U.S. patent application number 10/423912 was filed with the patent office on 2004-01-15 for modified carrier particles for use in dry powder inhalers.
This patent application is currently assigned to Chiesi Farmaceutici S.p.A.. Invention is credited to Bilzi, Roberto, Chiesi, Paolo, Musa, Rossella, Ventura, Paolo.
Application Number | 20040009127 10/423912 |
Document ID | / |
Family ID | 11382167 |
Filed Date | 2004-01-15 |
United States Patent
Application |
20040009127 |
Kind Code |
A1 |
Musa, Rossella ; et
al. |
January 15, 2004 |
Modified carrier particles for use in dry powder inhalers
Abstract
The invention relates to carrier particles for use in
pharmaceutical compositions for the pulmonary administration of
medicaments by means of dry powder inhalers. In particular, the
invention relates to a novel technological process for obtaining a
carrier modified so as to improve the efficiency of redispersion of
active particles and hence increase the respirable fraction. After
the treatment of the invention, the surface of said modified
carrier particles can also be coated with a suitable additive so as
to further improve the respirable fraction.
Inventors: |
Musa, Rossella; (Parma,
IT) ; Bilzi, Roberto; (Parma, IT) ; Ventura,
Paolo; (Parma, IT) ; Chiesi, Paolo; (Parma,
IT) |
Correspondence
Address: |
OBLON, SPIVAK, MCCLELLAND, MAIER & NEUSTADT, P.C.
1940 DUKE STREET
ALEXANDRIA
VA
22314
US
|
Assignee: |
Chiesi Farmaceutici S.p.A.
Via Palermo, 26/A
Parma
IT
I-43100
|
Family ID: |
11382167 |
Appl. No.: |
10/423912 |
Filed: |
April 28, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10423912 |
Apr 28, 2003 |
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09926105 |
Sep 27, 2001 |
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6641844 |
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09926105 |
Sep 27, 2001 |
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PCT/EP00/01773 |
Mar 2, 2000 |
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Current U.S.
Class: |
424/46 ;
241/14 |
Current CPC
Class: |
A61K 9/0075 20130101;
A61K 9/145 20130101 |
Class at
Publication: |
424/46 ;
241/14 |
International
Class: |
A61L 009/04; A61K
009/14 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 5, 1999 |
IT |
MI99A000455 |
Claims
1. A process for modifying the surface properties of particles for
use as carrier particles for the pulmonary administration of
micronised drugs by means of dry powder inhalers, the process
including the step of subjecting said carrier particles to a mixing
treatment in a mixer equipped with a rotating element in order to
produce in situ a fine fraction of said carrier.
2. A process according to claim 1, in which the particles of said
carrier have a starting diameter ranging from 90 to 150 .mu.m and
said fine fraction of the carrier has a mean aerodynamic diameter
of less than 10 .mu.m.
3. A process according to claims 1-2 in which the mixer is selected
from those with a stationary or rotating body equipped with any
rotatory element (blade, screw) or the high energy ones such as
"high-shear".
4. A process according to claims 1-3 in which the mixer is a sigma
blade mixer and the rate of mixing is comprised between 100 and 300
r.p.m.
5. A process according to claims 1-4, in which the mixing time of
the carrier powder range from 5 to 360 minutes.
6. A process according to claims 1-5, in which the mixing time is
30 minutes.
7. A process according to claims 1-6, in which said carrier
consists of one or more saccharides.
8. A process according to claims 1-7, in which said carrier
consists of .alpha.-lactose monohydrate.
9. A process according to claims 1-8, which yields a fraction of
carrier particles whose variation of the starting mean aerodynamic
diameter is less than 20%.
10. A process according to the preceding claims in which, after
mixing in the mixer, a suitable amount of an additive selected from
lubricants, anti-adherent agents and glidants is added to the
carrier.
11. A process according to claim 10, in which the amount of
additive ranges from 0.05 to 2%.
