U.S. patent application number 16/701616 was filed with the patent office on 2020-05-21 for formulation comprising glycopyrrolate, method and apparatus.
This patent application is currently assigned to Vectura Limited. The applicant listed for this patent is Vectura Limited. Invention is credited to Fergus MANFORD.
Application Number | 20200155506 16/701616 |
Document ID | / |
Family ID | 51542160 |
Filed Date | 2020-05-21 |
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United States Patent
Application |
20200155506 |
Kind Code |
A1 |
MANFORD; Fergus |
May 21, 2020 |
FORMULATION COMPRISING GLYCOPYRROLATE, METHOD AND APPARATUS
Abstract
A method is disclosed for making a pharmaceutical composition
for pulmonary administration comprising co-jet milling
glycopyrrolate and magnesium stearate, wherein the co-jet milled
glycopyrrolate and magnesium stearate is then subjected to a
conditioning step which includes exposure of the co-jet milled
glycopyrrolate and magnesium stearate to humidity. A composition
made by this method is also disclosed.
Inventors: |
MANFORD; Fergus;
(Chippenham, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Vectura Limited |
Chippenham |
|
GB |
|
|
Assignee: |
Vectura Limited
|
Family ID: |
51542160 |
Appl. No.: |
16/701616 |
Filed: |
December 3, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15509769 |
Mar 8, 2017 |
10532041 |
|
|
PCT/EP2015/070660 |
Sep 9, 2015 |
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16701616 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 43/00 20180101;
A61P 9/00 20180101; A61K 31/573 20130101; A61K 31/40 20130101; A61K
31/167 20130101; A61K 9/1688 20130101; A61K 9/145 20130101; A61K
31/4704 20130101; A61K 9/5015 20130101; A61P 11/06 20180101; A61K
45/06 20130101; A61P 11/00 20180101; A61K 9/0075 20130101; A61K
31/138 20130101; A61K 9/5192 20130101; A61K 31/137 20130101; A61P
11/04 20180101; A61K 31/40 20130101; A61K 2300/00 20130101; A61K
31/4704 20130101; A61K 2300/00 20130101; A61K 31/573 20130101; A61K
2300/00 20130101; A61K 31/137 20130101; A61K 2300/00 20130101; A61K
31/167 20130101; A61K 2300/00 20130101 |
International
Class: |
A61K 31/40 20060101
A61K031/40; A61K 31/138 20060101 A61K031/138; A61K 9/51 20060101
A61K009/51; A61K 9/50 20060101 A61K009/50; A61K 9/00 20060101
A61K009/00; A61K 31/573 20060101 A61K031/573; A61K 31/4704 20060101
A61K031/4704; A61K 31/137 20060101 A61K031/137; A61K 31/167
20060101 A61K031/167; A61K 45/06 20060101 A61K045/06; A61K 9/16
20060101 A61K009/16; A61K 9/14 20060101 A61K009/14 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 9, 2014 |
EP |
14184164.3 |
Claims
1-36. (canceled)
37. A particle formulation prepared by a process comprising: co-jet
milling unmicronised glycopyrrolate and magnesium stearate with
milling gas having a humidity below 20% Relative Humidity to
produce micronized composite particles; and subjecting the
micronized composite particles to a conditioning step comprising
exposing the micronized composite particles to humidity in the
range of 10%-95% Relative Humidity at temperatures ranging from
5.degree. C. to 88.degree. C. for at least 60 minutes; wherein the
formulation further comprises indacaterol and mometasone.
38. The particle formulation of claim 37, wherein the
glycopyrrolate is a racemate.
39. The particle formulation of claim 37, wherein the
glycopyrrolate is a single enantiomer.
40. The particle formulation of claim 37, wherein the magnesium
stearate forms a coating on the surface of the glycopyrrolate
particles as measured by energy-dispersive X-ray spectroscopy.
41. The particle formulation of claim 37, wherein the span of the
co-jet milled and co-conditioned glycopyrrolate and magnesium
stearate agent is less than 150 prior to blending with carrier
particles.
42. The particle formulation of claim 41, wherein the span of the
co-jet milled and co-conditioned glycopyrrolate and magnesium
stearate agent is less than 50 prior to blending with carrier
particles.
43. The particle formulation of claim 37, wherein the fraction of
the conditioned co-jet milled formulation which is greater than 10
.mu.m is less than 20% by volume or mass immediately after the
co-jet milling and after the conditioning process as suitably
determined by laser diffraction equipment.
44. The particle formulation of claim 37, wherein the micronized
composite particles are blended with a carrier, optionally after
the conditioning step.
45. The particle formulation of claim 44, wherein the micronized
composite particles are blended with alpha-lactose monohydrate,
optionally after the conditioning step.
46. A particle formulation prepared by a process comprising: co-jet
milling unmicronised glycopyrrolate and magnesium stearate with
milling gas having a humidity below 20% Relative Humidity to
produce micronized composite particles; subjecting the micronized
composite particles to a conditioning step comprising exposing the
micronized composite particles to humidity in the range of 10%-95%
Relative Humidity at temperatures ranging from 5.degree. C. to
88.degree. C. for at least 10 minutes; and subsequently adding
indacaterol and mometasone to the formulation.
47. The particle formulation of claim 46, wherein the
glycopyrrolate is a racemate.
48. The particle formulation of claim 46, wherein the
glycopyrrolate is a single enantiomer.
49. The particle formulation of claim 46, wherein the magnesium
stearate forms a coating on the surface of the glycopyrrolate
particles as measured by energy-dispersive X-ray spectroscopy.
50. The particle formulation of claim 46, wherein the span of the
co-jet milled and co-conditioned glycopyrrolate and magnesium
stearate agent is less than 150 prior to blending with carrier
particles.
51. The particle formulation of claim 46, wherein the span of the
co-jet milled and co-conditioned glycopyrrolate and magnesium
stearate agent is less than 50 prior to blending with carrier
particles.
52. The particle formulation of claim 46, wherein the fraction of
the conditioned co-jet milled formulation which is greater than 10
.mu.m is less than 20% by volume or mass immediately after the
co-jet milling and after the conditioning process as suitably
determined by laser diffraction equipment.
53. The particle formulation of claim 46, wherein the micronized
composite particles are blended with a carrier, optionally after
the conditioning step.
54. The particle formulation of claim 53, wherein the micronized
composite particles are blended with alpha-lactose monohydrate,
optionally after the conditioning step.
55. A particle formulation prepared by a process comprising: co-jet
milling unmicronised glycopyrrolate and magnesium stearate with
milling gas having a humidity below 20% Relative Humidity to
produce micronized composite particles; and subjecting the
micronized composite particles to a conditioning step comprising
exposing the micronized composite particles to humidity in the
range of 10%-95% Relative Humidity at temperatures ranging from
5.degree. C. to 88.degree. C. for at least 10 minutes; wherein the
formulation further comprises indacaterol and mometasone.
Description
INTRODUCTION
[0001] The present invention relates to inhalable pharmaceutical
compositions comprising the antimuscarinic agent glycopyrrolate. In
particular, the present invention relates to dry powder
compositions which exhibit excellent physical stability and aerosol
performance over time, and provides an improved process for
preparing inhalable dry powder formulations of glycopyrrolate.
BACKGROUND
[0002] Glycopyrrolate is an antimuscarinic agent which is useful in
the treatment of conditions such as chronic obstructive pulmonary
disease (COPD), asthma, cystic fibrosis (CF) and related airway
diseases. Glycopyrrolate is also useful as a heart rate lowering
agent when administered by inhalation to patients, in particular
patients with conditions such as chronic obstructive pulmonary
disease (COPD), asthma, cystic fibrosis (CF) and related airway
diseases. It is known to provide glycopyrrolate formulations in the
form of dry powder formulations, for administration using dry
powder inhalers. Frequently salts of glycopyrrolate are used, such
as glycopyrronium bromide.
[0003] Glycopyrrolate is commercially available or may be prepared
using the method described in U.S. Pat. No. 2,956,062. The most
physically stable configuration is when the particles are
crystalline and they contain few amorphous regions on their
surfaces.
[0004] Glycopyrrolate has been found to have an acute problem with
respect to its stability, especially immediately following a
conventional micronisation process.
[0005] Micronisation of glycopyrrolate involves the milling of a
relatively coarse source powder into a system which involves
multiple high-speed or high energy collisions. Typically, source
powders of unmicronised glycopyrrolate will exist in particle sizes
substantially greater than 10 .mu.m, with typical distributions
resembling D10>10 .mu.m, D50>90, D90>250 .mu.m. The
primary objective of the micronisation process is to reduce the
primary particle size to a size which is small enough to be
delivered to the respiratory airways. For example, it is known that
a suitable size may be where the majority of the particles as
measured by mass or volume fall within the inhalable range of 0.1
.mu.m to 10 .mu.m, preferably 0.1 .mu.m to 6 .mu.m or more
preferably 0.5 .mu.m to 5 .mu.m.
[0006] The multiple collisions that occur with high-speed or high
energy micronisation provide the milling action which is required
to break the particles down to the appropriate size. It is also
well known that such milling action may also induce the generation
of non-crystalline material, especially on the surface of the
particles where particles have collided either with each other as
in the case of jet milling, or with the milling medium as in the
case of ball milling, or with the milling machine as in the case of
knife milling. Such non-crystalline material may be amorphous
material.
[0007] The presence of non-crystalline or amorphous regions in
glycopyrrolate material can lead to significant physical
instability.
[0008] International patent application WO2001076575 discloses a
pharmaceutical composition for pulmonary delivery comprising
glycopyrrolate in a controlled release formulation, wherein, on
administration, the glycopyrrolate exerts its pharmacological
effect over a period greater than 12 hours.
[0009] US publication number US 2014/0080890 discloses
glycopyrrolate for use as a heart rate lowering agent and more
particularly, but not exclusively, for use in patients suffering
from respiratory conditions such as chronic obstructive pulmonary
disease. It discloses conducting micronisation under increased
Relative Humidity (RH) to reduce the formation of amorphous
material.
[0010] International patent application WO2005105043 discloses dry
powder compositions which exhibit improved stability over time, and
methods for producing the same.
[0011] International patent application WO2008000482 discloses a
process for preparing dry powder formulations of a glycopyrronium
salt for inhalation that have good stability. The process involves
(a) micronising a glycopyrronium salt together with an
anti-adherent agent, and (b) admixing carrier particles to form the
dry powder formulation.
[0012] International patent application WO2008000482 discloses a
process for reducing the tendency of a drug substance to aggregate
and/or agglomerate during storage. The process involves micronising
the drug substance to give a mean particle size of less than about
10 .mu.m, and exposing the micronised drug substance to a dry
environment at an elevated temperature between 40.degree. C. and
120.degree. C. for at least six hours.
[0013] It has been also suggested that conducting micronisation
with humidified air or other gas may help to reduce the generation
of amorphous materials. Both WO1999054048 and WO2000032165 disclose
that milling crystalline particles, especially medicament powders
intended for administration by inhalation under increased humidity
can reduce the generation of amorphous material.
[0014] WO2000032313 discloses the milling of highly crystalline
material, exemplified with triamcinolone acetonide at reduced
temperature using helium or a mixture of helium and another gas in
order to reduce the formation of amorphous material.
SUMMARY OF THE INVENTION
[0015] The present application teaches a method of making dry
powder formulation, the method comprising co-jet milling
unmicronised glycopyrrolate and magnesium stearate with gas having
a humidity below 20% Relative Humidity to produce micronized
composite particles, wherein the micronized composite particles are
then subjected to a conditioning step which includes exposure of
the micronized composite particles to humidity at temperatures
between 5.degree. C. to 88.degree. C. for at least 60 minutes.
[0016] In another embodiment of the present invention, there is
disclosed a formulation comprising co-jet milled and then
co-conditioned particles comprising unmicronised glycopyrrolate and
magnesium stearate obtained or obtainable according to methods
disclosed herein, optionally for use in a treatment of a
respiratory disease, or for use in the preparation of a medicament
for the treatment of a respiratory disease.
[0017] In another embodiment of the present invention, there is
disclosed a method for making a dry powder formulation, the method
comprising co-jet milling unmicronised glycopyrrolate and magnesium
stearate with desiccated milling gas having a humidity below 20% RH
to produce micronized composite particles, wherein the micronized
composite particles are then subjected to a conditioning step which
includes exposure of the micronized composite particles to humidity
at temperatures between 5.degree. C. to 88.degree. C. for at least
60 minutes.
[0018] In another embodiment of the present invention, there is
disclosed a method for making a dry powder formulation, the method
comprising co-jet milling unmicronised glycopyrrolate and magnesium
stearate with desiccated milling gas having a humidity below 20% RH
to produce micronized composite particles, wherein the micronized
composite particles are then subjected to a conditioning step which
includes exposure of the micronized composite particles to humidity
at temperatures between 5.degree. C. to 88.degree. C. for at least
90 minutes.
[0019] In another embodiment of the present invention, there is
disclosed a method wherein the conditioning is initiated within 30
minutes of completing the milling, within 25 minutes, within 20
minutes, within 15 minutes, preferably within 10 minutes, more
preferably within 5 minutes, most preferably the conditioning is
initiated immediately after completing the co-jet milling of the
glycopyrrolate and magnesium stearate.
[0020] In another embodiment of the present invention, there is
disclosed a method wherein the fraction of the conditioned co-jet
milled formulation which is greater than 10 .mu.m is less than 20%
by volume or mass, preferably wherein the fraction which is greater
than 10 .mu.m is less than 15% by volume or mass, more preferably
wherein the fraction which is greater than 10 .mu.m is less than
10% by volume or mass, or more preferably wherein the fraction
which is greater than 10 .mu.m is less than 5% by volume or mass,
immediately after the co-jet milling and after the conditioning
process as suitably determined by a MALVERN MASTERSIZER.RTM. or
similar laser diffraction equipment.
[0021] In another embodiment of the present invention, there is
disclosed a method wherein the magnesium stearate is co-jet milled
with glycopyrrolate in an amount of from 1 to 25% (w/w), more
preferably from 2 to 20% (w/w), more preferably 3 to 15% (w/w),
more preferably 4 to 10% (w/w) but most preferably from 5 to 7.5%
(w/w) by weight of the co-jet milled combination of glycopyrrolate
and magnesium stearate.
[0022] In another embodiment of the present invention, there is
disclosed a method wherein the conditioning humidity is in the
range of 10%-95% RH, preferably 30-90% RH, 45-90% RH or 50-88% RH
or more preferably 60-87% RH.
[0023] In another embodiment of the present invention, there is
disclosed a method wherein the conditioning further comprises
subjecting the micronized composite particles to a ventilating
atmosphere having RH in the range of 10%-95% RH, preferably 30-90%
RH, 45-90% RH or 50-88% RH or more preferably 60-87%, preferably
wherein the atmosphere is air. Wherein ventilating atmosphere
passes over and through the micronized composite particles at a
rate of less than 100 cm.sup.3/s, less than 10 cm.sup.3/s, less
than 5 cm.sup.3/s, less than 2 cm.sup.3/s, less than 1 cm.sup.3/s,
preferably less than 0.8 cm.sup.3/s, preferably less than 0.6
cm.sup.3/s, preferably less than 0.4 cm.sup.3/s, preferably less
than 0.2 cm.sup.3/s, preferably less than 0.1 cm.sup.3/s, more
preferably about 0.001 cm.sup.3/s. Wherein the volume ratio of
ventilating atmosphere to poured bulk powder is more than 1:1,
preferably more than more than 10:1, preferably more than more than
100:1, preferably more than more than 1,000:1, preferably more than
10,000:1, preferably more than 100,000:1, preferably more than
1,000,000:1, more preferably more than 10,000,000:1.
