Note: Descriptions are shown in the official language in which they were submitted.
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METHOD TO PRODUCE POWDERS FOR PULMONARY OR NASAL ADMINISTRATION
This patent relates to a process for preparing combination pharmaceutical
formulations for
pulmonary or nasal administration. The invention also relates to formulations
for such
uses. The invention relates particularly to combinations of drugs used for the
treatment of
asthma.
Asthma can be categorised in a number of stages according to official
guidelines
e.g. British Thoracic Society (Thorax; 1997; 52 (suppl. 5) 51-528);Canadian
Thoracic
Society (Can Med Assoc. J; 1992; 147: 420 - 8);American Thoracic Society (Am J
Respir
Crit Care Med; 1995; 152 (supply 577 - 5120). In these guidelines regimens are
suggested
for treatment of symptoms of increasing severity. These normally start with a
(3, agonist or
antimuscarinic agent and then add a steroid if the symptoms are not well
enough
controlled. This means that many patients have to carry two or even three
inhalers with
the different types of drug. Combination products have found wide commercial
acceptability and a number are widely marketed. Others have been proposed in
the patent
literature.
Examples of (32 agonists are salbutamol, rimiterol, bambuterol, fenoterol,.
pirbuterol,
Isoetharine and terbutaline. Recently long acting ~3~ agonists have been
introduced e.e.
salmeterol, eformoterol (sometimes known as formoterol). Examples of
antimuscarinic
agents include ipatropium bromide and oxitropium bromide. Examples of steroids
include
beclomethasone esters, fluticasone, budesonide and mometasone.
Examples of combination products include:-
a) Short acting (3z agonist + antimuscarinic e.g. salbutamol + ipatropium
bromide
(Duovent~) fenoterol + ipatropium bromide (Combivent~).
b) Short acting (3z agonist + corticosteroid e.g. salbutamol + beclomethasone
(Ventide~).
c) Long acting (32 agonist + corticosteroid e.g. salmeterol + fluticasone EP
(Seretide~) eformoterol + budesonide EP
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Such products can be used normally as aerosols, either for delivery into the
lung or nose
i.e. as metered dose inhalers, as dry powder inhalers usually for pulmonary
use, as
pressurised pump solutions for nasal administration or by the use of
nebulizers.
If the formulation is a solution then there are few problems with uniformity
of dosage
apart from those normally associated with such devices e.g. valve design and
actuator
design. However, if the product is formulated as a suspension there are more
problems,
for example settling of the suspension in the aerosol over time, caking on the
sides of the
aerosol container or non uniformity of the mixture in dry powder devices.
These problems
are exacerbated by the fact that the powders have to be a controlled particle
size to ensure
delivery to the place of action. For example, in inhalation aerosols the
particle size is
normally controlled to a mass mean diameter of 1 - 5 microns.
The problems of non-uniformity are particularly pronounced when one of the
drugs is
given in a low dosage or there is some form of interaction or non
compatibility between
the two active ingredients in suspension.
Problems of low dose arise with ipatropium bromide because the dose can be as
low as 20
micrograms per shot; eformoterol where a common dose is 12 micrograms per
shot; and
salmeterol where a dose of 25 micrograms is often given.
According to a first aspect of the present invention a pharmaceutical
formulation
comprises a mixture of two or more drugs optionally together with one or more
excipients,
the mixture being formed by the steps of:
co-crystallisation or co-precipitation of the drugs followed by micronisation
or milling to
produce a uniform powder having a particle size and other properties suitable
for
formulation for pulmonary or nasal administration.
Formulations of this invention may be used to ensure uniform dosing of each
drug in a
combination and to reduce any physical incompatibilities in suspension. The co-
crystallisation or co-precipitation of the two components, and subsequent
micronisation is
used to produce a uniform powder suitable for formulation in pharmaceutical
products for
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pulmonary or nasal administration. The preferred method of manufacture may
depend on
the two (or more) drugs needed for the specific combination product. The
following
methods may be employed.
