U.S. patent number RE38,912 [Application Number 10/766,748] was granted by the patent office on 2005-12-06 for process for preparing powder formulations.
This patent grant is currently assigned to Boehringer Ingelheim Pharma KG. Invention is credited to Georg Boeck, Michael Walz.
United States Patent |
RE38,912 |
Walz , et al. |
December 6, 2005 |
Process for preparing powder formulations
Abstract
The invention relates to a new process for producing powdered
preparations for inhalation.
Inventors: |
Walz; Michael (Bingen,
DE), Boeck; Georg (Mainz, DE) |
Assignee: |
Boehringer Ingelheim Pharma KG
(Ingelheim, DE)
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Family
ID: |
26007343 |
Appl.
No.: |
10/766,748 |
Filed: |
January 28, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
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Reissue of: |
977911 |
Oct 11, 2001 |
06585959 |
Jul 1, 2003 |
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Foreign Application Priority Data
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Oct 12, 2000 [DE] |
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100 50 635 |
Aug 10, 2001 [DE] |
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101 38 022 |
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Current U.S.
Class: |
424/46; 424/434;
424/493; 424/435; 424/489 |
Current CPC
Class: |
A61K
31/439 (20130101); A61P 43/00 (20180101); A61P
11/00 (20180101); A61P 11/06 (20180101); A61K
9/145 (20130101); A61K 9/14 (20130101); A61K
9/0075 (20130101) |
Current International
Class: |
A61K 009/14 ();
A61K 009/16 (); A61L 009/04 (); A61F 013/02 () |
Field of
Search: |
;424/46,434,435,489,493 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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44 25 255 |
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Jan 1996 |
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DE |
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8.142 M |
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Aug 1970 |
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FR |
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WO93/11746 |
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Jun 1993 |
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WO |
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WO 93/11746 |
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Jun 1993 |
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WO |
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WO 95/11666 |
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May 1995 |
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WO |
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WO 95/24889 |
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Sep 1995 |
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WO |
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WO 00/28979 |
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May 2000 |
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WO |
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WO 00/47200 |
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Aug 2000 |
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WO |
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Other References
Derwent Abstract: AN 1966-36583F[00] WPIDS (French Patent 8.142M;
Fisons Pharm. Ltd). .
Bechtold-Peters, K. et al; "Inhalable Powder Containing
Tiotropium"; U.S. Appl. No. 09/975,418; Nov. 11, 2001..
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Primary Examiner: Azpuru; Carlos A.
Attorney, Agent or Firm: Morris; Michael Small; Andrea D.
Devlin; MaryEllen M.
Parent Case Text
RELATED APPLICATIONS
Benefit of U.S. Provisional Application Serial No. 60/252,683,
filed on Nov. 22, 2000 is hereby claimed, and said Provisional
Application is herein incorporated by reference.
The invention relates to a new process for preparing powdered
preparations for inhalation.
Claims
We claim:
1. A process for preparing an inhalable powder, wherein N+m
substantially equal portions of an excipient having a larger
.Iadd.average .Iaddend.particle size .[.distribution.]. and N equal
portions of an active substance having a smaller .Iadd.average
.Iaddend.particle size .[.distribution.]. are added in alternate
layers into a suitable mixing vessel and after all the excipient
and active substance have been added the 2N+m layers of the two
components are mixed together using a suitable mixer, wherein a
portion of the excipient having the larger particle size is added
first, and wherein N is an integer >5 and m denotes 0 or
1..[.
2. A process according to claim 1, wherein N is an integer
>5..].
3. A process according to claim 1, characterised in that the
individual portions of excipient and active substance are added in
layers through a suitable screening apparatus.
4. A process according to claim 1, characterised in that m denotes
1.
5. A process according to claim 1, characterised in that the
inhalable powder obtained contains less than 5% of active
substance.
6. A process according to claim 5, characterised in that the
inhalable powder obtained contains less than 2% of active
substance.
7. A process according to claim 1, characterised in that the active
substance has a.Iadd.n average .Iaddend.particle size of from 0.5
to 10 .mu.m.
8. A process according to claim 7, characterised in that the active
substance has a.Iadd.n average .Iaddend.particle size of from 1 to
6 .mu.m.
9. A process according to claim 1, characterised in that the
excipient has a.Iadd.n average .Iaddend..[.mean.]. particle size of
from 10 to 100 .mu.m.
10. A process according to claim 9, characterised in that the
excipient has a.Iadd.n average .Iaddend..[.mean.]. particle size of
from 15 to 80 .mu.m.
11. A process according to claim 1, wherein the excipient is a
single excipient or a mixture of different excipients.
12. A process according to claim 1, characterised in that the
excipient consists of a mixture of coarser excipient with an
average particle size of 15 to 80 .mu.m and finer excipient with an
average particle size of 1 to 9 .mu.m, the proportion of finer
excipient constituting 1 to 20% of the total amount of
excipient.
