Note: Descriptions are shown in the official language in which they were submitted.
1.
CA 02427583 2003-04-29
Case 1/1162 FF Boehringer lngelheim Pharma KG
1
76653fft.205
Inhalable formulation of a solution containing a tiotropium salt
The present invention relates to a propellant-free inhalable formulation of a
pharmaceutically acceptable salt of tiotropium dissolved in water or a mixture
of
water and ethanol, in conjunction with at least one other active substance
preferably
administered by inhalation, and propellant-free inhalable aerosols resulting
.therefrom. The formulation according to the invention is particularly
suitable for
administering the active substance by inhalation, especially for treating
asthma and
COPD.
Tiotropium, chemically (1a,2[i,4[3,5a,7[i)-)-7-[(hydroxydi-2-
thienylacetyl)oxy]-9,9-
dimethyl-3-oxa-9-azoniatricyclo[3.3.1.024]nonane, is known as tiotropium
bromide
from European Patent Application EP 418 716 Al. The bromide salt of tiotropium
has
the following chemical structure:
+ Me
Me'N'
H Br
O
S O
OH
S
The compound has valuable pharmacological properties and is known by the name
tiotropium bromide. Tiotropium and its salts are highly effective
anticholinergics and
can provide therapeutic benefit in the treatment of asthma or COPD (chronic
obstructive pulmonary disease). The monohydrate of tiotropium bromide is also
pharmacologically valuable.
Both compounds are a preferred object of the present invention.
The present invention relates to liquid active substance formulations of these
compounds which can be administered by inhalation; the liquid formulations
according to the invention have to meet high quality standards.
Case 1/1162 FF CA 02427583 2003-04-29 goehringer Ingelheim Pharma KG
2
To achieve an optimum distribution of active substances in the lung it makes
sense
to use a liquid formulation without propellant gases administered using
suitable
inhalers. Those inhalers which are capable of nebulising a small amount of a
liquid
formulation in the dosage needed for therapeutic purposes within a few seconds
into
an aerosol suitable for therapeutic inhalation are particularly suitable.
Within the
scope of the invention, preferred nebulisers are those in which an amount of
less
than 100 microlitres, preferably less than 50 microlitres, most preferably
less than 20
microlitres of active substance solution can be nebulised preferably in one
puff to
form an aerosol having an average particle size of less than 20 microns,
preferably
less than 10 microns, so that the inhalable part of the aerosol already
corresponds to
the therapeutically effective quantity.
An apparatus of this kind for the propellant-free administration of a metered
amount
of a liquid pharmaceutical composition for inhalation is described in detail
for
example in Intemational Patent Application WO 91/14468 "Atomizing Device and
Methods" and also in WO 97/12687, cf. Figures 6a and 6b and the accompanying
description. In a nebuliser of this kind a pharmaceutical solution is
converted by
means of a high pressure of up to 500 bar into an aerosol destined for the
lungs,
which is sprayed. Within the scope of the present specification reference is
expressly
made to the entire contents of the literature mentioned above.
In inhalers of this kind the formulations of solutions are stored in a
reservoir. It is
essential that the active substance formulations used are sufficiently stable
when
stored and at the same time are such that they can be administered directly,
if
possible without any further handling, in accordance with their medical
purpose.
Moreover, they must not contain any ingredients which might interact with the
inhaler
in such a way as to damage the inhaler or the pharmaceutical quality of the
solution
or of the aerosol produced.
To nebulise the solution a special nozzle is used as described for example in
WO
94/07607 or WO 99/16530. Reference is expressly made here to both these
publications.
Case 1/1162 FF CA 02427583 2003-04-29 goehringer Ingelheim Pharma KG
3
WO 98/27959 discloses formulations of solutions for the inhaler described
above
which contain as additive the disodium salt of editic acid (sodium edetate).
For
aqueous formulations of solutions which are to be converted into inhalable
aerosols
using the inhaler described above, the specification favours a minimum
concentration
of sodium edetate of 50 mg/100 ml, in order to reduce the incidence of spray
anomalies. Among the Examples disclosed there is a formulation containing
tiotropium bromide. In this formulation the active substance is dissolved in
water. The
proportion of sodium edetate is again 50 mg / 100 ml.
Surprisingly, it has now been found that formulations of solutions of
tiotropium salts in
water or a water-ethanol mixture wherein the proportion of the additive sodium
edetate is significantly less than 50 mg / 100 mi show a reduction in the
scattering of
the composition delivered, compared with the formulation containing tiotropium
bromide known from the prior art. In addition, the spray quality is very good.
The
resulting aerosol has very good properties for administration by inhalation.
Another advantage of the formulation is that, thanks to the absence of or
reduction in
the additive sodium, edetate in the active substance formulation, the pH of
the
solution formulation can be lowered. Low pH levels are necessary for the long-
term
stability of the tiotropium salts in the formulation.