Drying of both components from a mixed solution in either an aqueous or non-
aqueous
solvent is preferred. Spray drying is particularly preferred.
Alternative methods include co-precipitation of both drugs from an aqueous or
organic
solution by addition of a less polar solvent. In this case it is necessary to
ensure that both
drugs are precipitated to a similar extent to ensure uniformity of drug ratio
throughout the
mixture.
Co-crystallisation of both drugs may be carried out from aqueous or non-
aqueous
solutions. Uniformity of drug ratio also needs to be ensured. An alternative
method is the
precipitation or crystallisation of one drug onto crystals of another. Co-
crystallisation may
be carried out using a super critical fluid, for example super critical carbon
dioxide.
Suitable apparatus is disclosed in GB-A-2322326, GB-A-2334900 and GB-A-
2339165.
The particles of the combined drugs may be subsequently milled or micronised
to the
appropriate size e.g. 3 - 5 microns for pulmonary inhalation. However in
preferred
embodiments of the invention the resultant co-crystallised or co-precipitated
drugs have a
particle size suitable for inhalation without micronisation. Spray drying of
salbutamol
sulphate and ipratropium bromide from aqueous solutions is particularly
advantageous as
particles of 3 - 7 ,um may be obtained. These may have smooth configurations
suitable for
use in inhalation formulators without milling or micronising.
In cases where there are stability concerns due to the intimate mixing of the
two drugs
causing instability of one, other ingredients e.g. antioxidants may be added.
Examples of mixed products include drugs listed in two or more of the columns
below.
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Salmeterol Beclomethasone Ipatropium Bromide
Eformoterol (Formoterol) Fluticasone
Salbutamol Budesonide Other antimuscuranic
Fenoterol Mometasone agents
Other steroids
Other short or longer
acting (32 agonists
All drugs can be present either as bases, salts or esters as appropriate to
give the best
mixed product, that is a crystalline or amorphous mixture which can be milled
or
micronised as necessary at ambient temperatures and which is stable on
storage.
Preferred mixtures of drugs include salbutamol sulphate and ipratropium
bromide, and
salbutamol and ipratropium bromide, eformoterol and a steroid for example
beclamethasone fluticasone or budesonide. Various ratios of weights may be
employed,
for example but not limited to 10:1, 5:1 and 2:1.
According to a second aspect of the present invention a pharmaceutical
composition
includes a homogeneous mixture of salbutamol and ipratropium bromide
comprising
crystalline particles.
According to a third aspect of the present invention there is provided use of
a
pharmaceutical composition as previously described for manufacture of an
aerosol for
delivery into the lung or nose.
The invention is further described by means of example but not in any
limitative sense.
The following drugs and mixtures were prepared by spray drying using a Buchi
190
MiniSpray Drier:
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(i) salbutamol sulphate from aqueous solution: l Og of salbutamol sulphate was
spray dried as a 10% w/v aqueous solution using the spray drying parameters
outlined
below. These parameters are similar to those used by Chawla, A. et al
(International
Journal of Pharmaceutics 108 (1994) 233-240).
Inlet temperature: 151-153 °C
Outlet temperature: 75-78 °C
Pump setting: 7
Air flow rate: 600-700 lhr-'
(ii) salbutamol sulphate from ethanolic solution: 8g of salbutamol sulphate
was
dissolved in ethanolic solution for spray drying. The solvent used consisted
of ethanol
75%, water 25%. A 0.6% w/v solution was spray dried using the following spray
drying
parameters:
Inlet temperature: 100-102 °C
Outlet temperature: 60-64 °C
Pump setting: 6
Air flow rate: S00 lhr-'
(iii) salbutamol from ethanolic solution: salbutamol was spray dried from
ethanol
(98%) as a 2.5% w/v solution. Initially a solution containing 12.5g was spray
dried. The
spray drying parameters used were:
Inlet temperature: 91-94 °C
Outlet temperature: 62 °C
Pump setting: 7
Air flow rate: 700 lhr-'
The yield was extremely low (6.9%) and material was collected only from the
cyclone
separator since no powder was present in the collecting vessel.