13. A process according to claim 1, wherein the active substance is
a single active substance or two or more different active
substances.
14. A process according to claim 1, characterised in that the
active substance consists of one or more compounds selected from
among the betamimetics, anticholinergics, corticosteroids and
dopamine agonists.
15. An inhalable powder obtained by the process according to claim
1..Iadd.
16. The process according to claim 1 wherein the active substance
is selected from the group consisting of betamimetics,
anticholinergics, corticosteroids, dopamine agonists, and
pharmaceutically acceptable salts, solvates or hydrates thereof,
and mixtures thereof..Iaddend..Iadd.
17. The process according to claim 16 wherein the active substance
consists of an anticholinergic compound or its pharmaceutically
acceptable solvate, hydrate or salt..Iaddend..Iadd.
18. The process according to claim 17 wherein the anticholinergic
compound comprises tiotropium..Iaddend..Iadd.
19. The process according to claim 17 wherein the pharmaceutically
acceptable salt of the anticholinergic compound comprises
tiotropium bromide..Iaddend..Iadd.
20. The process according to claim 17 wherein the pharmaceutically
acceptable solvate or hydrate of the anticholinergic compound
comprises tiotropium bromide monohydrate..Iaddend..Iadd.
21. The process according to claim 1 wherein the excipient is
selected from the group consisting of monosaccharides,
disaccharides, oligosaccharides, polysaccharides, polyalcohols,
salts, and mixtures thereof, each optionally in its hydrate
forms..Iaddend..Iadd.
22. The process according to claim 21 wherein the excipient
consists of a monosaccharide or a disaccharide, or a combination
thereof..Iaddend..Iadd.
23. The process according to claim 21 wherein the excipient
consists of glucose or lactose or a combination thereof, each
optionally in its hydrate form..Iaddend..Iadd.
24. The process according to claim 22 wherein the excipient
consists of a disaccharide..Iaddend..Iadd.
25. The process according to claim 23 wherein the excipient
consists of lactose or lactose monohydrate..Iaddend..Iadd.
26. The inhalable powder according to claim 15 wherein the active
substance is selected from the group consisting of betamimetics,
anticholinergics, corticosteroids, dopamine agonists, and
pharmaceutically acceptable salts, solvates or hydrates thereof,
and mixtures thereof..Iaddend..Iadd.
27. The inhalable powder according to claim 26 wherein the active
substance consists of an anticholinergic compound or its
pharmaceutically acceptable solvate, hydrate or
salt..Iaddend..Iadd.
28. The inhalable powder according to claim 27 wherein the
anticholinergic compound consists of tiotropium..Iaddend..Iadd.
29. The inhalable powder according to claim 27 wherein the
pharmaceutically acceptable salt of the anticholinergic compound
consists of tiotropium bromide..Iaddend..Iadd.
30. The inhalable powder according to claim 27 wherein the
pharmaceutically acceptable solvate or hydrate of the
anticholinergic compound consists of tiotropium bromide
monohydrate..Iaddend..Iadd.
31. The inhalable powder according to claim 1 wherein the excipient
is selected from the group consisting of monosaccharides,
disaccharides, oligosaccharides, polysaccharides, polyalcohols,
salts, and mixtures thereof, each optionally in its hydrate
form..Iaddend..Iadd.
32. The inhalable powder according to claim 31 wherein the
excipient consists of a monosaccharide or a disaccharide or a
combination thereof..Iaddend..Iadd.
33. The inhalable powder according to claim 32 wherein the
excipient consists of glucose or lactose or combinations thereof,
each optionally in its hydrate form..Iaddend..Iadd.
34. The inhalable powder according to claim 32 wherein the
excipient consists of a disaccharide..Iaddend..Iadd.
35. The inhalable powder according to claim 33 wherein the
excipient consists of lactose or lactose monohydrate..Iaddend.
Description
BACKGROUND OF THE INVENTION
treating a number of complaints, particularly respiratory diseases,
it is useful to administer the active substance by inhalation. In
addition to the administration of therapeutically active compounds
in the form of metered aerosols and inhalable solutions, the use of
inhalable powders containing active substance is of particular
importance.
With active substances which have a particularly high efficacy,
only small amounts of the active substance are needed per single
dose to achieve the desired therapeutic effect. In such cases, the
active substance has to be diluted with suitable excipients in
order to prepare the inhalable powder. Because of the large amount
of excipient, the properties of the inhalable powder are critically
influenced by the choice of excipient.
