U.S. patent application number 10/358174 was filed with the patent office on 2003-07-17 for powdery pharmaceutical compositions for inhalation.
This patent application is currently assigned to Chiesi Farmaceutici S.p.A.. Invention is credited to Chiesi, Paolo, Musa, Rossella, Ventura, Paolo.
Application Number | 20030133880 10/358174 |
Document ID | / |
Family ID | 8167234 |
Filed Date | 2003-07-17 |
United States Patent
Application |
20030133880 |
Kind Code |
A1 |
Musa, Rossella ; et
al. |
July 17, 2003 |
Powdery pharmaceutical compositions for inhalation
Abstract
Powdery pharmaceutical compositions including an active
ingredient and carrier particles containing only a small amount of
lubricant, 0.05-0.5% by weight, are used to prepare dry powder
inhalers in order to increase the fine particle dose. A process for
coating the surface of the carrier particles with such little
amount of lubricant is also provided. Use of limited amount of
lubricant is safe and provides ordered stable mixtures without
segregation of the active particles during handling and before
use.
Inventors: |
Musa, Rossella; (Parma,
IT) ; Ventura, Paolo; (Parma, IT) ; Chiesi,
Paolo; (Parma, IT) |
Correspondence
Address: |
NIXON & VANDERHYE, PC
1100 N GLEBE ROAD
8TH FLOOR
ARLINGTON
VA
22201-4714
US
|
Assignee: |
Chiesi Farmaceutici S.p.A.
|
Family ID: |
8167234 |
Appl. No.: |
10/358174 |
Filed: |
February 5, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10358174 |
Feb 5, 2003 |
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09603620 |
Jun 26, 2000 |
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6528096 |
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09603620 |
Jun 26, 2000 |
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PCT/EP99/01449 |
Mar 5, 1999 |
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Current U.S.
Class: |
424/46 ; 514/179;
514/630; 514/650 |
Current CPC
Class: |
A61P 1/00 20180101; C07C
45/298 20130101; A61K 31/232 20130101; C07C 45/00 20130101; A61P
27/00 20180101; A61P 37/08 20180101; A61P 19/00 20180101; A61P
37/00 20180101; C07C 45/00 20130101; A61K 47/26 20130101; A61P
11/06 20180101; A61P 1/04 20180101; A61P 13/08 20180101; A61K
31/203 20130101; C07C 45/29 20130101; C07C 47/47 20130101; A61P
17/06 20180101; C07C 47/277 20130101; C07C 47/575 20130101; C07C
49/84 20130101; C07C 47/277 20130101; C07C 45/71 20130101; A61P
17/00 20180101; C07C 59/64 20130101; C07C 45/298 20130101; A61P
19/10 20180101; C07C 69/734 20130101; A61P 27/16 20180101; A61P
15/00 20180101; C07C 47/47 20130101; C07C 59/72 20130101; A61K
9/1647 20130101; A61P 35/00 20180101; A61P 13/00 20180101; C07C
45/298 20130101; A61K 31/231 20130101; A61K 31/00 20130101; A61P
17/10 20180101; C07C 45/29 20130101; C07C 45/71 20130101; A61K
9/0075 20130101; A61P 11/00 20180101 |
Class at
Publication: |
424/46 ; 514/650;
514/179; 514/630 |
International
Class: |
A61L 009/04; A61K
009/14; A61K 031/573; A61K 031/137 |
Claims
What is claimed is:
1. A powder for use in a dry powder inhaler, the powder including
an active ingredient and a carrier, wherein the carrier further
includes a lubricant in an amount up to 0.5% by weight of the total
weight composition.
2. A powder according to claim 1 wherein the lubricant is present
in an amount between about 0.1 and 0.5% by weight of the total
weight of the composition.
3. A powder according to claim 1 or 2 wherein the lubricant
particles at least partially coat the carrier particles
surface.
4. A powder according to claim 1 wherein the lubricant is selected
from magnesium stearate, stearic acid, sodium lauryl sulphate,
sodium stearyl fumarate, stearyl alcohol, sucrose monopalmitate and
sodium benzoate.
5. A powder according to claim 3 wherein the carrier particles are
coated with 0.10 to 0.25% by weight of magnesium stearate.
6. A powder according to claim 5 wherein the carrier particles are
coated with 0.25% by weight of magnesium stearate.
7. A powder according to claim 4 wherein magnesium stearate is a
crystalline or amorphous material.
8. A powder according to claim 4 wherein magnesium stearate is of
animal or vegetal origin.