It is therefore an aim of the present invention to provide an aqueous active
substance
formulation containing a pharmaceutically acceptable tiotropium salt which
meets the
high standards needed in order to be able to achieve optimum nebulisation of a
solution using the inhalers mentioned hereinbefore. The active substance
formulations according to the invention must be of sufficiently high
pharmaceutical
quality, i.e. they should be pharmaceutically stable over a storage time of
some
years, preferably at least one year, more preferably two years.
Another aim is to provide propellant-free formulations of solutions containing
tiotropium salts which are nebulised under pressure using an inhaler, the
composition
delivered by the aerosol produced falling reproducibly within a specified
range.
CA 02427583 2006-07-11
25771-802
4
Another aim is to provide formulations of
solutions with tiotropium and another active substance which
can be administered by inhalation.
According to one aspect of the present invention,
there is provided a liquid, propellant-free pharmaceutical
preparation comprising at least two combinable active
substances containing a tiotropium salt as one of the at
least two active substances, in a concentration based on
tiotropium of between 0.0005 and 5 % by weight, a steroid,
an antiallergic, an antihistamine, or a leukotriene
antagonist as the second of the at least two active
substances, water as solvent, in which at least the
tiotropium salt is dissolved, acid for achieving a pH
between 2.0 and 3.1, a pharmacologically acceptable
preservative, and an etidic acid salt in an amount of up to
mg/100 ml.
According to the invention, any pharmaceutically
acceptable salts of tiotropium may be used for the
formulation. When the term tiotropium salt is used within
20 the scope of the present invention, this is to be taken as a
reference to tiotropium. According to the invention a
reference to tiotropium, which is the free ammonium cation,
corresponds to a reference to tiotropium in the form of a
salt (tiotropium salt) which contains an anion as counter-
25 ion. Tiotropium salts which may be used within the scope of
the present invention are preferably compounds which
contain, in addition to tiotropium as counter-ion (anion),
chloride, bromide, iodide, methanesulphonate, para-
toluenesulphonate and/or methylsulphate.
CA 02427583 2006-07-11
25771-802
4a
Within the scope of the present invention
tiotropium bromide is preferred as the salt. References to
tiotropium bromide within the scope of the present invention
must always be taken as references to all possible amorphous
and crystalline modifications of tiotropium bromide. These
may for example contain molecules of solvent in their
crystalline structure. Of all the crystalline modifications
of tiotropium bromide those which also contain water
(hydrates) are preferred according to the invention. It is
particularly preferred within the scope of the present
invention to use tiotropium bromide monohydrate.
In the formulations according to the invention
combinations with a tiotropium salt and only one other
active substance are preferred.
In the formulations according to the invention the
tiotropium salts are dissolved in a solvent. The solvent
may be exclusively water, or it may be a mixture of water
and ethanol. Ethanol may be added to the formulation in
order to increase the solubility of additives or other
active substances apart from the tiotropium salt, preferably
tiotropium bromide or tiotropium bromide monohydrate. The
relative proportion of ethanol to water is not limited; it
may be 90 % by volume, for example. Preferably, the maximum
limit of ethanol is 70 % by volume, particularly 60 % by
volume and most preferably 30 % by volume. The remaining %
by volume consist of water. The preferred solvent is water
without the addition of ethanol.
Case 1/1162 FF CA 02427583 2003-04-29 goehringer Ingelheim Pharma KG
The concentration of the tiotropium salt based on the proportion of tiotropium
in the
finished pharmaceutical preparation depends on the therapeutic effect sought.
For
most of the complaints which respond to tiotropium the concentration of
tiotropium is
5 between 0.0005 and 5 % by weight, preferably between 0.001 and 3 % by
weight.
The pH of the formulation according to the invention is between 2.0 and 4.5,
preferably between 2.5 and 3.5 and more preferably between 2.7 and 3.5 and
particularly preferably between 2.7 and 3.2. Most preferred are pHs with an
upper
limit of 3.1.
The pH is adjusted by the addition of pharmacologically acceptable acids.
Examples of inorganic acids which are preferred for this purpose include:
hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/or
phosphoric
acid.
Examples of particularly suitable organic acids are: ascorbic acid, citric
acid, malic
acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid,
formic acid
and/or propionic acid, etc. Preferred inorganic acids are hydrochloric acid
and
sulphuric acid. It is also possible to use acids which form an acid addition
salt with
the active substance or, in the case of combined preparations, with one of the
active
substances.
Of the organic acids, ascorbic acid, fumaric acid and citric acid are
preferred,
especially citric acid. If desired, mixtures of the abovementioned acids may
also be
used, particularly in the case of acids which have other properties in
addition to their
acidifying properties, e.g. those which act as flavourings or antioxidants,
such as for
example citric acid or ascorbic acid.