In powder mixture technology, it is conventional to use mixing
processes based on the dilution method. All the active substance is
used and then excipient is added in proportions of 1:1, 1:2 or 1:4
and they are mixed together. More excipient is then added to the
resulting mixtures in comparable proportions. This procedure is
usually repeated until all the excipient has been added. The
drawback of this type of procedure it that is some cases there are
problems of homogeneity. These arise particularly with mixtures in
which the substances have a widely varying spectrum of particle
sizes. This is particularly apparent in powder mixtures in which
the substance having the smaller particle size distribution, the
active substance, makes up only a very small proportion of the
total amount of powder.
The problem of the present invention is therefore to provide a
process which can be used to produce inhalable powders
characterised by a high degree of homogeneity in the sense of a
uniformity of content.
DETAILED DESCRIPTION OF THE INVENTION
It was found that, surprisingly, the problem outlined above can be
solved by means of a process in which the substance with the
smaller particle size distribution can be added to the substance
with the coarser particle size distribution by a layered mixing
process.
The process according to the invention for preparing inhalable
powders is characterised in that N+m substantially equal portions
of the substance having a larger particle size distribution and N
equal portions of the substance having a smaller particle size
distribution are placed in alternate layers in a suitable mixing
vessel and after they have all been added the 2N+m layers of the
two components are mixed together using a suitable mixer, a portion
of the substance having the larger particle size being put in
first, while N is an integer >0, preferably >5, and m denotes
0 or 1.
Preferably, the individual fractions are added in layers through a
suitable screening apparatus. If desired, once the mixing process
is finished, the entire powder mixture can be subjected to one or
more additional screening processes. In the process according to
the invention, N is naturally dependent inter alia on the total
quantity of powder mixture to be produced. When producing smaller
batches, the desired effect of high homogeneity in the sense of
uniformity of content can be achieved with a smaller N. In
principle, it is preferable according to the invention if N is at
least 10 or more, more preferably 20 or more, better still 30 or
more. The greater N is and, as a result, the greater the total
number of layers of the powder fractions formed, the more
homogeneous the powder mixture becomes in the sense of uniformity
of content.
The number m may represent 0 or 1 within the scope of the process
according to the invention. If m denotes 0 the last fraction added
to the mixing apparatus, preferably screened into it, in a layer is
the last portion of the substance with a smaller particle size
distribution. If m represents the number 1, the last fraction added
to the mixing apparatus, preferably screened into it, in a layer is
the last portion of the substance with a larger particle size
distribution. This may prove advantageous inasmuch as, when m=1,
any residues of the last fraction of the substance with the finer
particle size distribution still remaining in the screening unit
can be carried into the mixing unit by means of the last portion of
excipient.
Within the scope of the present invention, unless otherwise
defined, the substance with the smaller particle size distribution,
which is very finely ground and is present in the resulting powder
formulation in a very small proportion by mass, represents the
active substance. Within the scope of the present invention, unless
otherwise defined, the substance with the larger particle size
distribution, which is coarsely ground and is present in the
resulting powder formulation in a large proportion by mass,
represents the excipient.
The present invention relates in particular to a process for
preparing inhalable powders containing less than 5%, preferably
less than 2%, most preferably less than 1% of active substance
mixed with a physiologically acceptable excipient. A preferred
process according to the invention is a process for preparing
inhalable powders containing 0.04 to 0.8%, most preferably 0.08 to
0.64%, better still 0.16 to 0.4% of active substance mixed with a
physiologically acceptable excipient.
The active substance used according to the invention preferably has
an average particle size of 0.5 to 10 .mu.m, preferably 1 to 6
.mu.m, most preferably 2 to 5 .mu.m. The excipient which may be
used in the process according to the invention preferably has an
average particle size of 10 to 100 .mu.m, preferably 15 to 80
.mu.m, most preferably 17 to 50 .mu.m. Particularly preferred
according to the invention are processes for preparing inhalable
powders wherein the excipient has an average particle size of 20-30
.mu.m.
The two components are preferably added through a screening
granulator with a mesh size of 0.1 to 2 mm, most preferably 0.3 to
1 mm, even more preferably 0.3 to 0.6 mm.
Preferably, the first portion of the N+m portions of the excipient
is put in first, and then the first portion of the N portions of
the active substance is placed in the mixing container. Whereas
within the scope of the process according to the invention the
individual components are normally added in roughly equal portions,
it may be advantageous in some cases if the first of the N+m
portions of excipient which is put into the mixing apparatus has a
larger volume than the subsequent portions of excipient.
Preferably, the two components are added alternately through a
screening unit and in more than 20, preferably more than 25, most
preferably more than 30 layers. For example, with a desired total
amount of powder of 30-35 kg containing 0.3-0.5% of active
substance, for example, and using common excipients, the two
components can be screened in in about 30 to 60 layers each
(N=30-60). The upper limit of 60 layers mentioned above is given
purely from the point of view of economy of the process. It should
not be regarded in any way as restricting the number of possible
layers according to the invention. As will be clearly apparent to
anyone skilled in the art, the process can equally well be carried
out with N>60 to achieve the desired effect of the maximum
possible homogeneity of the powder mixture.
