and does not require the addition of further excipients to
bulk up the matter so that it can be formulated. In addition, the
composite particles made by the methods of the invention comprises
both biologically active material and matrix material and these
composite particles have superior flow properties compared to those
made by conventional processes.
[0158] This translates into significant advantages in the
preparation of nanoparticle and/or microparticles. For example,
during the formulation of micronized actives by a conventional
process, the actives must be blended with bulking excipients and
then further processed (dry or wet granulation to improve product
flow) carefully so as to avoid segregation of poor content
uniformity. However, actives made by this invention (which can be
made at sizes less than 1 .mu.m, which the skilled addressee would
expect to have significantly worse segregation problems) are in the
same process made into composite particles with the matrix material
thus having superior uniformity properties compared to actives made
by conventional processes, and do not need further processing
steps.
[0159] Preferably, the biologically active material subject to this
invention has reduced levels of dust compared to a biologically
active material with the same, similar or larger particle size
manufactured using a conventional process. Preferably, the
biologically active material subject to this invention has improved
rheology compared to a biologically active material with the same,
similar or larger particle size manufactured using a conventional
process.
[0160] Preferably the sheer Stress of the product is selected from
the group: less than 3 kPa, less than 2.75 kPa, less than 2.5 kPa,
less than 2.35 kPa, less than 2.25 kPa, less than 2.1 kPa, less
than 2.0 kPa, less than 1.85 kPa, less than 1.75 kPa, less than
1.50 kPa, less than 1.25 kPa or less than 1.0 kPa. Preferably the
basic flow energy of the product is selected from the group: less
than 500 mJ, less than 450 mJ, less than 400 mJ, less than 375 mJ,
less than 350 mJ, less than 325 mJ, less than 300 mJ, or less than
250. Preferably, the biologically active material subject to this
invention has reduced segregation compared to a biologically active
material with the same, similar or larger particle size
manufactured using a conventional process. Preferably, the
biologically active material subject to this invention has
increased bulk density or tapped bulk density compared to a
biologically active material with the same, similar or larger
particle size manufactured using a conventional process. Preferably
the bulk density of the product is selected from the group
consisting of: greater than 0.3 g/ml, greater than 0.4 g/ml,
greater than 0.45 g/ml, greater than 0.5 g/ml, greater than 0.55
g/ml, greater than 0.60 g/ml, greater than 0.65 g/ml, greater than
0.7 g/ml, greater than 0.75 g/ml, greater than 0.80 g/ml, greater
than 0.85 g/ml. greater than 0.90 g/ml or greater than 1.0 g/ml.
Preferably the tapped bulk density of the product is selected from
the group consisting of: greater than 0.3 g/ml, greater than 0.4
g/ml, greater than 0.45 g/ml, greater than 0.5 g/ml, greater than
0.55 g/ml, greater than 0.60 g/ml, greater than 0.65 g/ml, greater
than 0.7 g/ml, greater than 0.75 g/ml, greater than 0.80 g/ml,
greater than 0.85 g/ml. greater than 0.90 g/ml or greater than 1.0
g/ml. Preferably, the biologically active material subject to this
invention has superior powder flow as defined by the Hausner ratio
or Carr's index compared to a biologically active material with the
same, similar or larger particle size manufactured using a
conventional process. Preferably, the biologically active material
subject to this invention has lower compressibility compared to a
biologically active material with the same, similar or larger
particle size manufactured using a conventional process. Preferably
the % compressibility, as measured using a powder rheometer is less
than the % selected for the group: 30, 25, 20, 17, 15, 13 and 10.
Preferably, the biologically active material subject to this
invention has increased permeability compared to a biologically
active material with the same, similar or larger particle size
manufactured using a conventional process. Preferably the pressure
drop (where a low pressure drop indicates superior permeability),
as measured as the pressure drop across a bed of powder in a powder
rheometer, is selected for the group consisting of: less than 20
mBar, less than 15 mBar, less than 10 mBar, less than 7 mBar, less
than 5 mBar, less than 4 mBar or less than 3 mBar. Preferably, the
biologically active material subject to this invention has a higher
minium ignition energy compared to a biologically active material
with the same, similar or larger particle size manufactured using a
conventional process. Preferably, the biologically active material
subject to this invention has higher hopper flow rates compared to
a biologically active material with the same, similar or larger
particle size manufactured using a conventional process.
Preferably, the biologically active material subject to this
invention has smaller critical orifice diameter compared to a
biologically active material with the same, similar or larger
particle size manufactured using a conventional process.
Preferably, the biologically active material subject to this
invention has smaller angle of repose compared to a biologically
active material with the same, similar or larger particle size
manufactured using a conventional process. Preferably, the
biologically active material subject to this invention has smaller
dynamic angle of repose compared to a biologically active material
with the same, similar or larger particle size manufactured using a
conventional process.
[0161] In one preferred embodiment, the powder handling
characteristics of a blend made using this invention is an
improvement over the powder handling characteristics of a blend
(containing biologically active material of the same, similar or
larger particle size) manufactured using a conventional process.
Preferably, the blend made using this invention has superior powder
flow properties compared to the powder flow properties of a blend
(containing biologically active material of the same, similar or
larger particle size) manufactured using a conventional process.
This is a particular advantage during processing of the material.
Preferably, the blend made using this invention has a lower static
charge compared to the static charge of a blend (containing
biologically active material of the same, similar or larger
particle size) manufactured using a conventional process.
Preferably the static charge of the product is selected from the
group consisting of: less than 10 nC/g, less than 5 nC/g, less than
3 nC/g, less than 2 nC/g, less than 1.5 nC/g, less than 1.25 nC/g,
less than 1 nC/g less than 0.75 nC/g, less than 0.5 nC/g, less than
0.25 nC/g or less than 0.1 nC/g. Preferably, the blend made using
this invention has a lower cohesiveness profile compared to the
cohesiveness profile of a blend (containing biologically active
material of the same, similar or larger particle size) manufactured
using a conventional process. Preferably the specific energy (were
a lower value indicates less cohesiveness), as measured by powder
rheology, of the product is selected from the group consisting of:
less than 12 mJ/g, less than 10 mJ/g, less than 9 mJ/g, less than 8
mJ/g, less than 7 mJ/g, less than 6 mJ/g, less than 5 mJ/g less
than 4 mJ/g or less than 3 mJ/g. Preferably, the blend made using
this invention has a lower propensity for aggregation compared to
the propensity for aggregation of a blend (containing biologically
active material of the same, similar or larger particle size)
manufactured using a conventional process. Preferably, the blend
made using this invention has a lower propensity for adherence to
other materials such as but not limited to stainless steel, glass,
plastic, polyethylene and polypropylene compared to the propensity
for adherence of a blend (containing biologically active material
of the same, similar or larger particle size) manufactured using a
conventional process.
[0162] Preferably, the blend made using this invention has
increased uniformity compared to a blend (containing biologically
active material of the same, similar or larger particle size)
manufactured using a conventional process. Preferably the
biological active material maintains its superior uniformity
despite numerous process steps and modifications to the material.
Preferably, the biological active material maintains its superior
uniformity despite some level of segregation. For example, even if
the biological material particles of varying size segregate, a
uniform amount of active is maintained in the particles. Preferably
the content uniformity of the biologically active material
throughout the blend (even after segregation) varies from the
average content by a percentage less than or equal to a percentage
selected from the group consisting of: 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%.
[0163] Preferably, the blend made using this invention has reduced
levels of dust compared to a blend (containing biologically active
material of the same, similar or larger particle size) manufactured
using a conventional process. Preferably, the blend made using this
invention has improved rheology compared to a blend (containing
biologically active material of the same, similar or larger
particle size) manufactured using a conventional process.
[0164] Preferably the sheer Stress of the product is selected from
the group: less than 3 kPa, less than 2.75 kPa, less than 2.5 kPa,
less than 2.35 kPa, less than 2.25 kPa, less than 2.1 kPa, less
than 2.0 kPa, less than 1.85 kPa, less than 1.75 kPa, less than
1.50 kPa, less than 1.25 kPa or less than 1.0 kPa. Preferably the
basic flow energy of the product is selected from the group: less
than 500 mJ, less than 450 mJ, less than 400 mJ, less than 375 mJ,
less than 350 mJ, less than 325 mJ, less than 300 mJ, or less than
250. Preferably, the blend made using this invention has reduced
segregation compared to a blend (containing biologically active
material of the same, similar or larger particle size) manufactured
using a conventional process. Preferably, the blend made using this
invention has increased bulk density or tapped bulk density
compared to a blend (containing biologically active material of the
same, similar or larger particle size) manufactured using a
conventional process. Preferably the bulk density of the blend is
selected from the group: greater than 0.3 g/ml, greater than 0.4
g/ml, greater than 0.45 g/ml, greater than 0.5 g/ml, greater than
0.55 g/ml, greater than 0.60 g/ml, greater than 0.65 g/ml, greater
than 0.7 g/ml, greater than 0.75 g/ml, greater than 0.80 g/ml,
greater than 0.85 g/ml. greater than 0.90 g/ml or greater than 1.0
g/ml. Preferably the tapped bulk density of the blend is selected
from the group: greater than 0.3 g/ml, greater than 0.4 g/ml,
greater than 0.45 g/ml, greater than 0.5 g/ml, greater than 0.55
g/ml, greater than 0.60 g/ml, greater than 0.65 g/ml, greater than
0.7 g/ml, greater than 0.75 g/ml, greater than 0.80 g/ml, greater
than 0.85 g/ml. greater than 0.90 g/ml or greater than 1.0 g/ml.
Preferably, the blend made using this invention has superior powder
flow as defined by the Hausner ratio or Carr's index compared to a
blend (containing biologically active material of the same, similar
or larger particle size) manufactured using a conventional process.
Preferably, the blend made using this invention has lower
compressibility compared to a blend (containing biologically active
material of the same, similar or larger particle size) manufactured
using a conventional process. Preferably the % compressibility, as
measured using a powder rheometer is less than the % selected for
the group: 30, 25, 20, 17, 15, 13 and 10. Preferably, the blend
made using this invention has increased permeability compared to a
blend (containing biologically active material of the same, similar
or larger particle size) manufactured using a conventional process.
Preferably the pressure drop (where a low pressure drop indicates
superior permeability), as measured as the pressure drop across a
bed of powder in a powder rheometer is selected for the group: less
than 20 mBar, less than 15 mBar, less than 10 mBar, less than 7
mBar, less than 5 mBar, less than 4 mBar or less than 3 mBar.
Preferably, the blend made using this invention has a higher minium
ignition energy compared to a blend (containing biologically active
material of the same, similar or larger particle size) manufactured
using a conventional process. Preferably, the blend made using this
invention has higher hopper flow rates compared to a blend
(containing biologically active material of the same, similar or
larger particle size) manufactured using a conventional process.
Preferably, the blend made using this invention has smaller
critical orifice diameter compared to a blend (containing
biologically active material of the same, similar or larger
particle size) manufactured using a conventional process.
Preferably, the blend made using this invention has smaller angle
of repose compared to a blend (containing biologically active
material of the same, similar or larger particle size) manufactured
using a conventional process. Preferably, the blend made using this
invention has smaller dynamic angle of repose compared to a blend
(containing biologically active material of the same, similar or
larger particle size) manufactured using a conventional process.
For example, the process improves powder handling characteristics
relative to conventional powders of the same, similar or larger
particle size when the biologically active material is
manufactured, processed and formulated and finally stored in a
capsule. The material is more easily poured into a capsule from a
dispensing device. The material has improved flow properties so
that it flows smoothly into the capsule and does not aggregate
significantly when it pores, nor does it adhere significantly to
any handling apparatuses or containers, and thus does not result in
a significant loss of product. It's static parameters have improved
such that the material does not adhere to the dispensing device or
containers. The powder handling characteristics have improved such
that it can be efficiently manufactured, processed and stored
without significant loss of material from poor product flow, high
aggregation, high adherence and high static properties. The powder
handling characteristics have improved such that it can be
manufactured to meet assay and content uniformity requirements as
set out in the USP. The material has improved powder handling
characteristics when dry. The material has improved powder handling
characteristics when combined with extra functional excipients. For
example the material has improved powder handling characteristics
when combined with disintegrants, binders, wetting agents, fillers,
disintegrants, binders, wetting agents and the like such that there
are no issues with segregation or uniformity of the active through
the blended material. The powder handling characteristics have
improved such that it can be easily processed through standard
processing equipment such as a roller compactor (dry granulator) or
a wet granulator.
[0165] Particle Size
[0166] There are a wide range of techniques that can be utilized to
characterize the particle size of a material. 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.
[0167] 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 micron.
This technique calculates a volume distribution of equivalent
spherical particles that can be expressed using descriptors such as
the median particle size or the % of particles under a given
size.
[0168] 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 will 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.
[0169] 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.
[0170] 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`.
[0171] The term "Dx of the particle size distribution" refers to
the xth percentile of the distribution; thus, D90 refers to the
90.sup.th percentile, D95 refers to the 95.sup.th 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.
[0172] 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.
[0173] 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.
[0174] 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.
[0175] 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. [0176] 1. 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.
[0177] 2. 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. [0178] 3. 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.
[0179] Other Definitions
[0180] Throughout this specification, unless the context requires
otherwise, the phrase "dry mill" or variations, such as "dry
milling", should be understood to 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.
[0181] "Flowable" means a powder having physical characteristics
rendering it suitable for further processing using typical
equipment used for the manufacture of pharmaceutical compositions
and formulations.
[0182] 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.
[0183] The term "millable" means that the grinding matrix is
capable of being physically degraded under the dry milling
conditions of the method of the invention. In one embodiment of the
invention, the milled grinding matrix is of a comparable particle
size to the biologically active material. In another embodiment of
the invention the particle size of the matrix is substantially
reduced but not as small as the biologically active material
[0184] 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.
[0185] Specific
[0186] In one embodiment, the present invention is directed to a
method for producing a composition, comprising the steps of: dry
milling a solid biologically active material and a millable
grinding matrix in a mill comprising a plurality of milling bodies,
for a time period sufficient to produce particles of the
biologically active material dispersed in an at least partially
milled grinding material.
[0187] The mixture of active material and matrix may then be
separated from the milling bodies and removed from the mill.
[0188] In one aspect the mixture of active material and matrix is
then further processed. In another aspect, the grinding matrix is
separated from the particles of biologically active material. In a
further aspect, at least a portion of the milled grinding matrix is
separated from the particulate biologically active material.
[0189] The milling bodies are essentially resistant to fracture and
erosion in the dry milling process. The quantity of the grinding
matrix relative to the quantity of biologically active material in
particulate form, and the extent of milling of the grinding matrix,
is sufficient to inhibit re-agglomeration of the particles of the
active material.
[0190] The present invention also relates to biologically active
materials produced by said methods, to medicaments produced using
said biologically active materials and to methods of treatment of
an animal, including man, using a therapeutically effective amount
of said biologically active materials administered by way of said
medicaments.
[0191] Commercial Scale
[0192] The present invention is directed to the unexpected finding
that particles of a biologically active material can be produced by
dry milling processes as described herein at commercial scale. In
one surprising aspect the particle size of the biologically active
material produced by the process is equal to or less than 20,000
nm. In another surprising aspect the particle size of the
biologically active material produced by the process is equal to or
less than 10,000 nm. In another surprising aspect the particle size
of the biologically active material produced by the process is
equal to or less than 5,000 nm. In another surprising aspect the
particle size of the biologically active material produced by the
process is equal to or less than 2000 nm. In another surprising
aspect the particle size of the biologically active material
produced by the process is equal to or less than 1000 nm. This can
result in a more efficient and cost effective process.
[0193] One of the key goals of reducing manufacturing costs is the
encapsulation of the nanoparticles into materials that do not have
to be removed. This enables a simple manufacturing process where
conventional formulation technologies can be used to progress the
matrix encapsulated nanoparticles directly to a final product. In
order to do this the materials used within the matrix must be
acceptable to industry regulators. In some cases materials may be
acceptable for use but only in limited quantities. Another aspect
of matrix choice is functionality. Some matrices that produce
superior encapsulated nanoparticles may be acceptable from a safety
perspective but these materials may make manufacture of a dosage
form such as tablet limited.
[0194] Improving the Dissolution Profile
[0195] The process results in the biologically active material
having an improved dissolution profile. An improved dissolution
profile has significant advantages including the improvement of
bioavailability of the biologically active material in vivo.
Preferably, the improved dissolution profile is observed in vitro.
Alternatively, 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 may 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 would indicate (assuming it is statistically significant),
that the sample material has an improved dissolution profile. The
measurement sample is herein defined as the mixture of biologically
active material with grinding matrix and/or other additives that
has been subject to the processes of the invention described here.
Herein a control sample is defined as a physical mixture (not
subject to the processes described in this invention) of the
components in the measurement sample with the same relative
proportions of active, matrix and/or additive as the measurement
sample. For the purposes of the dissolution testing a prototype
formulation of the measurement sample could also be used. In this
case the control sample would be formulated in the same way.
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 at a relevant gastrointestinal pH,
when it is observed in vitro. Preferably, the improved dissolution
profile is observed at a pH which is favourable at indicating
improvements in dissolution when comparing the measurement sample
to the control compound. 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. In one
preferred embodiment the method of quantification of dissolution is
determined in a solution with a pH selected from the group
consisting of: pH 1, pH 2, pH 3, pH 4, pH 5, pH 6, pH 7, pH 7.3, pH
7.4, pH 8, pH 9, pH 10, pH 11, pH 12, pH 13, pH 14 or a pH with 0.5
of a pH unit of any of this group.
[0196] Crystallization Profile
[0197] Methods for determining the crystallinity profile of the
biologically active material are widely available in the art.
Suitable methods may include X-ray diffraction, differential
scanning calorimetry, raman or IR spectrocopy.
[0198] Amorphicity Profile
[0199] Methods for determining the amorphous content of the
biologically active material are widely available in the art.
Suitable methods may include X-ray diffraction, differential
scanning calorimetry, raman or IR spectroscopy.
[0200] Grinding Matrix
[0201] As will be described subsequently, selection of an
appropriate grinding matrix affords particular advantageous
applications of the method of the present invention.