Hydrochloric acid deserves special mention as an inorganic acid.
If desired, pharmacologically acceptable bases may be used to titrate the pH
precisely. Suitable bases include for example alkali metal hydroxides and
alkali metal
carbonates. The preferred alkali ion is sodium. If bases of this kind are
used, care
must be taken to ensure that the resulting salts, which are then contained in
the
Case 1/1162 FF CA 02427583 2003-04-29 Boehringer Ingelheim Pharma KG
6
finished pharmaceutical formulation, are pharmacologically compatible with the
abovementioned acid.
According to the invention, there is no need to add editic acid (EDTA) or one
of the
known salts thereof, sodium edetate, to the present formulation as a
stabiliser or
complexing agent.
Another preferred embodiment contains editic acid and/ or the salts thereof.
In a preferred embodiment with sodium edetate the content based on sodium
edetate
is less than 10 mg / 100 ml. In this case, there is one preferred range from 5
mg/ 100
ml to less than 10 mg/100 ml or another from greater than 0 to 5 mg/100ml.
In another embodiment the content of sodium edetate is 10 to 30 mg / 100 mi,
i5 preferably not more than 25 mg/ 100 ml.
In a preferred embodiment this additive is omitted entirely.
The remarks made conceming sodium edetate also apply analogously to other
comparable additives which have complexing proprerties and can be used
instead,
such as for example nitrilotriacetic acid and the salts thereof.
By complexing agents is preferably meant within the scope of the present
invention
molecules which are capable of entering into complex bonds. Preferably, these
compounds should have the effect of complexing cations, most preferably metal
cations.
The other active substances apart from the tiotropium salt in the combined
preparation are selected in particular from among the antihistamines,
antiallergic
agents, leukotriene antagonists and/or steroids.
These active substances include:
As steroids:
Case 1/1162 FF CA 02427583 2003-04-29 Boehringer Ingelheim Pharma KG
7
Alclomethasone, Flunisolide ,
Alclomethasone-dipropionate, Fluocinolone acetonide,
Alisactide, Fluocinonide,
Amcinonide Fluocortin,
Aminoglutethimide, Fluocortolone capronate,
Aristocort-diacetate, Fluodexan,
Beclomethasone, Fluorometholone,
Beclomethasone, Douglas, Fluticasone,
Beclomethason e-1 7,21 -dipropionate, Fluticasone-propionate,
Betamethasone valerate, Formebolone,
Betamethasone adamantoate, Formocortal,
Budesonide, Halcinonide,
Butixocort, Halometasone,
Canesten-HC, Halopredone-acetate,
Ciclometasone, Hydrocortisone,
Clobetasol, Hydrocortisone-17-Butyrate,
Clobetasone, Hydrocortisone-aceponate,
Cloprednol, Hydrocortisone-butyrate propionate,
Cloprednol Icomethasone_enbutate
Fluocortin butyl, Ciclometasone,
Cortivazol, Lotrisone,
Deflazacort , Mazipredone,
Deflazacort, Medrysone,
Demetex, Meprednisone,
Deprodone, M ethyl pred n isol on e-Aceponate,
Deprodone Propionate, Mometasone,
Dexamethasone, Mometasone furoate,
Dexamethasone-21 -isonicotinate, Mycophenolate mofetil
Dexamethasone isonicotinate, Pranlukast,
Diflorasone, Paramethasone-acetate,
Difluprednate, Prednicarbate,
Endrisone, Promedrol,
Fluazacort, Seratrodast,
Fluclorolone acetonide, Tipredan,
Case 1/1162 FF CA 02427583 2003-04-29 Boehringer Ingelheim Pharma KG
8
Tixocortol-pivalate, Trimacinolone Benetonide,
Triamcinolone, Ulobetasol-propionate,
Triamcinolone-Hexacetonide, Zileuton
Trilostan,
methyl 9-alpha-chloro-6-alpha-fluoro-l1-beta-17-al pha--dihydroxy-16-alpha--
methyl-
3-oxo-1,4-androstad iene-17-beta-carboxylate-17-propionate,
Particularly preferred are the combinations of tiotropium bromide, or
tiotropium
bromide-monohydrate and budesonide, flunisolide, beclomethasone dipropionate
or
fluticasone, as well as the pharmacologically acceptable (possibly other)
salts
thereof.
The preferred combination comprises tiotropium bromide, or tiotropium bromide
monohydrate and budesonide.