In some cases the excipient may also consist of a mixture of
coarser excipient with an average particle size of 15 to 80 .mu.m
and finer excipient with an average particle size of 1 to 9 .mu.m,
wherein the proportion of finer excipient in the total quantity of
excipient may be 1 to 20%. If the inhalable powders which may be
produced using the process according to the invention contain a
mixture of coarser and finer excipient fractions, it is preferable
according to the invention to prepare inhalable powders wherein the
coarser excipient has an average particle size of 17 to 50 .mu.m,
most preferably 20 to 30 .mu.m, and the finer excipient has an
average particle size of 2 to 8 .mu.m, most preferably 3 to 7
.mu.m. By average particle size is meant here the 50% value of the
volume distribution measured with a laser diffractometer using the
dry dispersion method. In the case of an excipient mixture of
coarser and finer excipient fractions, the preferred processes
according to the invention are those that produce inhalable powders
in which the proportion of finer excipient constitutes 3 to 15%,
most preferably 5 to 10% of the total amount of excipient.
The percentages given within the scope of the present invention are
always percent by weight.
If the excipient used is one of the abovementioned mixtures of
coarser excipient and finer excipient, it is again expedient
according to the invention to produce the excipient mixture using
the process according to the invention from N roughly equal
portions of the finer excipient fraction with N+m roughly equal
portions of the coarser excipient fraction. In such a case it is
advisable first to generate the abovementioned excipient mixture
from the abovementioned excipient fractions, and then to produce
from it the total mixture including the active substance using the
process according to the invention.
For example, the excipient mixture may be obtained as follows,
using the process according to the invention. The two components
are preferably added through a screening granulator with a mesh
size of 0.1 to 2 mm, most preferably 0.3 to 1 mm, even more
preferably 0.3 to 0.6 mm. Preferably the first fraction of the N+m
portions of the coarser excipient is put in first and then the
first portion of the N portions of the finer excipient fraction is
added to the mixing container. The two components are added
alternately by screening them in in layers.
After the preparation of the excipient mixture, the inhalable
powder is produced from the mixture and the desired active
substance using the process according to the invention. The two
components are preferably added through a screening granulator with
a mesh size of 0.1 to 2 mm, most preferably 0.3 to 1 mm, even more
preferably 0.3 to 0.6 mm.
Preferably, the first portion of the N+m portions of the excipient
mixture is put in and then the first portion of the N portions of
the active substance is added to the mixing container. The two
components are preferably added through a screening unit in
alternate layers, in more than 20, preferably more than 25, most
preferably more than 30 layers. For example, with a desired total
amount of powder of 30-35 kg containing 0.3-0.5% of active
substance, for example, and using common excipients, the two
components can be screened in in about 30 to 60 layers each
(N=30-60). As will be clearly apparent to anyone skilled in the
art, the process can equally well be carried out with N>60 to
achieve the desired effect of the maximum possible homogeneity of
the powder mixture. The inhalable powders which may be obtained
using the method of preparation according to the invention may
contain, in general, any active substances which may reasonably be
administered by inhalation for therapeutic purposes. Preferably,
the active substances used are selected, for example, from among
the betamimetics, anticholinergics, corticosteroids and dopamine
agonists.
Example of betamimetics which may be used are preferably compounds
selected from among bambuterol, bitolterol, carbuterol,
clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol,
pirbuterol, procaterol, reproterol, salmeterol, sulphonterol,
terbutaline, tulobuterol, mabuterol,
4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl
]-2(3H)-benzothiazolone,
1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino
]ethanol,
1-[3-(4-methoxybenzylamino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-met
hyl-2-butylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophe
nyl)-2-methyl-2-propylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-met
hyl-2-propylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-
methyl-2-propylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,
2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol,
5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-on,
1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.butylamino)ethanol
and 1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.
butylamino)ethanol, optionally in the form of their racemates,
their enantiomers, their diastereomers, as well as optionally their
pharmacologically acceptable acid addition salts and hydrates. It
is particularly preferable to use, as betamimetics, active
substances of this kind selected from among fenoterol, formoterol,
salmeterol, mabuterol,
1-[3-(4-methoxybenzylamino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-met
hyl-2-butylamino]-ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophe
nyl)-2-methyl-2-propylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-met
hyl-2-propylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-
methyl-2-propylamino]ethanol,
1-[2H-5-hydroxy-3-oxo-4II-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1
,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol, optionally in the
form of their racemates, their enantiomers, their diastereomers, as
well as optionally their pharmacologically acceptable acid addition
salts and hydrates. Of the betamimetics mentioned above, the
compounds formoterol and salmeterol, optionally in the form of
their racemates, their enantiomers, their diastereomers, as well as
optionally their pharmacologically acceptable acid addition salts
and hydrates, are particularly important.