[0202] A highly advantageous application of the method of the
invention is the use of a water-soluble grinding matrix in
conjunction with a poorly water-soluble biologically active
material. This affords at least two advantages. The first being
when the powder containing the biologically active material is
placed into water--such as the ingestion of the powder as part of
an oral medication--the matrix dissolves, releasing the particulate
active material such that there is maximum surface area exposed to
solution, thereby allowing a rapid dissolution of the active
compound. The second key advantage is the ability, if required, to
remove or partially remove the matrix prior to further processing
or formulation.
[0203] Another advantageous application of the method of the
invention is the use of a water-insoluble grinding matrix,
particularly in the area of agricultural use, when a biologically
active material such as a fungicide is commonly delivered as part
of a dry powder or a suspension. The presence of a water insoluble
matrix will afford benefits such as increased rain fastness.
[0204] Without wishing to be bound by theory, it is believed that
the physical degradation (including but not limited to particle
size reduction) of the millable grinding matrix affords the
advantage of the invention, by acting as a more effective diluent
than grinding matrix of a larger particle size. Again, as will be
described subsequently, a highly advantageous aspect of the present
invention is that certain grinding matrixes appropriate for use in
the method of the invention are also appropriate for use in a
medicament. The present invention encompasses methods for the
production of a medicament incorporating both the biologically
active material and the grinding matrix or in some cases the
biologically active material and a portion of the grinding matrix,
medicaments so produced, and methods of treatment of an animal,
including man, using a therapeutically effective amount of said
biologically active materials by way of said medicaments.
[0205] Analogously, as will be described subsequently, a highly
advantageous aspect of the present invention is that certain
grinding matrixes appropriate for use in the method of the
invention are also appropriate for use in a carrier for an
agricultural chemical, such as a pesticide, fungicide, or
herbicide. The present invention encompasses methods for the
production of an agricultural chemical composition incorporating
both the biologically active material in particulate form and the
grinding matrix, or in some cases the biologically active material,
and a portion of the grinding matrix, and agricultural chemical
compositions so produced. The medicament may include only the
biologically active material together with the milled grinding
matrix or, more preferably, the biologically active material and
milled grinding matrix may be combined with one or more
pharmaceutically acceptable carriers, as well as any desired
excipients or other like agents commonly used in the preparation of
medicaments.
[0206] Analogously, the agricultural chemical composition may
include only the biologically active material together with the
milled grinding matrix or, more preferably, the biologically active
materials and milled grinding matrix may be combined with one or
more carriers, as well as any desired excipients or other like
agents commonly used in the preparation of agricultural chemical
compositions.
[0207] In one particular form of the invention, the grinding matrix
is both appropriate for use in a medicament and readily separable
from the biologically active material by methods not dependent on
particle size. Such grinding matrixes are described in the
following detailed description of the invention. Such grinding
matrixes are highly advantageous in that they afford significant
flexibility in the extent to which the grinding matrix may be
incorporated with the biologically active material into a
medicament.
[0208] In a highly preferred form, the grinding matrix is harder
than the biologically active material, and is thus capable of
reducing the particle size of the active material under the dry
milling conditions of the invention. Again without wishing to be
bound by theory, under these circumstances it is believed that the
millable grinding matrix affords the advantage of the present
invention through a second route, with the smaller particles of
grinding matrix produced under the dry milling conditions enabling
greater interaction with the biologically active material. The
quantity of the grinding matrix relative to the quantity of
biologically active material, and the extent of physical
degradation of the grinding matrix, is sufficient to inhibit
re-agglomeration of the particles of the active material
Preferably, the quantity of the grinding matrix relative to the
quantity of biologically active material, 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. The grinding matrix is not generally selected
to be chemically reactive with the biologically active material
under the milling conditions of the invention, excepting for
example, where the matrix is deliberately chosen to undergo a
mechanico-chemical reaction. Such a reaction might be the
conversion of a free base or acid to a salt or vice versa.
[0209] As stated above, the method of the present invention
requires the grinding matrix to be milled with the biologically
active material; that is, the grinding matrix will physically
degrade under the dry milling conditions of the invention to
facilitate the formation and retention of particulates of the
biologically active material with reduced particle size. The
precise extent of degradation required will depend on certain
properties of the grinding matrix and the biologically active
material, the ratio of biologically active material to grinding
matrix, and the particle size distribution of the particles
comprising the biologically active material.
[0210] 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.
[0211] A low hardness (typically a Mohs Hardness less than 7) of
the biologically active material 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.
[0212] Preferably, the grinding matrix is of low abrasivity. Low
abrasivity is desirable to minimise contamination of the mixture of
the biologically active material 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.
[0213] Preferably, the 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.
[0214] The grinding matrix may be an inorganic or organic
substance.
[0215] In one embodiment, the grinding matrix is selected from the
following, either as a single substance or a combination of two or
more substances: Polyols (sugar alcohols) for example (but not
limited to) mannitol, sorbitol, isomalt, xylitol, maltitol,
lactitol, erythritol, arabitol, ribitol, monosaccharides for
example (but not limited to) glucose, fructose, mannose, galactose,
disaccharides and trisaccharides for example (but not limited to)
anhydrous lactose, lactose monohydrate, sucrose, maltose,
trehalose, polysaccharides for example (but not limited to)
maltodextrins, dextrin, Inulin, dextrates, polydextrose, other
carbohyrates for example (but not limited to) starch, wheat flour,
corn flour, rice flour, rice starch, tapioca flour, tapioca starch,
potato flour, potato starch, other flours and starches, soy flour,
soy meal or other soy products, cellulose, microcrystalline
cellulose, microcrystalline cellulose based co blended excipients,
chemically modified excipients such as pregelatinized (or
partially) starch, modified celluloses such as HPMC, CMC, HPC,
enteric polymer coatings such as hypromellose phthalate, cellulose
acetate phthalate (Aquacoat.RTM.), polyvinyl acetate phthalate
(Sureteric.RTM.), hypromellose acetate succinate (AQOAT.RTM.), and
polmethacrylates (Eudragit.RTM. and Acryl-EZE.RTM.), Milk products
for example (but not limited to) milk powder, skim milk powders,
other milk solids and dreviatives, other functional Excipients,
organic acids for example (but not limited to) citric acid,
tartaric acid, malic acid, maleic acid fumaric acid, ascorbic acid,
succinic acid, the conjugate salt of organic acids for example (but
not limited to) sodium citrate, sodium tartrate, sodium malate,
sodium ascorbate, potassium citrate, potassium tartrate, potassium
malate, potassium ascorbate, inorganics such as sodium carbonate,
potassium carbonate, magnesium carbonate, sodium bicarbonate,
potassium bicarbonate and calcium carbonate. dibasic calcium
phosphate, tribasic calcium phosphate, sodium sulfate, sodium
chloride, sodium metabisulphite, sodium thiosulfate, ammonium
chloride, Glauber's salt, ammonium carbonate, sodium bisulfate,
magnesium sulfate, potash alum, potassium chloride, sodium hydrogen
sulfate, sodium hydroxide, crystalline hydroxides, hydrogen
carbonates, hydrogen carbonates of pharmaceutical acceptable alkali
metals, such as but not limited by, sodium, potassium, lithium,
calcium, and barium, ammonium salts (or salts of volatile amines),
for example (but not limited to) ammonium chloride, methylamine
hydrochloride, ammonium bromide, other inorganics for example (but
not limited to), thermal silica, chalk, mica, silica, alumina,
titanium dioxide, talc, kaolin, bentonite, hectorite, magnesium
trisilicate, other clay or clay derivatives or aluminium silicates,
a surfactant for example (but not limited to) sodium lauryl
sulfate, sodium stearyl sulfate, sodium cetyl sulfate, sodium
cetostearyl sulfate, sodium docusate, sodium deoxycholate,
N-lauroylsarcosine sodium salt, glyceryl monostearate, glycerol
distearate glyceryl palmitostearate, glyceryl behenate, glyceryl
caprylate, glyceryl oleate, benzalkonium chloride, CTAB, CTAC,
Cetrimide, cetylpyridinium chloride, cetylpyridinium bromide,
benzethonium chloride, PEG 40 stearate, PEG 100 stearate, poloxamer
188, poloxamer 407, poloxamer 338, polyoxyl 2 stearyl ether,
polyoxyl 100 stearyl ether, polyoxyl 20 stearyl ether, polyoxyl 10
stearyl ether, polyoxyl 20 cetyl ether, polysorbate 20, polysorbate
40, polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80,
polyoxyl 35 castor oil, polyoxyl 40 castor oil, polyoxyl 60 castor
oil, polyoxyl 100 castor oil, polyoxyl 200 castor oil, polyoxyl 40
hydrogenated castor oil, polyoxyl 60 hydrogenated castor oil,
polyoxyl 100 hydrogenated castor oil, polyoxyl 200 hydrogenated
castor oil, cetostearyl alcohol, macrogel 15 hydroxystearate,
sorbitan monopalmitate, sorbitan monostearate, sorbitan trioleate,
Sucrose Palmitate, Sucrose Stearate, Sucrose Distearate, Sucrose
laurate, Glycocholic acid, sodium Glycholate, Cholic Acid, Soidum
Cholate, Sodium Deoxycholate, Deoxycholic acid, Sodium
taurocholate, taurocholic acid, Sodium taurodeoxycholate,
taurodeoxycholic acid, soy lecithin, phosphatidylcholine,
phosphatidylethanolamine, phosphatidylserine, phosphatidylinositol,
PEG4000, PEG6000, PEG8000, PEG10000, PEG20000, alkyl naphthalene
sulfonate condensate/Lignosulfonate blend, Calcium Dodecylbenzene
Sulfonate, Sodium Dodecylbenzene Sulfonate, Diisopropyl
naphthaenesulphonate, erythritol distearate, Naphthalene Sulfonate
Formaldehyde Condensate, nonylphenol ethoxylate (poe-30),
Tristyrylphenol Ethoxylate, Polyoxyethylene (15) tallowalkylamines,
sodium alkyl naphthalene sulfonate, sodium alkyl naphthalene
sulfonate condensate, sodium alkylbenzene sulfonate, sodium
isopropyl naphthalene sulfonate, Sodium Methyl Naphthalene
Formaldehyde Sulfonate, sodium n-butyl naphthalene sulfonate,
tridecyl alcohol ethoxylate (poe-18), Triethanolamine isodecanol
phosphate ester, Triethanolamine tristyrylphosphate ester,
Tristyrylphenol Ethoxylate Sulfate,
Bis(2-hydroxyethyl)tallowalkylamines.
[0216] In a preferred embodiment, the grinding matrix is a matrix
that is considered GRAS (generally regarded as safe) by persons
skilled in the pharmaceutical arts.
[0217] In another preferred aspect a combination of two or more
suitable matrices, such as those listed above, can be used as the
grinding matrix to provide improved properties such as the
reduction of caking, and greater improvement of the dissolution
profile. Combination matrices may also be advantageous when the
matrices have different solubility's allowing the removal or
partial removal of one matrix, while leaving the other or part of
the other to provide encapsulation or partial encapsulation of the
biologically active material.
[0218] Another highly preferred aspect of the method is the
inclusion of a suitable milling aid in the matrix to improve
milling performance. Improvements to milling performance would be
things such as, but not limited to, a reduction in caking or higher
recovery of powder from the mill. Examples of suitable milling aids
include surfactants, polymers and inorganics such as silica
(including colloidal silica), aluminium silicates and clays.
[0219] There are a wide range of surfactants that will make
suitable milling aids. The highly preferred form is where the
surfactant is a solid, or can be manufactured into a solid.
Preferably, the surfactant is selected from the group consisting
of: polyoxyethylene alkyl ethers, polyoxyethylene stearates,
polyethylene glycols (PEG), poloxamers, poloxamines, sarcosine
based surfactants, polysorbates, aliphatic alcohols, alkyl and aryl
sulfates, alkyl and aryl polyether sulfonates and other sulfate
surfactants, trimethyl ammonium based surfactants, lecithin and
other phospholipids, bile salts, polyoxyethylene castor oil
derivatives, polyoxyethylene sorbitan fatty acid esters, Sorbitan
fatty acid esters, Sucrose fatty acid esters, alkyl
glucopyranosides, alkyl maltopyranosides, glycerol fatty acid
esters, Alkyl Benzene Sulphonic Acids, Alkyl Ether Carboxylic
Acids, Alkyl and aryl Phosphate esters, Alkyl and aryl Sulphate
esters, Alkyl and aryl Sulphonic acids, Alkyl Phenol Phosphates
esters, Alkyl Phenol Sulphates esters, Alkyl and Aryl Phosphates,
Alkyl Polysaccharides, Alkylamine Ethoxylates, Alkyl-Naphthalene
Sulphonates formaldehyde condensates, Sulfosuccinates,
lignosulfonates, Ceto-Oleyl Alcohol Ethoxylates, Condensed
Naphthalene Sulphonates, Dialkyl and Alkyl Naphthalene Sulphonates,
Di-alkyl Sulphosuccinates, Ethoxylated nonylphenols, Ethylene
Glycol Esters, Fatty Alcohol Alkoxylates, Hydrogenated
tallowalkylamines, Mono-alkyl Sulphosuccinamates, Nonyl Phenol
Ethoxylates, Sodium Oleyl N-methyl Taurate, Tallowalkylamines,
linear and branched dodecylbenzene sulfonic acids
[0220] Preferably, the surfactant is selected from the group
consisting of: sodium lauryl sulfate, sodium stearyl sulfate,
sodium cetyl sulfate, sodium cetostearyl sulfate, sodium docusate,
sodium deoxycholate, N-lauroylsarcosine sodium salt, glyceryl
monostearate, glycerol distearate glyceryl palmitostearate,
glyceryl behenate, glyceryl caprylate, glyceryl oleate,
benzalkonium chloride, CTAB, CTAC, Cetrimide, cetylpyridinium
chloride, cetylpyridinium bromide, benzethonium chloride, PEG 40
stearate, PEG 100 stearate, poloxamer 188, poloxamer 338, poloxamer
407 polyoxyl 2 stearyl ether, polyoxyl 100 stearyl ether, polyoxyl
20 stearyl ether, polyoxyl 10 stearyl ether, polyoxyl 20 cetyl
ether, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate
61, polysorbate 65, polysorbate 80, polyoxyl 35 castor oil,
polyoxyl 40 castor oil, polyoxyl 60 castor oil, polyoxyl 100 castor
oil, polyoxyl 200 castor oil, polyoxyl 40 hydrogenated castor oil,
polyoxyl 60 hydrogenated castor oil, polyoxyl 100 hydrogenated
castor oil, polyoxyl 200 hydrogenated castor oil, cetostearyl
alcohol, macrogel 15 hydroxystearate, sorbitan monopalmitate,
sorbitan monostearate, sorbitan trioleate, Sucrose Palmitate,
Sucrose Stearate, Sucrose Distearate, Sucrose laurate, Glycocholic
acid, sodium Glycholate, Cholic Acid, Soidum Cholate, Sodium
Deoxycholate, Deoxycholic acid, Sodium taurocholate, taurocholic
acid, Sodium taurodeoxycholate, taurodeoxycholic acid, soy
lecithin, phosphatidylcholine, phosphatidylethanolamine,
phosphatidylserine, phosphatidylinositol, PEG4000, PEG6000,
PEG8000, PEG10000, PEG20000, alkyl naphthalene sulfonate
condensate/Lignosulfonate blend, Calcium Dodecylbenzene Sulfonate,
Sodium Dodecylbenzene Sulfonate, Diisopropyl naphthaenesulphonate,
erythritol distearate, Naphthalene Sulfonate Formaldehyde
Condensate, nonylphenol ethoxylate (poe-30), Tristyrylphenol
Ethoxylate, Polyoxyethylene (15) tallowalkylamines, sodium alkyl
naphthalene sulfonate, sodium alkyl naphthalene sulfonate
condensate, sodium alkylbenzene sulfonate, sodium isopropyl
naphthalene sulfonate, Sodium Methyl Naphthalene Formaldehyde
Sulfonate, sodium n-butyl naphthalene sulfonate, tridecyl alcohol
ethoxylate (poe-18), Triethanolamine isodecanol phosphate ester,
Triethanolamine tristyrylphosphate ester, Tristyrylphenol
Ethoxylate Sulfate, Bis(2-hydroxyethyl)tallowalkylamines.
[0221] Preferably the polymer is selected from the list of:
polyvinylpyrrolidones (PVP), polyvinylalcohol, Acrylic acid based
polymers and copolymers of acrylic acid Preferably, the milling aid
has a concentration selected from the group consisting of: 0.1-10%
w/w, 0.1-5% w/w, 0.1-2.5% w/w, of 0.1-2% w/w, 0.1-1%, 0.5-5% w/w,
0.5-3% w/w, 0.5-2% w/w, 0.5-1.5%, 0.5-1 w/w, of 0.75-1.25% w/w,
0.75-1% and 1% w/w.
[0222] Milling Bodies
[0223] In the method of the present invention, the milling bodies
are preferably chemically inert and rigid. The term
"chemically-inert", as used herein, means that the milling bodies
do not react chemically with the biologically active material or
the grinding matrix.
[0224] As described above, the milling bodies are essentially
resistant to fracture and erosion in the milling process.
[0225] The milling bodies are desirably provided in the form of
bodies which may 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.
Preferably, 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).
[0226] Depending on the nature of the biologically active material
and the grinding matrix, the milling media bodies desirably have an
effective mean particle diameter (i.e. "particle size") between
about 0.1 and 30 mm, more preferably between about 1 and about 15
mm, still more preferably between about 3 and 10 mm.
[0227] The milling bodies may 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, for
example, balls fabricated from type 52100 chrome steel, type 316 or
440C stainless steel or type 1065 high carbon steel.
[0228] Preferred ceramics, 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.
Suitable densities for milling media can range from about 1 to 15
g/cm.sup.3', preferably from about 1 to 8 g/cm.sup.3. Preferred
ceramics 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.