The concentration of the steroid, e.g. budesonide, flunisolide, beclomethasone
dipropionate or fluticasone, in the formulations according to the invention is
1s preferably 0.05 to 10 wt.%, preferably up to 5 wt.%, more preferably 0.1 to
2.5 wt.%,
particularly preferably 0.2 to 2.5 wt.%. When the formulation is used with the
inhaler '
mentioned hereinbefore the concentration of steroid is preferably adjusted so
that
12.5 to 250 micrograms of steroid are delivered per spray. Particularly
preferred are
concentrations in which the pharmacologically active dose is administered in
one or
two sprays.
If the combined formulation contains a leukotriene antagonist, this is
preferably
selected from among montelukast, pranlukast, zafirlukast, 1-(((R)-(3-(2-(6,7-
difluoro-
2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)-
2s methylcyclopropane-acetic acid, 1-(((R)-3-(3-(2-(2,3-dichlorothieno[3,2-
b]pyridin-5-yl)-
(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)-
cyclopropane-acetic acid or [2-[[2-(4-tert-butyl-2-thiazolyl)-5-
benzofuranyl]oxymethyl]phenyl]acetic acid. Montelukast, pranlukast and/or
zafirlukast
are preferred.
Case 1/1162 FF CA 02427583 2003-04-29 Boehringer Ingelheim Pharma KG
9
The concentration of the leukotriene antagonist is from 0.05 to 10 wt.%,
preferably up
to 5 wt.%, more preferabiy 0.1 to 3.5 wt.%.
The following are mentioned as examples of antihistamines and antiallergic
agents:
Azelastine,
Astemizole,
Bamipine,
Carbinoxamine hydrogen maleate,
Cetirizine,
Cexchlorpheniramine,
Chlorphenoxamine,
Clemastine,
Clemastine hydrogen fumarate,
Desloratidine,
Dimenhydrinate,
Dimetindene,
Disodium cromoglycate,
Diphenhydramine,
Doxylamine,
Ebastine,
Emedastine,
Epinastine,
,t ..
Fexofenadine,
Ketotifen,
Levocabastine,
Loratadine,
Meclozine,
Mequitazine,
Mizolastine,
Nedocromil,
Pheniramine and/or
Promethazine.
Case 1/1162 FF CA 02427583 2003-04-29 Boehringer Ingelheim Pharma KG
Epinastine, nedocromil, disodium cromoglycate, astemizole, mequitazine,
carbinoxamine and/or clemastine and/or the corresponding pharmaceutically
acceptable salts are preferred.
In the combined preparation, the concentration of the antiallergic agents
and/or
antihistamines is preferably 0.05 to 15 wt.%, preferably up to 10 wt.%, more
preferably 0.1 to 10 wt.%, most preferably 0.1 to 7 wt.%.
All the abovementioned active substances may optionally also be used in the
form of
their pharmacologically acceptable salts thereof.
The combined preparations are preferably formulations in which tiotropium is
present
in solution. The other active substance may be dissolved or suspended; this is
generally determined by the other active substance and the particular solvent
used.
If the additional active substance is one which is vulnerable at low pHs, it
is
preferably formulated as a suspension. The advantage of a suspended form is
that
the pH can be made more acidic, which is to the benefit of the stability of
the
dissolved tiotropium. The preferred pH range of tiotropium bromide is between
2. 0
and 4.5, preferably 2.5 and 3.5, most preferably between 2.7 and 3.2.
In the case of steroids, these are preferably used in suspended form,
especially
fluticasone. This is particularly true if the solvent used is only water
without ethanol. If
ethanol is added, the steroid may also be formulated as a solution. However,
it has
been found that budesonide, for example, is also sufficiently stable at a pH
of 3.5 if it
is dissolved in a mixture of water and ethanol.
With regard to the use of the formulations according to the invention in the
inhaler
described within the scope of the present invention, it may be advantageous if
all the
ingredients of the formulation are present in solution.
Case 1/1162 FF CA 02427583 2003-04-29 Boehringer Ingelheim Pharma KG
11
As well as ethanol, other cosolvents and/or other adjuvants may be added to
the
formulation according to the invention.
Other preferred cosolvents are those which contain hydroxyl groups or other
polar
groups, for example alcohols - especially isopropylalcohol, glycols -
especially
propyleneglycol, polyethyleneglycol, polypropyleneglycol, glycolether,
glycerol,
polyoxyethylene alcohols and polyoxyethylene fatty acid esters.
By adjuvants and additives are meant, in this context, any pharmacologically
acceptable and therapeutically useful substance which is not an active
substance,
{ but can be formulated together with the active substance(s) in the
pharmacologically
suitable solvent, in order to improve the qualities of the active substance
formulation.
Preferably, these substances have no pharmacological effects or no appreciable
or
at least no undesirable pharmacological effects in the context of the desired
therapy.