12. A process according to claims 10 and 11, in which the lubricant
is magnesium stearate, stearic acid, sodium stearyl fumarate or
sodium benzoate.
13. A process according to the preceding claims, in which one or
more active ingredients, whose particles have a mean diameter of
less than 5 .mu.m, are added to the carrier.
14. A process according to claim 13, in which the active ingredient
is a .beta.-agonist selected from salbutamol, formoterol,
salmeterol, terbutaline or salts thereof.
15. A process according to claim 13, in which the active ingredient
is an antiinflammatory steroid selected from beclomethasone
dipropionate, flunisolide, budesonide and the epimers thereof.
16. A process according to 13 in which the active ingredient is an
anticolinergic selected from ipratropium bromide or oxytropium
bromide.
Description
PRIOR ART
[0001] Inhalation anti-asthmatics are widely used in the treatment
of reversible airway obstruction, inflammation and
hyperresponsiveness.
[0002] Presently, the most widely used systems for inhalation
therapy are the pressurised metered dose inhalers (MDIs) which use
a propellant to expel droplets containing the pharmaceutical
product to the respiratory tract.
[0003] However, despite their practicality and popularity, MDIs
have some disadvantages:
[0004] i) droplets leaving the actuator orifice could be large or
have an extremely high velocity resulting in extensive
oropharyngeal deposition to the detriment of the dose which
penetrates into he lungs;
[0005] ii) the amount of drug which penetrates the bronchial tree
may be further reduced by poor inhalation technique, due to the
common difficulty of the patient to synchronise actuation form the
device with inspiration;
[0006] iii) chlorofluorocarbons (CFCs), such as freons contained as
propellants in MDIs, are disadvantageous on environmental grounds
as they have a proven damaging effect on the atmospheric ozone
layer.
[0007] Dry powder inhalers (DPIs) constitute a valid alternative to
MDIs for the administration of drugs to airways. The main
advantages of DPIs are:
[0008] i) being breath-actuated delivery systems, they do not
require co-ordination of actuation since release of the drug is
dependent on the patient own inhalation;
[0009] ii) they do not contain propellants acting as environmental
hazards;
[0010] iii) the velocity of the delivered particles is the same or
lower than that of the flow of inspired air, so making them more
prone to follow the air flow than the faster moving MDI particles,
thereby reducing upper respiratory tract deposition.
[0011] DPIs can be divided into two basic types:
[0012] i) single dose inhalers, for the administration of
pre-subdivided single doses of the active compound;
[0013] ii) multidose dry powder inhalers (MDPIs), pre-loaded with
quantities of active ingredient sufficient for multiple doses; each
dose is created by a metering unit within the inhaler.
[0014] Drugs intended for inhalation as dry powders should be used
in the form of micronised powder so they are characterized by
particles of few micron particle size (.mu.m). Said size is
quantified by measuring a characteristic equivalent sphere
diameter, known as aerodynamic diameter, which indicates the
capability of the particles of being transported suspended in an
air stream. Respirable particles are generally considered to be
those with diameters from 0.5 to 6 .mu.m, as they are able of
penetrating into the lower lungs, i.e. the bronchiolar and alveolar
sites, where absorption takes place. Larger particles are mostly
deposited in the oropharyngeal cavity so they cannot reach said
sites, whereas the smaller ones are exhaled.
[0015] Although micronisation of the active drug is essential for
deposition into the lower lungs during inhalation, it is also known
that the finer that particles, the stronger are the cohesion
forces. Strong cohesion forces hinder the handling of the powder
during the manufacturing process (pouring, filling). Moreover they
reduce the flowability of the particles while favoring the
agglomeration and/or adhesion thereof to the walls. In multidose
DPI's, said phenomena impair the loading of the powder from the
reservoir to the aersolization chamber, so giving rise to handling
and metering accuracy problems.