[0229] Preferred glass milling media are spherical (e.g. beads),
have a narrow size distribution, are durable, and include, for
example, lead-free soda lime glass and borosilicate glass.
Polymeric milling media are preferably 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.
Preferred polymeric resins, for example, 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. Polymeric
resins typically can have densities ranging from about 0.8 to 3.0
g/cm.sup.3. Higher density polymeric resins are preferred.
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. Preferred
core substances have densities greater than about 2.5
g/cm.sup.3.
[0230] In one embodiment of the invention, 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.
[0231] 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.
[0232] Dry Milling
[0233] In the dry milling process of the present invention, the
biologically active material and grinding matrix, in the form of
crystals, powders, or the like, are combined in suitable
proportions with the plurality of milling bodies in a milling
chamber that is mechanically agitated (i.e. with or without
stirring) for a predetermined period of time at a predetermined
intensity of agitation. Typically, a milling apparatus is used to
impart motion to the milling bodies by the external application of
agitation, whereby various translational, rotational or inversion
motions or combinations thereof are applied to the milling chamber
and its contents, or by the internal application of agitation
through a rotating shaft terminating in a blade, propeller,
impeller or paddle or by a combination of both actions.
[0234] During milling, motion imparted to the milling bodies can
result in application of shearing forces as well as multiple
impacts or collisions having significant intensity between milling
bodies and particles of the biologically active material and
grinding matrix. The nature and intensity of the forces applied by
the milling bodies to the biologically active material and the
grinding matrix is influenced by a wide variety of processing
parameters including: the type of milling apparatus; the intensity
of the forces generated, the kinematic aspects of the process; the
size, density, shape, and composition of the milling bodies; the
weight ratio of the biologically active material and grinding
matrix mixture to the milling bodies; the duration of milling; the
physical properties of both the biologically active material and
the grinding matrix; the atmosphere present during activation; and
others.
[0235] Advantageously, the media mill is capable of repeatedly or
continuously applying mechanical compressive forces and shear
stress to the biologically active material and the grinding matrix.
Suitable media mills include but are not limited to the following:
high-energy ball, sand, bead or pearl mills, basket mill, planetary
mill, vibratory action ball mill, multi-axial shaker/mixer, stirred
ball mill, horizontal small media mill, multi-ring pulverizing
mill, and the like, including small milling media. The milling
apparatus also can contain one or more rotating shafts.
[0236] In a preferred form of the invention, the dry milling is
performed in a ball mill. Throughout the remainder of the
specification reference will be made to dry milling being carried
out by way of a ball mill. Examples of this type of mill are
attritor mills, nutating mills, tower mills, planetary mills,
vibratory mills and gravity-dependent-type ball mills. It will be
appreciated that dry milling in accordance with the method of the
invention may also be achieved by any suitable means other than
ball milling. For example, dry milling may also be achieved using
jet mills, rod mills, roller mills or crusher mills.
[0237] Biologically Active Material
[0238] The biologically active material includes active compounds,
including compounds for veterinary and human use such as but not
limited to, pharmaceutical actives, nutraceuticals, cosmeceuticals,
cosmetics, complementary medicines, natural products, vitamins,
nutrients, biologics, amino acids, proteins, peptides, nucleotides,
nucleic acids. and agricultural compounds such as pesticides,
herbicides and fungicides, germinating agents and the like.
[0239] Other biologically active materials include, but are not
limited to, foods, seeds, cocoa, cocoa powder, cocoa nibs, cocoa
mass, cocoa liquor, cocoa solids, coffee, herbs, spices, other
plant materials, minerals, animal products, shells and other
skeletal material.
[0240] In a preferred form of the invention, the biologically
active material is an organic compound. In a highly preferred form
of the invention, the biologically active material is an organic,
therapeutically active compound for veterinary or human use.
[0241] In a preferred form of the invention, the biologically
active material is an inorganic compound. In a highly preferred
form of the invention, the biologically active material is sulphur,
copper hydroxide, an organometallic complex or copper
oxychloride.
[0242] The biologically active material is ordinarily a material
for which one of skill in the art desires improved dissolution
properties. The biologically active material may be a conventional
active agent or drug, although the process of the invention may be
employed on formulations or agents that already have reduced
particle size compared to their conventional form.
[0243] Biologically active materials suitable for use in the
invention include actives, biologics, amino acids, proteins,
peptides, nucleotides, nucleic acids, and analogs, homologs and
first order derivatives thereof. The biologically active material
can be selected from a variety of known classes of drugs,
including, but not limited to: anti-obesity drugs, central nervous
system stimulants, carotenoids, corticosteroids, elastase
inhibitors, anti-fungals, oncology therapies, anti-emetics,
analgesics, cardiovascular agents, anti-inflammatory agents, such
as NSAIDs and COX-2 inhibitors, anthelmintics, anti-arrhythmic
agents, antibiotics (including penicillins), anticoagulants,
antidepressants, antidiabetic agents, antiepileptics,
antihistamines, antihypertensive agents, antimuscarinic agents,
antimycobacterial agents, antineoplastic agents,
immunosuppressants, antithyroid agents, antiviral agents,
anxiolytics, sedatives (hypnotics and neuroleptics), astringents,
alpha-adrenergic receptor blocking agents, beta-adrenoceptor
blocking agents, blood products and substitutes, cardiac inotropic
agents, contrast media, cough suppressants (expectorants and
mucolytics), diagnostic agents, diagnostic imaging agents,
diuretics, dopaminergics (anti-Parkinsonian agents), haemostatics,
immunological agents, lipid regulating agents, muscle relaxants,
parasympathomimetics, parathyroid calcitonin and biphosphonates,
prostaglandins, radio-pharmaceuticals, sex hormones (including
steroids), anti-allergic agents, stimulants and anoretics,
sympathomimetics, thyroid agents, vasodilators, and xanthines.
[0244] A description of these classes of active agents and a
listing of species within each class can be found in Martindale's
The Extra Pharmacopoeia, 31st Edition (The Pharmaceutical Press,
London, 1996), specifically incorporated by reference. Another
source of active agents is the Physicians Desk Reference (60.sup.th
Ed., pub. 2005), familiar to those of skill in the art. The active
agents are commercially available and/or can be prepared by
techniques known in the art.
[0245] 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
virtually any drug to which the method of the invention may be
applied.
[0246] In addition it is also expected that new chemical entities
(NCE) and other actives for which the methods of the invention are
suitable will be created or become commercially available in the
future.
[0247] Notwithstanding the general applicability of the method of
the invention, more specific examples of biologically active
materials include, but are not limited to: haloperidol (dopamine
antagonist), DL isoproterenol hydrochloride (.beta.-adrenergic
agonist), terfenadine (H1-antagonist), propranolol hydrochloride
(.beta.-adrenergic antagonist), desipramine hydrochloride
(antidepressant), sildenafil citrate, tadalafil and vardenafil.
Minor analgesics (cyclooxygenase inhibitors), fenamic acids,
Piroxicam, Cox-2 inhibitors, and Naproxen, and others, may all
benefit from being prepared.
[0248] As discussed in the context of the background to the
invention, biologically active materials that are poorly water
soluble at gastrointestinal pH will particularly benefit from being
prepared, and the method of the present invention is particularly
advantageously applied to materials that are poorly water soluble
at gastrointestinal pH.
[0249] Such materials include, but are not limited to: albendazole,
albendazole sulfoxide, alfaxalone, acetyl digoxin, acyclovir
analogs, alprostadil, aminofostin, anipamil, antithrombin III,
atenolol, azidothymidine, beclobrate, beclomethasone, belomycin,
benzocaine and derivatives, beta carotene, beta endorphin, beta
interferon, bezafibrate, binovum, biperiden, bromazepam,
bromocryptine, bucindolol, buflomedil, bupivacaine, busulfan,
cadralazine, camptothesin, canthaxanthin, captopril, carbamazepine,
carboprost, cefalexin, cefalotin, cefamandole, cefazedone,
cefluoroxime, cefinenoxime, cefoperazone, cefotaxime, cefoxitin,
cefsulodin, ceftizoxime, chlorambucil, chromoglycinic acid,
ciclonicate, ciglitazone, clonidine, cortexolone, corticosterone,
cortisol, cortisone, cyclophosphamide, cyclosporin A and other
cyclosporins, cytarabine, desocryptin, desogestrel, dexamethasone
esters such as the acetate, dezocine, diazepam, diclofenac,
dideoxyadenosine, dideoxyinosine, digitoxin, digoxin,
dihydroergotamine, dihydroergotoxin, diltiazem, dopamine
antagonists, doxorubicin, econazole, endralazine, enkephalin,
enalapril, epoprostenol, estradiol, estramustine, etofibrate,
etoposide, factor ix, factor viii, felbamate, fenbendazole,
fenofibrate, fexofenedine, flunarizin, flurbiprofen,
5-fluorouracil, flurazepam, fosfomycin, fosmidomycin, furosemide,
gallopamil, gamma interferon, gentamicin, gepefrine, gliclazide,
glipizide, griseofulvin, haptoglobulin, hepatitis B vaccine,
hydralazine, hydrochlorothiazide, hydrocortisone, ibuprofen,
ibuproxam, indinavir, indomethacin, iodinated aromatic x-ray
contrast agents such as iodamide, ipratropium bromide,
ketoconazole, ketoprofen, ketotifen, ketotifen fumarate,
K-strophanthin, labetalol, lactobacillus vaccine, lidocaine,
lidoflazin, lisuride, lisuride hydrogen maleate, lorazepam,
lovastatin, mefenamic acid, melphalan, memantin, mesulergin,
metergoline, methotrexate, methyl digoxin, methylprednisolone,
metronidazole, metisoprenol, metipranolol, metkephamide,
metolazone, metoprolol, metoprolol tartrate, miconazole, miconazole
nitrate, minoxidil, misonidazol, molsidomin, nadolol, nafiverine,
nafazatrom, naproxen, natural insulins, nesapidil, nicardipine,
nicorandil, nifedipine, niludipin, nimodipine, nitrazepam,
nitrendipine, nitrocamptothesin, 9-nitrocamptothesin, olanzapine,
oxazepam, oxprenolol, oxytetracycline, penicillins such as
penicillin G benethamine, penecillin O, phenylbutazone, picotamide,
pindolol, piposulfan, piretanide, piribedil, piroxicam, pirprofen,
plasminogenici activator, prednisolone, prednisone, pregnenolone,
procarbacin, procaterol, progesterone, proinsulin, propafenone,
propanolol, propentofyllin, propofol, propranolol, raloxifene,
rifapentin, simvastatin, semi-synthetic insulins, sobrerol,
somastotine and its derivatives, somatropin, stilamine, sulfinalol
hydrochloride, sulfinpyrazone, suloctidil, suprofen, sulproston,
synthetic insulins, talinolol, taxol, taxotere, testosterone,
testosterone propionate, testosterone undecanoate, tetracane HI,
tiaramide HCl, tolmetin, tranilast, triquilar, tromantadine HCl,
urokinase, valium, verapamil, vidarabine, vidarabine phosphate
sodium salt, vinblastine, vinburin, vincamine, vincristine,
vindesine, vinpocetine, vitamin A, vitamin E succinate, and x-ray
contrast agents. Drugs can be neutral species or basic or acidic as
well as salts of an acid or base. Specifically the chemical makeup
and the functional groups, including an acid or base group, are
generally not the determinant factor, excepting a possible chemical
reaction with a specific matrix, for the successful creation of a
biologically active substance with a reduced particle size. This
invention is not limited to any drug specific class, application
type, chemical type or function grouping. Rather the suitability of
a biologically active material for use in this invention is
primarily determined by the mechanical properties of the material.
In addition, some biologically active materials may have the
benefit of absorption through the skin if presented in a particle
formulation. Such biologically active materials include, but are
not limited to, Voltaren (diclofenac), rofecoxib, and
ibuprofen.
[0250] Conveniently, the biologically active material is capable of
withstanding temperatures that are typical in uncooled dry milling,
which may exceed 80.degree. C. Therefore, materials with a melting
point about 80.degree. C. or greater are highly suitable. For
biologically active materials with lower melting points, the media
mill may be cooled, thereby allowing materials with significantly
lower melting temperatures to be processed according to the method
of the invention. For instance, a simple water-cooled mill will
keep temperatures below 50.degree. C., or chilled water could be
used to further lower the milling temperature. Those skilled in the
art will understand that a high energy ball mill could be designed
to run at any temperature between say -30 to 200.degree. C. For
some biologically active materials it may be advantageous to
control the milling temperature to temperatures significantly below
the melting points of the biologically active materials.
[0251] The biologically active material is obtained in a
conventional form commercially and/or prepared by techniques known
in the art.
[0252] It is preferred, but not essential, that the particle size
of the biologically active material be less than about 1000 .mu.m,
as determined by sieve analysis. If the coarse particle size of the
biologically active material is greater than about 1000 .mu.m, then
it is preferred that the particles of the biologically active
material substrate be reduced in size to less than 1000 .mu.m using
another standard milling method.
[0253] Processed Biologically Active Material
[0254] Preferably, the biologically active materials, which have
been subject to the methods of the invention, comprises particles
of biologically active material of an average particle size,
determined on a particle number basis, is equal to or less than a
size selected from the group 10,000 nm, 5000 nm, 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.
[0255] Preferably, the biologically active materials, which have
been subject to the methods of the invention, comprises particles
of biologically active material of a median particle size,
determined on a particle volume basis, equal or less than a size
selected from the group 20,000 nm, 15,000 nm, 10,000 nm, 5000 nm,
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.
[0256] These sizes refer to particles either fully dispersed or
partially agglomerated.
[0257] Agglomerates of Biologically Active Material after
Processing
[0258] Agglomerates comprising particles of biologically active
material, said particles having a particle size within the ranges
specified above, should be understood to fall within the scope of
the present invention, regardless of whether the agglomerates
exceed the ranges specified above. Agglomerates comprising
particles of biologically active material, said agglomerates having
a total agglomerate size within the ranges specified above, should
be understood to fall within the scope of the present
invention.
[0259] Agglomerates comprising particles of biologically active
material should be understood to fall within the scope of the
present invention if at the time of use, or further processing, the
particle size of the agglomerate is within the ranges specified
above.
[0260] Agglomerates comprising particles of biologically active
material, said particles having a particle size within the ranges
specified above, at the time of use, or further processing, should
be understood to fall within the scope of the present invention,
regardless of whether the agglomerates exceed the ranges specified
above.
[0261] Processing Time
[0262] Preferably, the biologically active material and the
grinding matrix are dry milled for the shortest time necessary to
form the mixture of the biologically active material in the
grinding matrix such that the active material has improved
dissolution to minimise any possible contamination from the media
mill and/or the plurality of milling bodies. This time varies
greatly, depending on the biologically active material and the
grinding matrix, and may range from as short as 1 minute to several
hours. Dry milling times in excess of 2 hours may lead to
degradation of the biologically active material and an increased
level of undesirable contaminants.
[0263] Suitable rates of agitation and total milling times are
adjusted for the type and size of milling apparatus as well as the
milling media, the weight ratio of the biologically active material
and grinding matrix mixture to the plurality of milling bodies, the
chemical and physical properties of the biologically active
material and grinding matrix, and other parameters that may be
optimized empirically.
[0264] Inclusion of the Grinding Matrix with the Biologically
Active Material and Separation of the Grinding Matrix from the
Biologically Active Material
[0265] In a preferred aspect, the grinding matrix is not separated
from the biologically active material but is maintained with the
biologically active material in the final product. Preferably the
grinding matrix is considered to be Generally Regarded as Safe
(GRAS) for pharmaceutical products.
[0266] In an alternative aspect, the grinding matrix is separated
from the biologically active material. In one aspect, where the
grinding matrix is not fully milled, the unmilled grinding matrix
is separated from the biologically active material. In a further
aspect, at least a portion of the milled grinding matrix is
separated from the biologically active material.
[0267] Any portion of the grinding matrix may be removed, including
but not limited to 10%, 25%, 50%, 75%, or substantially all of the
grinding matrix.
[0268] In some embodiments of the invention, a significant portion
of the milled grinding matrix may comprise particles of a size
similar to and/or smaller than the particles comprising the
biologically active material. Where the portion of the milled
grinding matrix to be separated from the particles comprising the
biologically active material comprises particles of a size similar
to and/or smaller than the particles comprising the biologically
active material, separation techniques based on size distribution
are inapplicable.
[0269] In these circumstances, the method of the present invention
may involve separation of at least a portion of the milled grinding
matrix from the biologically active material by techniques
including but not limited to electrostatic separation, magnetic
separation, centrifugation (density separation), hydrodynamic
separation, froth flotation.
[0270] Advantageously, the step of removing at least a portion of
the milled grinding matrix from the biologically active material
may be performed through means such as selective dissolution,
washing, or sublimation.
[0271] An advantageous aspect of the invention would be the use of
grinding matrix that has two or more components where at least one
component is water soluble and at least one component has low
solubility in water. In this case washing can be used to remove the
matrix component soluble in water leaving the biologically active
material encapsulated in the remaining matrix components. In a
highly advantageous aspect of the invention the matrix with low
solubility is a functional excipient.
[0272] A highly advantageous aspect of the present invention is
that certain grinding matrixes appropriate for use in the method of
the invention (in that they physically degrade to the desired
extent under dry milling conditions) are also pharmaceutically
acceptable and thus appropriate for use in a medicament. Where the
method of the present invention does not involve complete
separation of the grinding matrix from the biologically active
material, the present invention encompasses methods for the
production of a medicament incorporating both the biologically
active material and at least a portion of the milled grinding
matrix, medicaments so produced and methods of treatment of an
animal, including man, using a therapeutically effective amount of
said biologically active materials by way of said medicaments.
[0273] The medicament may include only the biologically active
material and the grinding matrix or, more preferably, the
biologically active materials and grinding matrix may be combined
with one or more pharmaceutically acceptable carriers, as well as
any desired excipients or other like agents commonly used in the
preparation of medicaments.