The adjuvants and additives include, for example, surfactants such as e.g.
soya
lecithin, oleic acid, sorbitan esters such as sorbitan trioleate,
polyvinylpyrrolidone,
other stabilisers, complexing agents, antioxidants and/or preservatives which
prolong
the shelf life of the finished pharmaceutical formulation, flavourings,
vitamins and/or
other additives known in the art. The additives also include pharmacologically
acceptable salts such as sodium chloride, for example.
Suitable surfactants or suspension-stabilising agents include all the
pharmacologically acceptable substances which have a lipophilic hydrocarbon
group
and one or more functional hydrophilic groups, especially C5-20-fatty
alcohols, C5,20-
fatty acids, C5_2o-fatty acid esters, lecithin, glycerides, propyleneglycol
esters,
polyoxyethylenes, polysorbates, sorbitan esters and/or carbohydrates. C5_20-
fatty
acids, propyleneglycol diesters and/or triglycerides and/or sorbitans of the
CF,20-fatty
acids are preferred, while oleic acid and sorbitan mono-, di- or trioleates
are
particularly preferred. Alternatively, toxicologically and pharmaceutically
acceptable
polymers and/or block polymers may be used as suspension stabilising agents.
The quantity of surfactant may be up to 1:1 based on the proportion by weight
of the
suspended active substances; amounts of 0.0001:1 to 0.5:1 are preferred while
amounts of from 0.0001:1 to 0.25:1 are especially preferred.
Case 1/1162 FF CA 02427583 2003-04-29 Boehringer Ingelheim Pharma KG
12
The preferred excipients include antioxidants such as ascorbic acid, for
example,
provided that it has not already been used to adjust the pH, vitamin A,
vitamin E,
tocopherols and similar vitamins or provitamins occurring in the human body.
Preservatives can be added to protect the formulation from contamination with
pathogenic bacteria. Suitable preservatives are those known from the prior
art,
particularly benzalkonium chloride or benzoic acid or benzoates such as sodium
benzoate in the concentration known from the prior art.
Preferred formulations contain only benzalkonium chloride, an acid for
adjusting the
pH and sodium edetate, in addition to the solvent water and/or water/ethanol
and the
tiotropium salt.
In another preferred embodiment, sodium edetate is omitted. These embodiments
may optionally also contain sodium chloride.
As already mentioned a number of times, tiotropium bromide is described in EP
418
716 Al and crystalline tiotropium bromide monohydrate may be obtained using a
process which is described in more detail below.
In order to prepare the crystalline monohydrate according to the present
invention,
the tiotropium bromide obtained by the method disclosed in EP 418 716 Al, for
example, first has to be taken up in water, heated, purified with activated
charcoal
and, after removal of the activated charcoal, the tiotropium bromide-
monohydrate is
slowly crystallised while cooling slowly.
The following procedure is preferably followed:
In a reaction vessel of suitable dimensions, the solvent is mixed with
tiotropium
bromide, which has been obtained by the method disclosed in EP 418 716 Al, for
example.
For each mol of tiotropium bromide put in, 0.4 to 1.5 kg, preferably 0.6 to 1
kg, most
preferably about 0.8 kg of water are used as solvent.
The mixture obtained is heated with stirring, preferably to above 50 C, most
preferably to above 60 C. The maximum temperature which can be selected is
determined by the boiling point of the solvent used. Preferably, the mixture
is heated
to a range from 80-90 C.
Case 1/1162 FF CA 02427583 2003-04-29 goehringer Ingelheim Pharma KG
13
Activated charcoal, either dry or moistened with water, is added to this
solution.
Preferably, 10 to 50 g, more preferably 15 to 35 g, most preferably about 25 g
of
activated charcoal are put in per mol of tiotropium bromide used. If desired
the
activated charcoal is suspended in water before being added to the solution
containing tiotropium bromide. 70 to 200 g, preferably 100 to 160 g, more
preferably
about 135 g of water are used, per mol of tiotropium bromide put in, in order
to
suspend the activated charcoal. If the activated charcoal is suspended in
water
beforehand, before being added to the solution containing tiotropium bromide,
it is
advisable to rinse again with the same amount of water.
After the activated charcoal has been added, stirring is continued at constant
temperature for between 5 and 60 minutes, preferably between 10 and 30
minutes,
more preferably for about 15 minutes and the mixture obtained is filtered to
remove
the activated charcoal. The filter is then rinsed with water. 140 to 400 g,
preferably
200 to 320 g, most preferably about 270 g of water are used for this, per mol
of
tiotropium bromide used.
The filtrate is then slowly cooled, preferably to a temperature of 20-25 C.
The cooling
preferably takes place at a cooling rate of 1 to 10 C every 10 to 30 minutes,
preferably 2 to 8 C every 10 to 30 minutes, more preferably 3 to 5 C every 10
to 20
minutes, most preferably 3 to 5 C about every 20 minutes. If desired, the
cooling to
20 to 25 C may be followed by further cooling to below 20 C, more preferably
to 10
to 15 C.