[0016] Said drawbacks are also detrimental to the respirable
fraction of the delivered dose being the active particles unable to
leave the inhaler and remaining adhered to the interior of the
inhaler or leaving the inhaler as large agglomerates; agglomerated
particles, in turn, cannot reach the bronchiolar and alveolar sites
of the lungs. The uncertainty as to the extent of agglomeration of
the particles between each actuation of the inhaler and also
between inhalers and different batches of particles, leads to poor
dose reproducibility as well.
[0017] In an attempt to improve both the handling and the
efficiency, the dry powders for inhalation are generally formulated
by mixing the micronised drug with a carrier material (generally
lactose, preferably .alpha.-lactose monohydrate) consisting of
coarser particles. In such ordered mixtures, the micronised active
particles, because of the electrostatic or Van der Waals
interactions, mainly adhere to the surface of the carrier particles
whilst in the inhaler device; on the contrary, during inhalation, a
redispersion of the drug particles from the surface of the carrier
particles occurs allowing the formers to reach the absorption site
in to the lungs.
[0018] Nevertheless, the use of a carrier is not free of drawbacks
in that the strong interparticle forces between the two ingredients
may prevent the separation of the micronised drug particles from
the surface of the coarse carrier ones on inhalation, so comprising
the availability of the drug to the respiratory tract. The surface
of the carrier particles is, indeed, not smooth but has asperities
and clefts, which are high energy sites on which the active
particles are preferably attracted to and adhere more strongly;
because of such strong, interparticle forces, they will be hardly
leave the surface of the carrier particles and be dispersed in the
respiratory tract.
[0019] Therefore the features of the carrier particles should be
such as to give sufficient adhesion force to hold the active
particles to the surface of the carrier particles during
manufacturing of the dry powder and in the delivery device before
use, but that force of adhesion should be low enough to allow the
dispersion of the active particles in the respiratory tract.
[0020] The prior art discloses several approaches for manipulating
the interparticle interactions between the drug and the carrier in
ordered powder mixtures.
[0021] First, the carrier particles can be chosen according to
their median particle size, taking into account the fact that a
decrease in median particle size increases the adhesion force
between drug and carrier particles.
[0022] GB 1,242,211 and GB 1,381,872 disclose pharmaceutical
powders for the inhalatory use in which the micronised drug
(0.01-10 .mu.m) is mixed with carrier particles of sizes 30 to 80
.mu.m and 80 to 150 .mu.m, respectively; said mixtures can also
contain a diluent of the same particle size as the micronised
drug.
[0023] The deaggregation of the active ingredient from the carrier
during inhalation can also be made more efficient by modifying the
surface properties of the carrier and/or by addition of a fine
fraction (<10 .mu.m), preferably of the same material of the
carrier (Podczeck F. Aerosol Sci. Technol. 1999, 31, 301-321; Lucas
P. et al Resp. Drug Deliv. 1998, VI, 243-250).
[0024] GB 2,240,337 A discloses, for example, a controlled
crystallization process for the preparation of carrier particles
with smoother surfaces, and, in particular, characterized by a
rugosity of less than 1.75 as measured by air permeametry; in
practice their smoothness is readily apparent under electronic
microscope examination. The use of said carrier particles allows to
increase the respirable fraction of the drug (Kassem, Doctoral
thesis of the London University, 1990).
[0025] EP 0,663,815 claims the use of carriers for controlling and
optimizing the amount of delivered drug during the aerosolisation
phase, consisting of suitable mixtures of particles of size >20
.mu.m and finer particles (<10 .mu.m).