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It was decided to alter the spray drying conditions and hence a lower inlet
temperature,
lower pump rate and decreased flow rate were used. The second attempt at spray
drying
Salbutamol BP from ethanolic solution (96%) consisted of 12.5g of solid spray
dried as a
2.5% w/v solution. The spray drying parameters used were:
Inlet temperature: 77-79 °C
Outlet temperature: 48-50 °C
Pump setting: S
Air flow rate: 500 lhr'
The percentage yield was approx 26%.
On this occasion powder was collected from both the collecting vessel and the
cyclone.
Salbutamol BP was spray dried again under similar conditions except that the
pump setting
was increased to 6. 9g of powder was weighed and spray dried as a 2.5% w/v
solution
from ethanol (96%). The spray drying parameters used were:
Inlet temperature: 77-78 °C
Outlet temperature: 54-56 °C
Pump setting: 6
Air flow rate: S00 lhr-'
The percentage yield was approx 38%.
(iv) ipratropium bromide from aqueous solution: Sg of ipratropium bromide was
spray dried as a 5% w/v aqueous solution. The spray drying parameters were
Inlet temperature: 151-153 °C
Outlet temperature: 102-104 °C
Pump setting: 7
Air flow rate: 700 lhr-'
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(v) ipratropium bromide from ethanolic solution: ipratropium bromide was spray
dried from an ethanolic solution (96%). lOg in total was spray dried as a 2.5%
w/v
solution. The spray drying parameters were:
Inlet temperature: 77-79 °C
Outlet temperature: 55-56 °C
Pump setting: 6
Air flow rate: 500 lhr'
Note: Practically no powder was collected from the collecting vessel. The
powder
appeared sticky initially. On storage under vacuum the following day the
powder was
observed to no longer be elastic/sticky but quite brittle and dry.
(vi) salbutamol sulphate: ipratropium bromide mixtures:
(a) 10:1 weight ratio, from aqueous solution: This co-spray dried system was
prepared
by weighting l Og of salbutamol sulphate and 1 g of ipratropium bromide to
give a total of
1 1g of solids. This was spray dried as a 5% w/v solution (5% total solids)
using the
parameters given below.
Inlet temperature: 151-153 °C
Outlet temperature: 100-102 °C
Pump setting: 7
Air flow rate: 600-700 lhr-'
(b) 5:1 weight ratio, from aqueous solution: This co-spray dried system was
prepared
by weighing l Og of salbutamol sulphate and 2g of ipratropium bromide to give
a total of
12g of solids. This was spray dried as a 5% w/v solution (5% total solids)
using the
parameters given below.
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_g_
Inlet temperature: 151-153 °C
Outlet temperature: 99-103 °C
Pump setting: 7
Air flow rate: 700 lhr~'
(c) 2:1 weight ratio, from aqueous solution: This co-spray dried system was
prepared
by weighing lOg of salbutamol sulphate and Sg of ipratropium bromide to give a
total of
15g of solids. This was spray dried as a 5% w/v solution (5% total solids)
using the
parameters given below.
Inlet temperature: 151-153 °C
Outlet temperature: 99-100 °C
Pump setting: 7
Air flow rate: 600-700 lhr-'
After spray drying all samples were stored in a vacuum dessicator at 4
°C.
The physical characteristics of the spray-dried compounds and mixtures were
determined
by xray diffraction (XRD), differential scanning calorimetry (DSC),
thermogravimetric
analysis (TGA), Fourier transform infrared (FTI) and scanning electron
microscopy
(SEM).
Preparation of physical mixes
Physical mixture of salbutamol sulphate or salbutamol BP and ipratropium
bromide were
prepared by weighing appropriate quantities of the two materials, loading into
30g amber
glass jars and mixing in a TurbulaTM mixer for 5 minutes. The weights taken
were: for the
10:1 weight ratio, 1 g salbutamol sulphate or Salbutamol BP and 0.1 g of
ipratropium
bromide; for the 5:1 weight ratio, 1 g salbutamol sulphate or Salbutamol BP
and 0.2 g of
ipratropium bromide; and for the 2:1 weight ratio, 1g salbutamol sulphate or
Salbutamol
BP and O.Sg of ipratropium bromide.