[0274] Analogously, a highly advantageous aspect of the present
invention is that certain grinding matrixes appropriate for use in
the method of the invention (in that they physically degrade to a
desirable extent under dry milling conditions) are also appropriate
for use in an agricultural chemical composition. Where the method
of the present invention does not involve complete separation of
the grinding matrix from the biologically active material, the
present invention encompasses methods for the production of a
agricultural chemical composition incorporating both the
biologically active material and at least a portion of the milled
grinding matrix, agricultural chemical composition so produced and
methods of use of such compositions.
[0275] The agricultural chemical composition may include only the
biologically active material and the grinding matrix or, more
preferably, the biologically active materials and grinding matrix
may be combined with one or more acceptable carriers, as well as
any desired excipients or other like agents commonly used in the
preparation of agricultural chemical compositions.
[0276] In one particular form of the invention, the grinding matrix
is both appropriate for use in a medicament and readily separable
from the biologically active material by methods not dependent on
particle size. Such grinding matrixes are described in the
following detailed description of the invention. Such grinding
matrixes are highly advantageous in that they afford significant
flexibility in the extent to which the grinding matrix may be
incorporated with the biologically active material into a
medicament.
[0277] The mixture of biologically active material and grinding
matrix may then be separated from the milling bodies and removed
from the mill.
[0278] In one embodiment, the grinding matrix is separated from the
mixture of biologically active material and grinding matrix. Where
the grinding matrix is not fully milled, the unmilled grinding
matrix is separated from the biologically active material. In a
further aspect, at least a portion of the milled grinding matrix is
separated from the biologically active material.
[0279] The milling bodies are essentially resistant to fracture and
erosion in the dry milling process.
[0280] The quantity of the grinding matrix relative to the quantity
of biologically active material, and the extent of milling of the
grinding matrix, is sufficient to provide reduced particle size of
the biologically active material.
[0281] The grinding matrix is neither chemically nor mechanically
reactive with the pharmaceutical material under the dry milling
conditions of the method of the invention except, for example,
where the matrix is deliberately chosen to undergo a
mechanico-chemical reaction. Such a reaction might be the
conversion of a free base or acid to a salt or vice versa.
[0282] Preferably, the medicament is a solid dosage form, however,
other dosage forms may be prepared by those of ordinary skill in
the art.
[0283] In one form, after the step of separating said mixture of
biologically active material and grinding matrix from the plurality
of milling bodies, and before the step of using said mixture of
biologically active material and grinding matrix in the manufacture
of a medicament, the method may comprise the step of:
[0284] removing a portion of the grinding matrix from said mixture
of biologically active material and grinding matrix to provide a
mixture enriched in the biologically active material;
[0285] and the step of using said mixture of biologically active
material and grinding matrix in the manufacture of a medicament,
more particularly comprises the step of using the mixture of
biologically active material and grinding matrix enriched in the
biologically active material form in the manufacture of a
medicament.
[0286] The present invention includes medicaments manufactured by
said methods, and methods for the treatment of an animal, including
man, by the administration of a therapeutically effective amount of
the biologically active materials by way of said medicaments.
[0287] In another embodiment of the invention, a facilitating agent
or a combination of facilitating agents is also comprised in the
mixture to be milled. Such facilitating agents appropriate for use
in the invention include diluents, surfactants, polymers, binding
agents, filling agents, lubricating agents, sweeteners, flavouring
agents, preservatives, buffers, wetting agents, disintegrants,
effervescent agents and agents that may form part of a medicament,
including a solid dosage form, or other excipients required for
other specific drug delivery, such as the agents and media listed
below under the heading Medicinal and Pharmaceutical Compositions,
or any combination thereof.
[0288] Biologically Active Materials and Compositions
[0289] The present invention encompasses pharmaceutically
acceptable materials produced according to the methods of the
present invention, compositions including such materials, including
compositions comprising such materials together with the grinding
matrix with or without milling aids, facilitating agents, with at
least a portion of the grinding matrix or separated from the
grinding matrix.
[0290] The pharmaceutically acceptable materials within the
compositions of the invention are present at a concentration of
between about 0.1% and about 99.0% by weight. Preferably, the
concentration of pharmaceutically acceptable materials within the
compositions will be about 5% to about 80% by weight, while
concentrations of 10% to about 50% by weight are highly preferred.
Desirably, the concentration will be in the range of about 10 to
15% by weight, 15 to 20% by weight, 20 to 25% by weight, 25 to 30%
by weight, 30 to 35% by weight, 35 to 40% by weight, 40 to 45% by
weight, 45 to 50% by weight, 50 to 55% by weight, 55 to 60% by
weight, 60 to 65% by weight, 65 to 70% by weight, 70 to 75% by
weight or 75 to 80% by weight for the composition prior to any
later removal (if desired) of any portion of the grinding matrix.
Where part or all of the grinding matrix has been removed, the
relative concentration of pharmaceutically acceptable materials in
the composition may be considerably higher depending on the amount
of the grinding matrix that is removed. For example, if all of the
grinding matrix is removed the concentration of particles in the
preparation may approach 100% by weight (subject to the presence of
facilitating agents).
[0291] Compositions produced according to the present invention are
not limited to the inclusion of a single species of
pharmaceutically acceptable materials. More than one species of
pharmaceutically acceptable materials may therefore be present in
the composition. Where more than one species of pharmaceutically
acceptable materials is present, the composition so formed may
either be prepared in a dry milling step, or the pharmaceutically
acceptable materials may be prepared separately and then combined
to form a single composition.
[0292] Medicaments
[0293] The medicaments of the present invention may include the
pharmaceutically acceptable material, optionally together with the
grinding matrix or at least a portion of the grinding matrix, with
or without milling aids, facilitating agents, combined with one or
more pharmaceutically acceptable carriers, as well as other agents
commonly used in the preparation of pharmaceutically acceptable
compositions.
[0294] As used herein "pharmaceutically acceptable carrier"
includes any and all solvents, dispersion media, coatings,
antibacterial and antifungal agents, isotonic and absorption
delaying agents, and the like that are physiologically compatible.
Preferably, the carrier is suitable for parenteral administration,
intravenous, intraperitoneal, intramuscular, sublingual, pulmonary,
transdermal or oral administration. Pharmaceutically acceptable
carriers include sterile aqueous solutions or dispersions and
sterile powders for the extemporaneous preparation of sterile
injectable solutions or dispersion. The use of such media and
agents for the manufacture of medicaments is well known in the art.
Except insofar as any conventional media or agent is incompatible
with the pharmaceutically acceptable material, use thereof in the
manufacture of a pharmaceutical composition according to the
invention is contemplated.
[0295] Pharmaceutical acceptable carriers according to the
invention may include one or more of the following examples: [0296]
(1) surfactants and polymers including, but not limited to
polyethylene glycol (PEG), polyvinylpyrrolidone (PVP),
polyvinylalcohol, crospovidone,
polyvinylpyrrolidone-polyvinylacrylate copolymer, cellulose
derivatives, hydroxypropylmethyl cellulose, hydroxypropyl
cellulose, carboxymethylethyl cellulose, hydroxypropyllmethyl
cellulose phthalate, polyacrylates and polymethacrylates, urea,
sugars, polyols, and their polymers, emulsifiers, sugar gum,
starch, organic acids and their salts, vinyl pyrrolidone and vinyl
acetate [0297] (2) binding agents such as various celluloses and
cross-linked polyvinylpyrrolidone, microcrystalline cellulose; and
or [0298] (3) filling agents such as lactose monohydrate, lactose
anhydrous, microcrystalline cellulose and various starches; and or
[0299] (4) lubricating agents such as agents that act on the
flowability of the powder to be compressed, including colloidal
silicon dioxide, talc, stearic acid, magnesium stearate, calcium
stearate, silica gel; and or [0300] (5) sweeteners such as any
natural or artificial sweetener including sucrose, xylitol, sodium
saccharin, cyclamate, aspartame, and accsulfame K; and or [0301]
(6) flavouring agents; and or [0302] (7) preservatives such as
potassium sorbate, methylparaben, propylparaben, benzoic acid and
its salts, other esters of parahydroxybenzoic acid such as
butylparaben, alcohols such as ethyl or benzyl alcohol, phenolic
chemicals such as phenol, or quarternary compounds such as
benzalkonium chloride; and or [0303] (8) buffers; and or [0304] (9)
Diluents such as pharmaceutically acceptable inert fillers, such as
microcrystalline cellulose, lactose, dibasic calcium phosphate,
saccharides, and/or mixtures of any of the foregoing; and or [0305]
(10) wetting agents such as corn starch, potato starch, maize
starch, and modified starches, croscarmellose sodium,
crosspovidone, sodium starch glycolate, and mixtures thereof; and
or [0306] (11) disintegrants; and or [0307] (12) effervescent
agents such as effervescent couples such as an organic acid (e.g.,
citric, tartaric, malic, fumaric, adipic, succinic, and alginic
acids and anhydrides and acid salts), or a carbonate (e.g. sodium
carbonate, potassium carbonate, magnesium carbonate, sodium glycine
carbonate, L-lysine carbonate, and arginine carbonate) or
bicarbonate (e.g. sodium bicarbonate or potassium bicarbonate); and
or [0308] (13) other pharmaceutically acceptable excipients.
[0309] Medicaments of the invention suitable for use in animals and
in particular in man typically must be stable under the conditions
of manufacture and storage. The medicaments of the invention
comprising the biologically active material can be formulated as a
solid, a solution, a microemulsion, a liposome, or other ordered
structures suitable to high drug concentration. Actual dosage
levels of the biologically active material in the medicament of the
invention may be varied in accordance with the nature of the
biologically active material, as well as the potential increased
efficacy due to the advantages of providing and administering the
biologically active material (e.g., increased solubility, more
rapid dissolution, increased surface area of the biologically
active material, etc.). Thus as used herein "therapeutically
effective amount" will refer to an amount of biologically active
material required to effect a therapeutic response in an animal.
Amounts effective for such a use will depend on: the desired
therapeutic effect; the route of administration; the potency of the
biologically active material; the desired duration of treatment;
the stage and severity of the disease being treated; the weight and
general state of health of the patient; and the judgment of the
prescribing physician.
[0310] In another embodiment, the biologically active material,
optionally together with the grinding matrix or at least a portion
of the grinding matrix, of the invention may be combined into a
medicament with another biologically active material, or even the
same biologically active material. In the latter embodiment, a
medicament may be achieved which provides for different release
characteristics--early release from the biologically active
material, and later release from a larger average size biologically
active material.
[0311] Modes of Administration of Medicaments Comprising
Biologically Active Materials
[0312] Medicaments of the invention can be administered to animals,
including man, in any pharmaceutically acceptable manner, such as
orally, rectally, pulmonary, intravaginally, locally (powders,
ointments or drops), transdermal, parenteral administration,
intravenous, intraperitoneal, intramuscular, sublingual or as a
buccal or nasal spray
[0313] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, pellets, and granules. Further,
incorporating any of the normally employed excipients, such as
those previously listed, and generally 5-95% of the biologically
active agent, and more preferably at a concentration of 10%-75%
will form a pharmaceutically acceptable non-toxic oral composition.
Medicaments of the invention may be parenterally administered as a
solution of the biologically active agent suspended in an
acceptable carrier, preferably an aqueous carrier. A variety of
aqueous carriers may be used, e.g. water, buffered water, 0.4%
saline, 0.3% glycine, hyaluronic acid and the like. These
compositions may be sterilized by conventional, well known
sterilization techniques, or may be sterile filtered. The resulting
aqueous solutions may be packaged for use as is, or lyophilized,
the lyophilized preparation being combined with a sterile solution
prior to administration.
[0314] For aerosol administration, medicaments of the invention are
preferably supplied along with a surfactant or polymer and
propellant. The surfactant or polymer must, of course, be
non-toxic, and preferably soluble in the propellant. Representative
of such agents are the esters or partial esters of fatty acids
containing from 6 to 22 carbon atoms, such as caproic, octanoic,
lauric, palmitic, stearic, linoleic, linolenic, olesteric and oleic
acids with an aliphatic polyhydric alcohol or its cyclic anhydride.
Mixed esters, such as mixed or natural glycerides may be employed.
The surfactant or polymer may constitute 0.1%-20% by weight of the
composition, preferably 0.25-5%. The balance of the composition is
ordinarily propellant. A carrier can also be included, as desired,
as with, e.g., lecithin for intranasal delivery.
[0315] Medicaments of the invention may also be administered via
liposomes, which serve to target the active agent to a particular
tissue, such as lymphoid tissue, or targeted selectively to cells.
Liposomes include emulsions, foams, micelles, insoluble monolayers,
liquid crystals, phospholipid dispersions, lamellar layers and the
like. In these preparations the composite microstructure
composition is incorporated as part of a liposome, alone or in
conjunction with a molecule that binds to or with other therapeutic
or immunogenic compositions.
[0316] As described above, the biologically active material can be
formulated into a solid dosage form (e.g., for oral or suppository
administration), together with the grinding matrix or at least a
portion of it. In this case there may be little or no need to add
stabilizing agents since the grinding matrix may effectively act as
a solid-state stabilizer.
[0317] However, if the biologically active material is to be
utilized in a liquid suspension, the particles comprising the
biologically active material may require further stabilization once
the solid carrier has been substantially removed to ensure the
elimination, or at least minimisation of particle
agglomeration.
[0318] Inhaled and Intranasal Delivery
[0319] Dry powder formulations of active pharmaceutical ingredients
(including blends of active and excipients) for inhalation or nasal
delivery are important tools for the delivery of medications.
Common uses have been in the delivery of pharmaceutical agents that
act locally. Examples of this are astma medications delivered to
the lungs or decongestants delivered by an intranasal route. These
delivery routes are also becoming more important for systemic
delivery. Thus the pharmaceutical formulator will require more and
improved techniques to manufacture formulations for these
purposes.
[0320] Two of the critical parameters for inhaled or intranasal 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.
[0321] One common measure of particle size used to characterize dry
powder formulations is the Mass Median Aerodynamic Diameter (MMAD).
This is defined as the aerodynamic diameter at which 50% of the
particles by mass are larger and 50% are smaller. Aerodynamic
particle size measurements are typically made using devices such as
the Anderson Cascade Impactor or the New Generation Impactor which
use a series of stages that have decending cut off diameters. Other
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. For an
inhaled formulation the MMAD is preferably less than 10 microns,
more preferably less than 5 microns. Where dry powder sizing by
laser diffraction is used, the median particle size is preferably
less than 10 microns.
[0322] Powders suitable for intranasal delivery would preferably
have an aerodynamic particle size equal to or greater than 10
micron. Thus where dry powder sizing by laser diffraction is used
the median particle size is preferably equal to or greater than 10
microns. The area of deposition within the nasal cavity is also
governed by the particle size of the powder. Generally powder that
has an aerodynamic particle size greater than 20 micron will be
deposited in the anterior portion of the nose where longer
residence times occur. Generally powder that has an aerodynamic
particle size equal to or greater than 10 micron but less than 20
microns will be deposited in the posterior portion of the nose
where permeability is generally higher providing good systemic
absorption.
[0323] In the aspect of this invention relating to intranasal
formulations where dry powder sizing by laser diffraction is used,
the median particle size is preferably equal to or greater than 10
microns. Preferably, the median particle size is equal to or
greater than 10 microns and less than 20 micron for posterior
delivery. Preferably, the median particle size is equal to or
greater than 20 micron for anterior delivery.
[0324] Suitable methods for preparing formulations for intranasal
delivery are widely known in the art. For example, WO2009/027337
(Applicant: Novartis AG, and hereby incorporated by reference),
provides methods for making formulations for intranasl delivery
using wet processes followed by spray drying steps. The methods
described in the WO2009/027337 publication use complex recipes,
equipment and multiple steps. In contrast, the invention which is
the subject of this application is a simple one step dry milling
process.
[0325] Therapeutic Uses
[0326] Therapeutic uses of the medicaments of the invention include
pain relief, anti-inflammatory, migraine, asthma, and other
disorders that require the active agent to be administered with a
high bioavailability.
[0327] One of the main areas when rapid bioavailability of a
biologically active material is required is in the relief of pain.
The minor analgesics, such as cyclooxgenase inhibitors (aspirin
related drugs) may be prepared as medicaments according to the
present invention.
[0328] Medicaments of the invention may also be used for treatment
of eye disorders. That is, the biologically active material may be
formulated for administration on the eye as an aqueous suspension
in physiological saline, or a gel. In addition, the biologically
active material may be prepared in a powder form for administration
via the nose for rapid central nervous system penetration.
[0329] Treatment of cardiovascular disease may also benefit from
biologically active materials according to the invention, such as
treatment of angina pectoris and, in particular, molsidomine may
benefit from better bioavailability.
[0330] Other therapeutic uses of the medicaments of the present
invention include treatment of hair loss, sexual dysfunction, or
dermal treatment of psoriasis.
[0331] The present invention will now be described with reference
to the following non-limiting Examples. The description of the
Examples is in no way limiting on the preceding paragraphs of this
specification, but is provided for exemplification of the methods
and compositions of the invention.
EXAMPLES
[0332] It will be apparent to persons skilled in the milling and
pharmaceutical arts that numerous enhancements and modifications
can be made to the above described processes without departing from
the basic inventive concepts. For example, in some applications the
biologically active material may be pretreated and supplied to the
process in the pretreated form. All such modifications and
enhancements are considered to be within the scope of the present
invention, the nature of which is to be determined from the
foregoing description and the appended claims. Furthermore, the
following Examples are provided for illustrative purposes only, and
are not intended to limit the scope of the processes or
compositions of the invention.
[0333] The Following Materials were Used in the Examples
[0334] Active pharmaceutical ingredients were sourced from
commercial suppliers, excipients from either commercial suppliers
such as Sigma-Aldrich or retailers, while food ingredients were
sourced from retailers.
[0335] The Following Mills were Used for the Grinding
Experiments
[0336] Spex-Type Mill:
[0337] Small scale milling experiments were conducted using a
vibratory Spex 8000D mixer/mill. Twelve 3/8'' stainless steel balls
were used as the grinding media. The powder charge and grinding
media were loaded into a hardened steel vial with an internal
volume of approximately 75 mL. Following milling, the milled
material was discharged from the vial and sieved to remove grinding
media.