[0024] In another embodiment of the present invention, there is
disclosed a method wherein the conditioning step is carried out for
at least 30 minutes, preferably for at least 60 minutes, preferably
for at least 1.5 hours, at least 2 hours, at least 3 hours, at
least 5 hours, at least 6 hours, at least 12 hours, at least 18
hours, preferably at least 24 hours, preferably for at least 36
hours or more preferably for at least 48 hours.
[0025] In another embodiment of the present invention, there is
disclosed a method wherein the conditioning step includes exposing
the micronized composite particles to a temperature in the range
from 10.degree. C. to 50.degree. C., more preferably 24.degree. C.
to 50.degree. C.
[0026] In another embodiment of the present invention, there is
disclosed a method wherein the conditioning step takes place by
distributing the micronized composite particles on a surface,
optionally wherein the conditioning step takes place on a tray.
[0027] In another embodiment of the present invention, there is
disclosed a method wherein the conditioning step involves exposing
the micronized composite particles to the humidity for sufficient
time for amorphous glycopyrrolate to re-crystallise after co-jet
milling, as determined by Dynamic Vapour Sorption (DVS).
[0028] In another embodiment of the present invention, there is
disclosed a method wherein the conditioning step involves powder
agitation, optionally wherein the agitation is intermittent powder
agitation, wherein powder agitation takes place within 30 minutes
of completing the milling, within 25 minutes, within 20 minutes,
within 15 minutes, preferably within 10 minutes, more preferably
within 5 minutes, most preferably immediately after completing the
milling of the glycopyrrolate and magnesium stearate.
[0029] In another embodiment of the present invention, there is
disclosed a method wherein the milling gas has a humidity
preferably below 15% RH, preferably below 10% RH, preferably below
5% RH, more preferably below 2.5% RH.
[0030] In another embodiment of the present invention, there is
disclosed a method wherein the milling gas is preferably air,
nitrogen or helium or combination thereof.
[0031] In another embodiment of the present invention, there is
disclosed a method wherein the co-jet milling is carried out at an
averaged powder feed rate of between 0.1 and 50 g/min, preferably
at a feed rate of between 0.5 and 40 g/min, preferably at a feed
rate of between 1 and 30 g/min, preferably at a feed rate of
between 1.5 and 25 g/min, preferably at a feed rate of between 0.1
and 20 g/min, preferably at a feed rate of between 0.5 and 15
g/min, preferably at a feed rate of between 1 and 10 g/min,
preferably at a feed rate of between 1.5 and 5 g/min.
[0032] In another embodiment of the present invention, there is
disclosed a method wherein the formulation further comprises a
beta-2 adrenoceptor agonist, preferably wherein the beta-2
adrenoceptor agonist is albuterol (salbutamol), metaproterenol,
terbutaline, salmeterol fenoterol, procaterol, preferably,
formoterol, carmoterol and pharmaceutically acceptable salts
thereof, more preferably wherein the beta-2 adrenoceptor agonist is
(R)-5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quin-
olin-2-one maleate.
[0033] In another embodiment of the present invention, there is
disclosed a formulation according to any preceding embodiment for
use in treatment of a respiratory condition.
FIGURES
[0034] FIG. 1 shows the particle size distribution for unmicronised
glycopyrrolate which has been stored under sealed conditions,
D.sub.10=11.3 .mu.m, D.sub.50=98.0 .mu.m, D.sub.90=281 .mu.m. The
cumulative fraction under 5 .mu.m was 4.68%.
[0035] FIG. 2 shows the particle size distribution for freshly jet
milled glycopyrrolate only, the cumulative fraction under 5 .mu.m
was 85.75%.
[0036] FIG. 3 shows the particle size distribution for jet milled
glycopyrrolate without magnesium stearate which has been tipped out
as a compact heap of powder and the heap of powder was exposed to
40.degree. C. at 75% RH for 1 hour on a tray thereby preventing the
conditioning environment from reaching the internal particles in
the heap of powder. The cumulative fraction under 5 .mu.m was
1.44%.
[0037] FIG. 4 shows the particle size distribution for Formulation
1, jet milled glycopyrrolate only; t=0 hours.
[0038] FIG. 5 shows the particle size distribution for Formulation
1, jet milled glycopyrrolate only; Conditioned at 25.degree. C. at
60% RH for 49 hours, analysed 72 hours after micronisation.
[0039] FIG. 6 shows the particle size distribution for Formulation
1, jet milled Glycopyrrolate only; Conditioned at 25.degree. C. at
60% RH for 52 hours, analysed 72 hours after micronisation, the
cumulative fraction under 5 .mu.m was 62.22%.
[0040] FIG. 7 shows the particle size distribution for Formulation
1, jet milled Glycopyrrolate only; Conditioned at 25.degree. C. at
60% RH for 71 hours, analysed 72 hours after micronisation, the
cumulative fraction under 5 .mu.m was 63.69%.
[0041] FIG. 8 shows the particle size distribution for Formulation
2, co-jet milled glycopyrrolate and magnesium stearate, t=0
hours.
[0042] FIG. 9 shows the particle size distribution for Formulation
2, co-jet milled glycopyrrolate and magnesium stearate; conditioned
at 25.degree. C. at 60% RH for 49 hours, analysed 72 hours after
co-micronisation.
[0043] FIG. 10 shows the particle size distribution for Formulation
2, co-jet milled glycopyrrolate and magnesium stearate; conditioned
at 25.degree. C. at 60% RH for 52 hours, analysed 72 hours after
co-micronisation, the cumulative fraction under 5 .mu.m was
88.66%.
[0044] FIG. 11 shows the particle size distribution for Formulation
2, co-jet milled glycopyrrolate and magnesium stearate; conditioned
at 25.degree. C. at 60% RH for 71 hours, analysed 72 hours after
co-micronisation, the cumulative fraction under 5 .mu.m was
89.54%.
[0045] FIG. 12 shows a comparison of the 0 90 values for
Formulation 1 and Formulation 2 conditioned for 5 minutes until 71
hours, all the samples were analysed at 72 hours.
[0046] FIG. 13 shows a comparison of the 0 50 values for
Formulation 1 and Formulation 2 conditioned for 5 minutes until 71
hours, all the samples were analysed at 72 hours.
[0047] FIG. 14 shows a comparison of the 0 50 values for
Formulation 1 and Formulation 2 conditioned for 5 minutes until 72
hours wherein the x-axis shows values from 45 minutes until 71
hours, all the samples were analysed at 72 hours.
[0048] FIG. 15 shows a comparison of the 0 10 values for
Formulation 1 and Formulation 2 conditioned for 5 minutes until 71
hours, all the samples were analysed at 72 hours.
[0049] FIG. 16 shows a comparison of the 0 10 values for
Formulation 1 and Formulation 2 conditioned for 5 minutes until 71
hours, all the samples were analysed at 72 hours wherein the x-axis
shows values from 45 minutes until 72 hours.
[0050] FIG. 17 shows the particle size distribution for Formulation
3, jet milled glycopyrrolate only, t=0 hours.
[0051] FIG. 18 shows the particle size distribution for Formulation
3, jet milled glycopyrrolate only; conditioned at 50.degree. C. at
50% RH for 49 hours, analysed 49 hours after co-micronisation.
[0052] FIG. 19 shows the particle size distribution for Formulation
4, co-jet milled glycopyrrolate and magnesium stearate, t=0
hours.
[0053] FIG. 20 shows the particle size distribution for Formulation
4, co-jet milled glycopyrrolate and magnesium stearate; Conditioned
at 50.degree. C. at 50% RH for 49 hours, analysed 49 hours after
co-micronisation.
[0054] FIG. 21 shows the particle size distribution for Formulation
5, jet milled glycopyrrolate only.
[0055] FIG. 22 shows the particle size distribution for Formulation
5, jet milled glycopyrrolate only; Conditioned at 6.degree. C. at
86% RH for 49 hours, analysed 49 hours after micronisation.
[0056] FIG. 23 shows the particle size distribution for Formulation
6, co-jet milled glycopyrrolate and magnesium stearate, t=0
hours.
[0057] FIG. 24 shows the particle size distribution for Formulation
6, co-jet milled glycopyrrolate and magnesium stearate; Conditioned
at 6.degree. C. at 86% RH for 49 hours, analysed 49 hours after
co-micronisation.
[0058] FIG. 25 shows the particle size distribution for Formulation
7, co-jet milled glycopyrrolate and magnesium stearate; conditioned
at 24.degree. C. at 45% RH on a tray for 72 hours, analysed 72
hours after co-micronisation.
[0059] FIG. 26 shows the particle size distribution for Formulation
8, co-jet milled glycopyrrolate and magnesium stearate; Conditioned
at 24.degree. C. at 45% RH in an open glass vial for 144 hours,
analysed 144 hours after co-micronisation.
[0060] FIG. 27 shows the DVS trace for Formulation 1, jet milled
glycopyrrolate only, analysis commenced immediately after jet
milling. The presence of multiple peaks is a reliable indicator of
the presence of amorphous material.
[0061] FIG. 28 shows the DVS trace for Formulation 1, jet milled
glycopyrrolate only, conditioned at 25.degree. C. at 60% RH for 49
hours, analysis commenced 49 hours after jet milling. The absence
of multiple peaks is a reliable indicator of the absence of
amorphous material.
[0062] FIG. 29 shows the DVS trace for Formulation 2, co-jet milled
glycopyrrolate and magnesium stearate, analysis commenced
immediately after co-jet milling.
[0063] FIG. 30 shows the DVS trace for Formulation 2, co-jet milled
glycopyrrolate and magnesium stearate conditioned at 25.degree. C.
at 60% RH for 49 hours, analysis commenced 49 hours after co-jet
milling.
[0064] FIG. 31 shows the DVS trace for Formulation 4, co-jet milled
glycopyrrolate and magnesium stearate conditioned at 50.degree. C.
at 50% RH for 49 hours, analysis commenced 49 hours after co-jet
milling.
[0065] FIG. 32 shows the DVS trace for Formulation 5, jet milled
glycopyrrolate only, conditioned at 6.degree. C. at 86% RH for 49
hours, analysis commenced 49 hours after jet milling.
[0066] FIG. 33 shows the DVS trace for Formulation 6, co-jet milled
glycopyrrolate and magnesium stearate conditioned at 6.degree. C.
at 86% RH for 49 hours, analysis commenced 49 hours after co-jet
milling.
[0067] FIG. 34 shows the DVS trace for Formulation 7, co-jet milled
glycopyrrolate and magnesium stearate conditioned 24.degree.
C..+-.3.degree. C. at 45% RH.+-.5% RH for 72 hrs, analysis
commenced 72 hours after co-jet milling.
[0068] FIG. 35 shows the DVS trace for Formulation 8, co-jet milled
glycopyrrolate and magnesium stearate, analysis commenced
immediately after co-jet milling.
[0069] FIG. 36 shows the DVS trace for Formulation 8, co-jet milled
glycopyrrolate and magnesium stearate conditioned at 24.degree.
C..+-.3.degree. C. at 45% RH.+-.5% RH for 144 hours and the
analysed at 144 hours after co-micronisation. The absence of
multiple peaks is a reliable indicator of the absence of amorphous
material.
[0070] FIG. 37 shows the DVS trace for Formulation 13a, jet milled
glycopyrrolate only using a milling gas having humidity <20% RH
(2.8-3.5% RH) and the analysed immediately after micronisation.
[0071] FIG. 38 shows the OVS trace for Formulation 13b, jet milled
glycopyrrolate only using a milling gas having an elevated humidity
(31.6-36.2% RH) and then analysed immediately after
micronisation.
[0072] FIG. 39 shows the OVS trace for Formulation 13c, co-jet
milled glycopyrrolate and magnesium stearate using a milling gas
having an elevated humidity (32.4-37.1% RH) and then analysed
immediately after co-micronisation.
[0073] FIG. 40 shows the OVS trace for Formulation 13d, co-jet
milled glycopyrrolate and magnesium stearate using a milling gas
having humidity <20% RH (3.4-3.9% RH) and then analysed
immediately after co-micronisation.
[0074] FIG. 41 shows a comparison of the 0 90 values for
Formulations 13a-d analysed using the Malvern dry analysis
method.
[0075] FIG. 42 shows a specific comparison of the 0 90 values for
Formulation 13b and Formulation 13d analysed using the Malvern dry
analysis method.
[0076] FIG. 43 shows a specific comparison of the 090 values for
Formulation 13c and Formulation 13d analysed using the Malvern dry
analysis method.
[0077] FIG. 44 shows a comparison of the 0 50 values for
Formulations 13a-d analysed using the Malvern dry analysis
method.
[0078] FIG. 45 shows a specific comparison of the 0 50 values for
Formulation 13b and Formulation 13d analysed using the Malvern dry
analysis method.
[0079] FIG. 46 shows a specific comparison of the 050 values for
Formulation 13c and Formulation 13d analysed using the Malvern dry
analysis method.
[0080] FIG. 47 shows a comparison of the 0 10 values for
Formulations 13a-d analysed using the Malvern dry analysis
method.
[0081] FIG. 48 shows a specific comparison of the 0 10 values for
Formulation 13b and Formulation 13d analysed using the Malvern dry
analysis method.
[0082] FIG. 49 shows a specific comparison of the 0 10 values for
Formulation 13c and Formulation 13d analysed using the Malvern dry
analysis method.
[0083] FIG. 50 shows a comparison of the 0 90 values for
Formulations 13a-d analysed using the Malvern wet analysis method.
Operator error resulted in the loss of the 10 minute sample for
Formulation 13a.
[0084] FIG. 51 shows a specific comparison of the 0 90 values for
Formulation 13b and Formulation 13d analysed using the Malvern wet
analysis method.
[0085] FIG. 52 shows a specific comparison of the 090 values for
Formulation 13c and Formulation 13d analysed using the Malvern wet
analysis method.
[0086] FIG. 53 shows a comparison of the 0 50 values for
Formulations 13a-d analysed using the Malvern wet analysis method.
Operator error resulted in the loss of the 10 minute sample for
Formulation 13a.
[0087] FIG. 54 shows a specific comparison of the 050 values for
Formulation 13c and Formulation 13d analysed using the Malvern wet
analysis method.
[0088] FIG. 55 shows a comparison of the 0 10 values for
Formulations 13a-d analysed using the Malvern wet analysis method.
Operator error resulted in the loss of the 10 minute sample for
Formulation 13a.
[0089] FIG. 56 shows a specific comparison of the 0 10 values for
Formulation 13c and Formulation 13d analysed using the Malvern wet
analysis method.
[0090] FIG. 57 shows the OVS trace for the co-micronised material
used in Formulations 14a and 14b, co-jet milled glycopyrrolate and
magnesium stearate, OVS analysis commenced immediately after co-jet
milling.
[0091] FIG. 58 shows a comparison of the Fine Particle Fraction (%
FPF(EO)<5 .mu.m for Formulations 14a and 14b. Mean.+-.range,
n=3. FPF was assessed immediately, 24 hrs and 1 week after
manufacture.
[0092] FIG. 59 shows a comparison of the Fine Particle Fraction (%
FPF(ED)<3 .mu.m for Formulations 14a and 14b. Mean.+-.range,
n=3. FPF was assessed immediately, 24 hrs and 1 week after
manufacture.