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Powder X-Ray Diffraction (XRD)
The powder X-Ray Diffractometer used was a Siemens D500 Diffractometer which
consist
of a DACO MP wide-range goniometer. A 1.00° dispersion slit, a
1.00° anti-scatter slit
and a 0.15 ° receiving slit were used. The Cu anode x-ray tube was
operated at 40kV and
30mA in combination with a Ni filter to give monochromatic Cu Ka X-rays. All
measurements were taken from 5 to 35 on the 2 theta scale at a step size of
0.05 °/second.
Differential Scanning Calorimetry (DSC)
The Differential Scanning Calorimeter used was a Mettler Toledo DSC 821e,
Mettler
Toledo STARe software Version 5.1 with a Solaris operating system. Samples
were placed
in open (hermetically sealed aluminium with three vent holes) pan types under
nitrogen
purge. Sample weights were between 5 and lOmg. DSC experiments were run
generally
from 30 to 250 or 350°C (depending on degradation products) at a
heating rate of
10°C/minute. Two DSC scans were obtained from each system.
Thermogravimetric Analysis (TGA)
Thermogravimetric analysis was carried out using a Mettler TG 50 linked to a
Mettler
MTS balance. Data was processed using Mettler Toledo STARe software Version
5.1 with
a Solaris operating system. Sample weights between 5 and l Omg were used and
analysis
carned out under nitrogen purge. The scans were generally run from 30 to
350°C at a
heating rate of 10 ° C/minute. Two TGA scans were obtained for each
system.
Scanning Electron Microscopy (SEM)
The scanning electron microscope used was the Hitachi S-3500N variable
pressure
scanning electron microscope. Samples were mounted and sputtered with gold
spray for
SEM.
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Fourier Transform Infra-red Spectroscopy (FTIR)
The spectrometer used was a Perkin Elmer Paragon 1000 FTIR. KBr discs were
prepared
based on lmg% sample loading. Discs were prepared by grinding the sample with
KBr in
an agate mortar and pestle, placing the sample in an evacuable KBr die and
applying 8 tons
of pressure in a Graseby Specac IR press. Two FTIR spectra were obtained for
each
system.
Salbutamol sulphate as supplied was a crystalline material by XRD. When spray
dried
from aqueous solution it was amorphous as evidenced by XRD, The amorphous
material
was relatively stable on heating. There was no obvious exotherm in the DSC
thermogram,
reflective of recrystallisation from the glass. The infrared spectrum of the
spray dried
sample compared to the spectrum of the original material showed a change in
the OH
region and no match for bands at 1546 and 1244 cm-' seen in the original
spectrum. There
was inconsistency in the intensity of some bands between the two spectra.
Small spherical
particles, typical of amorphous material were observed by SEM. Particle
diameters ranged
from ~l~cm to ~8,um. The surface of the particles was slightly dimpled.
Spray drying from ethanolic solution also resulted in an amorphous material by
XRD.
Again the DSC showed no obvious exotherm indicative of recrystallisation.
Small
spherical particles, typical of amorphous material were observed by SEM.
Comparisons of
SEMs showed that particles were smaller than those produced from the aqueous
solution,
with particle diameters less than ~3~m. The surface of the particles was
slightly dimpled.
Salbutamol as supplied was a crystalline material by XRD. On spray drying from
ethanolic solute, the XRD indicated the same crystalline form was present,
although some
peak intensity differences were evident. As the initial conditions used to
spray dry the
material resulted in a lower yield, the spray drying conditions were adjusted
appropriately
to improve the yield. A lower inlet temperature, lower pump rate (2 different
settings) and
decreased flow rate were used. Three spray dried samples were analysed by DSC.