[0338] Attritor-Type Mill:
[0339] Small scale attritor milling experiments were performed
using a 1HD Union Process attritor mill with a 110 mL grinding
chamber. The grinding media consisted of 330 g 5/16'' stainless
steel balls. The mill was loaded through the loading port, with dry
materials added initially, followed by the grinding media. The
milling process was conducted with the jacket cooled at
10-20.degree. C. and the shaft rotating at 500 rpm. Upon completion
of milling, the milled material was discharged from the mill and
sieved to remove the grinding media.
[0340] Medium scale attritor milling experiments were performed
using a 1HD Union Process attritor mill with a 1 L grinding chamber
or a 1S Union Process attritor mill with a 750 mL grinding chamber.
The grinding media consisted of 3 kg of 5/16'' stainless steel
balls or 1.5 kg of 3/8'' stainless steel balls for the 1S attritor.
The 1HD mill was loaded through the loading port, with dry
materials added initially, followed by the grinding media, while
the grinding media was added initially, followed by the dry
materials in the 1S attritor mill. The milling process was
conducted with the jacket cooled at 10-20.degree. C. with the shaft
rotating at 350 rpm in the 1HD attritor or 550 rpm in the 1S
attritor. Upon completion of milling, the milled material was
discharged from the mill and sieved to remove the grinding
media.
[0341] Medium to large scale attritor milling experiments were
performed using a 1S Union Process attritor mill with a 1/2 gallon
grinding chamber. The grinding media consisted of 7 kg of 3/8''
stainless steel balls. The mill was loaded through the loading
port, with the grinding media added initially, followed by the dry
powders. The milling process was conducted with the jacket cooled
at 18.degree. C. and the shaft rotating at 550-555 rpm. Upon
completion of milling, the milled powder was discharged from the
mill through the bottom discharge port at 77 rpm for 5 min.
[0342] Large scale attritor milling experiments were performed
using a 1S Union Process attritor mill with a 11/2 gallon grinding
chamber. The grinding media consisted of 20 kg of 3/8'' stainless
steel balls. 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 ambient
temperature and the shaft rotating at 300 rpm. Upon completion of
milling, the milled powder was discharged from the mill through the
bottom discharge port at 77 rpm for 5 min.
[0343] The largest scale attritor millings were done in a 30S Union
Process mill with a 25 gallon grinding chamber (Union Process,
Akron Ohio, USA). The grinding media consisted of 454 kg of 3/8''
stainless steel balls. The mill was loaded through its split top
lid, with the grinding media added initially, then followed by the
dry powders (25 kg). The milling process was conducted with the
jacket cooled to 10.degree. C. and the shaft rotating at 130 rpm.
Upon completion of milling, the milled powder was discharged from
the mill through the bottom discharge port at 77 rpm for 5 min.
[0344] Siebtechnik Mill
[0345] Medium scale milling experiments were also performed in a
Siebtechnik GSM06 (Siebtechnik, GmbH, Germany) with two 1 L milling
chambers. Each chamber was filled with 2.7 kg stainless steel media
with a diameter of 3/8''. The media and powder were loaded with the
lid off. The mill was operated at ambient temperature. The
vibration speed was the standard mill settings. Upon completion of
the milling the media was separated from the powder by sieving.
[0346] Simoloyer Mill
[0347] Medium scale milling experiments were performed in a
Simoloyer CM01 (ZOZ GmbH, Germany) with a 2 L milling chamber. The
grinding media consisted of 2.5 kg stainless steel media with a
diameter of 5 mm. the media was loaded though the loading port
followed by the dry materials. The milling vessel was cooled using
water at a temperature of about 18.degree. C. The mill speed was
operated in cycle mode: at 1300 rpm for two minutes and at 500 rpm
for 0.5 min and so forth. Upon completion of the milling the media
was discharged from the mill using a grated valve to retain the
grinding media.
[0348] Large scale milling experiments were performed in a
Simoloyer CM100 (ZOZ GmbH, Germany) with a 100 L milling chamber.
The grinding media consisted of 100 kg stainless steel media with a
diameter of 3/16''. The powder charge (11 kg) was added to the
milling chamber, which already contained the grinding media,
through a loading port. The milling chamber was cooled to
18.degree. C. and the powder was milled for a total of 20 minutes
using a cycling mode equivalent to a tip speed at 1300/500 rpm for
2/0.5 min in the CM-01 type mill. Upon completion of the milling
the mill was discharged by sucking the powder into a cyclone.
[0349] Hicom Mill
[0350] Millings performed in a nutating Hicom mill utilized 14 kg
of stainless steel 0.25'' grinding media together with a powder
charge of 480 g. The mill was loaded by pre-mixing media and
powder, then adding the mixture to the grinding chamber through the
loading port at the top of the mill. The milling was done at 1000
rpm and the mill discharged by inverting the mill and emptying
through the loading port. The recovered material was sieved to
separate the grinding media from the powder.
[0351] Variations to the milling conditions set out above are
indicated in the variations column in the data tables. The key to
these variations is shown in Table A.
[0352] Particle Size Measurement:
[0353] The particle size distribution (PSD) was determined using a
Malvern Mastersizer 2000 fitted with a Malvern Hydro 2000S pump
unit. Measurement settings used: Measurement Time: 12 seconds,
Measurement cycles: 3. Final result generated by averaging the 3
measurements. Samples were prepared by adding 200 mg of milled
material to 5.0 mL of 1% PVP in 10 mM hydrochloric acid (HCl),
vortexing for 1 min and then sonicating. From this suspension
enough was added into the dispersant (10 mM HCl) to attain a
desired obscuration level. If necessary an extra 1-2 minutes of
sonication was applied using the internal sonication probe in the
measurement cell. The refractive index of the active ingredient to
be measured was in the range of 1.49-1.73. Any variations to this
general method are summarized in Table B.
[0354] XRD Analysis:
[0355] Powder X-Ray diffraction (XRD) patterns were measured with a
Diffractometer D 5000, Kristalloflex (Siemens). The measurement
range was from 5-18 degrees 2-Theta. The slit width was set to 2 mm
and the cathode ray tube was operated at 40 kV and 35 mA.
Measurements were recorded at room temperature. The recorded traces
were subsequently processed using Bruker EVA software to obtain the
diffraction pattern.
TABLE-US-00001 TABLE A Variations to milling conditions. Only
conditions reported in the table have changed as compared to
conditions reported above. Varia- Milling Media Media Offload tion
# Mill type Speed (rpm) size (inch) Mass (kg) spped (rpm) A 1HD 1 L
0.25 B 1S 0.5 gal 5 C 1S 0.5 gal 4 D 1S 0.5 gal 500 E 1S 0.5 gal
550-555 F 1S 1.5 gal 316-318 21 G 1S 1.5 gal 500 21 H 1S 1.5 gal
355 21 I 1S 1.5 gal 355 18 J 1S 1.5 gal 21 K 1S 1.5 gal 18.4 L 1S
1.5 gal 400 M 1S 1.5 gal 21 57 N 1S 1.5 gal 57 O 1S 0.5 gal 400 400
P 1S 0.5 gal 500 350 Q HICOM 1/8 R HICOM 11.7
TABLE-US-00002 TABLE B Variations to particle size measurement
conditions. Variation # Sample Dispersant Measurement Dispersant
Addition Method 1 0.1% PVP in DI water Powder addition 2 0.2%
Pluronic L81 in DI water DI water 3 Saturated glyphosate in DI
Powder addition water 4 Saturated glyphosate in DI Powder addition
water 5 1% PVP in DI water DI water 6 DI water Powder addition 7 1%
PVP in DI water Saturated creatine in DI water 8 1% PVP in Dl water
10 mM HCl 9 0.2% Pluronic L81 in DI water Acidified with 1M HCl 10
1% PVP in DI water 0.1% PVP in DI water 11 1% PVP in DI water 1%
PVP in DI water 12 Filtered before PSD measurement
[0356] Abbreviations:
[0357] HCl: Hydrochloric acid
[0358] Nap: Naproxen acid
[0359] PSD: Particles size distribution
[0360] PVP: Polyvinyl pyrrolidone
[0361] RI: Refractive index
[0362] Rpm: Revolutions per minute
[0363] SLS: Sodium lauryl sulphate
[0364] SSB: Stainless Steel Balls
[0365] XRD: X-Ray Diffraction
[0366] Other abbreviations used in the data tables are listed below
in Table C (for actives), Table D (for matrices) and Table E (for
surfactants). In the data tables single letter with example number
abbreviations have been used to identify specific sample numbers
within the table. The data tables shown in the figures the use of
surfactant, matrix are interchangeable and do not necessarily
define the nature of that material.
TABLE-US-00003 TABLE C Abbreviations used for active pharmaceutical
ingredients. Abbreviation API Name 2,4-Dichlorophenoxyacetic 2,4D
acid Anthraquinone ANT Celecoxib CEL Cilostazol CIL Ciprofloxacin
CIP Creatine Monohydrate CRM Cyclosporin A CYA Diclofenac Acid DIC
Glyphosate GLY Halusulfuron HAL Indomethacin IND Mancozeb MAN
Meloxicam MEL Metaxalone MTX Metsulfuron MET Naproxen Acid NAA
Naproxen Sodium NAS Progesterone PRO Salbutamol SAL Sulfur SUL
Tribenuran TRI FOOD Apricot kernel APR Cinnamon Ground CNG Cinnamon
Quills CNQ Cocoa Nibs CON Cocoa Powder COP Coffee Beans COF Cloves
CLO Dehydrated Peas PEA Dehydrated Beans BEA Fenegreek FEN Goji
Berry GOJ Green Tea GTE Ground Ginger GIN Lavender LAV Linseed LIN
Mangosteen MST Raspberry Leaf RAS Turmeric TUR
TABLE-US-00004 TABLE D Abbreviations used for excipients. Matrix
Name Abbreviation Calcium Carbonate CAC Full Cream Milk Powder FCM
Glucose GLU Lactose Anhydrous LAA Lactose Monohydrate LAC Lactose
Monohydrate Food LFG Grade Malic Acid MAA Maltitol MAL Mannitol MAN
Skimmed Milk Powder SMP Sodium Bicarbonate SB Sodium Chloride SC
Sorbitol SOR Sucrose SUC Tartaric Acid TA TriSodium Citrate
Dihydrate TCD Whey Powder WP Xylitol XYL
TABLE-US-00005 TABLE E Abbreviations used for surfactants
Surfactant Name Abbreviation Aerosil R972 Silica AS Benzalkonium
Chloride BC Brij700 B700 Brij76 B76 Cremophor EL CEL Cremophor
RH-40 C40 Dehscofix 920 D920 Docusate Sodium DS Kollidon 25 K25
Kraftsperse 1251 K1251 Lecithin LEC Poloxamer 188 P188
Microcrystalline Cellulose MCC Poloxamer 407 P407 Polyethylene
Glycol 3000 P3000 Polyethylene Glycol 8000 P8000 Polyoxyethylene 40
Stearate P40S Polyvinyl Pyrrolidone (Kollidon 30) PVP Primellose
PML Primojel PRI Sodium Deoxycholate SDC Sodium Dodecyl Sulphate
SDS Sodium Dodecylbenzenesulphonic SDA Acid Sodium N-Lauroyl
Sarcosine SNS Sodium Octadecyl Sulphate SOS Sodium Pentane
Sulphonate SPS Soluplus HS15 SOL Teric 305 T305 Tersperse 2700
T2700 Terwet 1221 T1221 Terwet 3785 T3785 Tween 80 T80
Example 1
Spex Milling
[0367] A range of actives, matrices and surfactants in a variety of
combinations were milled using the Spex mill. The details of these
millings are shown in FIGS. 1A-1G together with the particle size
distributions of actives that were milled.
[0368] These millings demonstrate that the addition of a small
amount of surfactant to the milling matrix delivers a smaller
particle size compared to millings of just an active and a single
matrix. Some examples of this are samples Z and AA compared to
sample Y; Sample AB compared to sample AC; sample AE compared to
sample AD; sample AG compared to sample AF; sample AP compared to
sample AO; sample AR compared to sample AQ, sample AT compared to
sample AS; Samples AX, AY and AZ compared to sample AW; sample BC
compared to sample BD; sample BI compared to BH; samples BL-BR
compared to sample BK; samples CS-DB compared to sample DC. This
last example is particularly noteworthy as these millings were
undertaken at 45% v/v. This demonstrates the broad applicability of
this invention. Some other examples of surfactant addition being
beneficial for size reduction are samples DD-DG and DI-DK compared
to sample DH; sample DM compared to sample DL. Other samples such
as samples DY-EC compared to sample DX; sample AV compared to
sample AU; samples B-H compared to sample A and samples K-M
compared to sample J show this ti be also true when particle size
statistics such the %<1 micron as used.
[0369] Note that this applies to mechanochemcial matrix milling as
well. This is demonstrated by sample BI where naproxen sodium is
milled with tartaric acid and converted to naproxen acid. FIG. 1H
shows XRD data that demonstrates the transformation.
[0370] Other samples such as CB-CR show examples were surfactants
suitable for use with IV formulations can be used to manufacture
very small particles.
[0371] It is also noteworthy that samples DS and DT could be sized
using a saturated solution of the active (salbutamol) demonstrating
that actives with high water solubility can be measured as long as
care is taken when measuring the size.
[0372] Two sets of data, samples N-Q and samples R-U, also
demonstrate that the invention described herein is unique. In these
samples the active milled with a matrix and surfactant produces
small particles. When milled with matrix alone the particles sizes
are larger, in the case of sample Q they are not even
nanoparticles. When the active is milled with just 1% surfactant
the resultant particle size is very large. Even when 80% surfactant
is used the size is large.
Example 2
110 mL Attritor
[0373] A range of actives, matrices and surfactants in a variety of
combinations were milled using the 110 ml stirred attritor mill.
The details of these millings are shown in FIG. 2A together with
the particle size distributions of actives that were milled.
[0374] These millings also demonstrate that the addition of a small
amount of surfactant to the milling matrix delivers a smaller
particle size compared to millings of just an active and a single
matrix in a small scale stirred mill as well as the vibratory Spex
mill. Sample F also demonstrates that small particles can be
achieved at high % actives when a surfactant is present. Sample D
and E also show that the addition of the surfactant also increased
the yield of powder from the mill.
Example 3
Second Matrix
[0375] In this example naproxen was milled with a mixture of two
matrices using the Spex mill. The details of these millings are
shown in FIG. 3A together with the particle size distributions of
actives that were milled. Samples A and B were milled in a primary
matrix of lactose monohydrate and 20% of second matrix. The
particle size of these millings is smaller than the same milling
with just lactose monohydrate (See example 1 sample No AH, FIG.
1B). The particle size is also smaller than naproxen milled in the
secondary matrices (See example 1 sample No AI and AJ, FIG. 1B).
This shows the mixed matrices have synergy together.
[0376] Samples C-E were milled in anhydrous lactose with 20% of a
second matrix. All these samples had a particle size much smaller
than naproxen milled in anhydrous lactose alone (See example 1
sample No AK, FIG. 1B).
[0377] These millings demonstrate that the addition of a second
matrix to the primary milling matrix delivers a smaller particle
size compared to millings with just a single matrix.
Example 4
1 L Attritor
[0378] Two actives with various combinations of lactose monohydrate
and SDS were milled using the 1 L stirred attritor mill. The
details of these millings are shown in FIG. 4A together with the
particle size distributions of actives that were milled.
[0379] Sample A and B are millings of meloxicam at 20%. While
sample B has a slightly smaller particle size than sample A there
is a dramatic difference in the amount of material recovered from
the milling. Sample A, milled with 3% SDS has a high yield of 90%
whereas sample B with no surfactant has practically no yield with
all the powder caked in the mill.
[0380] In samples C-F the milling of 13% indomethacin shows that
the use of a second matrix (tartaric acid) in combination with 1%
SDS delivers the best outcome of a good particle size and high
yield. Sample D which has just the mixed matrix has very good
particle size but poor yield.
[0381] These results show that the addition of a small amount of
surfactant improves milling performance.
Example 5
750 mL Attritor
[0382] Two actives with various combinations surfactants were
milled using the 750 ml stirred attritor mill. The details of these
millings are shown in FIG. 5A together with the particle size
distributions of actives that were milled.
[0383] In samples A-C three millings of naproxen are shown. Sample
A has just 1% SDS as a surfactant. Samples B and C have a second
surfactant present and these samples have a smaller particle size
as measured by the %<500 nm, %<1000 nm and %<2000 nm.
[0384] In samples D-F three millings of indomethacin are shown.
Sample D has just 1% SDS as a surfactant. Samples E and F have a
second surfactant present and these samples have a smaller particle
size compared to sample D.
[0385] These examples demonstrate that the use of combination of
surfactants can be useful to achieve better reduction in particle
size.
Example 6
1/2Gallon 1S
[0386] A range of actives, matrices and surfactants in a variety of
combinations were milled using the 1/2 gallon 1S mill. The details
of these millings are shown in FIGS. 6A-C together with the
particle size distributions of actives that were milled.
[0387] The following examples demonstrate the increased yield
obtained when milling an active in a 1/2 gallon 1S attritor mill
with a surfactant as compared to no surfactant, with all other
factors being identical. Sample C and D (FIG. 6A) shows Naproxen
acid milled in Mannitol with yields of 92% and 23%, with and
without surfactant. Sample S and AL (FIGS. 6B and C) show the same
for glyphosate with yields of 95% and 26%, respectively. Sample AI
and AJ (FIG. 6B) show Ciprofloxacin yields of 94% and 37% with and
without surfactant while sample AM an AN (FIG. 6C) show Celecoxib
yields of 86% and 57% with and without surfactants. Finally,
samples AP and AQ (FIG. 6C) shows milling Mancozeb with or without
surfactants results in yields of 90% and 56%, respectively.
[0388] The following examples illustrates that milling an active in
a 1/2 gallon 1S attritor mill with a surfactant as compared to
without surfactant and all other factors identical, leads to
smaller particle size after milling. Sample C and D (FIG. 6A) shows
a D(0.5) of 0.181 and 0.319 with or without surfactant, while
sample AM and AN (FIG. 6C) shows D(0.5) of 0.205 and 4.775 with and
without surfactants.