After cooling is complete, stirring is continued for between 20 minutes and 3
hours,
preferably between 40 minutes and 2 hours, more preferably for about one hour
to
complete the crystailisation.
The crystals obtained are then isolated by filtering or suction filtering to
remove the
solvent. If it should prove necessary to subject the crystals obtained to a
further
washing step, it is advisable to use water or acetone as the washing solvent.
0.1 to
1.0 L, preferably 0.2 to 0.5 L, more preferably about 0.3 L of solvent may be
used per
mol of tiotropium bromide put in, in order to wash the tiotropium bromide
monohydrate crystals obtained. If necessary the washing step may be repeated.
The
product obtained is dried in vacuo or using circulating heated air until a
water content
of 2.5 - 4.0 % is obtained.
According to one aspect the present invention therefore also relates to
formulations
of solutions of the type described above using crystalline tiotropium bromide
monohydrate which may be obtained by the procedure described above.
Case 1/1162 FF CA 02427583 2003-04-29 Boehringer Ingelheim Pharma KG
14
The pharmaceutical formulations containing tiotropium salts according to the
invention are preferably used in an inhaler of the kind described hereinbefore
in order
to produce the propellant-free aerosols according to the invention. At this
point we
should once again expressly mention the patent documents described
hereinbefore,
to which reference is hereby made.
As described at the beginning, a further developed embodiment of the preferred
inhaler is disclosed in WO 97/12687 and Figure 6 thereof. This nebuliser
(Respiniat )
can advantageously be used to produce the inhalable aerosols according to the
invention containing a tiotropium salt as active substance. Because of its
cylindrical
shape and handy size of less than 9 to 15 cm long and 2 to 4 cm wide, the
device
can be carried anywhere by the patient. The nebuliser sprays a defined volume
of the
pharmaceutical formulation out through small nozzles at high pressures, so as
to
produce inhalable aerosols.
The preferred atomiser essentially consists of an upper housing part, a pump
housing, a nozzle, a locking clamp, a spring housing, a spring and a storage
container, characterised by
- a pump housing fixed in the upper housing part and carrying at one end a
nozzle body with the nozzle or nozzle arrangement,
- a hollow piston with valve body,
- a power take-off flange in which the hollow body is fixed and which is
located in the upper housing part,
- a locking clamping mechanism located in the upper housing part,
- a spring housing with the spring located therein, which is rotatably mounted
on the upper housing part by means of a rotary bearing,
- a lower housing part which is fitted onto the spring housing in the axial
direction.
The hollow piston with valve body corresponds to a device disclosed in WO
97/12687. It projects partially into the cylinder of the pump housing and is
disposed to
be axially movable in the cylinder. Reference is made particularly to Figures
1-4 -
especially Figure 3 - and the associated parts of the description. At the
moment of
release of the spring the hollow piston with valve body exerts, at its high
pressure
Case 1/1162 FF CA 02427583 2003-04-29 Boehringer Ingelheim Phanna KG
end, a pressure of 5 to 60 Mpa (about 50 to 600 bar), preferably 10 to 60 Mpa
(about
100 to 600 bar) on the fluid, the measured amount of active substance
solution.
Volumes of 10 to 50 microlitres are preferred, volumes of 10 to 20 microlitres
are
more preferable, whilst a volume of 15 microlitres per actuation is
particularly
preferred.
The valve body is preferably mounted at the end of the hollow piston which
faces the
nozzle body.
The nozzle in the nozzle body is preferably microstructured, i.e. manufactured
by
micro-engineering. Microstructured nozzle bodies are disclosed for example in
WO-94/07607 and in WO 99/16530; reference is hereby made to the contents
thereof, especially Figure 1 of WO-94/07607 and the associated description.
The nozzle body consists for example of two sheets of glass and/or silicon
securely
fixed together, at least one of which has one or more microstructured channels
which
connect the nozzle inlet end to the nozzle outlet end. At the nozzle outlet
end there is
at least one round or non-round opening 2 to 10 microns deep and 5 to 15
microns
wide, the depth preferably being 4.5 to 6.5 microns and the length being 7 to
9
microns.
If there is a plurality of nozzle openings, preferably-two, the directions of
spraying of
the nozzles in the nozzle body may run parallel to each other or may be
inclined
relative to one another in the direction of the nozzle opening. In the case of
a nozzle
body having at least two nozzle openings at the outlet end, the directions of
spraying
may be inclined relative to one another at an angle of 20 degrees to 160
degrees,
preferably at an angle of 60 to 150 degrees, most preferably 80 to 1000.
The nozzle openings are preferably arranged at a spacing of 10 to 200 microns,
more preferably at a spacing of 10 to 100 microns, still more preferably 30 to
70
microns. A spacing of 50 microns is most preferred.