The acid addition salts of the betamimetics selected from among the
hydrochloride, hydrobromide, sulphate, phosphate, fumarate,
methanesulphonate and xinafoate are preferred according to the
invention. In the case of salmeterol, the salts selected from among
the hydrochloride, sulphate and xinafoate are particularly
preferred, especially the sulphates and xinafoates. Of outstanding
importance according to the invention are
salmeterol.times.1/2II.sub.2 SO.sub.4 and salmeterol xinafoate. In
the case of formoterol, the salts selected from among the
hydrochloride, sulphate and fumarate are particularly preferred,
especially the hydrochloride and fumarate. Of outstanding
importance according to the invention is formoterol fumarate.
Anticholinergics which may be used in the processes according to
the invention are preferably salts selected from among tiotropium
salts, oxitropium salts and ipratropium salts, of which tiotropium
and ipratropium salts are particularly preferred. In the
abovementioned salts the cations tiotropium, oxitropium and
ipratropium are the pharmacologically active ingredients. By the
salts which may be used within the scope of the present invention
are meant the compounds which contain, in addition to tiotropium,
oxitropium or ipratropium as counter-ion (anion) chloride, bromide,
iodide, sulphate, methanesulphonate or para-toluenesulphonate.
Within the scope of the present invention, of all the salts of the
abovementioned anticholinergics, the methanesulphonate, chloride,
bromide and iodide are preferred, the methanesulphonate or bromide
being especially preferred. Of outstanding importance according to
the invention are the anticholinergics selected from among
tiotropium bromide, oxitropium bromide and ipratropium bromide.
Tiotropium bromide is particularly preferred. The abovementioned
anticholinergics may optionally occur in the form of their solvates
or hydrates. In the case of tiotropium bromide, for example,
tiotropium bromide monohydrate is particularly important according
to the invention.
Within the scope of the present invention, the term corticosteroids
denotes compounds selected from among flunisolide, beclomethasone,
triamcinolone, budesonide, fluticasone, mometasone, ciclesonide,
rofleponide, GW 215864, KSR 592, ST-126 and dexamethasone. The
preferred corticosteroids within the scope of the present invention
are those selected from among flunisolide, beclomethasone,
triamcinolone, budesonide, fluticasone, mometasone, ciclesonide and
dexamethasone, while budesonide, fluticasone, mometasone and
ciclesonide, especially budesonide and fluticasone, are of
particular importance. The term steroids may be used on its own,
within the scope of the present patent application, instead of the
term corticosteroids. Any reference to steroids within the scope of
the present invention also includes a reference to salts or
derivatives which may be formed from the steroids. Examples of
possible salts or derivatives include: sodium salts,
sulphobenzoates, phosphates, isonicotinates, acetates, propionates,
dihydrogen phosphates, palmitates, pivalates or furoates. The
corticosteroids may optionally also be in the form of their
hydrates.
Within the scope of the present invention, the term dopamine
agonists denotes compounds selected from among bromocriptine,
cabergolin, alpha-dihydroergocryptine, lisuride, pergolide,
pramipexol, roxindol, ropinirol, talipexol, tergurid and viozan. It
is preferable within the scope of the present invention to use
dopamine agonists selected from among pramipexol, talipexol and
viozan, pramipexol being of particular importance. Any reference to
the abovementioned dopamine agonists also includes, within the
scope of the present invention, a reference to any
pharmacologically acceptable acid addition salts and hydrates
thereof which may exist. By the physiologically acceptable acid
addition salts thereof which may be formed by the abovementioned
dopamine agonists are meant, for example, pharmaceutically
acceptable salts selected from among the salts of hydrochloric
acid, hydrobromic acid, sulphuric acid, phosphoric acid,
methanesulphonic acid, acetic acid, fumaric acid, succinic acid,
lactic acid, citric acid, tartaric acid and maleic acid.
The process according to the invention for preparing powder
mixtures for inhalation may be used to prepare powders which
contain one or more of the abovementioned active ingredients. If,
for example, inhalable powders are to be prepared in which the
pharmaceutically active ingredients consist of two different active
substances, this can be achieved using the process according to the
invention, for example, by screening N+m roughly equal portions of
excipient or excipient mixture with O roughly equal portions of one
active substance component and P roughly equal portions of the
other active substance component into the mixing apparatus in
alternate layers. The number of fractions P and O may be selected,
for example, so that P+O=N. If the process according to the
invention is to be used to prepare inhalable powders which contain
two active ingredients, for example, preferred possible
combinations of active substances might consist of a combination of
one of the abovementioned anticholinergics with one of the
abovementioned corticosteroids or a combination of one of the
abovementioned anticholinergics with one of the abovementioned
betamimetics.