9. A powder according to claim 1 wherein the carrier particles
comprise one or more crystalline sugars.
10. A powder according to claim 1 wherein the carrier particles are
.alpha.-lactose monohydrate.
11. A powder according to claim 1 wherein the carrier particles
have a particle size which lies between 20 and 1000 .mu.m.
12. A powder according to claim 11 wherein the carrier particles
have a particle size which lies between 90 and 150 .mu.m.
13. A powder according to claim 1 wherein at least 50% of the
lubricant has a particle size more than 4 .mu.m.
14. A powder according to claim 1 wherein the lubricant is
magnesium stearate and has a specific surface area which lies in
the range 0.5-1.5 m.sup.2g measured by Malvern.
15. A powder according to claim 1 wherein the active ingredient has
a particle size less than 10 .mu.m, preferably less than 6
.mu.m.
16. A powder according to claim 1 wherein the active ingredient
includes a steroid.
17. A powder according to claim 14 wherein the active ingredient is
beclomethasone dipropionate or budesonide and its epimers or
flunisolide.
18. A powder according to claim 1 wherein the active ingredient
includes a .beta..sub.2-agonist selected from salbutamol,
formoterol, salmeterol, terbutaline and their salts.
19. A powder according to claim 18 wherein the active ingredient
includes salbutamol base.
20. A carrier for use in a powder according to claim 1 made of
carrier particles and up to 0.5% by weight of lubricant
particles.
21. A carrier according to claim 20 wherein the lubricant particles
at least partially coat the surface of the carrier particles.
22. A method for producing the carrier according to claim 21, the
method including the step of mixing the carrier particles with up
to 0.5% by weight of lubricant thereby coating the highest as
possible percentage of carrier particles surface, thus achieving an
increase of the fine particle dose.
23. A method according to claim 22 wherein the carrier particles
and lubricant particles are mixed for between 2 min. and 480
min.
24. A method according to claim 22 wherein the carrier particles
and lubricant particles are mixed using a rotating body mixer or a
stationary body mixer with a rotating mixing blade or a high-speed
mixer.
25. A method according to claim 22 wherein the mixer is a tumbling
blender rotating at 5-100 r.p.m.
26. A method according to claim 22 wherein the coated carrier
particles have a water contact angle of at least 30.degree..
Description
[0001] This invention relates to improved powdery pharmaceutical
compositions for use in dry powder inhalers. The improvement is
concerned with mechanical stability, performances and safety.
[0002] Inhalation anti-asthmatics are widely used in the treatment
of reversible airway obstruction, inflammation and
hyperresponsiveness.
[0003] 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.
[0004] However, despite their practicality and popularity, MDIs
have some disadvantages:
[0005] i) the majority of the dose released deposits in the
oropharynx by impaction and only a small percentage penetrates
directly into the lower lungs;
[0006] ii) the already small proportion of drug which penetrates
the bronchial tree may be further reduced by poor inhalation
technique;
[0007] iii) last but not least, 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.
[0008] Dry powder inhalers (DPIs) constitute a valid alternative to
MDIs for the administration of drugs to airways. The main
advantages of DPIs are:
[0009] i) being breath-actuated delivery systems, they do not
require coordination of actuation since release of the drug is
dependent on the patient own inhalation;
[0010] ii) they do not contain propellants acting as environmental
hazards;
[0011] iii) the quantity deposited by impaction in the oropharynx
is lower.
[0012] DPIs can be divided into two basic types:
[0013] i) single dose inhalers, for the administration of single
subdivided doses of the active compound;
[0014] ii) multidose dry powder inhalers (MDPIs), pre-loaded with
quantities of active principles sufficient for longer treatment
cycles.
[0015] MDPIs are considered more convenient to the patient than
single dose DPIs, not only because they provide a number of doses
sufficient for longer treatment cycles but also because of their
ease of use and unobtrusiveness.
[0016] Dry powder dosage forms are generally formulated by mixing
the cohesive micronised drug with coarse carrier particles, giving
rise to ordered mixture where the micronised active particles
adhere to the surface of the carrier particles whilst in the
inhaler device.
[0017] The carrier material, most commonly lactose, makes the
micronised powder less cohesive and improves its flowability,
making easier handling the powder during the manufacturing process
(pouring, filling etc.). During inhalation, the small drug
particles separate from the surface of carrier particles and
penetrates into the lower lungs, while the larger carrier particles
are mostly deposited in the oropharyngeal cavity.