The
major peak in the DSC occurred at the same position as the melting endotherm
of
salbutamol base. An exotherm, typical of the presence of an amorphous material
that is
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physically unstable, occurred before the melting endotherm. The position and
size of this
peak varied between the three samples. The energy change associated with the
exotherm
was lower if the DSC was performed the day after spray drying. The exotherm
was also
at a higher temperature. This suggests that the spray dried material contains
some
amorphous material which rapidly converted to the crystalline form. The
infrared
spectrum was a good match to the spectrum of the original material. Rough,
irregular
shaped particles were observed by SEM, with diameters ranging from less than 1
~m to ~8
or 7~cm.
Ipratropium bromide as supplied was a crystalline material by XRD. The DSC
showed a
major endotherm with a peak at 237°C, which can be attributed to
melting. However two
further lower temperature overlapping endotherms between 80 and 120°C
were also
evident. TGA indicated that these lower temperature endotherms represented 3
to 4% to
the total solid mass. This suggested the presence of solvent. When spray dried
from
aqueous solution the material remained crystalline, although the XRD pattern
was
somewhat different. The DSC of the spray dried material showed four
endothermic
events. There were two low temperature endotherms between about 85 and
120°C. The
TGA did not detect any mass loss associated with these endotherms and the
combined
energy change associated with them was ~4J/g compared to ~122J/g for the
ipratropium
bromide original raw material. There was another small endothermic peak at
208°C
before the large melting endotherm. Rough, irregular shaped particles were
observed by
SEM, with diameters ranging from about S to 20~m.
When spray dried from ethanolic solution, the XRD was very similar to that of
the starting
material. The DSC showed two low temperature endothermic peaks as well as a
higher
melting endotherm. The energy changes associated with the lower temperature
endotherms was smaller than that of the low temperature endotherms of the
starting
material (~49J/g versus 122J/g) and the TGA did not detect any mass loss
associated with
them. The shape of the endotherms was also somewhat different to hose of the
starting
material. The spray dried sample in the IR showed some changes in the OH
region relative
to the original material. Large crystalline particles were evidence under SEM
with
diameters of the order of 60~cm and larger.
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Salbutamol sulphate : ipratropium bromide mixtures on spray drying from
aqueous
solution gave amorphous materials with physicochemical characterisation (XRD,
DSC)
similar to the spray dried salbutamol sulphate alone. Both DSC and XR.D were
similar to
those of spray dried salbutamol sulphate. At the three ratios studied, the
ipratropium
bromide appeared to be dispersed in salbutamol sulphate in an amorphous form.
When the infrared spectrum of the 10:1 systems was compared to the equivalent
physical
mix, the spray dried sample showed changes in appearance in the OH region.
There was
no match in the spray dried spectrum for bands at 1087cm-', 1031cm-' and
1245cm-' and
there were new bands at 1044cm~' and 1002cm-' in the spray dried sample.
The infrared spectrum of the 5:1 system showed some differences in the OH
region. There
was no match in the spray dried spectrum for bands in the mechanical mix at
1087cm-',
1031cm-' and 978cm-' and there were additional bands at 1267cm-', 1448cm-',
1404crri'
and 1734cm-' in the spray dried sample.
The infrared spectrum of the 2:1 system showed some differences in the OH
region and a
change in intensity of some bands when compared to the equivalent physical
mix. The
spray dried sample showed loss of 1245cm-', 1087cm~' and 1030cm-' bands and
showed
new bands at 1508crri', 1268cm-', 1044cm-' and 1003cm-'. Some other minor
inconsistencies were apparent.
SEM showed particles from all three systems prepared to be small and
spherical, typical of
amorphous material.
The 10:1 sample displayed slightly dimpled particles less than 3,um in
diameter.
The 5:1 systems displayed more significantly dimpled particles, with diameters
less than
S,um.
The 2:1 system displayed smooth spherical particles with diameters less than
7,um.
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The samples were tested for degradation of salbutamol. In the co-spray dried
systems the
level of degradants was below the acceptable limits.