Examples of physiologically acceptable excipients which may be used
to prepare the inhalable powders according to the invention
include, for example, monosaccharides (e.g. glucose or arabinose),
disaccharides (e.g. lactose, saccharose, maltose), oligo- and
polysaccharides (e.g. dextrane), polyalcohols (e.g. sorbitol,
mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate)
or mixtures of these excipients with one another. Preferably, mono-
or disaccharides are used, while the use of lactose or glucose is
preferred, particularly, but not exclusively, in the form of their
hydrates. For the purposes of the invention, lactose is the
particularly preferred excipient, while lactose monohydrate is most
particularly preferred.
The inhalable powders which may be obtained by the preparation
process according to the invention are characterised by an
exceptional degree of homogeneity in terms of uniformity of
content. This is in a range of <8%, preferably <6%, most
preferably <4%. The inhalable powders which may be prepared
according to the invention may possibly even have levels of
homogeneity, in the sense of single dose accuracy, of <3%,
possibly <2%. Thus, in a further aspect, the present invention
relates to inhalable powders as such which may be obtained by the
preparation process according to the invention.
The inhalable powders which may be obtained by the process
according to the invention may for example be administered using
inhalers which meter a single dose from a reservoir by means of a
measuring chamber (e.g. according to U.S. Pat. No. 4,570,630A) or
by other means (e.g. according to DE 36 25 685 A). Preferably,
however, the inhalable powders which may be obtained according to
the invention are packed into capsules (to make so-called
inhalettes), which are used in inhalers such as those described in
WO 94/28958, for example. If the inhalable powder obtained by the
process according to the invention is to be packed into capsules
(inhalettes) in accordance with the preferred application mentioned
above, it is advisable to fill the capsules with amounts of from 3
to 10 mg, preferably from 4 to 6 mg of inhalable powder per
capsule, this amount depending to a large extent on the choice of
active substance used. In the case of the active substance
tiotropium bromide, the capsules contain between 1.2 and 80 .mu.g
of tiotropium cation, for the amounts of filling mentioned above.
With a filling of 4 to 6 mg of inhalable powder per capsule, the
preferred amount for tiotropium bromide, the content of tiotropium
per capsule is between 1.6 and 48 .mu.g, preferably between 3.2 and
38.4 .mu.g, most preferably between 6.4 and 24 .mu.g. A content of
18 .mu.g of tiotropium, for example, corresponds to a content of
about 21.7 .mu.g of tiotropium bromide.
Consequently, capsules containing 3 to 10 mg of powder for
inhalation preferably hold between 1.4 and 96.3 .mu.g of tiotropium
bromide, according to the invention. When the filling is from 4 to
6 mg of inhalable powder per capsule, as is preferred, each capsule
contains between 1.9 and 57.8 .mu.g, preferably between 3.9 and
46.2 .mu.g, most preferably between 7.7 and 28.9 .mu.g of
tiotropium bromide. A content of 21.7 .mu.g of tiotropium bromide,
for example, corresponds to a content of about 22.5 .mu.g of
tiotropium bromide monohydrate.
Consequently, capsules containing 3 to 10 mg of powder for
inhalation preferably hold between 1.5 and 100 .mu.g of tiotropium
bromide monohydrate. When the filling is from 4 to 6 mg of
inhalable powder per capsule, as is preferred, each capsule
contains between 2 and 60 .mu.g, preferably between 4 and 48 .mu.g,
most preferably between 8 and 30 .mu.g of tiotropium bromide
monohydrate.
The Examples which follow describe a possible method of carrying
out the process according to the invention, taking a powder mixture
containing tiotropium bromide monohydrate as the example. The fact
that this process described by way of example can be used directly
for preparing inhalable powders which contain one or more of the
other active substances mentioned above will be apparent to anyone
skilled in the art. Accordingly, the following Examples serve only
to illustrate the present invention further without restricting its
scope to the embodiments provided hereinafter by way of
example.
Starting Materials
In the Examples which follow, lactose-monohydrate (200M) is used as
the coarser excipient. It may be obtained, for example, from Messrs
DMV International, 5460 Veghel/NL under the product name Phannatose
200M.
In the Examples which follow, lactose-monohydrate (5.mu.) is used
as the finer excipient. It may be obtained from lactose-monohydrate
200M by conventional methods (micronising). Lactose-monohydrate
200M may be obtained, for example, from Messrs DMV International,
5460 Veghel/NL under the product name Pharmatose 200M.
Preparation of Tiotropium Bromide Monohydrate:
15.0 kg of tiotropium bromide, which may be prepared as disclosed
in EP 418 716 A1, are added to 25.7 kg of water in a suitable
reaction vessel. The mixture is heated to 80-90.degree. C. and
stirred at constant temperature until a clear solution is formed.