[0018] The redispersion of drug particles from the carrier surface
is regarded as the most critical factor which governs the
availability of the medicament to the lungs. This will depend on
the mechanical stability of the powder mix and the way this is
influenced by the adhesion characteristics between the drug and the
carrier and the external forces required to break up the non
covalent bonds formed between adhering particles. Too strong bonds
between adhering particles may prevent indeed the separation of the
micronised drug particles from the surface of carrier particles. In
particular, the efficiency of the redispersion process is strictly
dependent on the carrier surface properties, the actual particle
size of both the drug and the carrier and the drug to carrier
ratio. Consequently, different approaches aimed at modulating one
or more of these parameters have been proposed to promote the
release of the drug particles from the carrier particles and,
hence, to increase the percentage of the respirable fraction. In
the prior art, the use of a ternary component, with lubricant or
anti-adherent properties, has been also suggested as a solution of
the technical problem.
[0019] Fisons patents GB 1242211 and GB 1381872 described powders
for inhalation obtained by simple mixing of a medicament with a
particle size of less than 10 microns and a coarse carrier whose
particle size falls in a well defined range. They also disclosed
that it may be useful to coat the surfaces of the particles and/or
carrier with pharmaceutically acceptable material, such as stearic
acid or polymers for giving a sustained release action to the
medicament.
[0020] Chiesi WO A 87 05213 described a carrier, comprising a
conglomerate of a solid water-soluble carrier and a lubricant,
preferably 1% magnesium stearate, for improving the technological
properties of the powder in such a way as to remedy to the
reproducibility problems encountered after the repeated use of the
inhaler device.
[0021] Staniforth et al. (J. Pharm. Pharmacol. 34, 141-145, 1982)
observed that magnesium stearate is able to modify the adhesion of
salicylic acid to sucrose but, the amount used (0.5-4.0%)
destabilises the mixture to the extent that significant segregation
occurs.
[0022] Kassem (London University Thesis, 1990) studied the effect
of 1.5% w/w magnesium stearate or Aerosil 200 (trade name for
colloidal silicon dioxide) on the de-aggregation of powders made of
salbutamol sulphate and lactose. Although the `respirable` fraction
increased when magnesium stearate was added, the reported amount is
too great and reduces the mechanical stability of the mixture
before use. Furthermore, being magnesium stearate poorly
water-soluble, its presence in such amount may rise some concerns
as to a potential irritation or toxicity of this excipient, part of
which can be inhaled by the patient together with the active
ingredient. According to Staniforth (WO 96/23485), the reported
drawbacks can be solved by adding physiologically
acceptable/water-solubl- e additives with anti-adherent properties
which do not make segregation of the active particles from the
surfaces of the carrier particles during manufacturing of the dry
powder and in the delivery device before use. In the said document,
the anti-adherent material, preferably 1-2% leucine in particulate
form, promote the release of the active particles by saturating the
high energy sites of the carrier particles. Although it is
generically disclosed that magnesium stearate, being highly surface
active, should be added in particularly small amounts', the use of
such excipient is considered not advisable.
[0023] It has now been discovered, and this is an object of the
present invention, that lubricants like magnesium stearate can be
advantageously and safely used as excipient for powdery
pharmaceutical composition in such amount by weight based on the
total weight of the powder of less than 0.5%; for steroids, the
optimum amount of additive turned out to be 0.25%, whereas, for
salbutamol base, it turned out to be 0.10%. Contrary to the
teaching of the prior art (Peart et al. Pharm. Res. 14, S 142,
1997), 0.1% of magnesium stearate is sufficient for increasing in a
significant way the fine particle dose, when salbutamol base
instead of sulphate is used.
[0024] The invention also provides a method for producing a
homogeneous carrier for powders for inhalation independently on the
scale of mixing, the method including a step for coating the most
as possible surface of the carrier particles with a little amount
of lubricant. We have indeed found that it is advantageous to
attain the highest as possible degree of coating of the carrier
particles surface with the lubricant to increase the release of the
active particles and, hence, the `respirable` fraction. In the
prior art, it was already known that the film forming properties of
lubricants depend on the mixing time and significantly affect the
compressibility characteristics of powders for tablets, but an
advantageous relationship between the degree of coating and the
`respirable` fraction has never been reported before. We have also
found, and this is another aspect of the invention, that use of
lubricants in such little amount for coating the carrier, is
sufficient for improving the flowability of the powder without
causing mechanical stability problems of the mixture before
use.
[0025] Finally we have found that the introduction of magnesium
stearate in such a small amount is safe and does not produce any
toxicologically relevant effect after repeated administration.