[0389] The series of samples Q-S are timepoints taken from a single
glyphosate milling. The data demonstrates that the size of the
actives decreases with milling time.
[0390] Other samples such as V-AA show examples were surfactants
suitable for use with IV formulations can be used to manufacture
very small particles.
[0391] Some of the particle size data in FIGS. 6A-C was converted
to a number average particle size and is shown in the tables. This
number was calculated in the following way. The Volume distribution
was transformed to the number distribution using the Malvern
Mastersizer software. For each size bin the size of the bin was
multiplied by the % of particles in the bin. This numbers were
added together and divided by 100 to give the number average
particle size.
Example 7
Metaxalone
[0392] Metaxalone was milled with various combinations of matrices
and surfactants using a variety of mills. The details of these
millings are shown in FIG. 7A together with the particle size
distributions of actives that were milled. Samples A, B, E, G, H
and I were milled in a Spex mill. Samples C, D and F were milled in
the 750 ml atrittor. The remaining samples were milled in the 1/2
gallon 1S mill.
[0393] Samples A compared to sample B and sample H compared to
sample G demonstrate that the addition of one or more surfactants
enables the production of smaller active particles. Other millings
such as samples C-F show that metaxalone can be milled small at
very high active loadings. Sample I shows that disintegrant can be
added during milling and not effect the production of small active
particles. Note that the particle size in sample I is after
filtration through a 10 micron filter. Sample N shows an
alternative way to manufacture a formulation with small particles
and disintegrants. In this example the powder from sample M was
left in the mill and a wetting agent (PVP) and disintegrant were
added. The powder was milled for a further 2 minutes and then
unloaded with a very high yield of 97%.
[0394] The series of samples J-M are timepoints taken from a single
milling. The data demonstrates that the size of the actives
decreases with milling time.
Example 8
Hicom
[0395] A range of actives, matrices and surfactants in a variety of
combinations were milled using the Hicom mill. The details of these
millings are shown in FIG. 8A together with the particle size
distributions of actives that were milled.
[0396] The data shows that the invention described herein can be
used with the Hicom mill with its nutating action. The data in FIG.
8A shows that a variety of actives can be milled small in very
short times and give very good yields at 500 gram scale.
[0397] Sample N and O show that cocoa powder can be reduced to very
fine sizes in short times using the invention describes here in in
combination with the Hicom nutating mill. Likewise Sample P shows
that this is also the case for cocoa nibs.
Example 9
1.5 Gallon 1S
[0398] A range of actives, matrices and surfactants in a variety of
combinations were milled using the 1.5 Gallon 1S mill. The details
of these millings are shown in FIGS. 9A-B together with the
particle size distributions of actives that were milled.
[0399] The following examples demonstrate the increased yield
obtained when milling an active in a 1.5 gallon 1S attritor mill
with a surfactant as compared to no surfactant, with all other
factors being identical. Sample J and N (FIG. 9A) shows yields of
51% and 80%, without and with surfactant. Sample K and P (FIG. 9A)
show yields of 27% and 80%, without and with surfactant, while
sample L (FIG. 9A) show a yield of 94% with surfactant and the
control without surfactant (sample M, FIG. 9A) resulted in no yield
due to caking within the mill.
[0400] The following examples illustrates that milling an active in
a 1.5 gallon 1S attritor mill with a surfactant as compared to
without surfactant and all other factors identical, leads to
smaller particle size after milling. Sample F and G (FIG. 9A) shows
a D(0.5) of 0.137 and 4.94 with or without surfactant, while sample
K and P (FIG. 9A) shows D(0.5) of 0.242 and 0.152 without and with
surfactants.
[0401] The series of samples AI-AL are timepoints taken from a
single meloxicam milling. The data demonstrates that the size of
the actives decreases with milling time.
[0402] Other samples such as A-E show examples were surfactants
suitable for use with IV formulations can be used to manufacture
very small particles.
[0403] Sample M was a milling of meloxicam in lactose monohydrate
without surfactant. 3 minutes into the milling the mill refused to
turn. The milling was stopped and started again but only ran for
another 3 minutes before stopping again. At this point the mill was
taken apart and no evidence of caking was found. However the powder
had a gritty feeling to it and was locking the medium and shaft
such that it was not possible to turn. The media was weighed and it
as found that 150 grams of powder was on the media indicating that
it was sticking to the media and making it hard to move. At this
point the mill was re-assembled and the powder and media put back
in. 30.4 grams of SDS was included in the milling making it similar
to milling L. After the addition of the surfactant the mill was run
for another 14 minutes (giving a total of 20 mins) without
incident. After offloading the powder the media was weighed and the
weigh of powder on the media was only 40.5 grams. This indicates
the addition of surfactant has improved the milling performance and
ability to mill the powder.
[0404] Some of the particle size data in FIGS. 9A-B was converted
to a number average particle size and is shown in the tables. This
number was calculated in the following way. The Volume distribution
was transformed to the number distribution using the Malvern
Mastersizer software. For each size bin the size of the bin was
multiplied by the % of particles in the bin. This numbers were
added together and divided by 100 to give the number average
particle size.
Example 10
Large Scale 25/11 kg
[0405] Sample A (FIG. 10A) was milled in the Siebtechnik mill for
15 minutes. After this time the powder was completely caked onto
the walls of the mill and the media. No powder could be removed to
measure the particle size. At this point 0.25 g (1 w/w %) SLS was
added to mill chamber and milling was then undertaken for a further
15 minutes. After the second period of milling in the presence of
SLS powder was no longer caked onto the media and some free powder
was also present. The observations made before and after the
addition of the SLS demonstrate that the addition of the surfactant
lessens the problem of caking. With the addition of surfactant the
caked material could be recovered to become free powder again with
small particle size.
[0406] Sample B-E was milled in horizontal Simoloyer mills. The
details of these millings are shown in FIG. 10A together with the
particle size distributions of actives that were milled.
[0407] The data shows that the invention described herein can be
used with Simoloyer mills with their horizontal attritor action. Of
particular note is example E which was milled at 11 kg scale. This
demonstrates the invention described herein is suitable for
commercial scale milling.
[0408] Sample F was milled in a vertical attritor mill (Union
Process S-30). The details of this milling is shown in FIG. 10A
together with the particle size distribution of the active
milled.
[0409] The data shows that the invention described herein can be
used with a S-30 mills with its vertical attritor action. Of
particular note is that this milling was at 25 kg scale. This
demonstrates the invention described herein is suitable for
commercial scale milling.
Example 11
Food Spex
[0410] A range of actives, matrices and surfactants in a variety of
combinations were milled using the spex. The details of these
millings are shown in FIGS. 11A-C together with the particle size
distributions of actives that were milled.
[0411] This millings show that the invention disclosed herein is
useful for milling food such as cocoa powder and cocoa nibs and
other natural products such as seeds, flowers and berries to a
small size.
[0412] The milling of dried berries (with some residual moisture)
was successfully undertaken in sample AG. In contrast milling the
berries on there own sample AQ resulted is sticky mass that
incorporated the milling media. This shows that the invention
described herein is useful for milling materials with residual
water content and achieving a small particle size.
Example 12
Food 1/2 Gallon 1S
[0413] A range of actives, matrices and surfactants in a variety of
combinations were milled using the 1/2 gallon 1S mill. The details
of these millings are shown in FIG. 12A together with the particle
size distributions of actives that were milled.
[0414] This millings show that the invention disclosed herein is
useful for milling food and natural products such as coffee, cocoa
powder and cocoa nibs.
[0415] The milling of coffee (a material with a natural oil
content) was successfully undertaken in sample A. In contrast
milling the coffee with 1% lecithin (sample B) resulted is sticky
mass that was caked at the top of the mill (see FIG. 12B). This
shows that the invention described herein is useful for milling
materials with natural oil content and achieving a small particle
size as well as giving a good yield.
Example 13
Naproxen
[0416] Naproxen was milled in mannitol with a range of surfactants
using the 1/2 Gallon 1S mill. The details of these millings are
shown in FIG. 13A together with the particle size distributions of
actives that were milled.
[0417] Naproxen acid milled in Mannitol with a surfactant (Sample
A, D-J in FIG. 13A) leads to higher yields, as compared to Naproxen
acid milled in Mannitol without surfactant (Sample K, FIG. 13A).
Naproxen acid milled in Mannitol and either microcrystalline
cellulose or the disintegrant primellose (sample L or M, FIG. 13A)
leads to small particle size with D(0.5) around 0.25 in both
cases.
Example 14
Filtration
[0418] Some matrices, milling aids or facilitating agents that are
used by this invention are not water soluble. Examples of these are
microcrystalline cellulose and disintegrants such as croscarmellose
and sodium starch glycolate. In order to more easily characterise
the particle size of the active after milling with these materials
filtration methods can be used to remove them allowing a
characterisation of the active. In the following examples naproxen
was milled with lactose monohydrate and microcrystalline cellulose
(MCC). The particle size was characterised before and after
filtration and the ability of the filters to let through the
naproxen was demonstrated using HPLC assays. The milling details
and the particle size are shown in FIG. 14a. Note in this table the
particle size with milling details is un-filtered. The particle
size in the rows with no milling details is after filtration. The
sample that was filtered is indicated in the Active material
section. The HPLC assays were performed by taking samples before
and after filtration through 10 micron poroplast filters. The
samples taken were diluted to give a nominal concentration of 100
.mu.g/ml. The HPLC assay data is shown in Table 14
[0419] Sample A was milled with 5% MCC. Before filtration the D50
was 2.5 .mu.m, after filtration (sample B) the D50 was 183 nm. When
sample B was assayed the concentration was 94 .mu.g/ml indicating
that filtration process retained little naproxen. A second milling
(sample C) was undertaken without MCC. The D50 was 160 nm as would
be expected. After filtration (sample D) the particle size was
unchanged indicating that if the filtration process did remove any
naproxen then it was removed in an even way. Some of sample C was
then milled with MCC for 1 minute. This is long enough to
incorporate the MCC into the powder but not long enough to affect
the particle size distribution. Two millings were undertaken.
Sample E incorporated 5% w/w MCC into the powder and Sample F 9%
w/w. After incorporation of the MCC the particle size increased
dramatically. These samples where then filtered (Sample E and F)
and the size remeasured. After filtration the particle size is the
same as Sample C which was the starting material. The assay of
samples E-H indicates that filtration did not remove any naproxen
of any significance. The combination of particle size and assay
data clearly shows that material such as MCC can easily and
successfully be removed allowing the true particle size of the
active to be measured.
[0420] Samples I and J were millings conducted with 10 and 20% w/w
MCC. The particle size post filtration is show as sample K and L.
Again the filtration has delivered a reduction in particle size due
to the removal of the MCC component. And again the HPLC assay of
sample I-L shows little naproxen was lost during filtration.
[0421] This data also demonstrates that MCC can successfully be
used as co matrix in the invention disclosed herein.
TABLE-US-00006 TABLE 14 The HPLC assay of naproxen before and after
filtration of samples. Sample No. HPLC Assay (.mu.g/ml) B 94 D 93 E
99 F 96 G 98 H 97 I 94 J 89 K 91 L 84
Example 15
Dissolution of Nanoformulation Capsules
Example 15(a) Manufacture of Naproxen (200 mg) Nanoformulation
Capsules
[0422] Nine sublots of naproxen nanoformulation milled powder were
combined (Example 9, Sample Z-AH), roller compacted, processed in a
Quadro.RTM. Comil.RTM., and encapsulated. For each milling sublot,
334 g of naproxen, 599 g of mannitol, 9.55 g of povidone K30, and
9.55 g of sodium lauryl sulfate were charged into an 8-qt V blender
and mixed for 10 minutes, yielding a powder of approximate
composition 35% naproxen, 63% mannitol, 1% povidone K30, and 1%
sodium lauryl sulfate.
[0423] The blends were then milled individually and during the
milling processes, unmilled material and samples were periodically
discharged and their amounts recorded. After completion of each of
the individual millings, an amount of croscarmellose sodium was
added to each milling. The amount of croscarmellose sodium added
was based on the theoretical amount of milled powder remaining in
the mill, such that the final concentration of croscarmellose
sodium in the powder would be 5.38% w/w upon addition of the
calculated amount. After adding the croscarmellose sodium to the
attritor mill, the mill was run for 2 minutes. The milled powder of
approximate final composition 33.11% naproxen, 59.61% mannitol,
0.95% sodium lauryl sulfate, 0.95% povidone K30, and 5.38%
croscarmellose sodium was then discharged from the mill.
[0424] Materials obtained from Example 9, Samples Z-AH were
combined in a 1 cu. ft V-blender and mixed for 20 min. The mixed
powder was processed in a Freund Model TF-156 roller compactor
(screw speed=13.4, roll speed=4.1, pressure=55 kg/cm.sup.2). The
powder was processed for approximately 55 min, yielding ribbons of
2.3 to 2.7 mm thickness.
[0425] The roller compacted ribbons were manually crushed and fed
into the hopper of a Quadro.RTM. Comil.RTM. 197 equipped with an
1143 micron screen and 0.225 inch spacer, operating at 2000 rpm.
The net yield of milled granular material was 4.183 kg.
[0426] The milled roller compacted granules were encapsulated into
size 00 white opaque hard gelatin capsules using a MiniCap 100
Capsule Filling Machine equipped with size 00 change parts. The
capsules were filled manually with a scraper and periodically
checked for gross weight, closure integrity, and appearance. The
target fill weight was 604 mg, and the average weight of an empty
capsule shell was 117 mg. The filled capsules were then polished in
a capsule polishing machine. The net yield of filled, polished
capsules was 4,183 g (approximately 6,925 capsules).
Example 15(b)
Manufacture of Indomethacin (20 mg) Nanoformulation Capsules
[0427] Indomethacin milled powder (750.0 g, Example 9, Sample T)
was charged into the bowl of a KG-5 high shear granulator.
Separately, a 30% solution of povidone K30 in purified water was
prepared by dissolving 47.8 g of povidone in 111.6 g of purified
water.
[0428] The high shear granulator was operated with an impeller
speed of 250 rpm and a chopper speed of 2500 rpm. A portion of the
povidone solution (80.3 g) was introduced into the granulator over
a period of approximately 8 minutes using a peristaltic pump. An
additional 30 g of purified water was then added to the
granulation.
[0429] After the additions of povidone solution and water were
completed, the wet granules were spread on to paper-lined trays to
a thickness of approximately 1/2'', and were dried in an oven at
70.degree. C. for approximately 1 hour. The granules were then
manually screened through a 10 mesh hand screen, and spread on to
paper-lined trays for additional drying. The granules were dried
for a second hour, and then tested for loss on drying; the LOD
value was 1.987%.
[0430] The dried granules were processed in a Quadro CoMill (20
mesh screen, 0.225 inch spacer) at 2500 rpm, yielding 689.9 g of
milled granules having the final composition of 12.60%
indomethacin, 62.50% lactose monohydrate, 20.86% tartaric acid,
0.95% sodium lauryl sulfate, 3.09% povidone K30.
[0431] The granules were manually filled into size 4 white opaque
hard gelatin capsules using a MiniCap 100 Capsule Filling Machine
set up with size 4 capsule change parts. The target fill weight of
each capsule was 158.7 mg and the average empty capsule shell
weight was 38 mg. Capsules were filled manually using a scraper and
periodically tested for gross weight. Tamping and vibration were
adjusted as necessary to achieve the target fill weight.
[0432] The filled capsules were polished in a Capsule Polishing
Machine, yielding a net weight of 803 g of filled capsules
(approximately 4,056 capsules).
Example 15(c)
Manufacture of Indomethacin (40 mg) Nanoformulation Capsules
[0433] Two separate granulation sublots were manufactured and
combined to produce Indomethacin Nanoformulation capsules 40
mg.
[0434] Granulation sublot A was prepared by charging indomethacin
milled powder (750.0 g, Example 9, Sample U) into the bowl of a
KG-5 high shear granulator. Separately, a 30% solution of povidone
K30 in purified water was prepared by dissolving 47.8 g of povidone
in 111.5 g of purified water. The granulator was operated with an
impeller speed of 250 rpm and a chopper speed of 2500 rpm. A
portion of the povidone solution (80.3 g) was introduced into the
granulator over a period of approximately 9 minutes, using a
peristaltic pump. An additional 20 g of purified water was then
added to the granulation.
[0435] After the additions of povidone solution and water were
completed, the wet granules were spread on to paper-lined trays to
a thickness of approximately 1/2''.
[0436] Granulation sublot B was prepared by charging indomethacin
milled powder (731.6 g, Example 9, Sample V and 18.4 g, Example 9,
Sample U) into the bowl of a KG-5 high shear granulator.
Separately, a 30% solution of povidone K30 in purified water was
prepared by dissolving 47.8 g of povidone in 111.5 g of purified
water. The granulator was operated with an impeller speed of 250
rpm and a chopper speed of 2500 rpm. A portion of the povidone
solution (80.3 g) was introduced into the granulator over a period
of approximately 10 minutes, using a peristaltic pump. An
additional 20 g of purified water was then added to the
granulation. After the additions of povidone solution and water
were completed, the wet granules were spread on to paper-lined
trays to a thickness of approximately 1/2''. The wet granules from
both sublots were dried in an oven at 70.degree. C. for
approximately 2.5 hours. The granules were then manually screened
through a 10 mesh hand screen, and spread on to paper-lined trays
for additional drying. The granules were dried for another 1.5
hours, until the LOD value was 1.699%.
[0437] The dried granules were processed in a Quadro CoMill (20
mesh screen, 0.225 inch spacer) at 2500 rpm. The milled granules
were then added to an 8 qt V-blender and mixed for 5 minutes,
yielding 1390.7 g of granules with a final composition of 12.60%
indomethacin, 62.50% lactose monohydrate, 20.86% tartaric acid,
0.95% sodium lauryl sulfate, 3.09% povidone K30.
[0438] An IN-CAP.RTM. automated capsule filling machine (Dott.