[0026] Staniforth et al. (WO 95/11666) combine both the
aforementioned teachings (i.e. modification of the surface
properties of the carrier and addition of a fine fraction) by
exploiting the effects of a milling process, preferably carried out
in a ball mill, referred to as corrasion (corrasion is a term used
in geology and it describes either the effect of the wind on rocks
and the filling of valley with stones during the ice age). Said
process modifies the surface properties and it gets rid of the
waviness of the carrier particles by dislodging any asperities in
the form of small grains without substantially changing the size of
the particles; the small grains, in turn, can be reattached to the
surfaces of the particles either during the milling phase or after
preventive separation followed by mixing, in order to saturate
other high energy sites such as clefts. Said preliminary handling
of the carrier causes the micronised drug particles to preferably
link to the lower energy sites, thus being subjected to weaker
interparticle adhesion forces.
[0027] Podceck (J. Adhesion Sci. Technol. 1998, 12, 1323-1339),
after having studied the influence of the corrasion process on the
adhesion forces by blending the carrier with different percentages
of fine particle fraction before addition of the drug, concluded
however that such process is not always sufficient to ensure
effective redispersion but the latter also depends on the initial
surface roughness of the coarse carrier particles.
[0028] Patient literature also suggests the use of powder
formulations for inhalation wherein the adhesion between the
carrier particles and the active ingredient particles is further
reduced by addition of suitable amounts of suitable additives.
[0029] In WO 96/23485, particles are mixed with an anti-adherent or
anti-friction material consisting of one or more compounds selected
from amino acids (preferably leucine); phospholipids or
surfactants; the amount of additive and the process of mixing are
preferably chosen in such a way as to not give rise to a real
coating, but instead a partial coating directed to the high energy
sites. The carrier particles blended with the additive are
preferably subjected to the corrasion process in a ball mill as
disclosed in WO 95/11666.
OBJECT OF THE INVENTION
[0030] It has now been found, and it is the object of the
invention, that it is possible to modify the surface properties of
the carrier particles and simultaneously modulate their interaction
with the micronised drug particles by producing in situ a fine
fraction of the carrier itself, without submitting the coarse
carrier particles to a milling process but by employing a
conventional mixer.
[0031] The use of a mixer, which intrinsically assures milder
conditions, allows to modify the surface properties of the carrier
particles without significantly changing their sizes, crystalline
structure and chemico-physical properties.
[0032] It has been indeed reported that the chemical compounds
preferably used as carrier, such as lactose, can undergo
chemico-physical alternations, when subjected to mechanical
stresses, such as milling (Otsuka et al. J. Pharm. Pharmacol. 43,
148-153, 1991).
[0033] Moreover, hard treatments such as corrasion may moderately
reduce the cristallinity of the additives used (Malcolmson R et al.
Respiratory Drug Deliv. 1998, VI, 365-367).
[0034] It has been also suprisingly found that, by virtue of the
milder operative conditions of the invention, the fraction of fine
particles of size larger than 10 .mu.m is poor, as proved by the
particle size analysis via laser diffractometry (Malvern). It is
well known that only the fine fraction below 10 .mu.m, once
redistributed onto the surface of the coarse carrier particles, is
indeed responsible for the decrease of the interparticle forces,
whereas the fine particles of size larger than 10 .mu.m, contribute
to decrease the flowability of the powder.
[0035] On the contrary, milling, as reported above, is a hard
process which produces a fine fraction with a much wider particle
size distribution which, in turn, could be detrimental for the flow
properties of the mixture. Therefore, the powders made with
carriers preventively subjected to milling processes could turn out
to be not flowable enough to be suitable for multidose inhalers.
Accordingly, the carriers subjected to the milling process often
require a further separation step in order to select the fine
fraction suitable for being mixed with the coarse carrier particles
and discard that one which can be detrimental to the flow
properties of the powder.
[0036] By operating according to the process of the present
invention, the flow properties of the carrier are not significantly
affected, as indicated by the Carr index as well as by the Flodex
test. The process of the invention allows therefore to avoid the
further separation step of the fine fraction suitable for being
mixed with the coarse carrier particles.