The directions of spraying therefore meet in the region of the nozzle
openings.
As already mentioned, the liquid pharmaceutical preparation hits the nozzle
body at
an entry pressure of up to 600 bar, preferably 200 to 300 bar and is atomised
through
the nozzle openings into an inhalable aerosol. The preferred particle sizes of
the
aerosol are up to 20 microns, preferably 3 to 10 microns.
Case 1/1162 FF CA 02427583 2003-04-29 Boehringer ingeiheim Pharma KG
16
The locking clamping mechanism contains a spring, preferably a cylindrical
helical
compression spring as a store for the mechanical energy. The spring acts on
the
power take-off flange as a spring member the movement of which is determined
by
the position of a locking member. The travel of the power take-off flange is
precisely
limited by an upper stop and a lower stop. The spring is preferably tensioned
via a
stepping-up gear, e.g. a helical sliding gear, by an external torque which is
generated
when the upper housing part is turned relative to the spring housing in the
lower
housing part. In this case, the upper housing part and the power take-off
flange
contain a single- or multi-speed spline gear.
The locking member with the engaging locking surfaces is arranged in an
annular
configuration around the power take-off flange. It consists for example of a
ring of
plastics or metal which is inherently radially elastically deformable. The
ring is
arranged in a plane perpendicular to the axis of the atomiser. After the
locking of the
spring, the locking surfaces of the locking member slide into the path of the
power
take-off flange and prevent the spring from being released. The locking member
is
actuated by means of a button. The actuating button is connected or coupled to
the
locking member. In order to actuate the locking clamping mechanism the
actuating
button is moved parallel to the annular plane, preferably into the atomiser,
and the
deformable ring is thereby deformed in the annular plane. Details of the
construction
of the locking clamping mechanism are described in WO 97/20590.
The lower housing part is pushed axially over the spring housing and covers
the
bearing, the drive for the spindle and the storage container for the fluid.
When the atomiser is operated, the upper part of the housing is rotated
relative to the
lower part, the lower part taking the spring housing with it. The spring
meanwhile is
compressed and biased by means of the helical sliding gear, and the clamping
mechanism engages automatically. The angle of rotation is preferably a whole-
number fraction of 360 degrees, e.g. 180 degrees. At the same time as the
spring is
tensioned, the power take-off component in the upper housing part is moved
along
by a given amount, the hollow piston is pulled back inside the cylinder in the
pump
Case 1/1162 FF CA 02427583 2003-04-29 Boehringer Ingelheim Pharma KG
17
housing, as a result of which some of the fluid from the storage container is
sucked
into the high pressure chamber in front of the nozzle.
If desired, a plurality of replaceable storage containers containing the fluid
to be
atomised can be inserted in the atomiser one after another and then used. The
storage container contains the aqueous aerosol preparation according to the
invention.
The atomising process is initiated by gently pressing the actuating button.
The
clamping mechanism then opens the way for the power take-off component. The
biased spring pushes the piston into the cylinder in the pump housing. The
fluid
-~~
emerges from the nozzle of the atomiser in the form of a spray.
Further details of the construction are disclosed in PCT applications WO
97/12683
and WO 97/20590, to which reference is hereby made.
The components of the atomiser (nebuliser) are made of a material suitable for
their
function. The housing of the atomiser and - if the function allows - other
parts as well
are preferably made of plastics, e.g. by injection moulding. For medical
applications,
physiologically acceptable materials are used.
Figures 1a/b, which are identical to Figures 6 a/b of WO 97/12687, show the
Respimat nebuliser with which the aqueous aerosol preparations according to
the
invention can advantageously be inhaled.
Figure 1 a shows a longitudinal section through the atomiser with the spring
under
tension, Figure 1 b shows a longitudinal section through the atomiser with the
spring
released.
The upper housing part (51) contains the pump housing (52), on the end of
which is
mounted the holder (53) for the atomiser nozzle. In the holder is the nozzle
body (54)
and a filter (55). The hollow piston (57) fixed in the power take-off flange
(56) of the
locking clamping mechanism projects partly into the cylinder of the pump
housing. At
its end the hollow piston carries the valve body (58). The hollow piston is
sealed off
Case 1/1162 FF CA 02427583 2003-04-29 Boehringer Ingelheim Pharma KG
18
by the gasket (59). Inside the upper housing part is the stop (60) on which
the power
take-off flange rests when the spring is relaxed. Located on the power take-
off flange
is the stop (61) on which the power take-off flange rests when the spring is
under
tension. After the tensioning of the spring, the locking member (62) slides
between
the stop (61) and a support (63) in the upper housing part. The actuating
button (64)
is connected to the locking member. The upper housing part ends in the
mouthpiece
(65) and is closed off by the removable protective cap (66).