DETAILED DESCRIPTION OF INVENTION
[0093] In the present invention we have determined that milling of
glycopyrrolate with magnesium stearate produces a more useful
particle size distribution profile than milling glycopyrrolate in
the absence of the magnesium stearate because the co-jet milled
formulation has a Particle Size Distribution (PSD) with a portion
greater than 10 .mu.m which is less than 20% by volume or mass.
Co-jet milling glycopyrrolate with magnesium stearate also produces
an inhalable formulation with suitable D.sub.10, D.sub.50 and
D.sub.90 values (D.sub.50<10 .mu.m) but co-jet milling with
magnesium stearate significantly reduces the fraction >10 .mu.m.
This results in a composite formulation wherein almost all the
co-jet milled formulation is less than 10 .mu.m as suitably
determined by a MALVERN MASTERSIZER.RTM. or similar laser
diffraction equipment. The subsequent conditioning of the active in
the presence of the magnesium stearate allows the improved particle
size distribution profile of the active particle size to be
maintained.
[0094] Without wishing to be bound by theory, we consider that the
presence of the magnesium stearate helps to reduce the >10 .mu.m
fraction during the milling process and then also helps to maintain
it during conditioning, because it assists in the conversion of
physically unstable amorphous surfaces to physically stable
crystalline surfaces and allows conditioning to act rapidly on the
milled glycopyrrolate particles.
[0095] (1) Firstly, the magnesium stearate facilitates a more
consistent powder flow into the milling chamber which promotes a
more consistent milling action. A more efficient milling action
ensures the milling energy is able to act more evenly across all
the particles rather than a punctuated milling action as seen when
the powder is introduced unevenly into the milling chamber.
Consequently the particle sizes are smaller for formulations
co-micronised with a magnesium stearate, as demonstrated by the
D.sub.10, D.sub.50 and D.sub.90 values exemplified below.
Furthermore the particle size distributions are narrower for
formulations co-micronised with magnesium stearate, as demonstrated
by D.sub.10, D.sub.50 and D.sub.90 values, especially when
calculated using the span equation:
Span = D 90 - D 10 D 50 ##EQU00001##
[0096] (2) Secondly, the magnesium stearate coating on the
glycopyrrolate acts as a physical spacer between the glycopyrrolate
particles allowing the conditioning environment to permeate the
glycopyrrolate powder bed more efficiently than a glycopyrrolate
only formulation. This greater permeation efficiency assists in the
conversion of the physically unstable amorphous surfaces to
physically stable crystalline surfaces minimising the occurrences
when glycopyrrolate particles are in contact with one another,
[0097] (3) Thirdly, the magnesium stearate may cover regions of
amorphous glycopyrrolate material. Since the magnesium stearate is
present during the micronisation process it is able to immediately
minimise contact between amorphous surfaces on neighbouring
particles by covering the amorphous surfaces. This results in a
reduced tendency for the amorphous surfaces to bind to one another
upon re-crystallisation as measured by a reduced >10 .mu.m
fraction. Since the particles are so small the conditioning
environment (e.g. moisture and temperature) is still able to
permeate via the non-covered parts, in particular the juncture
between the glycopyrrolate and the magnesium stearate on the
composite glycopyrrolate particle and facilitate conversion of its
unstable amorphous parts to create a physically stable crystalline
particle, and
[0098] (4) Finally, the desiccated milling environment, especially
a milling environment with a humidity below 20% RH, suspends or
retards a reversion of the physically unstable amorphous
glycopyrrolate surfaces to physically stable crystalline surfaces
of the micronized composite particles whilst in the milling chamber
and associated collection vessel.
[0099] Reduction of the fraction of active greater than 10 .mu.m
reduces active pharmaceutical ingredient (API) wastage because
otherwise the >10 .mu.m fraction might have to be physically
removed prior to blending with other API or excipient.
[0100] The process of the invention provides for a more predictable
starting material because there is no longer an appreciable >10
.mu.m fraction. Furthermore the stability conferred by the process
of the invention ensures that a >10 .mu.m fraction is much less
likely to develop. Optionally, this improved process removes the
need for further processing prior to blending with a carrier
thereby speeding up formulation manufacture.
[0101] A further potential advantage of the present invention is
that it allows the administration of even smaller doses than
previously used. The reduction of the dose is made possible by the
more consistent and predictable administration of the
glycopyrrolate, for example, through a consistently improved Fine
Particle Fraction (FPF(MD) or FPF(ED)) and Fine Particle Dose (FPO)
compared to that observed in connection with the conventional
formulations. Consequently, while the dose dispensed is smaller,
the amount of active agent being administered to the desired parts
of the airways is the same, with the same therapeutic effect being
achieved.
[0102] Milling
[0103] Preferably the glycopyrrolate and the magnesium stearate are
pre-mixed to give a roughly homogeneous blend before being co-jet
milled together as measured as a percentage coefficient of
variation, as known in the art, of less than 25%, preferably less
than 20%, more preferably less than 15%.
[0104] The terms "co-micronise" and "co-jet mill" are synonymous
when used herein.
[0105] Suitable mixing equipment for any initial pre-mix of the
magnesium stearate and the glycopyrrolate includes low shear tumble
blenders such as a Turbula.RTM. powder blender and high-shear
mixers such as a MiPro.RTM. powder blender or a Diosna.RTM..
[0106] Micronising reduces the particle size of the glycopyrrolate
to a size that is suitable for administration by inhalation. The
diameter of these inhalable particles is preferably less than 10
.mu.m, preferably 0.1 .mu.m to 10 .mu.m, and preferably 0.1 .mu.m
to 6 .mu.m or more preferably 0.5 .mu.m to 5 .mu.m as measured by
mass or volume as suitably determined by a MALVERN MASTERSIZER or
similar laser diffraction equipment. Particles having diameters
greater than about 10 .mu.m are likely to impact the walls of the
throat and generally do not reach the lung. Particles having
diameters in the range of about 2 .mu.m to about 5 .mu.m will
generally be deposited in the respiratory bronchioles whereas
smaller particles having diameters in the range of about 0.5 .mu.m
to about 2 .mu.m are likely to be deposited in the alveoli and to
be absorbed into the bloodstream.
[0107] Co-jet milling glycopyrrolate with magnesium stearate,
significantly reduces the propensity of the micronised drug
substance to form >10 .mu.m aggregates/agglomerates immediately
after milling. When co-jet milled, magnesium stearate particles
form a physically fused and proud particulate coating on the
glycopyrrolate particles, and they create inter-particulate spaces
between the particles of glycopyrrolate. These spaces are thought
to facilitate permeation of the conditioning atmosphere into the
glycopyrrolate powder bed during the conditioning step. The
presence of this coating can be established by energy-dispersive
X-ray spectroscopy (EDX). The presence of composite particles can
be determined by aerosolising a sample from an inhaler into a Next
Generation Impactor (NGI) at 90 L/min (equivalent to a 4 kPa
pressure drop). Double coated carbon conductive tabs are placed
directly under the air nozzles of stages 5, 6 and 7 of the NGI to
capture the smaller powder particles. Double coated adhesive tabs
prevent movement of the tab during the NGI assessment but are also
small enough so that the overall airflow characteristics of the NGI
pathway are not adversely affected. Once done, the powder-coated
carbon conductive tabs can be transferred to SEM carbon specimen
mounts, or similar. The sample can be viewed using SEM and EDX
specifically looking for co-location of magnesium and bromine, in
the case of magnesium stearate and glycopyrronium bromide.
[0108] When the conditioning step is complete the >10 .mu.m
fraction of the co-jet milled and co-conditioned glycopyrrolate and
magnesium stearate suitably remains less than 15% by volume or
mass, more preferably less than 10% by volume or mass, or more
preferably less than 5% by volume or mass after 6 months, 12
months, 24 months or 36 months, suitably after packaging into a
blister or capsule or inhaler when stored at ambient conditions,
which are considered to be between 20 and 26.degree. C.; relative
humidities depends on the specific temperature and the pressure of
the system of interest but are typically 50% and 60%.
[0109] When the conditioning step is complete the span, as defined
above, of the co-jet milled and co-conditioned glycopyrrolate and
magnesium stearate suitably remains less than 150, more preferably
less than 120, or more preferably less than 100. Preferably the
span of the co-jet milled and co-conditioned glycopyrrolate and
magnesium stearate is less than 150, more preferably less than 120,
more preferably less than 100, or more preferably less than 50
prior to blending with carrier particles.
[0110] Jet milling involves the supply of gas, such as nitrogen,
helium or air at pressures in the region of about 6 to 12 bar and
particles to be milled are entrained in the feed gas. The jet
milling operation occurs at close to atmospheric pressure, and has
a milling duration measured in milliseconds. The final outlet
temperature of the jet milling is typically at about room
temperature (preferably 10.degree. C. and 35.degree. C., more
preferably 20.degree. C. and 26.degree. C.). The milling gas is
introduced into the mill at about room temperature, and exits the
mill at about the same temperature. During the process however, the
gas will change temperature significantly as it exits the
supersonic nozzle (lower pressure and temperature) and is
subsequently warmed by the energy released in the jet milling
operation. Preferably the co-milling temperature is above 0.degree.
C.
[0111] According to the prior art, U.S. Pat. No. 8,235,314 B2 for
example, it is considered advantageous to perform the micronization
process with humidified gas (typically air or nitrogen) to produce
the best particles in terms of size, stability and other valuable
properties. The prior art, and U.S. Pat. No. 8,235,314 B2 in
particular considered it advantageous to maximize the amount of
water vapour present during the micronization process, without
producing liquid condensate.
[0112] In contrast we have found that when co-jet milling with
magnesium stearate it is particularly preferred to adopt different
milling parameters. A preferred embodiment is a method comprising
co-jet milling unmicronised glycopyrrolate and magnesium stearate
with a desiccated milling gas in particular the desiccated milling
gas having reduced RH, preferably a humidity below 20% RH,
preferably below 15% RH, preferably below 10% RH, preferably below
5% RH, more preferably below 2.5% RH.
[0113] The conditioning step is preferably carried out prior to
blending with any moisture-laden particulates, for example prior to
addition of lactose or in particular alpha-lactose monohydrate.
Therefore the conditioning is carried out in the absence of lactose
or alpha-lactose monohydrate. If the unconditioned or partially
conditioned glycopyrrolate particles are blended prematurely with
moisture-laden particles any amorphous glycopyrrolate may revert to
crystalline material whilst in contact with the moisture-laden
particles and fuse to these other particles, forming agglomerates.
Consequently, the aerosol performance will be adversely affected
because the particle size will have increased. This is particularly
problematic when the moisture-laden particles include carrier
lactose, for example alpha-lactose monohydrate, because the
glycopyrrolate will remain attached to the carrier and then be
swallowed rather than inhaled into the airways.
[0114] In a preferred embodiment crystalline glycopyrrolate is jet
milled in a Hosokawa Alpine.RTM. 100 AFG fluid bed opposed jet
mill. Other suitable jet milling equipment include, for example,
the MC 44 IR Chrispro.RTM. Jet-Mill (Micromacinazione SA),
Hosokawa's Alpine.RTM. AS-50, AS-100, AFG 140, AFG200, AFG280 and
AFG400 jet mills.
[0115] The co-jet milling powder feed rates for a 50 mm diameter
jet mill, for example a Hosakowa AS-50, should be kept low
(preferably <20 g/min) to ensure an optimal coating of the
glycopyrrolate by the magnesium stearate. Feed rates higher than 20
g/min still achieve coating by the magnesium stearate but it will
be sub-optimal because too much powder passes through the mill to
ensure sufficient energy is applied to each particle to achieve the
desired coating with magnesium stearate. When feed rates higher
than 20 g/min are used, powder conditioning factor (vi) mentioned
below must be employed, optionally with powder conditioning factors
(i)-(viii). Feed rates will vary depending on the size of the mill
used. Consequently, jet mills with 100 mm diameters, for example a
Hosakowa AS-100 spiral jet mill, will be able to accommodate higher
feed rates, typically <50 g/min. The jet milling may be carried
out at an averaged powder feed rate of preferably between 0.1 and
50 g/min, preferably at a feed rate of between 0.5 and 40 g/min,
preferably between 1 and 30 g/min, preferably between 1.5 and 25
g/min, preferably between 0.1 and 20 g/min, preferably between 0.5
and 15 g/min, preferably between 1 and 10 g/min, preferably between
1.5 and 5 g/min.
[0116] The co-micronised particles extracted from the micronisation
process may be collected and may be transported to a suitable
conditioning vessel, in which the powder conditioning factors
(i)-(viii) mentioned below may be used. In such a system preferably
the particles are all exposed to the humidity for sufficient time,
as detailed herein, such as at least 10 minutes. Preferably all the
powder remains in the vessel from start to finish of this
process.
[0117] In accordance with a preferred embodiment of the present
invention, the dry powder formulation comprising glycopyrrolate is
prepared by co-jet milling with magnesium stearate, then undergoes
any one of the powder conditioning steps (i)-(viii) mentioned
below.
[0118] In a preferred embodiment the glycopyrrolate is mixed with
the magnesium stearate to give a homogeneous blend prior to being
co-jet milled, the admixture is then co-jet milled and then
undergoes any one of the powder conditioning steps (i)-(viii)
mentioned below.
[0119] Preferably the glycopyrrolate is co-jet milled with from 1
to 25% (w/w), more preferably from 2 to 20% (w/w), more preferably
3 to 15% (w/w), more preferably 4 to 10% (w/w) but most preferably
from 5 to 7.5% (w/w) magnesium stearate.
[0120] Where necessary or useful, the glycopyrrolate and/or
magnesium stearate are sieved prior to co-jet milling.
[0121] Conditioning
[0122] To produce an improved formulation, after co-micronisation
the glycopyrrolate and magnesium stearate are subjected to
conditioning variables which might include:
[0123] (i) Relative Humidity (RH)
[0124] The present invention utilises humidity to assist in
conditioning of the glycopyrrolate. In one embodiment of the
invention, the conditioning involves exposing the co-jet milled
glycopyrrolate and magnesium stearate to moisture within the
humidity ranges of 20%-95% RH, preferably 40-90% RH, 45-90% RH or
50-88% RH or more preferably 60-87%.
[0125] In a preferred embodiment of the invention, the conditioning
humidity is greater than ambient humidity, preferably greater than
50% RH.
[0126] (ii) Temperature
[0127] In one embodiment of the invention, the conditioning
temperature is preferably in the range 5.degree. C. to 88.degree.
C., more preferably 10.degree. C. to 50.degree. C., more preferably
24.degree. C. to 50.degree. C.
[0128] The RH at these temperatures may be in the range of 20 to
100%, preferably 30 to 97%, more preferably 40 to 95%, more
preferably 45 to 95% and most preferably 50 to 90%, suitably
provided the conditioning environment is maintained above the dew
point temperature (Td)-The dew point is the temperature at which
the water vapour in air at constant barometric pressure condenses
into liquid water at the same rate at which it evaporates. At
temperatures below the dew point, water will leave the air and
condense on an available solid surface which is of suitable
temperature. Condensed water on micronized glycopyrrolate should be
carefully controlled and consequently the selected conditioning
parameters of temperature and humidity should be chosen to avoid
this problem.
[0129] The conditioning may be provided by ambient conditions or by
stability cabinets or by supersaturated salt solutions, all of
which are exemplified below.