Bonapace & C., Milano, Italy) was set up with size (2) 16 mm
dosing disc and size (2) tamping pins. Milled granules were charged
into the encapsulator, along with size 1 white opaque hard gelatin
capsule shells. The target capsule fill weight was 317.7 mg, and
the average empty capsule shell weight was 75 mg. Tamping pins 1-4
were all set to 9 mm, and the encapsulator was run at speed 2.
Weight checks, closure checks, and appearance checks were performed
every 15 minutes. Filled capsules were polished in a capsule
polishing machine. The net weight of filled, polished capsules was
1225.5 g (approximately 3,183 capsules).
Example 15(d)
Manufacture of Meloxicam (7.5 mg) Nanoformulation Capsules
[0439] Milled powder (Example 9, Sample Q) was manually
encapsulated using a capsule filling device (Cooper plate and
capsule loader) into size "4" white-opaque hard-gelatin capsules.
Upon encapsulation, each capsule contains 7.5 mg active ingredient
with a total fill weight of 105 mg. The finished capsules were
packaged in 40 cc HDPE bottles (50 counts per bottle) with the
bottles being enclosed using an induction seal.
Example 15(e)
Manufacture of Diclofenac (18 mg) Nanoformulation Capsules
[0440] Diclofenac milled powder (666.2 g, from Example 9, Sample W)
was charged into the bowl of a KG-5 high shear granulator.
Separately, a 30% w/w solution of povidone K30 was prepared by
dissolving 60.0 g of povidone K30 in 140.0 g of purified water. The
granulator was operated at a chopper speed of 250 rpm and impeller
speed of 2500 rpm. A portion of the povidone solution (88.6 g) was
introduced into the granulation over a period of approximately 9
minutes with a peristaltic pump. An additional 30 g of water was
then added to the granulation.
[0441] The wet granules were spread on to paper-lined trays and
dried in an oven at 70.degree. C. for 2 hours. They were then
manually screened through a 10 mesh hand screen. After
approximately 2.25 hours of drying time, the loss on drying was
determined to be 0.559%.
[0442] The dried granules were processed in a Quadro CoMill fitted
with a 200 mesh screen and 0.225 inch spacer, run at 1265 rpm. The
process yielded 539.0 g of milled, dried granules.
[0443] The granules were filled into size 4 white opaque hard
gelatin capsules using an IN-CAP.RTM. automated capsule filling
machine (Dott. Bonapace & C., Milano, Italy). The machine was
set up with size 4 change parts and a 10 mm dosing disc. The target
fill weight was 124.8 mg, and the average weight of an empty
capsule shell was 38 mg. The machine was run at speed setting #2.
Tamping pin #4 was set to 21 mm; all other tamping pin settings
were N/A.
[0444] The filled capsules were polished in a capsule polishing
machine, and the net yield of filled capsules was 480.2 g
(approximately 2,910 capsules).
Example 15(f)
Manufacture of Diclofenac (35 mg) Nanoformulation Capsules
[0445] Two separate granulation sublots were used for the
manufacture of Diclofenac Nanoformulation Capsules 35 mg.
Granulation sublot A: 642.7 g of milled diclofenac powder (Example
9, Sample X) was charged into the bowl of a KG-5 high shear
granulator. Separately, a 30% w/w solution of povidone K30 was
prepared by dissolving 60.0 g of povidone K30 in 140.0 g of
purified water. The granulator was operated at an impeller speed of
250 rpm and a chopper speed of 2500 rpm. A portion of the binder
solution (85.5 g) was introduced into the granulation over a period
of approximately 8.5 minutes via a peristaltic pump. An additional
30 g of purified water was then added to the granulation at the
same rate. The wet granules were spread on to paper-lined trays to
a thickness of approximately 1/2''.
[0446] Granulation sublot B: 519.6 g of milled diclofenac powder
(Example 9, Sample Y) was charged into the bowl of a KG-5 high
shear granulator. Separately, a 30% povidone solution was prepared
by dissolving 60.0 g of povidone K30 in 140.0 g of purified water.
The granulator was operated at an impeller speed of 250 rpm and a
chopper speed of 2500 rpm. A portion of the povidone solution (69.1
g) was added to the granulation over a period of approximately 6.5
minutes. An additional 30 g of water was then added at the same
rate. The wet granules were spread on to paper-lined trays to a
thickness of approximately 1/2''.
[0447] The wet granules from sublots A and B were dried in an oven
at 70.degree. C. for approximately 2 hours. They were then manually
screened through a 10 mesh hand screen and tested for loss on
drying. The LOD result was 0.316%.
[0448] The dried granules were milled in a Quadro CoMill fitted
with a 200 mesh screen and 0.225 inch spacer, operated at 2500 rpm.
The milled granules were charged into an 8 qt V-blender and mixed
for 5 minutes, yielding 1020.2 g of granules.
[0449] The granules were filled into size 3 white opaque hard
gelatin capsules using a MiniCap Capsule Filling Machine equipped
with size 3 change parts. The target fill weight was 242.7 mg and
the average weight of an empty capsule shell was 47 mg. The
granules were filled into the capsule shells manually using a
scraper. Vibration and tamping were adjusted to achieve the target
fill weight. The filled capsules were polished on a capsule
polishing machine, yielding 1149.2 g of filled capsules
(approximately 3,922 capsules).
Example 15(g) Manufacture of Metaxalone (100 mg) Nano formulation
Capsules
[0450] Milled powder (Example 7, Sample N) was manually
encapsulated using a capsule filling device (Profil) into
hard-gelatin capsules.
Example 15(h) Dissolution Rate of Milled Naproxen
[0451] The Dissolution of milled naproxen (200 mg) capsules (see
example 15a), and commercial Naprosyn.RTM. 250 mg (naproxen)
tablets (Roche Pharmaceuticals.RTM., Inc., USA) were determined
using dissolution equipment set up as USP Apparatus II (paddles)
with a stirrer speed of 50 rpm. The dissolution media was 900 ml of
0.3% SLS in 0.1 M sodium phosphate buffer at pH 5. The vessel
temperature was 37.degree. C. The capsules where weighted down with
a wire sinker. Six test articles were tested and the data average
for each time point. At each time point a 1 ml sample was taken
from each dissolution vessel, filtered through a 0.45 .mu.m filter
and analyzed by HPLC. The data in Table 15a below reports the
percent dissolved of the amount of active in each test article, for
the specified time points.
TABLE-US-00007 TABLE 15a Dissolution Profiles of Naprosyn .RTM.
Tablets 250 mg and Naproxen Nanoformulation Capsules 200 mg Percent
of Label Claim Dissolved (%) Naproxen Naprosyn Tablets
Nanoformulation Capsules Time 250 mg 200 mg 0 0 0 5 24 19 10 40 53
15 49 77 20 55 90 45 73 98 60 79 99
[0452] The results demonstrate that the milled naproxen capsules
dissolve more quickly and more completely than the commercial
reference naproxen. Those of skill in the art will readily
appreciate the advantages conferred by more rapid dissolution--more
active agent is available at any given time point. Put another way,
an equal quantity of dissolved naproxen may be obtained with an
initially smaller dosage amount of milled naproxen, as opposed to
the larger initial dose required for the reference naproxen to
reach to the same quantity of dissolved naproxen. Additionally, as
the results make clear, the reference naproxen does not achieve
complete dissolution even by the final time point, while the milled
naproxen achieves greater than 90% dissolution within 20 minutes,
and substantially complete dissolution by the 45 minute time point.
Again, a smaller dose of milled naproxen yields a quantity of
dissolved naproxen for which a larger dose of reference naproxen
would be required to equal.
Example 15(i)
Dissolution Rate of Milled Indomethacin
[0453] In this example, dissolution rate is compared between 20 mg
and 40 mg nanoformulations of the invention (Example 15(b) and
15(c)), and commercial reference indomethacin USP 25 mg capsules
(Mylan Pharmaceuticals Inc). The dissolution was performed using
Apparatus I (baskets) according to USP <711>. The dissolution
medium (900 ml at 37.degree. C.) was 100 mM citric acid buffer (pH
5.5.+-.0.05); The apparatus was stirred at 100 rpm. Sampling times
were 5, 10, 20, 30, 45, and 60 min plus an additional time point at
75 min (250 rpm). Sample of 8 mL were taken and filtered through a
0.45 .mu.m PVDF filter. The samples were assay by UV-visible
spectroscopy with a detection wavelength=319 nm. The data in Table
15b below reports the percent dissolved of the amount of active in
each test article, for the specified time points.
TABLE-US-00008 TABLE 15b Dissolution Profiles of Indomethacin
Capsules USP (25 mg) and Indomethacin Nanoformulation Capsules (20
mg and 40 mg) Percent of Label Claim Dissolved (%) Indomethacin
Indomethacin Indomethacin capsules Nanoformulation Nanoformulation
Time (min) USP, 25 mg Capsules 20 mg Capsules 40 mg 0 0 0 0 5 20 47
31 10 28 83 66 20 36 99 93 30 40 100 96 45 43 100 96 60 46 101 97
75 63 101 97
[0454] The results demonstrate that the milled indomethacin
capsules dissolve more quickly and more completely than the
commercial reference indomethacin. Those of skill in the art will
readily appreciate the advantages conferred by more rapid
dissolution--more active agent is available at any given time
point. Put another way, an equal quantity of dissolved indomethacin
may be obtained with an initially smaller dosage amount of milled
indomethacin, as opposed to the larger initial dose required for
the reference indomethacin to reach to the same quantity of
dissolved indomethacin. Additionally, as the results make clear,
the reference indomethacin does not achieve complete dissolution
even by the final time point, while the milled indomethacin, in
both dosage forms, achieves greater than 90% dissolution within 20
minutes. Again, a smaller dose of milled indomethacin yields a
quantity of dissolved indomethacin for which a larger dose of
reference indomethacin would be required to equal.
Example 15(J)
Dissolution Rate of Milled Meloxicam
[0455] In this example, dissolution rate is compared between a 7.5
mg nanoformulation of this invention (Example 15(d)), and two
commercial reference products Mobicox.RTM. 7.5 mg Tablets and
Mobic.RTM. 7.5 mg Capsules (Both Boehringer Ingelheim). Dissolution
was performed using Apparatus II (paddles) according to USP
<711>. The dissolution medium was 10 mM phosphate buffer (pH
6.1) with 0.1% w/w sodium lauryl sulfate (500 ml at 37.degree. C.).
The apparatus was stirred at 50 rpm. Samples were taken at various
time points from 5 to 60 minutes. For each sample 1 mL was taken,
filtered through a 0.45 .mu.m filter and assayed by HPLC using a
detection wavelength of 362 nm. The data in Table 15c below report
the percent dissolved of the amount of active in each test article,
for the specified time points.
TABLE-US-00009 TABLE 15C Dissolution profiles of Commercial
Meloxicam Tablets and Capsules and Meloxicam Nanoformulation
Capsules Percent of Label Claim Dissolved (%) Meloxicam Mobicox
.RTM. Mobic .RTM. Capsules Nanoformulation Time (min) Tablets 7.5
mg 7.5 mg Capsules 7.5 mg 0 0 0 0 5 39 19 44 10 50 43 68 15 57 52
20 82 30 66 64 86 45 89 60 73 72 93
[0456] The results demonstrate that the milled meloxicam capsules
dissolve more quickly and more completely than the commercial
reference meloxicam. Those of skill in the art will readily
appreciate the advantages conferred by more rapid dissolution--more
active agent is available at any given time point. Put another way,
an equal quantity of dissolved meloxicam may be obtained with an
initially smaller dosage amount of milled meloxicam, as opposed to
the larger initial dose required for the reference meloxicam to
reach to the same quantity of dissolved meloxicam. Additionally, as
the results make clear, the reference meloxicam does not achieve
complete dissolution even by the final time point, while the milled
meloxicam achieves about 82% dissolution within 20 minutes, and
reaches over 90% by the 60 minute time point. Again, a smaller dose
of milled meloxicam yields a quantity of dissolved meloxicam for
which a larger dose of reference meloxicam would be required to
equal.
Example 15(K)
Dissolution rate of milled Diclofenac
[0457] In this example, dissolution rate is compared between 18 mg
and 35 mg nanoformulations of the invention (Example 15(e) and
15(f)), and commercial reference diclofenac Voltarol Dispersible
Tablets 50 mg (Novartis, U.K) which contain 46.5 mg of diclofenac
free acid, equivalent to 50 mg of diclofenac sodium. The
dissolution method used was Apparatus I (baskets) according to USP
<711> with a stirring speed of 100 rpm. The dissolution media
was 0.05% sodium lauryl sulfate and citric acid solution buffered
to pH 5.75. The dissolution volume was 900 mL and dissolution
medium temperature was 37.degree. C. Samples were tested at 15, 30,
45, and 60 minutes and at infinity. Infinity was defined as an
additional 15 minutes at a higher rotation speed. A sample of 1 ml
was taken at each time point, filtered and assayed by HPLC with the
detection wavelength set at 290 nm. The data in Table 15d below
report the percent dissolved of the amount of active in each test
article, for the specified time points.
TABLE-US-00010 TABLE 15d Dissolution Profiles for Voltarol .RTM.
Dispersible Tablets 50 mg, Diclofenac Nanoformulation Capsules 18
mg, and Diclofenac Nanoformulation Capsules 35 mg Percent Label
Claim Dissolved (%) Voltarol Diclofenac Diclofenac Dispersible
Nanoformulation Nanoformulation Time Tablets 50 mg Capsules 18 mg
Capsules 35 mg 0 0 0 0 15 52 91 82 30 59 94.0 95 45 63 94 95 60 65
94 95 75 87 94 95
[0458] The results demonstrate that the milled diclofenac capsules
dissolve more quickly and more completely than the commercial
reference diclofenac. Those of skill in the art will readily
appreciate the advantages conferred by more rapid dissolution--more
active agent is available at any given time point. Put another way,
an equal quantity of dissolved diclofenac may be obtained with an
initially smaller dosage amount of milled diclofenac, as opposed to
the larger initial dose required for the reference diclofenac to
reach to the same quantity of dissolved diclofenac. Additionally,
as the results make clear, the reference diclofenac does not
achieve complete dissolution even by the final time point, while
the milled diclofenac achieves about 90% dissolution within 15
minutes. Again, a smaller dose of milled diclofenac yields a
quantity of dissolved diclofenac for which a larger dose of
reference diclofenac would be required to equal.
Example 15(l)
Dissolution Rate of Milled Metaxalone
[0459] The dissolution of milled metaxalone (100 mg) capsules
(Example 15(g)), and a portion (equivalent to 100 mg metaxalone) of
commercial Skelaxin.RTM. 800 mg (metaxalone) tablets (King
Pharmaceuticals.RTM., Inc., USA) were determined using dissolution
equipment set up as USP Apparatus II (paddles) with a stirrer speed
of 100 rpm. The dissolution media was 1000 ml of 0.01 M HCL (pH 2).
The vessel temperature was 37.degree. C. The capsules were weighted
down with a wire sinker. Three to six test articles were tested and
the data averaged for each time point. At each time point each
dissolution vessel was automatically sampled through a 1 .mu.m
filter and analyzed in flow through UV/Vis cells. The data in Table
15e below report the percent dissolved of the amount of active in
each test article, for the specified time points.
TABLE-US-00011 TABLE 15e Dissolution profiles of Skelaxin Tablets
(100 mg portion) and Metaxalone Nanoformulation Capsules 100 mg.
Percent of Label Claim Dissolved (%) Metaxalone Nanoformulation
Time (min) Capsules 100 mg Skelaxin (100 mg portion) 0 0 0 5 4 0 9
43 1 13 75 1 20 88 2 30 93 5 40 93 7 50 94 9 60 94 11
[0460] The results demonstrate that the milled metaxalone capsules
dissolve more quickly and more completely than the commercial
reference metaxalone. Those of skill in the art will readily
appreciate the advantages conferred by more rapid dissolution--more
active agent is available at any given time point. Put another way,
an equal quantity of dissolved metaxalone may be obtained with an
initially smaller dosage amount of milled metaxalone, as opposed to
the larger initial dose required for the reference metaxalone to
reach to the same quantity of dissolved metaxalone. Additionally,
as the results make clear, the reference metaxalone does not
achieve complete dissolution even by the final time point, while
the milled metaxalone achieves about 87% dissolution within 20
minutes. Again, a smaller dose of milled metaxalone yields a
quantity of dissolved metaxalone for which a larger dose of
reference metaxalone would be required to equal.
Example 16
Materials for Powder Handling Characteristic Testing
[0461] Blends of powders with a range of actives were prepared
using a variety of mills for a range of powder handling
characteristic testing. These are detailed in FIG. 15 along with
the particle size of the actives as determined by laser diffraction
measurement in water based solvents.
[0462] Four samples of micronized active were also obtained from
commercial API manufacturers. Two sample of meloxicam (G and H and
two samples of indomethacin (M and N) were also tested. The
particle size of these actives as determined by laser diffraction
measurement in water based solvents is also shown in FIG. 15.
[0463] Three samples were prepared by blending micronized material
into lactose/SDS mixture that had been previously been milled in an
attritor mill. E is a blend of 6.8% w/w micronized meloxicam (G)
and 93.2% w/w D for a total of 10.0 g. F is a blend of 6.8% w/w
micronized meloxicam (H) and 93.2 w/w % D for a total of 10.0 g.
These blends were prepared by mixing the respective ingredients. in
a SPEX mill for 10 min, without the use of any media. (J) is a
blend of powdersize milled lactose (I) and 13% micronized
indomethacin (N) prepared by combining I and N in a polyethylene
bag and tumbling the bag end over end for a minimum of 10 times.
The particle size of active in this blend is shown in FIG. 15.
[0464] A blend of 13% w/w indomethacin, 1% w/w SDS and 86% w/w
lactose monohydrate was jetmilled (L) in a 10'' Spiral Jet Mill
(Powdersize Inc). The particle size of active in this blend is
shown in FIG. 15.
[0465] The particle size of the blend as a dry powder was measured
for a selection of the blends. The measurements were performed on a
Malvern Mastersizer 2000 with a Scirocco 2000 measurement cell. All
measurements were performed at a pressure of 3 Bar excepting O, P
and Q which were measured at 4 Bar. Note also that example S and T
were passed through a 100 micron sieve prior to measurement. The
particle size of blends measured in this way is shown in FIG.