[0026] Advantageously the carrier of the invention is prepared by
mixing the carrier particles and the lubricant particles for at
least 2 min in a mixer in such a way as that no significant change
in the particle size of the carrier particle occurs. Preferably,
the carrier is mixed for at least 30 min using a rotating body
mixer with a rotating speed between 5-100 r.p.m. or a stationary
body mixer with a rotating mixing blade or a high-speed mixer. More
preferably, the carrier is mixed for al least two hours in a
Turbula mixer at 16 r.p.m.
[0027] Advantageously, the carrier particles and the lubricant
particles are mixed until the degree of molecular surface coating
is more than 10% as determined by water contact angle measurement.
Preferably, carrier particles and lubricant particles made of
magnesium stearate are mixed until the water contact angle of the
`coated` carrier particles is more than 36.degree. corresponding to
more than 10% degree of molecular surface coating; more preferably,
the water contact angle should be more than 50.degree.
corresponding to more than 23% degree of molecular surface
coating.
[0028] The carrier particles may be composed of any
pharmacologically inert material or combinations of material
acceptable for inhalation. Advantageously, the carrier particles
are composed on one or more crystalline sugars. Preferably, the
carrier particles are particles of .alpha.-lactose monohydrate.
[0029] Advantageously, all the carrier particles have a particle
size in the range 20-1000 .mu.m, more preferably in the range
90-150 .mu.m.
[0030] The preferred lubricant is any type of magnesium stearate
which may be crystalline or amorphous; its use is described in the
embodiments of the invention by way of examples which do not limit
it in any way.
[0031] Other lubricants, such as stearic acid, sodium lauryl
sulphate, sodium stearyl fumarate, stearyl alcohol, sucrose
monopalmitate and sodium benzoate, could turn out to be suitable
depending on the type of carrier and drug used.
[0032] Advantageously, at least 50% by weight of the lubricant
particles have a particle size more than 4 .mu.m. Preferably, at
least 60% of the lubricant particles made of magnesium stearate
have a particle size more than 5 .mu.m, with a specific surface
area in the range 0.5-2.5 m.sup.2/g measured by Malvern.
[0033] The ratio between the carrier and the drug are mixed will
depend on the type of inhaler device used and the required
dose.
[0034] Advantageously, the at least 90% of the particles of the
drug have a particle size less than 10 .mu.m, preferably less than
6 .mu.m.
[0035] Drugs include those products which are usually administered
by inhalation for the treatment of respiratory diseases, i.e.
.beta.-agonists, like salbutamol, formoterol, salmeterol,
terbutaline and their salts, steroids like beclometasone
dipropionate, flunisolide, budesonide, others like ipratropium
bromide.
[0036] In a general aspect, the invention also provides a powdery
pharmaceutical composition for use in a dry powder inhaler, the
powder including active particles and a carrier where the surface
of the carrier particles carrying the active particles is partially
coated with a film of lubricant.
EXAMPLE 1
[0037] Determination of the Suitable Amount of Magnesium Stearate
to be Added in Beclomethasone-17,21-dipropionate (BDP) Powders for
Inhalation
[0038] Samples of the carrier were prepared by mixing of
.alpha.-lactose monohydrate (Meggle D 30) fraction 90-150 .mu.m
with 0.1%, 0.25% or 0.5% magnesium stearate for several hours in a
Turbula mixer. Powders mixtures with different BDP concentrations
(100, 200 and 400 .mu.g/dose) were prepared by mixing of the
carrier and the active ingredient for 30 min in a Turbula mixer at
32 r.p.m.
[0039] Multidose devices (Pulvinal.RTM.) filled with the mixtures
were then tested by using a twin-stage impinger (TSI), Apparatus A
(BP 93, Appendix XVII C, A194). The fine particle dose is
calculated as a percentage of the total amount of drug delivered
from the device (stage 1+stage 2), that reaches stage 2 of TSI. The
results are summarised in Tables 1, 2 and 3 (standard deviations,
S.D., given in parentheses).
[0040] No significant increase in fine particle dose is obtained
from increasing the concentration of magnesium stearate above
0.25%.