[0130] (iii) Conditioning surface
[0131] In one embodiment of the invention, the co-jet milled
glycopyrrolate powder is preferably placed on a tray or equivalent
surface. The broadest range of conditions involves the powder being
preferably agitated or turned to ensure that all of the particles
are equally exposed to the conditioning atmosphere. The turning or
agitating also helps to avoid or reduce agglomeration of the
particles during the conditioning process. When more energetic
conditioning environments are selected for conditioning on a tray
or equivalent surface, the frequency of turning or agitation may
need to be preferably every few minutes, preferably every few
seconds or more preferably continuous until the formation of a
stable material, for example where any amorphous surfaces of the
micronized glycopyrrolate revert to a crystalline state, suitably
as determined by dynamic vapour sorption.
[0132] The conditioning vessel may be for example a tray, or a
suitable surface for retaining the co-jet milled powder.
Alternatively the conditioning vessel may be a bag.
[0133] (iv) Duration
[0134] The conditioning of the co-jet milled glycopyrrolate powder
preferably takes place over a period of at least about 60 minutes,
at least about 65 minutes, at least about 70 minutes, at least
about 80 minutes, at least about 85 minutes, at least about 90
minutes, 2 hours, 3, 4, 5, 6, 8, 10, 12, 14, 18, 24, 36 or at least
48 hours. The broadest range involves a period of at least about 10
minutes. It is reiterated that the duration of required
conditioning is generally affected by the energy provided by
conditioning environment. Highly energetic conditioning
environments may result in a more rapid onset of changes in the
material being conditioned.
[0135] (v) Period for Initiating the Conditioning
[0136] In one preferred embodiment the conditioning is initiated
within 30 minutes of completing the milling, within 25 minutes,
within 20 minutes, within 15 minutes, preferably within 10 minutes,
more preferably within 5 minutes, more preferably within 2 minutes
of completing the co-jet milling of the glycopyrrolate and
anti-adherent. The broadest range involves conditioning immediately
after completing the co-jet milling of the glycopyrrolate and
anti-adherent.
[0137] (vi) Ensuring that all the Particles are all Exposed to the
Humidity
[0138] The conditioning vessel should preferably allow exposure of
all of the micronized composite particles to the moisture applied
from the conditioning atmosphere. The powder may be agitated or not
agitated. If the powder is not agitated it should preferably be
placed on a tray or suitable expansive surface, and preferably
spread evenly in a thin layer over the tray ensuring particle
contact is minimised. The broadest range of conditions involves a
suitable expansive surface.
[0139] (vii) A Fluidised Bed
[0140] As an alternative, the co-jet milled glycopyrrolate powder
may be transferred to a system which creates a fluidised bed of the
co-jet milled powder. Such systems are known in the art. The co-jet
milled powder may be difficult to fluidise alone, and consequently
fluidisation media are advantageously added, such as metal,
plastic, glass or ceramic beads, typically with diameters in the
range 100 .mu.m to 5 mm.
[0141] A fluidised bed aerosol technique for this purpose could be
one as described by Morton et al (J. Aerosol Science, Vol. 26, No.
3, p 353 and references therein).
[0142] In one preferred embodiment the conditioning takes place
using a Resonance Acoustic Mixer (RAM), optionally wherein the
powder conditioning is initiated within 30 minutes of completing
the milling, within 25 minutes, within 20 minutes, within 15
minutes, preferably within 10 minutes, more preferably within 5
minutes, preferably within 2 minutes or more preferably and in the
broadest range the conditioning is initiated immediately after
completing the co-jet milling of the glycopyrrolate and magnesium
stearate.
[0143] (viii) Ventilation
[0144] Immediately after co-jet milling, glycopyrrolate samples
possess numerous amorphous regions that contain moisture extracted
from the environment. When regions of amorphous glycopyrrolate
revert to the crystalline state, the crystal matrix extrudes the
bound moisture onto the surface of the glycopyrrolate particle.
Small hermetically sealed containers, wherein the ratio of
headspace volume (cm.sup.3) to poured bulk powder volume (cm.sup.3)
is less than 1:1 are considered unventilated conditions.
Glycopyrrolate samples that are stored in hermetically sealed
containers, glass vials for example, are less efficient at
releasing this moisture into the atmosphere and it remains on the
particle surface. This retained moisture is then able to adversely
interact with the amorphous regions on neighbouring glycopyrrolate
particles and catalyse additional amorphous to crystalline
reversions. This is particularly problematic when glycopyrrolate
particles remain in contact with one another whilst the amorphous
regions undergo amorphous to crystalline reversion because the
amorphous regions on particles then form solid bridges as they
crystallise, solid bridging results in agglomerates.
[0145] In contrast, a ventilated conditioning atmosphere permits
permanent removal of this surface moisture away from the particle
surface after amorphous regions of glycopyrrolate have undergone
amorphous to crystalline reversion. Consequently there is
insufficient moisture to cause significant agglomeration.
Ventilation is the pervasive movement of unsaturated atmosphere
between stationary particles comprising the powder bed.
[0146] A preferred embodiment utilises a ventilating atmosphere to
assist in conditioning of the co-jet milled glycopyrrolate. It is
preferred that the glycopyrrolate powder bed is subjected to a
ventilated atmosphere to ensure permanent removal of surface
moisture from the co-jet milled glycopyrrolate. The ventilating
atmosphere is unsaturated and always has the capacity to absorb
more moisture from the powder bed. This ability to absorb moisture
is found with a ventilating atmosphere having relative humidity in
the range of 10%-95% RH, preferably 30-90% RH, 45-90% RH or 50-88%
RH or more preferably 60-87%. The broadest range involves a
ventilating atmosphere having relative humidity in the range of
20%-95% RH.
[0147] In a preferred embodiment, the conditioning involves
exposing the co-jet milled glycopyrrolate and magnesium stearate to
a ventilating atmosphere, preferably wherein the atmosphere passes
over and through the co-jet milled glycopyrrolate particles.
Preferably, the ventilating atmosphere is air; preferably the
ventilating atmosphere is air having relative humidity in the range
of 10%-95% RH, preferably 30-90% RH, 45-90% RH or preferably 50-88%
RH or more preferably 60-87% RH.
[0148] In a preferred embodiment, the conditioning involves
exposing the co-jet milled glycopyrrolate and magnesium stearate
agent to a ventilating atmosphere, preferably wherein the
ventilating atmosphere passes over and through the co-jet milled
glycopyrrolate and magnesium stearate at a rate of less than 100
cm.sup.3/s, less than 10 cm.sup.3/s, less than 5 cm.sup.3/s, less
than 2 cm.sup.3/s, less than 1 cm.sup.3/s, preferably less than 0.8
cm.sup.3/s, preferably less than 0.6 cm.sup.3/s, preferably less
than 0.4 cm.sup.3/s, preferably less than 0.2 cm.sup.3/s,
preferably less than 0.1 cm.sup.3/s, more preferably about 0.001
cm.sup.3/s.
[0149] In a preferred embodiment, the conditioning involves
exposing the co-jet milled glycopyrrolate and magnesium stearate to
a ventilating atmosphere, preferably wherein the ventilating
atmosphere passes over and through the co-jet milled glycopyrrolate
and magnesium stearate. The ventilating atmosphere is surplus to
requirement, for example provided by a large volume (>0.5
m.sup.3), for example a powder control booth, so the moisture
released by the co-jet milled glycopyrrolate and magnesium stearate
in to the ventilating atmosphere does not alter the relative
humidity by more than 5% RH, preferably not more than 4% RH,
preferably not more than 3% RH, preferably not more than 2% RH,
preferably not more than about 1% RH.
[0150] During the conditioning, the ventilating atmosphere can
undergo partial or complete supplementation.
[0151] In a preferred embodiment, the conditioning involves
exposing the co-jet milled glycopyrrolate and magnesium stearate to
a ventilating atmosphere, preferably wherein the ventilating
atmosphere passes over and through the co-jet milled glycopyrrolate
and magnesium stearate. Preferably, the volume ratio of ventilating
atmosphere (cm.sup.3) to poured bulk powder (cm.sup.3) is more than
1:1, preferably more than more than 10:1, preferably more than more
than 100:1, preferably more than more than 1,000:1, preferably more
than 10,000:1, preferably more than 100,000:1, preferably more than
1,000,000:1, more preferably more than 10,000,000:1.
[0152] As the examples discussed below indicate, a combination of
two or more of these measures (i) to (viii) leads to acceptable
results.
[0153] In one preferred embodiment for conditioning the co-jet
milled glycopyrrolate, the powder conditioning factors (i), (ii),
(iii), (iv), (v), (vi), (vii) and (viii) above are all selected for
conditioning the co-jet milled glycopyrrolate and magnesium
stearate, using the broadest ranges of conditions where
relevant.
[0154] In a preferred embodiment for conditioning the co-jet milled
glycopyrrolate and magnesium stearate, the powder conditioning
factors include 60-87%. RH, 24.degree. C. to 50.degree. C., the
co-jet milled glycopyrrolate powder is preferably placed on surface
for at least about 1 hour, wherein the conditioning vessel should
preferably allow exposure of all of the co-jet milled powder to the
moisture applied from the conditioning atmosphere.
[0155] Force Control Agent
[0156] In a yet further embodiment, the dry powder formulation
comprising glycopyrrolate further comprises an additional additive
material, such as a so-called force control agent. A force control
agent is an agent which reduces the cohesion between the fine
particles within the powder formulation, thereby promoting
deagglomeration upon dispensing of the powder from the dry powder
inhaler. Suitable force control agents are disclosed in
WO1996023485 and they preferably consist of physiologically
acceptable material, despite the fact that the material may not
always reach the lung.
[0157] The force control agent may comprise or consist of one or
more compounds selected from amino acids and derivatives thereof,
and peptides and derivatives thereof, the peptides preferably
having a molecular weight from 0.25 to 1 000 Kda. Amino acids,
peptides and derivatives of peptides are physiologically acceptable
and give acceptable release or deagglomeration of the particles of
active material on inhalation. Where the force control agent
comprises an amino acid, it may be one or more of any of the
following amino acids: leucine, isoleucine, lysine, valine,
methionine, and phenylalanine. The force control agent may be a
salt or a derivative of an amino acid, for example aspartame or
acesulfame K. The D- and DL-forms of amino acids may also be
used.
[0158] Force control agents which are particularly suitable for use
in the present invention include, amino acids including leucine,
lysine, arginine, histidine, cysteine and their derivatives,
lecithin and phospholipids. The inclusion of these force control
agents may improve the efficacy of the glycopyrrolate for treating
respiratory disorders such as COPD, asthma or CF.
[0159] Force control agents may include one or more water soluble
substances. This helps absorption of the force control agent by the
body if it reaches the lower lung. The force control agent may
include dipolar ions, which may be zwitterions. It is also
advantageous to include a spreading agent as a force control agent,
to assist with the dispersal of the composition in the lungs.
[0160] Suitable spreading agents include surfactants such as known
lung surfactants (e.g. ALEC, Registered Trade Mark) which comprise
phospholipids, for example, mixtures of DPPC (dipalmitoyl
phosphatidylcholine) and PG (phosphatidylglycerol). Other suitable
surfactants include, for example, dipalmitoyl
phosphatidylethanolamine (DPPE), dipalmitoyl phosphatidylinositol
(DPPI).
[0161] The force control agent may include or consist of one or
more surface active materials, in particular materials that are
surface active in the solid state, which may be water soluble or
water dispersible, for example lecithin, in particular soya
lecithin, or substantially water insoluble, for example solid state
fatty acids such as oleic acid, lauric acid, palmitic acid, stearic
acid, erucic acid, behenic acid, or derivatives (such as esters and
salts) thereof such as glyceryl behenate. Specific examples of such
materials are phosphatidylcholines, phosphatidylethanolamines,
phosphatidylglycerols and other examples of natural and synthetic
lung surfactants; lauric acid and its salts, for example, sodium
lauryl sulphate, magnesium lauryl sulphate; triglycerides such as
Dynsan 118 and Cutina HR; and sugar esters in general.
Alternatively, the force control agent may be cholesterol.
[0162] Other possible force control agents include sodium benzoate,
hydrogenated oils which are solid at room temperature, talc,
titanium dioxide, aluminium dioxide, silicon dioxide and starch.
Also useful as force control agents are film-forming agents, fatty
acids and their derivatives, as well as lipids and lipid-like
materials.
[0163] The inclusion of an additive material in the dry powder
formulation may suitably confer one or more of the following
benefits: enhancing the powder's dispersability; protecting the
formulation from the ingress of moisture; enhancing the speed and
reproducibility of the conditioning process.
[0164] In a preferred embodiment the magnesium stearate is suitably
located on the surface of the glycopyrrolate after milling. Where
an additional additive material is present, it is also suitably
located on the glycopyrrolate surface.
[0165] Lactose fines also modify the interaction between the
glycopyrrolate and carrier particles affecting aerosol performance.
In one embodiment the dry powder formulation may comprise fine
lactose which is in an amount of preferably >3% (w/w), more
preferably >5% (w/w) more preferably >8% (w/w) of the
formulation residing in a blister or capsule or other suitable
dispensing receptacle.
[0166] Powder Storage
[0167] Co-jet milled glycopyrrolate formulations are suitably
packaged for storage and/or delivery and are preferably stable for
at least 1, 2 or 3 years when stored at ambient temperatures and
humidities, i.e. the packaged formulations or products comprising
the formulations do not have to be stored in a controlled
environment in order to exhibit the desired stability.
[0168] According to one aspect, the co-jet milled glycopyrrolate
formulation is stable for a period of at least 6 months, preferably
at least 1 year, more preferably a period of at least 2 years and
most preferably a period of at least 3 years as determined by a
Fine Particle Fraction (FPF(MO)) (<5 .mu.m), suitably wherein
the FPF does not decrease by preferably more than 20%, preferably
more than 15%, preferably more than 10% or more preferably by more
than 5% of the FPF exhibited by the newly manufactured co-jet
milled formulation.
[0169] In one aspect the co-jet milled glycopyrrolate formulation
can be consistently dispersed over periods of at least 6 months,
preferably 1 year, preferably at least 2 years or preferably at
least 3 years when stored at ambient temperature and ambient
humidity, meaning that the FPF does not decrease by preferably more
than 20%, preferably more than 15%, preferably more than 10% or
more preferably by more than 5% of the FPF exhibited by the newly
receptacle filled formulation.
[0170] In one aspect the co-jet milled glycopyrrolate formulation
has a consistent particle size distribution as measured by, for
example MALVERN MASTERSIZER.RTM. meaning that the 090 does not
increase by preferably more than 20%, preferably more than 15%,
preferably more than 10% or more preferably by more than 5% of the
090 exhibited by the newly manufactured co-jet milled
formulation.
[0171] In one aspect the co-jet milled glycopyrrolate formulation
has a consistent FPF or FPO over the same period of time, meaning
that the FPF or FPO does not decrease by preferably more than 20%,
preferably more than 15%, preferably more than 10% or more
preferably by more than 5% of the FPF or FPO exhibited by the newly
receptacle filled co-jet milled formulation.
[0172] In one embodiment, the co-jet milled glycopyrrolate
formulation has a Particle Size Distribution having the profile of
D10<10 .mu.m, D50<15, D90<30 .mu.m, for a period of at
least 6 months, preferably 1 year, preferably at least 2 years or
preferably at least 3 years after the conditioning process has been
completed, when stored at ambient temperature and ambient
humidity.