Activated charcoal (0.8 kg), moistened with water, is suspended in
4.4 kg of water, this mixture is added to the solution containing
the tiotropium bromide and rinsed with 4.3 kg of water. The mixture
thus obtained is stirred for at least 15 min at 80-90.degree. C.
and then filtered through a heated filter into an apparatus which
has been preheated to an outer temperature of 70.degree. C. The
filter is rinsed with 8.6 kg of water. The contents of the
apparatus are cooled at 3-5.degree. C. every 20 minutes to a
temperature of 20-25.degree. C. The apparatus is further cooled to
10-15.degree. C. using cold water and crystallisation is completed
by stirring for at least one hour. The crystals are isolated using
a suction drier, the crystal slurry isolated is washed with 9
liters of cold water (10-15.degree. C.) and cold acetone
(10-15.degree. C.). The crystals obtained are dried in a nitrogen
current at 25.degree. C. over 2 hours. Yield: 13.4 kg of tiotropium
bromide monohydrate (86% of theory)
The crystalline tiotropium bromide monohydrate thus obtained is
micronised by known methods, to bring the active substance into the
average particle size which meets the specifications according to
the invention.
For the purposes of the present invention, the average particle
size is the value in .mu.m at which 50% of the particles from the
volume distribution have a particle size which is smaller than or
equal to the value specified. The laser diffraction/dry dispersal
method of measurement is used to determine the total distribution
of the particle size distribution.
The method of determining the average particle size of the various
ingredients of the formulation according to the invention is
described as follows. A) Determining the Particle Size of Finely
Divided Lactose: Measuring Equipment and Settings:
The equipment is operated according to the manufacturer's
instructions.
Measuring equipment: HELOS Laser-diffraction spectrometer
(SympaTec) Dispersing unit: RODOS dry disperser with suction
funnel, (SympaTec) Sample quantity: from 100 mg Product feed: Vibri
Vibrating channel, Messrs. Sympatec Frequency of vibrating channel:
40 rising to 100% Duration of sample feed: 1 to 15 sec. (in the
case of 100 mg) Focal length: 100 mm (measuring range: 0.9-175
.mu.m) Measuring time: about 15 s (in the case of 100 mg) Cycle
time: 20 ms Start/stop at: 1% on channel 28 Dispersing gas:
compressed air Pressure: 3 bar Vacuum: maximum Evaluation method:
HRLD
Sample Preparation/Product Feed:
At least 100 mg of the test substance are weighed onto a piece of
card. Using another piece of card all the larger lumps are broken
up. The powder is then sprinkled finely over the front half of the
vibrating channel (starting about 1 cm from the front edge). After
the start of the measurement the frequency of the vibrating channel
is varied from about 40% up to 100% (towards the end of the
measurement). The time taken to feed in the entire sample is 10 to
15 sec.
Determining the Particle Size of Micronised Tiotropium Bromide
Monohydrate:
Measuring Equipment and Settings:
The equipment is operated according to the manufacturer's
instructions.
Measuring equipment: Laser diffraction spectrometer (HELOS),
Sympatec Dispersing unit: RODOS dry disperser with suction funnel,
Sympatec Sample quantity: 50 mg-400 mg Product feed: Vibri
Vibrating channel, Messrs. Sympatec Frequency of vibrating channel:
40 rising to 100% Duration of sample feed: 15 to 25 sec. (in the
case of 200 mg) Focal length: 100 mm (measuring range: 0.9-175
.mu.m) Measuring time: about 15 s (in the case of 200 mg) Cycle
time: 20 ms Start/stop at: 1% on channel 28 Dispersing gas:
compressed air Pressure: 3 bar Vacuum: maximum Evaluation method:
HRLD
Sample Preparation/Product Feed:
About 200 mg of the test substance are weighed onto a piece of
card. Using another piece of card all the larger lumps are broken
up. The powder is then sprinkled finely over the front half of the
vibrating channel (starting about 1 cm from the front edge). After
the start of the measurement the frequency of the vibrating channel
is varied from about 40% up to 100% (towards the end of the
measurement). The sample should be fed in as continuously as
possible. However, the amount of product should not be so great
that adequate dispersion cannot be achieved. The time over which
the entire sample is fed in is about 15 to 25 seconds for 200 mg,
for example. C) Determining the Particle Size of Lactose 200M:
Measuring Equipment and Settings:
The equipment is operated according to the manufacturer's
instructions.