1TABLE 1 Fine Mg Shot Delivered particle Formulation stearate
weight Stage 2 dose dose* (100 .mu.g/dose) (%) (mg) (.mu.g) (.mu.g)
(BDP %) BDP 1 0.10 26.7 (0.3) 22.5 (3.5) 99.7 (0.6) 21.9 (2.8) BDP
2 0.25 26.8 (0.1) 33.0 (5.6) 95.3 (0.6) 34.5 (6.2)
[0041]
2TABLE 2 Delivered Fine Formulation Mg stearate Shot Stage 2 dose
particle dose* (200 .mu.g/dose) (%) weight (mg) (.mu.g) (.mu.g)
(BDP %) BDP 1 0 24.8 (0.4) 14.2 (5.7) 192 (14.0) 7.3 (2.6) BDP 2
0.10 26.6 (0.4) 20.3 (4.6) 215 (2.3) 9.5 (2.2) BDP 3 0.25 26.8
(0.6) 48.0 (8.5) 192 (7.8) 25.0 (3.7) BDP 4 0.50 26.7 (0.2) 32.3
(2.3) 193 (4.6) 16.7 (1.0)
[0042]
3TABLE 3 Delivered Fine Formulation Mg stearate Shot Stage 2 dose
particle dose* (400 .mu.g/dose) (%) weight (mg) (.mu.g) (.mu.g)
(BDP %) BDP 1 0 -- -- 355 (22.8) 7.3 (0.4) BDP 2 0.10 25.4 (0.3)
100 (11.0) 351 (4.5) 28.7 (3.4) BDP 3 0.25 25.1 (0.4) 142 (22.1)
375 (9.3) 37.9 (5.7) BDP 4 0.50 25.5 (0.3) 98 (44.7) 421 (18.4)
23.2 (10.3)
EXAMPLE 2
[0043] Determination of the Suitable Amount of Magnesium Stearate
to be Added in Salbutamol Base Powders for Inhalation
[0044] Samples of the carrier were prepared as reported in Example
1.
[0045] Powder mixtures containing 200 .mu.g/dose of micronised
salbutamol base were prepared by mixing of the carrier and the
active ingredient for 30 min a Turbula mixer at 32 r.p.m.
[0046] The powder mixtures were filled into inhalers and tested as
reported in Example 1.
[0047] The results are summarised in Table 4.
[0048] 0.1% Magnesium stearate is sufficient for increasing in a
significant way (t=10.47, p<0.001) the fine particle dose, when
salbutamol base instead of sulphate is used; no increase is
obtained from increasing the concentration of magnesium stearate
above this percentage.
4TABLE 4 Delivered Fine Formulation Mg stearate Shot dose particle
dose* (200 .mu.g/dose) (%) weight (mg) Stage 2 (.mu.g) (.mu.g)
(Salbutamol %) SALB 1 0 22.4 (0.4) 62.7 (5.3) 185 (5.1) 33.6 (2.9)
SALB 2 0.1 26.8 (0.5) 71.3 (3.1) 171 (5.0) 41.8 (0.9) SALB 3 0.25
26.9 (0.2) 71.7 (6.1) 171 (1.7) 41.6 (3.2) SALB 4 0.5 26.5 (0.5)
68.7 (6.4) 172 (6.0) 39.9 (3.5)
EXAMPLE 3
[0049] Determination of the Suitable Amount of Magnesium Stearate
to be Added in Budesonide Powders for Inhalation
[0050] A sample of the carrier was prepared by mixing of
.alpha.-lactose monohydrate (Meggle D 30) fraction 90-150 .mu.m
with 0.25% magnesium stearate for two hours in Turbula-T100 mixer
at 16 r.p.m.
[0051] Powder mixtures containing 100 .mu.g/dose of micronised
budesonide were prepared by mixing of the carrier and the active
ingredient for 30 min in a Turbula mixer at 32 r.p.m.
[0052] The powder mixtures were filled into inhalers and tested as
reported in Example 1.
[0053] The results are summarised in Table 5.
[0054] 0.25% Magnesium stearate significantly increases the fine
particle dose of budesonide (t=8.8, p<0.001);
5TABLE 5 Fine particle Formulation Mg stearate Shot Delivered dose*
(.mu.g) (100 .mu.g/dose) (%) weight (mg) Stage 2 (.mu.g) dose
(Budesonide %) BUD 1 0 22.0 -- 80.0 21.4 (4.7) BUD 2 0.25 21.5 --
79.3 33.6 (2.6) *Average values obtained from three inhalers by
actuating 5 shots from each inhaler.
EXAMPLE 4
[0055] Preparation of the Carrier--Study of the Mixing
Conditions
[0056] 40.528 kg (99.75% w/w) of a-Lactose monohydrate fraction
90-150 .mu.m and 0.102 kg (0.25% w/w) of magnesium stearate were
mixed in a Turbula mixer T 100 at 16 r.p.m. for several hours. At
different mixing times samples were withdrawn and tested for
uniformity of distribution of magnesium stearate, particle size,
water contact angle and degree of molecular surface coating
calculated according to Cassie et al. (Transactions of the Faraday
Society 40; 546, 1944). To validate the process, three batches (40
kg) of the carrier were prepared.