[0173] In one embodiment of the invention, the FPF (<5 .mu.m) of
the co-jet milled glycopyrrolate formulation is greater than about
30% over a period of at least 6 months, at least 1 year, at least 2
years or at least 3 years when stored at ambient temperature and
ambient humidity.
[0174] In another embodiment of the invention, the FPF (<5
.mu.m) of the co-jet milled glycopyrrolate formulation is greater
than about 40% over a period of at least 1 year, at least 2 years
or at least 3 years when stored at ambient temperature and ambient
humidity.
[0175] Preferably, the fine particle fraction FPF(MD) (<5 .mu.m)
of the co-jet milled glycopyrrolate formulation is consistently
greater than 30% or greater than 40% when the co-jet milled and
co-conditioned glycopyrrolate formulations are stored under
standard testing conditions, such as 25.degree. C./60% RH for 1
year, 30.degree. C./60% RH for 6 months, or 40.degree. C./70% RH
for 3 months or 40.degree. C./75% RH for 3 months. These standard
testing conditions are employed after the co-jet milled
glycopyrrolate has been conditioned and made stable, preferably
wherein the co-jet milled glycopyrrolate has been conditioned and
formulated with lactose and filled into a receptacle suitably to be
delivered from an inhaler.
[0176] Carrier Particles
[0177] Dry powder formulations for inhalation in the treatment of
respiratory diseases are generally formulated by mixing a
micronised active pharmaceutical ingredient with coarse carrier
particles to give an ordered mixture. The carrier particles make
the micronised active pharmaceutical ingredient less cohesive and
improve its flowability. This makes the powder easier to handle
during the manufacturing process. The micronised active particles
tend to adhere to the surface of the carrier particles when stored
in a dry powder inhaler device but are dispersed from the surfaces
of the carrier particles on inhalation into the respiratory tract
to give a fine aerosol. The larger carrier particles impact on the
throat due to their inertia and are mostly deposited in the
oropharyngeal cavity.
[0178] One embodiment may include carrier particles which are mixed
with the co-micronised glycopyrrolate in a ratio of from 2000:1 to
5:1 by mass, especially from 200:1 to 20:1 by mass. The carrier
particles may be composed of any pharmacologically inert material
or combination of materials which is acceptable for inhalation.
They are suitably composed of one or more crystalline sugars
including monosaccharides, disaccharides, polysaccharides and sugar
alcohols such as arabinose, glucose, fructose, ribose, mannose,
sucrose, trehalose, lactose, maltose, starches, dextran, mannitol
or sorbitol. An especially preferred carrier is lactose, for
example lactose monohydrate or alpha lactose monohydrate or
anhydrous lactose.
[0179] Preferably substantially all (by weight or volume) of the
carrier particles have a diameter of 20 to 1000 .mu.m, more
preferably 50 to 500 .mu.m, but especially 20 to 250 .mu.m. The
diameter of substantially all (by weight) of the carrier particles
is suitably less than 355 .mu.m. This provides good flow and
entrainment characteristics and improved release of the active
particles in the airways to increase deposition of the active
particles in the lower lung.
[0180] It will be understood that throughout this specification the
diameter of the particles referred to is the diameter of the
particles as suitably determined by a MALVERN MASTERSIZER.RTM. or
similar laser diffraction equipment.
[0181] Additional Active Ingredients
[0182] The formulations may include one or more further active
agents, in addition to the glycopyrrolate. Especially preferred
additional classes of active agents may include, pharmaceutically
active agents which are known to be useful in the treatment of
respiratory disorders, such as .beta..sub.2-agonists, steroids,
anticholinergics, phosphodiesterase-4-inhibitors, A.sub.2a
agonists, IL-13 inhibitors and calcium blockers and the like. In
one embodiment, the formulation of the present invention does not
include formoterol.
[0183] In a further aspect the glycopyrrolate and the antiadherent
agent are micronised together with at least one (preferably one,
two or three) additional active ingredients to give a fixed dose
combination. That or each additional active ingredient is
preferably selected from the group consisting of anti-inflammatory,
bronchodilatory, antihistamine, decongestant and anti-tussive drug
substances that are suitable for administration by inhalation, for
example for the treatment of a respiratory disease.
[0184] Suitable .beta..sub.2-adrenoceptor agonists include
albuterol (salbutamol), metaproterenol, terbutaline salmeterol,
fenoterol, indacaterol, procaterol, and especially, formoterol,
carmoterol, TA-2005, GSK159797 and pharmaceutically acceptable
salts thereof.
[0185] In a further aspect the formulation comprises co-micronised
and conditioned glycopyrrolate and magnesium stearate, subsequently
formulated with the .beta..sub.2-adrenoceptor agonist indacaterol
maleate.
[0186] In another aspect the co-jet milled and conditioned
glycopyrrolate and magnesium stearate are in combination with the
.beta..sub.2-adrenoceptor agonist indacaterol maleate for use in
simultaneous or sequential administration in the treatment of an
inflammatory or obstructive airways disease, optionally wherein any
single formulation, or any combined formulation, comprises at least
one particulate pharmaceutically acceptable carrier.
[0187] In an alternate embodiment a medicament comprising
co-micronised and co-conditioned glycopyrrolate and magnesium
stearate, and the .beta..sub.2-adrenoceptor agonist vilanterol
trifenatate, for simultaneous or sequential administration in the
treatment of an inflammatory or obstructive airways disease,
optionally wherein any single formulation, or any combined
formulation, comprises at least one particulate pharmaceutically
acceptable carrier.
[0188] Bronchodilatory drugs that may be used together with
glycopyrrolate include anticholinergic or antimuscarinic agents, in
particular umeclidinium bromide, ipratropium bromide, oxitropium
bromide, tiotropium salts, CHF 4226 (Chiesi) and SVT-40776.
[0189] Steroids that may be used together with glycopyrrolate
include glucocorticosteroids such as budesonide, beclamethasone,
fluticasone, ciclesonide or mometasone.
[0190] PDE4 inhibitors that may be used together with
glycopyrrolate include cilomilast (Ariflo.RTM. GlaxoSmithKline),
Roflumilast (Byk Gulden), V-11294A (Napp), BAY19-8004 (Bayer),
SCH-351591 (Schering-Plough), Arofylline (Almirall Prodesfarma),
PD189659/PD168787 (Parke-Davis), AWD-12-281 (Asta Medica), CDC-801
(Celgene), KW-4490 (Kyowa Hakko Kogyo), VM5541UM565 (Vernalis),
T-440 (Tanabe), KW-4490 (Kyowa Hakko Kogyo) and GRC 3886
(Oglemilast, Glenmark).
[0191] In a preferred embodiment any further active ingredient is
salmeterol, indacaterol or mometasone.
[0192] Preferred triple combinations of active contain
glycopyrrolate, salmeterol and mometasone; glycopyrrolate,
indacaterol and mometasone; glycopyrrolate salmeterol and
ciclesonide; glycopyrrolate, indacaterol and ciclesonide;
glycopyrrolate, salmeterol and 3-methylthiophene-2-carboxylic acid
(6S, 9R, 10S, 11 S, 13S, 16R,
17R)-9-chloro-6-fluoro-11-hydroxy-17-methoxycarbonyl-10, 13,
16-trimethyl-3-oxo-6,7,8,9, 10, 11, 12, 13, 14, 15, 16,
17-dodeca-hydro-3H-cyclopenta[a]phenanthren-17-yl ester; or
glycopyrrolate, indacaterol and 3-methylthiophene-2-carboxylic acid
(6S, 9R, 10S, 11 S, 13S, 16R, 1
?R)-9-chloro-6-fluoro-11-hydroxy-17-methoxycarbonyl-10, 13,
16-trimethyl-3-oxo-6,7,8,9, 10, 11, 12, 13, 14, 15, 16,
17-dodeca-hydro-3H-cyclopenta [a] phenanthren-17-yl ester.
[0193] In a preferred embodiment the medicament comprises co-jet
milled glycopyrrolate and magnesium stearate, which is conditioned,
and then combined with fluticasone furoate and vilanterol
trifenatate, and the combination is used in the treatment of an
inflammatory or obstructive airways disease, optionally for
simultaneous or sequential administration.
[0194] Packaging
[0195] Conditioned glycopyrrolate can be filled into capsules.
Capsules can be made with hypromellose (also known as hydroxypropyl
methyl cellulose, HPMC) or other celluloses or cellulose
derivatives which do not rely on moisture as a plasticizer. The
moisture content of such capsules is suitably 10% or less, such as
less than 10%, or even below 5% or 3%, and this makes such capsules
more suitable for use with glycopyrrolate.
[0196] It is known for gelatin capsules to contain in the order of
10 to 15% water and for this to provide a sufficient source of
water to create a moisture instability problem. Gelatin capsules
can also be made using one or more plasticizers other than water,
such as PEG, glycerol, sorbitol, propyleneglycol or other similar
polymers and co-polymers, hence allowing the moisture content to be
reduced to below 10%, or even below 5% or 3%, and such capsules are
preferred for use in the invention.
[0197] Alternatively, capsules for use with the formulation of the
invention can be made from synthetic plastics or thermoplastics
(polyethylene or polycarbonate or related plastics) containing
reduced moisture content below 10%, or even below 5% or 3%. Further
alternative capsules with reduced moisture content are made from
starch or starch derivatives or chitosan.
[0198] In an further approach to solving the problem of moisture
absorption by dry powder glycopyrrolate formulations, an inhaler
device may be used which includes a means for protecting the
formulation from moisture, for example storage within a sealed
blister pouch, such as a foil blister pouch, with suitable sealing
to prevent or reduce the ingress of moisture. Preferably, the
powder-containing receptacle (capsule or blister) is stored within
a sealed blister pouch, such as a foil sealed blister pouch, with
suitable sealing to prevent or reduce the ingress of moisture.
[0199] Inhaler devices suitable for delivering inhalable
glycopyrrolate formulations include, for example the Breezhaler
(Novartis), Turbuhaler (AstraZeneca), GyroHaler.RTM. (Vectura),
Diskus, Evohaler, Accuhaler or Ellipta (GSK), or Easi-Breathe.RTM.,
Autohaler.RTM. or Genuair (Teva) devices.
[0200] Thus, in a further preferred embodiment of the present
invention, the dry powder formulation comprising co-jet milled then
conditioned glycopyrrolate is stored in packaging made from a
material which itself has a moisture content of less than 10%,
preferably less than 5% and more preferably less than 3%.
[0201] In an alternative embodiment, the dry powder formulation is
dispensed from a multidose dry powder inhaler device wherein the
powder is stored in a reservoir as opposed to individually packaged
doses. In such an embodiment, the device should offer superior
moisture protection compared to conventional reservoir devices. For
example, the device should include one or more of the following
features: a sealed reservoir chamber (for example including a
sealing gasket to seal the reservoir chamber), plastics materials
exhibiting very low moisture permeability (for forming the walls of
the reservoir chamber), and a desiccant.
[0202] Powder Aerosol Performance
[0203] Preferably, the FPF(MD) of the dry powder formulations of
the present invention is at least about 30%, at least about 40%, at
least about 50%, at least about 60%, at least about 70% or at least
about 80%, suitably as measured using a Monohaler dry powder
inhaler used at 60 Umin in a NGI (Copley Scientific).
[0204] The Emitted Dose (ED) of the glycopyrrolate in the dry
powder formulations of the present invention is consistently
between 30 and 60 .mu.g, between 33 and 56 .mu.g, between 36 and 53
.mu.g, between 39 and 50 .mu.g, between 42 and 46 .mu.g or
preferably, between 43 and 45 .mu.g as measured using a Monohaler
dry powder inhaler used at 60 Umin in a NGI (Copley
Scientific).
[0205] The Fine Particle Dose (FPO) of the glycopyrrolate in the
dry powder formulations of the present invention is consistently at
least about 9 .mu.g at least about 10 .mu.g, at least about 11
.mu.g, at least about 12 .mu.g, or preferably at least about 13
.mu.g as measured using a Monohaler dry powder inhaler used at 60
Umin in a NGI (Copley Scientific).
[0206] Terms used in the specification have the following
meanings:
[0207] Glycopyrrolate
[0208] Glycopyrrolate is used herein to refer to any composition
comprising, or capable of creating in the body, the glycopyrrolate
cation. This term includes glycopyrronium salts, intended to
encompass any salt form or counterion of glycopyrronium, including
but not limited to glycopyrronium bromide, glycopyrronium chloride,
or glycopyrronium iodide, as well as any and all isolated
stereoisomers and mixtures or stereoisomers thereof. Derivatives of
glycopyrronium salts are also encompassed. Suitable counter ions
are pharmaceutically acceptable counter ions including, for
example, fluoride, chloride, bromide, iodide, nitrate, sulfate,
phosphate, formate, acetate, trifluoroacetate, propionate,
butyrate, lactate, citrate, tartrate, malate, maleate, succinate,
benzoate, p-chlorobenzoate, diphenyl-acetate or triphenylacetate,
o-hydroxy-benzoate, p-hydroxybenzoate,
l-hydroxynaphthalene-2-carboxylate,
3-hydroxynaphthalene-2-carboxylate, methanesulfonate and
benzene-sulfonate.
[0209] Glycopyrronium bromide has two stereogenic centres and hence
exists in four isomeric forms, namely (3R,2'R)-, (3S,2'R)-,
(3R,2'S)- and
(3S,2'S)-3-[(cyclopentyl-hydroxyphenylacetyl)oxy]-1,1-dimethylpyrrolidini-
um bromide. The present invention embraces using one or more of
these isomeric forms, especially the 3S,2'R isomer, the 3R,2'R
isomer or the 2S,3'R isomer, thus including single enantiomers,
mixtures of diastereomers, or racemates, especially
(3S,2'R/3R,2'S)-3-[(cyclopentyl-hydroxy-phenylacetyl)oxy]-1,
l-dimethylpyrrolidinium bromide. In one embodiment, the
glycopyrrolate is not R,R-glycopyrrolate.
[0210] Metered Dose
[0211] Metered dose" or "MD" of a dry powder formulation as used
herein is the total mass of active agent present in the metered
form presented by the inhaler device in question. For example, the
MD might be the mass of glycopyrronium salt present in a capsule
for a particular dry powder inhaler, or in a foil blister for use
in a particular dry powder inhaler device. The Metered dose is also
referred to as the Nominal Dose.
[0212] Emitted Dose
[0213] Emitted dose" or "ED" as used herein is the total mass of
the active agent emitted from the device following actuation. It
does not include the material left inside or on the surfaces of the
device. The ED is measured by collecting the total emitted mass
from the device in an apparatus frequently referred to as a Dose
Uniformity Sampling Apparatus (DUSA), and recovering this by a
validated quantitative wet chemical assay.
[0214] Fine Particle Dose
[0215] "Fine particle dose" or "FPO" as used herein is the total
mass of active agent which is emitted from the device following
actuation which is present in an aerodynamic particle size smaller
than a defined limit. This limit is generally taken to be 5 .mu.m
if not expressly stated to be an alternative limit, such as 1 .mu.m
or 3 .mu.m, etc. The FPO is measured using an impactor or impinger,
such as a twin stage impinger (TSI), multi-stage liquid impinger
(MSLI), Andersen Cascade Impactor (ACI) or a NGI. Each impactor or
impinger has a pre-determined aerodynamic particle size collection
cut-off point for each stage. The FPO value is obtained by
interpretation of the stage-by-stage active agent recovery
quantified by a validated quantitative wet chemical assay where
either a simple stage cut is used to determine FPO or a more
complex mathematical interpolation of the stage-by-stage deposition
is used.