[0037] The mixing process of the invention, compared with the
milling process as described in WO 95/11666, allows to remarkably
reduce the time of treatment. In a preferred embodiment of the
invention, carriers with suitable properties are indeed obtained
after 30 minutes of treatment in a sigma blade mixer whereas,
according to WO 95/11666, carrier particles should be milled for at
least one hour and preferably six hours.
[0038] Finally, the process of the invention provides a carrier for
dry powders for inhalation able of giving good performance in terms
of respirable fraction of the drug as demonstrated by the examples
reported.
[0039] Advantageously the carrier particles are treated in any
mixer, of any size and shape, equipped with a rotating element.
Preferably the carrier particles are treated in mixers constituted
of a stationary of rotating body equipped with any rotatory element
(blade, screw) or in the high energy mixers ("high-shear") and
blended for a total time ranging from 5 to 360 minutes.
[0040] Even more preferably the carrier particles are treated in a
sigma-blade mixer at a rate of 100-33 r.p.m and for 30 minutes.
[0041] The carrier particles may be constituted of any
pharmacologically acceptable inert material or combination thereof;
preferred carriers are those made of crystalline sugars, in
particular lactose; the most preferred are those made of
.alpha.-lactose monohydrate. Advantageously the diameter of the
carrier particles lies between 20 and 1000 .mu.m, preferably
between 90 and 150 .mu.m.
[0042] A further aspect of the invention relates to the preparation
of carrier powders in which, after treatment in a mixer, the
carrier particles are mixed with suitable amounts, preferably from
0.05 to 2% by weight, of additives able of further reducing the
drug-carrier interparticle forces, thereby increasing the
respirable fraction.
[0043] The additives can be selected from those belonging to the
class of the lubricants, such as metal stearates or to the classes
of anti-adherent agents or glidants.
[0044] The preferred lubricant is magnesium stearate, but stearic
acid, sodium stearyl fumarate and sodium benzoate can also be
used.
[0045] A further aspect of the invention are the formulations for
inhalation obtained by mixing the active ingredient particles (with
a mean aerodynamic diameter of less than 5 mm) with carrier powders
obtained according to the process of the inventon.
[0046] The preferred active particles will be particles of one or
mixture of drugs which are usually administered by inhalation for
he treatment of respiratory diseases, for example steroids such as
bechlomethasone dipropionate, flunisolide and budesonide;
.beta.-agonists such as salbutamol, formoterol, salmeterol,
terbutaline and corresponding salts; anticholinergics such as
ipratropium bromide. Any other active ingredient suitable for
pulmonary and/or nasal delivery can be anyway used in these
formulations.
[0047] The process of the invention is illustrated by the following
examples.
EXAMPLE 1
[0048] a) Preparation of the Carrier
[0049] .alpha.-Lactose monohydrate with a starting particle size
between 90 to 150 .mu.m is mixed for 30 minutes in a sigma blade
mixer. At the end of the treatment, only a slight reduction of the
particle size is observed.
[0050] The Malvern analysis pattern referring to the particle size
distribution of the carrier particles before (- -) and after (----)
the pre-mixing treatment is reported in FIG. 1 whereas the relevant
data are reported in Table 1.
1TABLE 1 Particle size distribution (.mu.m) Unmixed Pre-mixed
Malvern d (v, 0.1) 100.4 61.4 a (v, 0.5) 138.3 127.1 d (v, 0.9)
197.8 187.7
[0051] b) Preparation of the Beclomethasone Dipropionate
(BDP)/Lactose Binary Mixture
[0052] The carrier powder obtained according to the process a) is
mixed with such an amount of micronised beclomethasone dipropionate
as to obtain a ratio of 200 .mu.m of active to 26 mg total
mixture.
[0053] c) Characterization of the Mixture
[0054] The active ingredient/carrier mixture was characterized by
its density and flowability parameters.
[0055] The poured density (dv) and the tapped density (ds) were
calculated as follows. Powder mixtures (20 g) were poured into a
glass graduated cylinder and dv was calculated dividing the weight
by the volume; ds was calculated from the volume obtained after
tapping the powder mixture 500 times using a commercially available
apparatus.