[0057] The results are reported in Tables 6 and 7,
respectively.
[0058] A uniform distribution of magnesium stearate was already
achieved at 60 minutes blending time (mean value, {overscore (x)},
and coefficient of variation, CV %, are given); no significant
change in the particle size was observed after both Malvern
light-scattering and Alpine sieving analyses. By increasing the
mixing time, an increase of the degree of coating occurs.
[0059] The three different batches give comparable results.
6TABLE 6 Particle size Particle size Mg stearate Water contact
Degree of Time Alpine Malvern uniformity angle coating min % <
80.mu. % < 90.mu. % < 80.mu. % < 90.mu. {overscore (x)} %
CV % degree % 10' -- -- -- -- -- -- 34 15 20' -- .sub.-- -- -- --
-- 36 17 30' 1.5 4.8 0.9 2.7 0.228 6.8 36 17 60' 0.3 2.8 0.9 2.6
0.235 6.1 36 17 90' 0.6 3.8 1.0 2.9 0.244 3.7 37 18 120' 0.7 3.4
0.9 2.7 0.239 7.2 39 20 180' 0.8 4.2 0.8 2.6 0.246 2.9 46 29 240'
1.4 6.3 0.8 2.6 -- -- 48 32 300' 0.7 6.6 0.9 2.6 -- -- 50 34 360'
0.7 7.0 1.0 2.8 -- -- 51 36 420' 0.9 7.0 0.9 2.8 -- -- 51 36 480'
0.8 7.5 0.8 2.6 -- -- 51 36 .alpha.-Lactose monohydrate water
contact angle 12.degree. Magnesium stearate water contact angle
118.degree.
[0060]
7 TABLE 7 Magnesium Particle size Particle size stearate
Distribution Distribution content Water contact (Alpine) (Malvern)
uniformity angle Mixing Time % < 80.mu.m % < 90.mu.m % <
80.mu.m % < 90.mu.m x (%) CV (%) (degree) CARRIER 1 10 min 34 20
min 37 30 min 1.5 4.8 0.9 2.7 0.228 6.8 36 60 min 0.3 2.8 0.9 2.6
0.235 6.1 36 90 min 0.6 3.8 1.0 2.9 0.244 3.7 37 120 min 0.7 3.4
0.9 2.7 0.239 7.2 39 CARRIER 2 10 min 32 20 min 36 30 min 38 60 min
0.9 7.2 1.0 3.1 0.196 9.6 38 90 min 40 120 min 1.5 8.1 1.1 3.3
0.231 10.4 42 CARRIER 3 10 min 32 20 min 31 30 min 33 60 min 0.8
6.9 2.0 4.5 0.237 7.3 38 90 min 42 120 min 0.8 7.3 1.8 4.2 0.229
3.8 42
EXAMPLE 6
[0061] Relationship Between Different Mixing Time of the Carrier
and Delivered Fine Particle Dose
[0062] 40.528 kg (99.75% w/w) of .alpha.-Lactose monohydrate
fraction 90-150 .mu.m and 0.102 kg (0.25% w/w) of magnesium
stearate were mixed for several hours in Turbula T100 mixer at 16
r.p.m. At different mixing times, 2 kg samples were withdrawn and
micronised BDP was added to each sample so that the nominal weight
delivered by Pulvinal.RTM. inhaler contained 200 .mu.g BDP. The
powder mixtures were filled into inhalers and tested as reported in
Example 1.
[0063] The results are reported in Table 8.
[0064] By increasing the mixing time, a significant increase at 420
min of the fine particle dose occurs (t=5.2, p<0.001).
8TABLE 8 Formulation (BDP 200 .mu.g/dose) BDP 1 BDP 2 BDP 3 Mixing
time (min) 60 120 420 Shot weight (mg) 27.8 (0.6) 28.1 (0.7) 28.2
(0.5) Fine particle dose* (%) 34.1 (81) 37.4 (4.7) 49.5 (7.8) Stage
2 (.mu.g) 63.1 (12.0) 63.5 (8.1) 102.6 (17.1) Delivered dose
(.mu.g) 188.4 (21.1) 169.7 (7.1) 207.2 (9.0) *Average values
obtained from three inhalers by actuating 5 shots from each
inhaler
EXAMPLE 7
[0065] Preparation of the Carrier--Comparison Between Different
Mixers
[0066] 40.528 kg (99.75% w/w) of a-Lactose monohydrate fraction
90-150 .mu.m and 0.102 kg (0.25% w/w) of magnesium stearate were
mixed in a sigma-blade mixer for 30 min (water contact angle of
53.degree. corresponding to 26% of molecular coating)
[0067] Powder mixtures containing 200 .mu..mu.g/dose of micronised
BDP were prepared by mixing of the carrier and the active
ingredient for 30 min in a Turbula mixer at 32 r.p.m.