[0216] Fine Particle Fraction
[0217] "Fine particle fraction" or "FPF" as used herein is normally
defined as the FPO divided by the ED and expressed as a percentage.
Herein, the FPF of ED is referred to as FPF(ED) and is calculated
as FPF(ED)=(FPO/ED).times.100%. "Fine Particle Fraction" may also
be defined as the FPO divided by the MD and expressed as a
percentage. Herein, the FPF of MD is referred to as FPF(MD), and is
calculated as FPF(MD)=(FPO/MD).times.100%. Specific FPF values
cited herein are to be understood as achieved by testing 25 mg of
powder within a size 3 HPMC capsule delivered from a Monohaler Dry
Powder Inhaler Device tested using a NGI set at 90 L/minute for
2.67 seconds, to achieve a 4 kPa pressure drop across the
mouthpiece.
[0218] Ambient Conditions
[0219] "Ambient conditions" as used herein are defined as
22.degree. C..+-.5.degree. C. and 40-50% RH. The terms "ambient
temperature" and "ambient humidity" as used herein are defined as
22.degree. C..+-.5.degree. C. and 40-50% RH respectively.
[0220] It will be understood that particular embodiments described
herein are shown by way of illustration and not as limitations of
the invention. The principal features of this invention can be
employed in various embodiments without departing from the scope of
the invention. Those skilled in the art will recognize, or be able
to ascertain using no more than routine study, numerous equivalents
to the specific procedures described herein. Such equivalents are
considered to be within the scope of this invention and are covered
by the claims. All publications and patent applications mentioned
in the specification are indicative of the level of skill of those
skilled in the art to which this invention pertains. All
publications and patent applications are herein incorporated by
reference to the same extent as if each individual publication or
patent application was specifically and individually indicated to
be incorporated by reference. The use of the word "a" or "an" when
used in conjunction with the term "comprising" in the claims and/or
the specification may mean "one," but it is also consistent with
the meaning of "one or more," "at least one," and "one or more than
one." The use of the term "or" in the claims is used to mean
"and/or" unless explicitly indicated to refer to alternatives only
or the alternatives are mutually exclusive, although the disclosure
supports a definition that refers to only alternatives and
"and/or." Throughout this application, the term "about" is used to
indicate that a value includes the inherent variation of error for
the measurement, the method being employed to determine the value,
or the variation that exists among the study subjects.
[0221] As used in this specification and claim(s), the words
"comprising" (and any form of comprising, such as "comprise" and
"comprises"), "having" (and any form of having, such as "have" and
"has"), "including" (and any form of including, such as "includes"
and "include") or "containing" (and any form of containing, such as
"contains" and "contain") are inclusive or open-ended and do not
exclude additional, unrecited elements or method steps.
[0222] The term "or combinations thereof" as used herein refers to
all permutations and combinations of the listed items preceding the
term. For example, "A, B, C, or combinations thereof is intended to
include at least one of: A, B, C, AB, AC, BC, or ABC, and if order
is important in a particular context, also BA, CA, CB, CBA, BCA,
ACB, BAC, or CAB. Continuing with this example, expressly included
are combinations that contain repeats of one or more item or term,
such as BB, AAA, BBC, AAABCCCC, CBBAAA, CABABB, and so forth. The
skilled artisan will understand that typically there is no limit on
the number of items or terms in any combination, unless otherwise
apparent from the context.
[0223] All of the compositions and/or methods disclosed and claimed
herein can be made and executed without undue experimentation in
light of the present disclosure. While the compositions and methods
of this invention have been described in terms of preferred
embodiments, it will be apparent to those of skill in the art that
variations may be applied to the compositions and/or methods and in
the steps or in the sequence of steps of the method described
herein without departing from the concept, spirit and scope of the
invention. All such similar substitutes and modifications apparent
to those skilled in the art are deemed to be within the spirit,
scope and concept of the invention as defined by the appended
claims.
[0224] While certain embodiments of the present invention are
described in detail above, the scope of the invention is not to be
considered limited by such disclosure, and modifications are
possible without departing from the spirit of the invention as
evidenced by the examples and claims.
EXAMPLES
[0225] Selected embodiments of the present invention will now be
explained with reference to the examples. It will be apparent to
those skilled in the art from this disclosure that the following
descriptions of the embodiments are for illustration only and not
for the purpose of limiting the invention as defined by the
appended claims and their equivalents.
[0226] The examples below illustrate how micronised drug particles
may be conditioned, in order to reduce the surface non-crystalline
material present.
[0227] Control Formulation 0 (Glycopyrrolate only)
[0228] The particle size distribution for unmicronised
glycopyrrolate was determined by MALVERN MASTERSIZER.RTM. analysis
(MALVERN MASTERSIZER.RTM. 3000, using the Aero S dry dispersion
method at 4 Bar) and found to be D.sub.10=11.3 .mu.m, D.sub.50=98.0
.mu.m, D.sub.90=281 .mu.m (see FIG. 1).
[0229] A 25 g sample from the same batch of unmicronised
glycopyrrolate was added to the powder inlet of an AS-50 spiral jet
mill (Inlet pressure=5 Bar, Grinding Pressure=3 Bar, Averaged Feed
Rate=2 g/min) using air having a humidity below 20% RH and the jet
milled glycopyrrolate was recovered from a bag filter with a 0.2
.mu.m pore size. The particle size distribution for this freshly
micronised glycopyrrolate was determined as above and found to be
D.sub.10=0.315 .mu.m, D.sub.50=2.05 .mu.m, D.sub.90=5.81 .mu.m (see
FIG. 2) with a cumulative fraction under 5 .mu.m of 85.75%.
[0230] This freshly micronised glycopyrrolate was tipped out as a
compact heap of powder and the heap of powder was exposed to
40.degree. C. at 75% RH for 1 hour on a tray thereby preventing the
conditioning environment from reaching the internal particles in
the heap of powder. The particle size distribution for freshly
micronised glycopyrrolate was determined as above and found to be
D.sub.10=88.4 .mu.m, D.sub.50=389 .mu.m, D.sub.90=963 .mu.m (see
FIG. 3) with a cumulative fraction under 5 .mu.m of 1.44%.
[0231] Formulation 1 (Glycopyrrolate Only; 25.degree. C. at 60% RH)
and Formulation 2 (Glycopyrrolate and Magnesium Stearate (95:5
w/w); 25.degree. C. at 60% RH)
[0232] Unmicronised glycopyrrolate 25 g (D.sub.10=11.3 .mu.m,
D.sub.50=98.0 .mu.m, D.sub.90=281 .mu.m) (see FIG. 1) was added to
the powder inlet of an AS-50 spiral jet mill (Inlet pressure=5 Bar,
Grinding Pressure=3 Bar, Averaged Feed Rate=2 g/min) using air
having a humidity below 20% RH and the jet milled glycopyrrolate
was recovered from a bag filter with a 0.2 .mu.m pore size.
Formulation 2 was produced as above for Formulation 1 but instead
used glycopyrrolate and magnesium stearate (95:5 w/w) which was
pre-blended in a glass beaker using a metal spatula for 30 seconds
before co-micronization.
[0233] The particle size distributions for Formulation 1
(D.sub.10=0.283 .mu.m, D.sub.50=1.66 .mu.m, D.sub.90=5.40 .mu.m)
and Formulation 2 (D.sub.10=0.270 .mu.m, D.sub.50=1.41 .mu.m,
D.sub.90=3.66 .mu.m were determined by MALVERN MASTERSIZER.RTM.
analysis (MALVERN MASTERSIZER.RTM. 3000, using the Aero S dry
dispersion method at 4 Bar). These are reported in FIGS. 4 and 8
respectively and Table 1 below.
[0234] The presence of amorphous material for the milled or co-jet
milled glycopyrrolate (t=0) was determined by DVS and are reported
in FIG. 27 (Formulation 1) and FIG. 29 (Formulation 2).
[0235] A stability cabinet (Vin don Scientific, 5600S, Serial
Number 167 43) was prepared and equilibrated at 25.degree. C. at
60% RH. Once micronized, the glycopyrrolate was immediately
subjected to a post-micronisation treatment by ensuring the
particles were equally exposed to these conditions. Humidity levels
were monitored for the duration of the equilibration and
conditioning process by using an electronic tiny tag placed within
the stability cabinet.
[0236] The milled glycopyrrolate (Formulation 1) and co-jet milled
glycopyrrolate and magnesium stearate (Formulation 2) were
conditioned by exposure to 25.degree. C. at 60% RH for 71 hours,
with samples being taken at intervals indicated in Table 2 and set
aside in sealed vials for analysis at 72 hours post milling. During
conditioning the powder bed was regularly moved by raking with a
metal spatula.
[0237] The particle size distributions for the conditioned samples
were determined by MALVERN MASTERSIZER.RTM. analysis (as above) and
are reported in FIGS. 5, 6, 7, 9, 10 and 11, and in Tables 1 and 2
below.
[0238] The presence of amorphous material for the conditioned
glycopyrrolate or co-jet milled glycopyrrolate (t=49 hrs) was
determined by DVS, reported in FIGS. 28 and 30.
[0239] Formulation 3 (Glycopyrrolate Only; 50.degree. C. at 50% RH)
and Formulation 4 (Glycopyrrolate and Magnesium Stearate (95:5
w/w); 50.degree. C. at 50% RH)
[0240] Unmicronised glycopyrrolate 15 g (D.sub.10=11.3 .mu.m,
D.sub.50=98.0 .mu.m, D.sub.90=281 .mu.m) was added to the powder
inlet of an AS-50 spiral jet mill (Inlet pressure=5 Bar, Grinding
Pressure=3 Bar, Averaged Feed Rate=2 g/min) using air having a
humidity below 20% RH and the jet milled glycopyrrolate was
recovered from a bag filter with a 0.2 .mu.m pore size. Formulation
4 was produced as above for Formulation 3 but instead used
glycopyrrolate and magnesium stearate (95:5 w/w) which was
pre-blended in a glass beaker using a metal spatula for 30 seconds
before co-micronization.
[0241] The particle size distributions for Formulation 3
(D.sub.10=0.283 .mu.m, D.sub.50=1.75 .mu.m, D.sub.90=7.41 .mu.m)
Formulation 4 (D.sub.10=0.266 .mu.m, D.sub.50=1.22 .mu.m,
D.sub.90=3.07 .mu.m) were determined by MALVERN MASTERSIZER.RTM.
analysis (as above) and are reported in FIGS. 17 and 19, and in
Table 1 below.
[0242] The stability cabinet was prepared and equilibrated at
50.degree. C. at 50% RH. Once micronized, the glycopyrrolate or the
co-jet milled glycopyrrolate was immediately(<5 minutes)
subjected to a post-micronisation treatment by ensuring the
particles were equally exposed to these conditions. Humidity levels
were monitored for the duration of the equilibration and
conditioning process as above.
[0243] The milled glycopyrrolate (Formulation 3) and co-jet milled
glycopyrrolate (Formulation 4) were each conditioned by exposure to
50.degree. C. at 50% RH for at least 49 hrs. The powder bed was
regularly moved by raking with a metal spatula. After 49 hrs,
samples of the conditioned glycopyrrolate and co-jet milled
glycopyrrolate were recovered for analysis.
[0244] The particle size distributions (t=49 hrs) were determined
by MALVERN MASTERSIZER.RTM. analysis as above (D.sub.10=1.94 .mu.m,
D.sub.50=16.5 .mu.m, D.sub.90=327 .mu.m for Formulation 3 and
D.sub.10=0.437 .mu.m, D.sub.50=3.74 .mu.m, D.sub.90=269 .mu.m for
Formulation 4) and are reported in FIGS. 18 and 20, and Table 1
below.
[0245] The presence of amorphous material for the conditioned
co-jet milled glycopyrrolate (t=49 hrs) was determined by OVS,
reported in FIG. 31.
[0246] Formulation 5 (Glycopyrrolate Only; 6.degree. C. at 86% RH)
and Formulation 6 (Glycopyrrolate and Magnesium Stearate (95:5
w/w); 6.degree. C. at 86% RH)
[0247] Unmicronised glycopyrrolate 15 g (D.sub.10=11.3 .mu.m,
D.sub.50=98.0 .mu.m, D.sub.90=281 .mu.m) was added to the powder
inlet of an AS-50 spiral jet mill (Inlet pressure=5 Bar, Grinding
Pressure=3 Bar, Averaged Feed Rate=2 g/min) using air having a
humidity below 20% RH and the jet milled glycopyrrolate was
recovered from a bag filter with a 0.2 .mu.m pore size. Formulation
6 was produced as above for Formulation 5 but instead used
glycopyrrolate and magnesium stearate (95:5 w/w) which was
pre-blended in a glass beaker using a metal spatula for 30 seconds
before co-micronization.
[0248] The particle size distribution for Formulation 5 (reported
as D.sub.10=96.7 .mu.m, D.sub.50=569 .mu.m, D.sub.90=1580 .mu.m)
and Formulation 6 (D.sub.10=0.276 .mu.m, D.sub.50=1.52 .mu.m,
D.sub.90=3.97 .mu.m) for the milled glycopyrrolate (t=0) was
determined by MALVERN MASTERSIZER.RTM. analysis as above and are
reported in FIGS. 21 and 23, and Table 1 below.
[0249] A refrigerator was prepared and equilibrated at 6.degree. C.
at 86% RH. Once micronized, the glycopyrrolate or the co-jet milled
glycopyrrolate was immediately(<5 minutes) subjected to a
post-micronisation treatment by ensuring the particles were equally
exposed to these conditions. Humidity levels were monitored for the
duration of the equilibration and conditioning process as
above.
[0250] The milled and co-jet milled glycopyrrolate was conditioned
by exposure to 6.degree. C. at 86% RH for 49 hrs. The powder bed
was regularly moved by raking with a metal spatula. After 49 hrs,
samples of the conditioned glycopyrrolate were recovered for
analysis.
[0251] The particle size distribution for Formulation 5 (reported
as D.sub.10=0.410 .mu.m, D.sub.50=3.03 .mu.m, D.sub.90=253 .mu.m)
and Formulation 6 (reported as D.sub.10=0.314 .mu.m, D.sub.50=2.01
.mu.m, D.sub.90=70.8 .mu.m) for the Conditioned glycopyrrolate
(t=49 hrs) was determined by MALVERN MASTERSIZER.RTM. analysis as
above and reported in FIG. 22 (Formulation 5), FIG. 24 (Formulation
6) and Table 1 below.
[0252] The presence of amorphous material for the conditioned
glycopyrrolate (t=49 hrs) was determined by OVS and reported in
FIGS. 32 and 33 for Formulations 5 and 6 respectively.
[0253] Formulation 7 (Glycopyrrolate and magnesium stearate (95:5
w/w); 24.degree. C. at 45% RH)
[0254] 15 g of unmicronised glycopyrrolate (D.sub.10=11.3 .mu.m,
D.sub.50=98.0 .mu.m, D.sub.90=281 .mu.m) was pre-blended with
magnesium stearate in a glass beaker using a metal spatula for 30
seconds before micronization in an AS-50 spiral jet mill (Inlet
pressure=5 Bar, Grinding Pressure=3 Bar, Averaged Feed Rate=2
g/min) using air having a humidity below 20% RH and the co-jet
milled glycopyrrolate was recovered from a bag filter with a 0.2
.mu.m pore size.