[0056] The flowability was evaluated from the Carr's index
calculated according to the following formula: 1 Carr ' s index ( %
) = s - v s .times. 100
[0057] A Carr index of less than 25 is usually considered
indicative of good flowability characteristics.
[0058] The flowability properties were also determined by using a
Flodex tester. The determination is based upon the ability of the
powder mixture to fall freely through holes of different diameters
placed at the bottom of a cylinder. The powder was poured into the
cylinder via a powder funnel. The flowability index is given in
millimetre diameter of the smallest hole through which the powder
falls freely.
[0059] d) Determination of the Aerosol Performances.
[0060] An amount of powder for inhalation was loaded in a multidose
inhaler (Pulvinal.RTM.--Chiesi Pharmaceutical SpA, Italy).
[0061] The evaluation of the aerosol performances was performed by
using a Twin Stage Impinger apparatus, TSI (Apparatus of type A for
the aerodynamic evaluation of fine particles described in FU IX,
4.degree. supplement 1996). The equipment consists of two different
glass elements, mutually connected to form two chambers capable of
separating the powder for inhalation depending on its aerodynamic
size; the chambers are referred to as higher (stage 1) and lower
(stage 2) separation chambers, respectively. A rubber adaptor
secures the connection with the inhaler containing the powder. The
apparatus is connected to a vacuum pump which produces an air flow
through the separation chambers and the connected inhaler. Upon
actuation of the pump, the air flow carries the particles of the
powder mixture, causing them to deposit in the two chambers
depending on their aerodynamic diameter. When the air flow is 10
l/min, the aerodynamic diameter limit value, dae, for the
deposition in the lower separation chamber is 6.4 .mu.m. Particles
with higher dae deposit in Stage 1 and particles with lower dae in
Stage 2. In both stages, a minimum volume of solvent is used (30 ml
in Stage 2 and 7 ml in Stage 1) to prevent particles from adhering
to the walls of the apparatus and to promote the recovery
thereof.
[0062] The determination of the aerosol performances of the mixture
obtained according to the preparation process b) was carried out
with the TSI applying an air flow rate of 60 l/min for 5
seconds.
[0063] After nebulization of each dose of the dry powder in the
Twin Stage Impinger, the apparatus was disassembled and the amounts
of drug deposited in the two separation chambers were recovered by
washing with a solvent mixture, then diluted to a volume of 50 ml
in two volumetric flasks, one for Stage 1 and one for Stage 2,
respectively. The amounts collected in the two volumetric flasks
were then determined by High-Performance Liquid Chromatography
(HPLC). The following parameters, as mean and relative standard
deviations (RSD) of the values obtained from three inhalers, by
actuating 5 shots from each inhaler, were calculated: i) the fine
particle dose (FPD) which is the amount of drug found in stage 1 of
TSI; ii) the emitted dose which is the amount of drug delivered
from the device recovered in stage 1+stage 2; iii) the fine
particle fraction (FPF) which is the percentage of the emitted
reaching stage 2 of TSI.
[0064] The results in terms of technological parameters and aerosol
performances are reported in Table 2, in comparison with a similar
preparation obtained by mixing the active ingredient with
.alpha.-lactose monohydrate lactose 90-150 .mu.m not pre-treated in
the mixer (standard preparation).
2TABLE 2 Preparation of Example 1 Standard Preparation
Technological Parameters Apparent Density (g/mL) Poured 0.71 0.75
Tapped 0.80 0.90 Flodex test (.0. 4 mm) 4 4 Flow rate through .0. 4
mm (g/min) 67 46 Carr Index (%) 11 17 TSI test Mean weight (mg)
22.8 (3.3) 25.6 (2.6) Emitted dose (.mu.g) 184.0 (3.3) 165.8 (6.9)
FPD (.mu.g) 31.0 (50.9) 37.4 (8.9) FPF (%) 16.9 (53.2) 22.7
(10.6)
[0065] The results show that the flowability properties of the
carrier are not significantly affected even in the presence of a
slight reduction of the particle size.