16.
Example 17
Content Uniformity of Meloxicam Milled with Lactose Monohydrate
[0466] Capsules containing the milled material were obtained using
the Profill capsule filling system, specifically the system using
size 4 capsules (100 units). Natural (clear) size 4 capsules
(Capsuline) were used in the process. The empty capsules were
loaded onto the equipment and the lids removed as per instructions.
The milled material was added to the capsules by moving powder
across the plate with a scraper until the surface was level. After
the capsules were filled in this manner the plate supporting the
capsules was tapped lightly (tapped on the side of the plate with
the plastic scraper), resulting in settling of the powder in the
capsules. Powder was then scraped across the capsules anew until
surface was level. This procedure was repeated a total of three
times. The lids of the capsules were repositioned and the capsules
closed and removed from the Profill system.
[0467] Content uniformity of the capsules was analyzed using High
Performance Liquid Chromatography (HPLC). Each sample was run
according to the Meloxicam USP method and results obtained using
the following formula:
[ Ru Rs .times. C .times. Dil .times. 100 LC ] = % LC
##EQU00001##
[0468] Where:
[0469] Ru=Peak Response (Area) of Meloxicam in Test Solution
[0470] Rs=Average Peak Response (Area) of Meloxicam obtained from
all Standard Solution injections
[0471] C=Concentration of Meloxicam in Standard (mg/mL)
[0472] Dil=Dilution factor (mL)
[0473] LC=Label Claim (7.5 mg, desired level in final product)
Example 17(a)
[0474] Powder of A (Example 16) was capsulated on Profill size 4
equipment (A total of 100 capsules produced). Content uniformity
(by HPLC) measured and the results summarized in Table 16.
TABLE-US-00012 TABLE 16 Assay of 10 individual Meloxicam capsules.
Sample # 1 2 3 4 5 6 7 8 9 10 Weight (mg) 148.3 150.8 142.6 152.1
146.2 146.4 151.6 147.1 152.0 143.9 Assay (% LC) 98.9 100.3 94.0
102.9 98.8 99.6 106.1 99.5 105.6 98.1 Weight 98.2 97.9 97.0 99.6
99.5 100.1 103.0 99.6 102.3 100.3 Corrected(% LC) Note: Weight
includes gelatin capsule.
[0475] A test of fill weight consistency was performed on 100
capsules by weighing each capsule individually and subtracting the
gelatin capsule weight. The data is shown in Table 17.
TABLE-US-00013 TABLE 17 Weight distribution of 100 size 4 capsules
filled on Profill system. Weight distribution No. of Capsules 110
mg .+-. 5 mg 78 capsules 110 mg .+-. 5-10 mg 21 capsules 110 mg
.+-. >10 mg .sup. 1 capsule
Example 17(b)
[0476] Sample B (Example 16) powder was capsulated on Profill size
4 equipment (A total of 600 capsules produced). Content uniformity
(by HPLC) was measured and the results summarized in Table 18.
TABLE-US-00014 TABLE 18 Assay of 10 individual Meloxicam capsules.
Sample # 1 2 3 4 5 6 7 8 9 10 Weight (mg) 138.1 143.3 139.0 141.9
144.1 143.4 133.7 137.5 147.9 142.7 Assay (% LC) 93.6 96.8 92.2
91.5 98.6 96.7 88.1 90.7 102.1 94.7 Weight 99.4 99.0 97.2 94.5
100.3 98.9 96.6 97.1 101.2 97.3 Corrected(% LC) Note: Weight
includes gelatin capsule.
[0477] A test of fill weight consistency was performed on 100
capsules by weighing each capsule individually. This data is shown
in Table 19.
TABLE-US-00015 TABLE 19 Weight distribution of 100 size 4 capsules
filled on Profill system. Weight distribution No. of Capsules 140
mg .+-. 5 mg 84 capsules 140 mg .+-. 5-10 mg 16 capsules 140 mg
.+-. >10 mg .sup. 0 capsule Note: Weight includes gelatin
capsule.
[0478] Subtracting the capsule weight the following weight
distributions were found:
[0479] Average fill weight of powder=104.1 mg
[0480] Average fill weight of Meloxicam=7.10 mg
[0481] Average % Label Claim of Meloxicam=94.6%
Example 17(c)
[0482] Sample C (Example 16) powder was capsulated on Profill size
4 equipment (A total of 600 capsules produced) Content uniformity
(by HPLC) measured and the results summarized in Table 20.
TABLE-US-00016 TABLE 20 Assay of 10 individual Meloxicam capsules.
Sample # 1 2 3 4 5 6 7 8 9 10 Weight (mg) 144.3 144.4 154.2 143.5
136.5 149.4 138.2 137.3 144.5 133.0 Assay (% LC) 97.6 96.7 106.6
97.7 91.2 102.8 90.8 91.6 96.0 87.3 Weight 99.2 98.2 101.3 99.8
97.9 100.9 96.3 97.8 97.4 96.2 Corrected(% LC) Note: Weight
includes gelatin capsule.
[0483] A test of fill weight consistency was performed on 52
capsules by weighing each capsule individually. The data is shown
in Table 21.
TABLE-US-00017 TABLE 21 Weight distribution of 52 size 4 capsules
filled on Profill system. Weight distribution No. of Capsules 140
mg .+-. 5 mg 44 capsules.sup. 140 mg .+-. 5-10 mg .sup. 6 capsules
140 mg .+-. >10 mg 2 capsule Note: Weight includes gelatin
capsule.
[0484] Subtracting the capsule weight the following weight
distributions were found:
[0485] Average fill weight of powder=105.1 mg
[0486] Average fill weight of Meloxicam=7.15 mg
[0487] Average % Label Claim of Meloxicam=95.3%
[0488] The above example illustrates that milling Meloxicam in
lactose monohydrate results in a homogenous mixture upon
completion, as indicated by the content uniformity results.
Furthermore, the simple hand-filling of size 4 capsules on Profill
equipment, using standard hard gelatine capsules, results in a
narrow weight distribution range of the filled capsules, indicating
excellent flow properties of the milled powder obtained in this
process. This indicates that nanoparticles of meloxicam have been
made by the process outlined herein with improved powder handling
characteristics. Such improved powder handling characteristics will
be highly beneficial in a commercial scale formulation process.
Example 18
Content Uniformity after Segregation
[0489] Seven materials from example 16 were subjected to a
segregation study. The blends were placed into 15 ml narrow plastic
tubes and placed on a roller table for 16 hours. The roller table
was placed on a gentle incline in order to promote segregation.
After doing this the powders were visibly segregated into coarse
and fine particles. The tubes were prepared with three holes
drilled at fixed levels and samples were taken from these and
assayed by HPLC. Samples were taken at the top, middle and bottom
positions. An assay was also taken of the blend prior to
segregation. Each assay was the average of three injections. The %
that each sample deviated from the assay of material before
segregation is shown in Table 22. Blends that have superior content
uniformity after segregation will have small % deviations, while
blends that have large % deviations that vary with sample position
indicate stratification of the active across the levels of the
tube, that is bad content uniformity. The data shows that all
blends produced by this invention (B, C, K) retain uniformity after
segregation. The blends of micronized active and attritor milled
lactose (D, E, J) all show very poor content uniformity after
segregation. The blend of active and excipients (L) that was jet
milled also have superior content uniformity. This is because the
particle size of the active and excipients are very similar meaning
that little or no segregation has occurred. However as the
following examples show this blend has many other power handling
characteristics that are very poor.
TABLE-US-00018 TABLE 22 Shows the deviation of the assay (from
before segregation) of active present in various blends at three
positions in a tube that the blends have segregated in. % Deviation
of assay from unsegregated blend Sample # Top Middle Bottom B 1.4
0.8 0.8 C 0.4 0.4 0.6 E 10.4 7.0 1.7 F 8.5 5.4 11.5 J 10.3 36.3 1.4
K 0.5 0.4 1.5 L 0.5 0.8 0.5
Example 19
Powder Adherence Measurements
[0490] Powder Adherence to material surfaces was measured using
three different media; Stainless steel, Polypropylene and Glass as
detailed below. Samples B,C,D,E,G,H,J,K,L and M from Example 16
were tested.
[0491] Stainless steel: A tared stainless steel spatula was used to
scoop a portion of each blend and deposit the sample back into the
container by a consistent action of inverting the spatula through
360.degree.. The residual mass of the powder remaining of the
spatula was recorded. Three measurements were performed for each
sample. The average of the mass measured and the % RSD between the
three measurements are shown in FIG. 16. In FIG. 17 some images of
the residual powder on the spatula are shown. Images A (sample M),
B (sample E) and C (Sample L), conventional active/blends, clearly
show more residual powder than D (sample K) which is a blend made
by this invention.
[0492] Polypropylene: The sample was loaded into a preweighed
polypropylene centrifuge tube, which was rolled on a roller table
for 5 minutes and subsequently inverted by a consistent action. The
residual mass on the tube was recorded The average of the mass
measured and the % RSD between the three measurements are shown in
FIG. 16. In FIG. 18 some images of the residual powder on the
plastic tubes are shown. Images B (sample E), C (sample G) and D
(Sample L) are conventional active/blends and show varying degrees
of powder clumped onto the tube. Image A (sample B), a blend made
by this invention has only a fine coating of residual powder.
[0493] Glass: Each sample was loaded into a preweighed glass tube,
rolled on a roller table for 5 minutes and subsequently inverted by
a consistent action. The residual mass on the glass tube was
recorded. Only one measurement was performed for each sample. The
data is shown in FIG. 16. In FIG. 19 some images of the residual
powder on the glass tubes are shown. Images A (sample G), B (sample
M) and C (sample F) are conventional active/blends and show varying
degrees of powder clumped onto the tube. Image D (Sample B), a
blend made by this invention has very little residual powder.
[0494] Overall the data of residual masses shown in FIG. 16
indicates that blends made by this invention show less adherence to
these three materials compared to actives and blends made by
conventional techniques.
Example 20
Angle of Repose Measurements
[0495] Angle of repose measurements were made on three indomethacin
blends and one micronized active from Example 16. Measurements were
made using a plastic column (diameter 23 mm) supported on paper.
The column was loaded with the powder sample (15-20 g). The powder
was deposited from the column by a consistent slow upward raising
of the column. The angle of repose was calculated from the
measurement of the height and the average radius of the powder
deposit. The measurement was repeated 4-7 times for each sample.
The angle of repose and % RSD across the measurements are shown in
FIG. 16. The data shows that the blend produced with this invention
(sample K) has a lower angle of repose compared to the blend of
active with attritor milled lactose (Sample J) and the micronized
indomethacin (Sample M) indicating powder with superior flow. The
blend that was jetmilled (Sample L) had a low angle of repose but
this was because the powder had agglomerated to form large balls of
powder. This is not a desirable power handling characteristic.
Example 21
Bulk and Tap Bulk Density
[0496] Bulk and tap bulk density measurements were made on a number
of the actives/blends from example 16. The measurements were
performed according to USP <616>. The data from these
measurements is shown in FIG. 20.
Example 22
Powder Rheology
[0497] Powder Rheology measurements were made on three indomethacin
blends and one micronized active from Example 16. The measurements
were conducted on Freeman Technology FT4 powder rheometer. The
analysis was conducted according to the standard operating
procedures of the instrument. The data from these measurements,
Basic Flow Energy (FBE), Specific Energy (SE), Pressure Drop (PD15)
and Compressibility (CPS18) are shown in FIG. 20. BFE is the energy
(mJ) needed to displace a conditioned and stabilized powder at a
given flow pattern (-5.degree. helix) and flow rate (100 mm/s). The
BFE was taken at the seventh test. The lower the BFE the more
superior the powder rheology. The data shows that the blend made by
this invention (Sample K) is superior to the active (Sample N) and
two other blends (Sample J, L) made using conventional approaches.
The SE is a measure of the energy per unit mass (mJ/g) needed to
displace a conditioned powder where the rheometer blade is used in
an upward lifting mode of displacement. The SE is a measure of
cohesivity. The higher the SE the more cohesive a powder is. The
data shows that the blend made by this invention (Sample K) is less
cohesive than the active (Sample N) and two other blends (Sample J,
L) made using conventional approaches. PD15 is the pressure drop
(mBar) across the powder bed with a normal stress of 15 kPa
applied. The air velocity across the bed was 2.0 mm/s. A highly
permeable powder has a low pressure drop and is a desirable powder
handling characteristic. The data shows that the blend made by this
invention (sample K) has a lower pressure drop than the active
(sample N) and two other blends (Sample J, L) made using
conventional approaches. CPS18 measures the percentage (%) by which
the bulk density has increased with a normal stress of 18 kPa
applied. A lower compressibility is an indication of superior
powder flow properties. The data shows that the blend made by this
invention (sample K) has a lower compressibility than the active
(Sample N) and two other blends (Sample J, L) made using
conventional approaches.
Example 23
Aerodynamic Particle Size
[0498] Two blends of 1% salbutamol (albuterol) where prepared
according to Example 16 sample S and T. These two blends where then
passed through a 100 micron sieve prior to measurement. The two
blends were then tested for aerodynamic particle size.
Example 23(a)
Aerosizer Measurements
[0499] The two samples were measured on a TSI Aerosizer with a
Aerodisperser set to a medium shear force and feed rate.
Deagglomeration was set to normal and pin vibration was on. The
particle size statistics (volume distribution) for these
measurements are shown in Table 23.
TABLE-US-00019 TABLE 23 Volume distribution particle size data from
Aerosizer measurements. Mean D[50] D[4, 3] Sample name (.mu.m)
(.mu.m) (.mu.m) Example 16 S 16.8 18.9 19.0 Example 16 T 19.7 21.9
21.9
Example 23(b)
Next Generation Impactor Measurements
[0500] The two blends of 1% salbutamol (Example 16 S, T) as well as
a commercial blend (Ventolin Rotocaps (200 .mu.g), Allen and
Hanburys) were all tested in triplicate on a Next Generation
Impactor (NGI). Approximately 20 mg of two 1% salbutamol blends
were filled into gelatine capsules to give a similar nominal dose
of 200 .mu.g. The data from these measurements is shown in Table
24. The mean of the three measurements and RSD (%) are shown. One
key finding is that the powder flow properties of the two blends
made using this invention (S, T) are superior to the commercial
blend. In the table the amount of material left in the capsule and
device after testing (Residual in Capsule+Device) was high in the
commercial sample compared to the other two blends. Another way of
expressing this result was the percent delivered. This is the % of
the total recovered dose that was delivered to the testing device.
For the two blends made with this invention the percentage
delivered was about 97% while the commercial blend only delivered
82%. All three blends delivered active into the Fine Particle
Fraction (FPF) size range. This is the range needed for a blend to
be useful as an inhaled formulation. The fact that the two blends
made with this invention could deliver active into the FPF range
and that the MMAD of the active was 5 micron or less indicates that
the invention herein is useful for formulating inhaled
pharmaceutical medicaments.
TABLE-US-00020 TABLE 24 Data from the NGI measurements on the two
blends from Example 16 and the commercial blend. Sample Ventolin
Example 16 S Example 16 T Mass Mass Mass (.mu.g) RSD (.mu.g) RSD
(.mu.g) RSD Induction Port 33.7 13.5 32.6 6.1 29.8 0.0
Pre-separator 86.0 4.7 104.3 2.7 111.6 1.5 Stage 1 14.7 9.0 18.1
9.9 14.2 4.3 Stage 2 (6.1 .mu.m) 18.2 12.5 11.2 7.6 10.6 35.5 Stage
3 (3.4 .mu.m) 21.8 8.9 6.0 3.8 5.7 10.0 Stage 4 (2.2 .mu.m) 23.3
10.3 3.8 5.3 3.9 8.3 Stage 5 (1.3 .mu.m) 12.3 11.7 1.7 6.9 2.8 22.3
Stage 6 (0.7 .mu.m) 3.0 24.0 1.0 6.0 1.1 23.6 Stage 7 (0.4 .mu.m)
1.4 27.7 0.4 25.0 0.4 0.0 MOF (0.2 .mu.m) 0.3 45.8 0.1 0.0 0.2 34.6
Residual in Capsule + 45.7 10.4 5.5 3.8 3.3 4.7 Device Total
recovered dose 260.5 1.7 184.7 2.0 183.4 2.2 Delivered dose (DD)
214.7 3.4 179.1 2.1 180.1 2.3 Percent delivered 82.4 2.3 97.0 0.2
98.2 0.1 FPD (.mu.g < 5 .mu.m) 74.6 6.7 20.2 3.7 20.9 17.4 FPF
(% < 5 .mu.m 34.7 5.2 11.3 1.6 11.6 15.1 relative to DD) MMAD
(.mu.m) 2.6 6.0 5.2 2.2 4.6 2.5
Example 23(c)
Content Uniformity
[0501] One of the blends measured S (Example 16) was also tested
for content uniformity before NGI testing. Ten samples were taken
from the blend and each was assayed. The data from those 10 assays
is shown in Table 25. The data shows that the blend has excellent
uniformity even at this low active loading. It should be noted that
the blend was manufactured in Australia and transported to the USA
for testing and the fact that the content uniformity has been
retained is strong testament to the excellent properties of
material made with this invention.
TABLE-US-00021 TABLE 25 Content uniformity data for sample S
(Example 16). Sample No. 1 2 3 4 5 6 7 8 9 10 Ave RSD (%) w/w %
0.92 0.91 0.90 0.90 0.91 0.91 0.90 0.90 0.90 0.90 0.91 0.54
Salbutamol
Example 24
SEM
[0502] For two of the blends in Example 16 S and R SEM images were
taken and are shown in FIGS. 21-27. For sample S images are shown
for a sample taken at the 20 minute time point of this milling and
at the end of the milling at 30 mins. For sample R the images are
taken for the sample taken at 20 minutes. The images at low
magnification show the composite particles which are or order 5-30
micron. The images at high magnification show that the composite
particles are made up of particles of order 200 nm or less.
* * * * *