[0255] The co-jet milled glycopyrrolate was conditioned by exposure
to ambient laboratory conditions (24.degree. C..+-.3.degree. C. at
45% RH.+-.5% RH for 72 hrs by emptying the micronized powder from
the jet mill onto a stainless steel tray. The powder bed was not
agitated at all during this time. After 72 hrs, a sample of the
glycopyrrolate was recovered.
[0256] The particle size distribution (reported as D.sub.10=0.272
.mu.m, D.sub.50=1.53 .mu.m, D.sub.90=3.96 .mu.m) for the
conditioned glycopyrrolate was determined by MALVERN
MASTERSIZER.RTM. analysis as above and reported in FIG. 25 and
Table 1 below.
[0257] The presence of amorphous material for the conditioned
co-jet milled glycopyrrolate was determined by OVS and reported in
FIG. 34 below.
[0258] Formulation 8 (Glycopyrrolate and Magnesium Stearate (95:5
w/w); 24.degree. C. at 45% RH; open glass vial)
[0259] 25 g of unmicronised glycopyrrolate (D.sub.10=11.3 .mu.m,
D.sub.50=98.0 .mu.m, D.sub.90=281 .mu.m) was pre-blended with
magnesium stearate in a glass beaker using a metal spatula for 30
seconds before micronization in an AS-50 spiral jet mill (Inlet
pressure=5 Bar, Grinding Pressure=3 Bar, Averaged Feed Rate=2
g/min) using air having a humidity below 20% RH and the co-jet
milled glycopyrrolate was recovered from a bag filter with a 0.2
.mu.m pore size.
[0260] The particle size distributions (reported as D.sub.10=0.270
.mu.m, D.sub.50=1.41 .mu.m, D.sub.90=3.66 .mu.m) for the co-jet
milled glycopyrrolate (t=0) were determined by MALVERN
MASTERSIZER.RTM. analysis as above and reported in FIG. 8 and Table
1 below.
[0261] A sample of the co-jet milled glycopyrrolate (approximately
5 g) was conditioned by exposure to ambient laboratory conditions
(24.degree. C..+-.3.degree. C. at 45% RH.+-.5% RH) for 144 hrs in
an un-sealed glass vial. The powder bed was not agitated at all
during this time. After 144 hrs, a sample of the conditioned co-jet
milled glycopyrrolate was recovered.
[0262] The particle size distribution (reported as D.sub.10=0.289
.mu.m, D.sub.50=1.70 .mu.m, D.sub.90=8.73 .mu.m) for the
conditioned co-jet milled glycopyrrolate was determined by MALVERN
MASTERSIZER.RTM. analysis as above and reported in FIG. 26 and
Table 1 below.
[0263] The presence of amorphous material for the t=0 and
conditioned co-jet milled glycopyrrolate samples was determined by
OVS and reported in FIGS. 35 and 36 respectively.
[0264] Formulation 9 (Co-Micronised Glycopyrrolate and Magnesium
Stearate (95:5 w/w) then immediately blended with lactose then FPF
performance)
[0265] To illustrate the improvement of the invention disclosed by
Formulation 10, the following control formulation can made as
follows:
[0266] 25 g of unmicronised glycopyrrolate are pre-blended with
magnesium stearate (95:5) in a glass beaker using a metal spatula
for 30 seconds before micronization in an AS-50 spiral jet mill
(Inlet pressure=5 Bar, Grinding Pressure=3 Bar, Averaged Feed
Rate=2 g/min) using air having a humidity below 20% RH and the
co-jet milled glycopyrrolate is recovered from a bag filter with a
0.2 .mu.m pore size.
[0267] Lactohale.RTM. 100 lactose carrier particles (49.85 g) is
immediately admixed with the co-jet milled glycopyrrolate and
magnesium stearate (0.15 g) using a Diosna (250 ml) at 1000 rpm for
10 minutes to give an inhalable dry powder.
[0268] The resulting inhalable dry powder is filled into size 3
HPMC capsules in 25 mg aliquots.
[0269] Formulation 10 (Co-Micronised Glycopyrrolate and Magnesium
Stearate (95:5 w/w) then Immediately Conditioned then Blended with
Lactose then Assessed for FPF Performance)
[0270] A sample (20 g) from the co-jet milled glycopyrrolate and
magnesium stearate (t=0) formulation produced in Example 9 (i.e.
the formulation before Lactohale.RTM. 100 lactose carrier particles
are added) is subjected to a conditioning process.
[0271] A stability cabinet (Vindon Scientific, 5600S, Serial Number
16743) is prepared and equilibrated at 25.degree. C. at 60% RH.
Once micronized, the co-jet milled glycopyrrolate and magnesium
stearate sample is immediately subjected to a post-micronisation
treatment by ensuring the particles are equally exposed to these
conditions. Humidity levels are monitored for the duration of the
equilibration and conditioning process by using an electronic tiny
tag placed within the stability cabinet.
[0272] The co-jet milled glycopyrrolate is conditioned by exposure
to 25.degree. C. at 60% RH. Samples (0.15 g) of this co-jet milled
glycopyrrolate and magnesium stearate undergoing conditioning are
removed after 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5
hours, 24 hours and 48 hours and admixed with Lactohale.RTM. 100
lactose carrier particles (49.85 g) .mu.m) using a Diosna (250 ml)
at 1000 rpm for 10 minutes to give an inhalable dry powder.
[0273] The resulting inhalable dry powders are filled into size 3
HPMC capsules in 25 mg aliquots.
[0274] Formulation 11 (Co-Milled Glycopyrrolate Magnesium Stearate
(95:5 w/w) then Conditioned at 25.degree. C. at 60% RH on a Steel
Tray (No Agitation) for 1 hr then Blended with Lactose)
[0275] To illustrate the improvement of the invention, the
following control formulation can be made using an alternate
milling technique as follows:
[0276] 25 g of unmicronised glycopyrrolate is pre-blended with
magnesium stearate (95:5) in a glass beaker using a metal spatula
for 30 seconds before co-milling with a knife mill (rotor
speed=1500 rpm, duration=10 minutes) and the co-milled
glycopyrrolate and magnesium stearate is recovered from the
co-milling chamber.
[0277] A stability cabinet (Vindon Scientific, 5600S, Serial Number
16743) is prepared and equilibrated at 25.degree. C. at 60% RH. The
co-milled glycopyrrolate and magnesium stearate is immediately
subjected to a post-milling treatment by ensuring the particles are
equally exposed to these conditions. Humidity levels are monitored
for the duration of the equilibration and conditioning process by
using an electronic tiny tag placed within the stability
cabinet.
[0278] The powder bed is not agitated.
[0279] The co-milled glycopyrrolate and magnesium stearate are
conditioned by exposure to 25.degree. C. at 60% RH for 5 minutes to
at least 49 hrs, and set aside in sealed vials for analysis at 72
hours post milling.
[0280] Formulation 12 (Co-Micronised Glycopyrrolate Magnesium
Stearate (95:5 w/w) then Stored Under Desiccated Environment
25.degree. C. at 0% RH (No Agitation) then Blended with
Lactose)
[0281] 25 g of unmicronised glycopyrrolate is pre-blended with
magnesium stearate in a glass beaker using a metal spatula for 30
seconds before micronization in an AS-50 spiral jet mill (Inlet
pressure=5 Bar, Grinding Pressure=3 Bar, Averaged Feed Rate=2
g/min) using air having a humidity below 20% RH and the co-jet
milled glycopyrrolate is recovered from a bag filter with a 0.2
.mu.m pore size.
[0282] Once micronized, the co-jet milled glycopyrrolate and
magnesium stearate is immediately subjected to a post-micronization
treatment which involved placing the powder on a tray under in a
sealed chamber containing the desiccant phosphorous pentoxide in
excess. The co-jet milled glycopyrrolate and magnesium stearate and
phosphorous pentoxide are not combined.
[0283] The sealed chamber is at 25.degree. C. with 0-5% RH whilst
ensuring the particles are equally exposed to these conditions for
the duration of this treatment. Humidity levels are monitored for
the duration of the chamber equilibration and treatment process by
using an electronic tiny tag placed within the stability
cabinet.
[0284] The powder bed is not agitated.
[0285] Control Experiment: Formulation 12a
[0286] Lactohale.RTM. 100 lactose carrier particles (49.85 g) are
immediately admixed with a sample of the treated co-jet milled
glycopyrrolate and magnesium stearate (0.15 g) using a Diosna (250
ml) at 1000 rpm for 10 minutes to give an inhalable dry powder.
[0287] The resulting inhalable dry powder is filled into size 3
HPMC capsules in 25 mg aliquots.
[0288] Formulation 12b
[0289] Once the sample of the treated (desiccated) co-jet milled
glycopyrrolate and magnesium stearate is taken for Formulation 12a,
the remaining treated co-jet milled glycopyrrolate and magnesium
stearate (Formulation 12b) is subjected to conditioning.
[0290] A stability cabinet (Vindon Scientific, 5600S, Serial Number
16743) is prepared and equilibrated at 25.degree. C. at 60% RH.
Humidity levels are monitored for the duration of the equilibration
and conditioning process by using an electronic tiny tag placed
within the stability cabinet.
[0291] The treated (desiccated) co-jet milled glycopyrrolate and
magnesium stearate (Formulation 12b) is conditioned by exposure to
25.degree. C. at 60% RH for 71 hours, with samples being taken at
regular intervals and these samples are set aside in sealed vials
for analysis at 72 hours from commencement of the conditioning
process. During conditioning the powder bed is regularly moved by
raking the powder bed with a metal spatula.
[0292] Lactohale.RTM. 100 lactose carrier particles (49.85 g) are
immediately admixed with samples of the now conditioned co-jet
milled glycopyrrolate and magnesium stearate (0.15 g) using a
Diosna (250 ml) at 1000 rpm for 10 minutes to give an inhalable dry
powder.
[0293] The resulting inhalable dry powder is filled into size 3
HPMC capsules in 25 mg aliquots.
[0294] Summary Data (Starting PSDs)
TABLE-US-00001 TABLE 1 Particle size (.mu.m) distributions D10 D50
D90 Volume (.mu.m) (.mu.m) (.mu.m) <5 (.mu.m) (%) Formulation 1
(t = 0 hrs) 0.283 1.66 5.40 88.56 Formulation 1 (t = 49 hrs)* 0.410
3.10 475 64.33 Formulation 2 (t = 0 hrs) 0.270 1.41 3.66 95.63
Formulation 2 (t = 0 hrs)* 0.308 1.87 69.6 82.35 Formulation 3 (t =
0 hrs) 0.283 1.75 7.41 84.53 Formulation 3 (t = 49 hrs) 1.940 16.5
327 32.77 Formulation 4 (t = 0 hrs) 0.266 1.22 3.07 98.45
Formulation 4 (t = 49 hrs) 0.437 3.74 269 54.44 Formulation 5 (t =
0 hrs) 96.7 569 1580 5.26 Formulation 5 (t = 49 hrs) 0.410 3.03 253
64.27 Formulation 6 (t = 0 hrs) 0.276 1.52 3.97 94.88 Formulation 6
(t = 49 hrs) 0.314 20.1 70.8 81.08 Formulation 7 (t = 0 hrs) Not
Not Not done Not done done done Formulation 7 (t = 72 hrs)* 0.272
1.53 3.96 94.91 Formulation 8 (t = 0 hrs) 0.270 1.41 3.66 95.63
Formulation 8 (t = 144 hrs) 0.289 1.70 8.73 86.94 *= Analysis at 72
hrs from Jet/co-jet milling.
TABLE-US-00002 TABLE 2 Particle size (.mu.m) distributions for
Formulation 1 and Formulation 2 for the period 5 minutes to 4260
minutes (71 hrs) conditioning Formulation 1 Formulation 2 Time D10
D50 D90 D10 D50 D90 (Minutes/hrs) (.mu.m) (.mu.m) (.mu.m) Span
(.mu.m) (.mu.m) (.mu.m) Span 5 0.602 4.38 791 180.5 1.05 186 1230
6.6 10 0.468 3.61 659 182.4 0.601 42.7 859 20.1 15 0.415 3.14 493
158.9 0.437 3.42 662 193.4 20 0.392 2.9 394 135.7 0.643 51.6 859
16.6 30 0.404 3.05 480 157.2 0.501 4.82 847 175.6 45 0.409 3.14 530
168.7 0.471 3.98 731 183.6 60 (1) 0.405 3.06 507 165.6 0.341 2.23
345 154.6 90 (1.5) 0.410 3.11 500 160.6 0.292 1.73 20.2 11.5 120
(2) 0.413 3.18 536 168.4 0.315 2.00 104 51.8 150 (2.5) 0.416 3.20
529 165.2 0.294 1.71 44.2 25.7 180 (3) 0.410 3.13 502 160.3 0.291
1.68 46.7 27.6 240 (4) 0.396 2.98 422 141.5 0.299 1.72 148 85.9 300
(5) 0.404 3.05 451 147.7 0.279 1.52 3.70 2.3 360 (6) 0.402 3.06 451
147.3 0.28 1.59 4.16 2.4 1440 (24) 0.421 3.22 515 159.8 0.286 1.65
5.11 2.9 1560 (26) 0.415 3.16 495 158.5 0.298 1.77 63.8 35.9 1680
(28) 0.429 3.29 568 172.5 0.33 2.03 349 171.8 1800 (30) 0.432 3.33
568 170.4 0.305 1.79 28.1 15.5 2940 (49) 0.410 3.10 475 153.1 0.308
1.87 69.6 37.1 3120 (52) 0.424 3.26 552 169.2 0.289 1.68 5.73 3.2
4260 (71) 0.415 3.16 497 157.1 0.295 1.7 5.17 2.9
[0295] Discussion: Formulations 0-8
[0296] Freshly micronized glycopyrrolate is inhalable (see FIG. 2
and FIG. 4) but possesses significant amounts of amorphous material
(see FIG. 27) which results in agglomerated non-inhalable
glycopyrrolate if not conditioned (see FIG. 3). To demonstrate this
phenomenon, Formulations 0 was jet milled and then tipped out as a
compact heap of powder. The heap of micronized glycopyrrolate was
not conditioned but instead the compact heap was exposed to
40.degree. C. at 75% RH for 1 hour on a tray. The physical
arrangement of the powder as a heap prevented conditioning of the
internal micronized particles leaving intrinsic moisture within the
heap of micronized glycopyrrolate to cause rapid recrystallisation
and agglomeration as shown by a PSO of D.sub.10=88.4 .mu.m,
D.sub.50=389 .mu.m and D.sub.90=963 .mu.m. The initial particle
size distributions (t=0) of freshly micronized glycopyrrolate have
a significant volume of the particles below 5 .mu.m (see
Formulations 1, 3 and 5). In contrast, co-jet milled formulations
according to the invention have even better initial particle size
distributions (t=0) (see Formulations 2, 4, 6 and 8). These
superior particle size distributions for Formulations 2, 4, 6, 7
and 8 are retained after conditioning which includes exposure of
the co-jet milled glycopyrrolate and magnesium stearate to humidity
at temperatures between 5.degree. C. to 88.degree. C. for at least
60 minutes.