[0066] The treatment of the carrier also causes a significant
increase of the fine particle fraction (t Student=2.42, p
<0.005).
EXAMPLE 2
Preparation of a Salbutamol Base/Lactose Binary Mixture
[0067] Analogously to what described in example 1, a mixture
containing micronised salbutamol base as active ingredient in a
ratio of 200 .mu.g to 24 mg total mixture was prepared.
[0068] The poured and tapped densities and the flowability
characteristics were determined as described in example 1. The dry
powder for inhalation was loaded in a Pulvinal.RTM. inhaler and the
aerosol performances were determined as described in example 1.
[0069] The results are reported in Table 3 in comparison with a
similar preparation obtained by mixing the active ingredient with
.alpha.-lactose monohydrate lactose 90-150 .mu.m not pre-treated in
a mixer (standard preparation).
3TABLE 3 Preparation of Example 2 Standard preparation
Technological parameters Apparent Density (g/mL) Poured 0.71 0.74
Tapped 0.78 0.83 Flodex test (.0. 4 mm) 4 4 Flow Rate through .0. 4
mm (g/min) 72 -- Carr Index (%) 9 11 TSI test Mean weight (mg) 22.2
(1.7) 25.2 (3.3) Emitted dose (.mu.g) 185.0 (2.6) 168.2 (4.7) FPD
(.mu.g) 60.21 (11.6) 80.9 (14.6) FPF (%) 32.2 (11.5) 47.9
(11.4)
[0070] Also in this case, the results show that the flowability
properties of the carrier do not significantly change.
[0071] Analogously, a significant increase (t=9.17, p<0.001) of
the fine particle fraction is observed with the carrier prepared
according to the process a) described in example 1.
EXAMPLE 3
Preparation of a BDP/Lactose/Magnesium Stearate Ternary Mixture
[0072] The powder carrier was prepared according to Example 1 a) by
mixing .alpha.-lactose monohydrate for 30 minutes in a sigma blade
mixer. Afterwards lactose was mixed with 0.25% by weight of
magnesium stearate in a Turbula mixer for two hours. Finally the
dry powder for inhalation was prepared by mixing an amount of
micronised beclomethasone dipropionate corresponding to a dose of
200 .mu.g and the carrier (lactose+magnesium stearate) for 30
minutes in a Turbula rotting mixer at 32 rpm.
[0073] The poured and tapped densities, the flowability
characteristics as well as the aerosol performances were determined
as described in example 1.
[0074] The results are reported in Table 4 in comparison with a
standard formulation obtained by mixing 200 .mu.g of micronised BDP
with a carrier powder consisting of 99.75% by weight of
.alpha.-lactose monohydrate 90-150 .mu.g not pre-treated in a
mixer, and 0.25% by weight of magnesium stearate (standard
preparation).
4TABLE 4 Preparation of Example 3 Standard preparation
Technological parameters Apparent Density (g/mL) Poured 0.76 0.83
Tapped 0.81 0.92 Flodex test (.0. 4 mm) 4 4 Flow Rate through .0. 4
mm (g/min) 56 42 Carr Index (%) 6 10 TSI test Mean weight (mg) 24.5
(1.5) 27.9 (3.2) Emitted dose (.mu.g) 188.9 (4.5) 199.8 (2.2) FPD
(.mu.g) 48.0 (19.5) 68.9 (5.6) FPF (%) 25.3 (15.3) 34.5 (5.2)
[0075] The flowability properties of the carrier do not
significantly change even in the presence of a ternary mixture and
a significant increase (t=8.29, p<0.001) of the fine particle
fraction is observed with the carrier prepared according to the
invention.
* * * * *