[0068] The powder mixtures were filled into inhalers and tested as
reported in Example 1.
[0069] The results are summarised in Table 9.
[0070] No significant difference was observed in the fine particle
dose with respect to the powder obtained with the carrier prepared
by using a Turbula mixer at 16 r.p.m. for 2 hours.
9TABLE 9 Fine Shot Stage particle Formulation weight 2 Delivered
dose (200 .mu.g/dose) (mg) (.mu.g) dose (.mu.g) (BDP %) Turbula
mixer 25.7 (2.8) 96.2 (7.6) 167.5 (5.7) 57.4 (4.3) Sigma-blade
mixer 26.6 (2.3) 106.2 (11.2) 192.1 (7.0) 55.2 (6.0)
EXAMPLE 8
[0071] Segregation Tendency of BDP Bulk Powder Formulation
Containing 0.25% Magnesium Stearate
[0072] Composition of BDP Pulvinal.RTM. (100, 200 and 400
.mu.g/dose):
10 Strength (.mu.g/dose) Ingredient (mg) 100 200 400 BDP 0.100
0.200 0.400 .alpha.-Lactose monohydrate 25.832 25.735 25.536
Magnesium stearate 0.067 0.064 0.064
[0073] The tendency of the powder to segregate was assessed
according to Staniforth et al. J. (Pharm. Pharmacol. 34, 700-706,
1982).
[0074] Approximately 15 g of powder was filled into a small plastic
cylinder, 80 mm long and 12 mm in diameter, closed at one end and
which could be split along its axis. This allowed the
characterisation of both BDP and magnesium stearate on the same
level in the same bulk mixture. The tube was mounted in a vibrator
(Derrinton VP4) and vibrated at 50 Hz at a force of 2 g for ten
minutes. The tube was then placed in a horizontal position, divided
and 15 samples, each of about 50 mg accurately weighed, taken from
along its length. The samples were analysed for BDP by HPLC and for
magnesium stearate by atomic absorption. The experiments were
carried out in duplicate. The results are reported in Tables 10 and
11.
[0075] Typical values in coefficient of variation (CV) of BDP
samples drawn from a mix judged to be satisfactory are
.ltoreq.5.0%. After the imposition of an enhanced gravitational
stress, BDP samples show a CV which varies from 2.7% and 7.8%.
Despite the intense vibration, these variations have not increased
significantly and are consistent with good inhaler performance when
judged in terms of dose uniformity. Samples taken from the top of
the bed are very similar to the bottom samples.
[0076] In the case of magnesium stearate, variability between
samples was somewhat greater than for BDP due to its lower
concentration. However, no consistent change in the uniformity of
distribution occurred after vibration and, as with BDP, the content
of samples drawn from the top of the bed were not different to
those drawn from the bottom. It can be concluded that the ordered
mix is very stable and no segregation of BDP and magnesium stearate
occurs.