Measuring equipment: Laser diffraction spectrometer (HELOS),
Sympatec Dispersing unit: RODOS dry disperser with suction funnel,
Sympatec Sample quantity: 500 mg Product feed: Vibri Vibrating
channel, Messrs. Sympatec Frequency of vibrating channel: 18 rising
to 100% Focal length (1): 200 mm (measuring range: 1.8-350 .mu.m)
Focal length (2): 500 mm (measuring range: 4.5-875 .mu.m) Measuring
time: 10 s Cycle time: 10 ms Start/stop at: 1% on channel 19
Pressure: 3 bar Vacuum: maximum Evaluation method: HRLD
Sample Preparation/Product Feed:
About 500 mg of the test substance are weighed onto a piece of
card. Using another piece of card all the larger lumps are broken
up. The powder is then transferred into the funnel of the vibrating
channel. A gap of 1.2 to 1.4 mm is set between the vibrating
channel and funnel. After the start of the measurement the
amplitude setting of the vibrating channel is increased from 0 to
40% until a continuous flow of product is obtained. Then it is
reduced to an amplitude of about 18%. Towards the end of the
measurement the amplitude is increased to 100%.
Apparatus
The following machines and equipment, for example, may be used to
prepare the inhalable powders according to the invention:
Mixing container or Gysowbeel mixer 200 L; type: DFW80N-4; powder
mixer: made by: Messrs Engelsmann, D-67059 Ludwigsbafen.
Granulating sieve: Quadro Cosnil; type: 197-S; made by: Messrs
Joisten & Kettenbaum, D-51429 Bergisch-Gimdbach.
EXAMPLE 1
Depending on the choice of active substances, the following step
1.1 for preparing an excipient mixture may not be necessary. If the
desired powder mixture is to contain only excipient of a uniform
coarser particle size distribution in addition to the active
substance, the procedure may continue directly according to step
1.2.
1.1: Excipient Mixture:
31.82 kg of lactose monohydrate for inhalation (200M) are used as
the coarser excipient component, 1.68 kg of lactose monohydrate (5
.mu.m) are used as the finer excipient component. In the resulting
33.5 kg of excipient mixture the proportion of the finer excipient
component is 5%.
About 0.8 to 1.2 kg of lactose monohydrate for inhalation (200M)
are added to a suitable mixing container through a suitable
granulating sieve with a mesh size of 0.5 mm. Then alternate layers
of lactose monohydrate (5 .mu.m) in batches of about 0.05 to 0.07
kg and lactose monohydrate for inhalation (200M) in batches of 0.8
to 1.2 kg are sieved in. Lactose monohydrate for inhalation (200M)
and lactose monohydrate (5 .mu.m) are added in 31 and 30 layers,
respectively (tolerance: .+-.6 layers).
The ingredients sieved in are then mixed together with a gravity
mixer (mixing at 900 rpm).
1.2: Powder Mixture Containing Active Substance:
To prepare the final mixture, 32.87 kg of the excipient mixture
(1.1) and 0.13 kg of micronised tiotropium bromide monohydrate are
used. The content of active substance in the resulting 33.0 kg of
inhalable powder is 0.4%.
About 1.1 to 1.7 kg of excipient mixture (1.1) are added to a
suitable mixing container through a suitable granulating sieve with
a mesh size of 0.5 mm. Then alternate layers of tiotropium bromide
monohydrate in batches of about 0.003 kg and excipient mixture
(1.1) in batches of 0.6 to 0.8 kg are sieved in. The excipient
mixture and the active substances are added in 46 or 45 layers,
respectively (tolerance: .+-.9 layers).
The ingredients sieved in are then mixed together in a gravity
mixer (mixing at 900 rpm). The final mixture is passed through a
granulating sieve twice more and then mixed (mixing at 900
rpm).
EXAMPLE 2
Inhalation capsules (inhalettes) having the following composition
were produced using the mixture obtained according to Example
1:
tiotropium bromide monohydrate: 0.0225 mg lactose monohydrate (200
M): 5.2025 mg lactose monohydrate (5 .mu.m): 0.2750 mg hard
gelatine capsule: 49.0 mg Total: 54.5 mg
EXAMPLE 3
Inhalation capsules having the composition:
tiotropium bromide monohydrate: 0.0225 mg lactose monohydrate (200
M): 4.9275 mg lactose monohydrate (5 .mu.m): 0.5500 mg hard
gelatine capsule: 49.0 mg Total: 54.5 mg
The inhalable powder needed to prepare the capsules was obtained
analogously to Example 1.
EXAMPLE 4
Inhalation capsules having the composition:
tiotropium bromide monohydrate: 0.0225 mg lactose monohydrate (200
M): 5.2025 mg lactose monohydrate (5 .mu.m): 0.2750 mg polyethylene
capsule: 100.0 mg Total: 105.50 mg
The inhalable powder needed to prepare the capsules was obtained
analogously to Example 1.
* * * * *