[0297] Formulations 1, 2, 3, 4, 5, 6, 7 and 8 were prepared using
various conditioning parameters and all have significant amounts of
inhalable glycopyrrolate (>30% by volume of the formulation is
less than 5 .mu.m). The conditioning parameters comprised
temperature ranges from 6.degree. C. to 50.degree. C. and humidity
ranges from 50% to 86% RH. Formulations 2, 4, 6, 7 and 8 according
to the invention have better results than Formulations 1, 3 and
5.
[0298] The D.sub.90, D.sub.50 and D.sub.10 traces for Formulations
1 and 2 provide greater detail of the superior product obtained
when co-jet milled glycopyrrolate is conditioned by exposing the
co-jet milled (glycopyrrolate and anti-adherent agent to humidity
at a temperature of 25.degree. C. and relative humidity of 60% RH
for at least 60 minutes. FIG. 12 shows that Formulation 1
(glycopyrrolate only) started with a high D.sub.90 of 791 .mu.m but
this rapidly reduces to 394 .mu.m after 20 minutes of conditioning
and the D.sub.90 remains within this range for the remaining
conditioning period. In contrast, Formulation 2 (co-jet milled
glycopyrrolate and magnesium stearate) started with a higher
D.sub.90 of 1230 .mu.m which had only reduced to 859 .mu.m after 20
minutes and remains above Formulation 1 until 60 minutes of
conditioning. From this we can conclude that Formulation 1 achieved
a stable D.sub.90 much more quickly than Formulation 2. Without
wishing to be bound by theory, it is thought that the magnesium
stearate retards the conditioning process as demonstrated by FIG.
12. Surprisingly, however the D.sub.90 for Formulation 2 continues
to decrease well below that of Formulation 1 achieving a D.sub.90
which is only 4% that of Formulation 1's D.sub.90 after 90 minutes.
The D.sub.90 for Formulation 2 continues to remain significantly
below that of Formulation 1 for the remaining conditioning process.
Conditioned particles are crystalline and physically stable;
consequently the D.sub.90 for post-conditioned Formulations 1 and 2
will continue to remain distinguishable.
[0299] Similarly, the D.sub.90 and 0 10 values for Formulation 2
are also superior compared with Formulation 1 after 60 minutes of
conditioning; the traces never again cross indicating that it is
possible to distinguish between a "milled and conditioned product"
and a "co-jet milled and conditioned product" based upon particle
size distributions (see FIGS. 13, 14, 15 and 16).
[0300] The t=0 sample which was taken from Formulation 5 for
analysis had an initial cumulative fraction under 5 .mu.m which was
only 5.26% and much lower than the other control formulations,
Formulation 1 and 3. There was a delay before this sample was
analysed allowing the agglomeration to complete, thereby
illustrating the technical challenge experienced with handling
glycopyrrolate (see FIG. 21).
[0301] The methodologies used to create Formulations 7 and 8
demonstrate that co-jet milling with magnesium imparts greater
flexibility to the conditioning process negating the need for
agitation or turning of the formulation during the condition
process (see FIG. 25 and FIG. 26).
[0302] The span for Formulation 2 is generally superior to
Formulation 1 but the span calculation is affected by
disproportionately high D.sub.90 values. Table 2 clearly
demonstrates that a co-jet milled and conditioned product is able
to retain a span value less than 50 prior to blending with carrier
particles.
[0303] In addition to the data on particle size, DVS analysis was
performed on many of the glycopyrrolate samples, both directly
after milling and after conditioning. These DVS traces demonstrate
that immediately after milling the micronized glycopyrrolate is
physically unstable, adsorbing and absorbing moisture, despite
initially possessing an acceptable particle size distribution (see
FIGS. 4 and 27). In contrast, conditioned micronised glycopyrrolate
adsorbs moisture onto its surface in an ordered and predictable
manner (depicted by the curved solid trace) in response to the
changes in vapour present in the DVS chamber (depicted by the
angular dotted trace) and similarly releases this surface moisture
when conditions are moderated (see FIGS. 28, 30 and 32). The DVS
analysis also shows that a "co-jet milled and conditioned product"
whilst initially possessing significant amounts of amorphous
material (see FIGS. 29 and 35) also achieves a physically stable
state (see FIGS. 30, 31, 33, 34 and 36). In some cases, peaks may
still be present on the DVS trace (solid line) for the conditioned
material but these are fewer in number than for the starting
material, indicating a reduction in amorphous material as a result
of the conditioning process. A further indicator that the amorphous
material has been reduced is the height of these peaks. The reduced
peak height corresponds to a reduced change in mass over the
duration of the DVS analysis procedure meaning that less moisture
has been absorbed by the sample (see FIG. 29 or FIG. 35). This
comparison is possible because the formulations have similar
surface areas.
[0304] Formulations 13a-d
[0305] Four separate glycopyrrolate formulations were made and
analysed as follows:
[0306] Particle Size Analysis (Dry Analysis)
[0307] The particle size distribution for the micronized
glycopyrrolate formulations was determined by MALVERN
MASTERSIZER.RTM. analysis (MALVERN MASTERSIZER.RTM. 3000, using the
Aero S dry dispersion method at 4 Bar and a feed rate of between
30-40%). The optical properties used included a refractive index of
1.52 and an absorption value of 1.0.
[0308] Particle Size Analysis (Wet Analysis)
[0309] The particle size distribution for the micronized
glycopyrrolate formulations was determined by MALVERN
MASTERSIZER.RTM. 3000 using the Hydro MV wet dispersion unit as
follows: the dispersion unit was filled with iso-octane
(2,2,4-trimethylpentane). The pump speed was set to 3000 rpm. Ten
millilitres of 0.1% lecithin in iso-octane was added to
approximately 10 mg of the micronized glycopyrrolate formulation,
this pre-dispersion was then sonicated for 3 minutes using a
Sonopuls sonic probe at 50% intensity. The dispersed particles were
added to the dispersion unit to reach an obscuration of 5-15%. The
optical properties used included a refractive index of 1.52 and an
absorption value of 1.0 for the glycopyrrolate, and a refractive
index of 1.45 and an absorption value of 1.0 for the magnesium
stearate and a refractive index of 1.391 for the iso-octane. Six
replicates were performed per measurement.
[0310] Dynamic Vapour Sorption
[0311] The amorphous content for micronized glycopyrrolate was
assessed by DVS using an SMS DVS Advantage instrument which was set
to a temperature of 25.degree. C. The humidity was increased from
0-90% RH then returned to 0% RH in steps of 10% RH, changes between
steps which were triggered by a mass change of 0.0001 (%
dm/dt).
[0312] Formulations 13a (Dry Milling Gas) and 13b (Humid Milling
Gas)
[0313] Unmicronised glycopyrrolate (15 g, D.sub.10=20.6 .mu.m,
D.sub.50=148.7 .mu.m, D.sub.90=409.7 .mu.m determined by MALVERN
MASTERSIZER.RTM. 3000 wet analysis method) was pre-stirred in a
glass beaker using a metal spatula for 30 seconds before
micronization in an AS-50 spiral jet mill (Inlet pressure=5 Bar,
Grinding Pressure=3 Bar, Averaged Feed Rate=2 g/min). Formulation
13a was produced by using a dry milling gas having a humidity
<20% RH (2.8-3.5% RH). Formulation 13b was produced by using a
milling gas at elevated humidity (31.6-36.2% RH). The humidities
were measured by a portable hygrometer with the probe placed in the
exiting gas stream at the outlet of the collection vessel. Samples
of the freshly micronized glycopyrrolate were immediately analysed
using DVS, wet and dry particle size analysis. The micronized
formulations were then immediately conditioned in an open jar in
which each micronized glycopyrrolate formulation was subjected to
the following conditioning parameters: 21.8.degree. C., with
ventilating air at 43.2% RH passing over and through the powder bed
at a rate of less than 0.1 cm.sup.3/s with the volume ratio of
ventilating atmosphere to poured bulk powder being more than 1:1.
Whilst undergoing these conditioning parameters, samples of the
micronized formulation were then analysed using wet and dry
particle size analysis at 10, 30, 45, 60, 90 and 120 minutes post
milling.
[0314] Formulations 13c (Humid Milling Gas and Magnesium Stearate)
and 13d (Dry Milling Gas and Magnesium Stearate)
[0315] Unmicronised glycopyrrolate (14.25 g, D.sub.10=20.6 .mu.m,
D.sub.50=148.7 .mu.m, D.sub.90=409.7 .mu.m determined by MALVERN
MASTERSIZER.RTM.3000 wet analysis method) was pre-stirred with
magnesium stearate (0.75 g, D.sub.10=2.8 .mu.m, D.sub.50=8.8 .mu.m,
D.sub.90=27.4 .mu.m determined by MALVERN MASTERSIZER.RTM. 3000 wet
analysis method) in a glass beaker using a metal spatula for 30
seconds before micronization in an AS-50 spiral jet mill (Inlet
pressure=5 Bar, Grinding Pressure=3 Bar, Averaged Feed Rate=2
g/min). Formulation 13c was produced by using a milling gas at
elevated humidity (32.4-37.1% RH). Formulation 13d was produced by
using a dry milling gas having a humidity <20% RH (3.4-3.9% RH).
The humidities were measured by a portable hygrometer with the
probe placed in the exiting gas stream at the outlet of the
collection vessel. Samples of the freshly co-micronized
glycopyrrolate were immediately analysed using OVS, wet and dry
particle size analysis. The co-micronized formulations were then
immediately conditioned in an open jar in which each co-micronized
glycopyrrolate formulation was subjected to the following
conditioning parameters: 21.8.degree. C., with ventilating air at
43.2% RH passing over and through the powder bed at a rate of less
than 0.1 cm.sup.3/s with the volume ratio of ventilating atmosphere
to poured bulk powder being more than 1:1. Whilst undergoing these
conditioning parameters, samples of the micronized formulation were
then analysed using wet and dry particle size analysis at 10, 30,
45, 60, 90 and 120 minutes post co-micronisation.
[0316] Results: Formulation 13a-d
TABLE-US-00003 TABLE 3 Particle size (.mu.m) distributions for
Formulation 13a following wet analysis (left-hand column) or dry
analysis (right-hand column) using the MALVERN MASTERSIZER .RTM..
Time (Minutes) D10 D50 D90 0 0.81 1.11 2.05 250 3.9 1340 10 -- 187
-- 762 -- 1860 30 1.18 141 3.47 610 74.9 1100 45 1.2 162 3.49 680
10.6 1500 60 1.18 104 3.38 563 7.88 1070 90 1.25 120 3.64 618 11.2
1300 120 1.22 91.3 3.45 610 8.82 1360
TABLE-US-00004 TABLE 4 Particle size (.mu.m) distributions for
Formulation 13b following wet analysis column) or dry analysis
(right-hand column) using the MALVERN MASTERSIZER .RTM.. Time
(Minutes) D10 D50 D90 0 1.38 0.355 4.06 2.74 9.08 9.17 10 1.39
0.339 4.41 2.55 10.5 8.91 30 1.38 0.387 4.77 2.82 20.5 11.1 45 1.47
0.372 4.85 2.68 13.1 9.45 60 1.34 0.38 4.54 2.79 15.9 9.70 90 1.41
0.381 4.94 2.81 20.4 9.58 120 1.39 0.385 4.77 2.81 18.7 9.55
TABLE-US-00005 TABLE 5 Particle size (.mu.m) distributions for
Formulation 13c following wet analysis (left-hand column) or dry
analysis (right-hand column) using the MALVERN MASTERSIZER .RTM..
Time (Minutes) D10 D50 D90 0 1.7 2.12 12.8 41.3 224 267 10 1.61
1.98 11.9 50.6 137 282 30 1.42 2.40 7.74 54.9 54.8 306 45 1.46 2.34
8.34 49.9 61.4 271 60 1.43 2.32 7.75 49.0 51.3 275 90 1.56 2.26
10.5 46.5 133 259 120 1.53 2.19 9.57 43.4 120 256
TABLE-US-00006 TABLE 6 Particle size (.mu.m) distributions for
Formulation 13d following wet analysis (left-hand column) or dry
analysis (right-hand column) using the MALVERN MASTERSIZER .RTM..
Time (Minutes) D10 D50 D90 0 0.626 0.269 1.52 1.35 2.91 4.56 10
0.630 0.268 1.50 1.28 2.77 3.70 30 0.635 0.271 1.50 1.31 2.78 4.19
45 0.617 0.272 1.47 1.32 2.73 4.71 0.619 0.271 1.48 1.28 2.73 3.86
90 0.616 0.278 1.47 1.38 2.73 6.20 120 0.631 0.264 1.50 1.25 2.77
3.40
[0317] Discussion: Formulations 13a-d
[0318] When milled under dry conditions, freshly jet milled
glycopyrrolate contains substantial amounts of amorphous material
as confirmed by the DVS data for Formulation 13a (FIG. 37). It is
the presence of this amorphous material in the company of moisture
that, if not controlled correctly, leads to the formation of large
agglomerates in an unpredictable fashion (FIG. 41, see Formulation
13a). In the case of Formulation 13a, three separate samples were
taken from jet milled powder and briefly transported in sealed
scintillation vials for DVS, Wet PSD and Dry PSD analysis. First,
the DVS analysis was started, followed by the Wet and Dry PSD
analysis. Formulation 13a developed a significant amount of large
agglomerates in the sealed scintillation vials prior to dry PSD
analysis as shown by the D.sub.90 and D.sub.50 values (FIGS. 41 and
44 respectively). The dry PSD analysis also demonstrates that
Formulation 13a had equivalent D.sub.10 values to the other
formulations 13b-d demonstrating that Formulation 13a still had a
micronized component (FIG. 47). The wet PSD analysis shows that
Formulation 13a had small PSD values prior to and during the
conditioning process indicating that these agglomerates were weak
in structure (FIGS. 50, 53 and 55). The large weak agglomerates
remained throughout the conditioning process with a D.sub.90 never
dropping below 1070 .mu.m (FIG. 41) as measured by dry particle
size analysis (Table 3).
[0319] When milled under humid conditions, freshly jet milled
glycopyrrolate formulations contain no amorphous material; thus, in
agreement with the teaching of WO1999054048, WO2000032165 and
WO2000032313, the humid milling conditions reduce the formation of
amorphous material on the surface of micronized glycopyrrolate. The
DVS trace demonstrates that no amorphous material was present in
this freshly micronized glycopyrrolate (t=0) (see FIG. 38). Without
this amorphous material on the surface of micronized
glycopyrrolate, the particles do not form large agglomerates and
remain respirable (i.e. D.sub.50 less than 5 .mu.m, see Table 4,
FIG. 42, FIG. 45 and FIG. 48). The wet and dry particle size
analysis showed that this freshly micronized glycopyrrolate
formulation remained stable throughout the conditioning process
with a D.sub.90 never exceeding 11.1 .mu.m (Table 4).
[0320] Similarly, freshly co-jet milled glycopyrrolate and
magnesium stearate formulations contain minimal amorphous material
when co-jet milled under humid conditions (Formulation 13c), as is
apparent from the DVS trace (FIG. 39). Without this amorphous
material on the surface of micronized glycopyrrolate, the
co-micronised particles do not form large agglomerates
(D.sub.90>1000 .mu.m) unlike Formulation 13a. The combination of
the humidity and the magnesium stearate, however, reduces the
milling efficiency resulting in an initial D.sub.50 of 12.8 .mu.m
for Formulation 13c (see Table 5, Wet Analysis) compared to 2.05
.mu.m, 4.06 .mu.m and 1.52 .mu.m (Wet Analysis for Formulations
13a, b and d respectively).