11TABLE 10 DRUG ASSAY (.mu.g/mg) BDP BDP BDP 400 .mu.g/dose 200
.mu.g/dose 100 .mu.g/dose SAMPLE 1 2 1 2 1 2 Top of Cylinder 1 17.9
17.3 8.6 8.5 4.4 4.4 2 20.5 17.1 7.5 7.6 3.5 3.5 3 16.9 17.6 7.7
7.7 3.7 3.9 4 18.0 16.9 7.7 7.8 3.8 3.9 5 17.0 17.0 7.5 9.0 4.1 4.2
6 17.2 17.1 7.6 7.8 3.9 3.8 7 17.4 17.6 7.4 8.1 3.7 3.8 8 17.2 17.1
7.6 7.7 4.2 3.8 9 16.8 17.3 7.7 7.6 4.5 3.9 10 16.9 16.5 8.3 8.0
3.6 3.8 11 16.9 18.9 7.8 8.0 4.4 4.0 12 21.1 18.1 7.9 7.9 3.9 3.9
13 17.3 17.5 7.8 7.3 3.9 4.2 14 19.4 17.1 7.7 7.7 4.2 4.1 15 18.0
19.1 7.8 8.0 4.4 3.9 Bottom of Cylinder Mean 17.9 17.5 7.8 7.9 4.0
3.9 SD 1.4 0.8 0.2 0.4 0.3 0.2 CV (%) 7.6 4.3 2.7 5.0 7.8 4.7
[0077]
12 TABLE 11 MAGNESIUM ASSAY (.mu.g/mg) BDP 400 .mu.g/dose BDP 200
.mu.g/dose BDP 100 .mu.g/dose SAMPLE 1 2 UN-VIBRATED 1 2
UN-VIBRATED 1 2 UN-VIBRATED Top of cylinder 1 0.115 0.124 0.101
0.101 0.092 0.125 0.082 0.076 0.103 2 0.116 0.122 0.103 0.105 0.091
0.121 0.105 0.073 0.150 3 0.114 0.123 0.107 0.108 0.093 0.125 0.096
0.091 0.104 4 0.113 0.119 0.109 0.100 0.093 0.118 0.107 0.085 0.101
5 0.114 0.126 0.110 0.115 0.089 0.135 0.094 0.083 0.110 6 0.108
0.108 0.107 0.103 0.100 0.208 0.098 0.080 0.109 7 0.111 0.113 0.110
0.111 0.096 0.107 0.104 0.114 0.109 8 0.118 0.108 0.108 0.107 0.096
0.101 0.102 0.076 0.102 9 0.107 0.104 0.106 0.106 0.094 0.102 0.099
0.082 0.103 10 0.113 0.119 0.107 0.094 0.097 0.101 0.104 0.081
0.109 11 0.114 0.120 0.109 0.091 0.094 0.096 0.090 0.086 0.105 12
0.116 0.117 0.105 0.083 0.093 0.098 0.100 0.084 0.107 13 0.112
0.101 0.103 0.114 0.077 0.100 0.092 0.079 0.104 14 0.115 0.104
0.107 0.081 0.095 0.097 0.091 0.072 0.107 15 0.106 0.097 0.102
0.080 0.076 0.100 0.086 0.085 0.105 Bottom of Cylinder Mean 0.113
0.114 0.106 0.100 0.092 0.116 0.097 0.083 0.109 SD 0.003 0.009
0.003 0.012 0.007 0.028 0.007 0.010 0.012 (CV %) 3.1 8.2 2.7 11.6
7.3 24.6 7.6 12.0 10.9
EXAMPLE 9
[0078] Fine Particle Delivery of Magnesium Stearate
[0079] A batch of BDP 400 .mu.g/shot powder was prepared by mixing
of the drug and the carrier (lactose/magnesium stearate 99.75/0.25%
w/w) under the conditions reported in Example 1. Devices were
filled with the mixture and the fine particle delivery of magnesium
stearate was determined using a TSI apparatus. The results are
reported in Table 12.
13 TABLE 12 Shot weight Total Mg Total Mg Mg stearate (mg) stearate
(%) stearate (.mu.g) stage 2 (.mu.g) Mean 26.4 0.259 68 19 S.D.
0.31 0.017 4.18 2.39 CV % 1.18 6.52 6.13 12.5
[0080] Considering the low concentration of magnesium stearate in
the formulation and the quantity found in stage 2 of TSI, the
amount to be respirable will be very low.
[0081] This amount has been demonstrated to be safe after toxicity
studies in dog.
[0082] Furthermore, acute and long term tolerance trials were
carried out to evaluate toxicity of magnesium stearate in
humans.
[0083] In the former, 18 healthy volunteers, included in a double
blind randomised controlled cross-over design study, received a
single dose containing 25.72 mg of lactose and 0.065 mg of
magnesium stearate via Pulvinal.RTM. inhaler. The introduction of
0.25% magnesium stearate in powdery pharmaceutical formulation
resulted to be safe.
[0084] In the long term randomised, controlled, parallel group
study, the safety of magnesium stearate as a carrier was compared
to that of lactose. 28 Mild asthmatic patients were treated for 3
months with 400 .mu.g BDP b.i.d. delivered either with
Pulvinal.RTM., containing 0.065 mg of magnesium stearate per dose,
or another commercially available DPI, containing 25.536 mg of
lactose per dose. Bronchial biopsies and broncho-alveolar lavages
performed at the beginning and at the end of trial did not evidence
accumulation of magnesium in bronchi or in alveolar cells either in
Pulvinal.RTM. or control group.
* * * * *