The spring housing (67) with compression spring (68) is rotatably mounted on
the
upper housing part by means of the snap-fit lugs (69) and rotary bearings. The
lower
housing part (70) is pushed over the spring housing. Inside the spring housing
is the
replaceable storage container (71) for the fluid (72) which is to be atomised.
The
storage container is closed off by the stopper (73), through which the hollow
piston
projects into the storage container and dips its end into the fluid (supply of
active
substance solution).
The spindle (74) for the mechanical counter is mounted on the outside of the
spring
housing. The drive pinion (75) is located at the end of the spindle facing the
upper
housing part. On the spindle is the slider (76).
The nebuliser described above is suitable for nebulising the aerosol
preparations
according to the invention to form an aerosol suitable for inhalation.
If the formulation according to the invention is nebulised using the method
described
above (Respimat ), the mass expelled, in at least 97%, preferably at least 98%
of all
the actuations of the inhaler (puffs), should correspond to a defined quantity
with a
range of tolerance of not more than 25%, preferably 20% of this quantity.
Preferably,
between 5 and 30 mg, more preferably between 5 and 20 mg of formulation are
delivered as a defined mass per puff.
The proportion of the rnass delivered which is outside a tolerance limit of
not more
than 25% in relation to the desired mass should be less than 1.5%, preferably
less
than 1.2%.
Case 1/1162 FF CA 02427583 2003-04-29 Boehringer Ingelheim Pharma KG
19
However, the formulation according to the invention can also be nebulised
using
inhalers other than those described above, for example jet-stream inhalers.
Case 1/1162 FF CA 02427583 2003-04-29 Boehringer Ingelheim Pharma KG
Examples
1. Example of the synthesis of tiotropium bromide monohydrate
15.0 kg of tiotropium bromide are added to 25.7 kg of water in a suitable
reaction
vessel. The mixture is heated to 80-90 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
tiotropium bromide and rinsed with 4.3 kg of water. The mixture thus obtained
is
stirred for at least 15 min. at 80-90 C and then filtered through a heated
filter into an
apparatus which has been preheated to an outer temperature of 70 C. The filter
is
rinsed with 8.6 kg of water. The contents of the apparatus are cooled to a
temperature of 20-25 C at a rate of 3-5 C every 20 minutes. Using cold water
the
apparatus is cooled further to 10-15 C and crystallisation is completed by
stirring for
at least another hour. The crystals are isolated using a suction filter drier,
the crystal
slurry isolated is washed with 9 L of cold water (10-15 C) and cold acetone
(10-
15 C). The crystals obtained are dried at 25 C for 2 hours in a nitrogen
current.
Yield: 13.4 kg of tiotropium bromide monohydrate (86 % of theory).
Case 1/1162 FF CA 02427583 2003-04-29 Boehringer Ingelheim Pharma KG
21
II. Examples of formulations
100 g of pharmaceutical preparation contain:
Example Amount of Amount of Amount of Amount of pH,
tiotropium tiotropium benzalkonium sodium adjusted
bromide, based bromide chloride edetate with HCI
on tiotropium: monohydrate, (1 N)
based on
tiotropium:
1 0.099 g -- 10 mg 25 mg 3.0
2 0.006 g -- 10 mg 25 mg 3.0
J 3 0.099 g -- 10 mg 10 mg 3.0
4 0.006 g -- 10 mg 10 mg 3.0
--- 0.099 g 10 mg 25 mg 3.0
6 --- 0.006 g 10 mg 25 mg 3.0
7 --- 0.099 g 10 mg 10 mg 3.0
8 -- 0.006 g 10 mg 10 mg 3.0
The remainder is water or water/ethanol and one of the abovementioned active
substances in an amount known from the prior art.
Examples 9 to 12: Budesonide
Each of Examples 1 to 8 may additionally contain:
Example 9a: budesonide: 0.3 g, pH, adjusted with HCI:3.0, solvent water only,
no
ethanol;
Example 9b: budesonide: 0.3 g, pH, adjusted with HCI:3,5;
Example 9c: budesonide: 0.3 g, pH, adjusted with HCI:4.0;
Example 10: analogous to Example 9a to 9c with budesonide: 0.6 g,
Example 11: analogous to Example 9a to 9c with budesonide: 1.3 g,
Example 12: analogous to Example 9a to 9c with budesonide: 2.0 g.
In Examples 9 to 12 the steroid is present in the formulation in suspension.
Sorbitan
trioleate may be used as a surfactant.
Case 1/1162 FF CA 02427583 2003-04-29 Boehringer Ingelheim Pharma KG
22
Examples 13 to 15
Analogous to Examples 9 to 12. Benzalkonium chloride is exchanged for sodium
benzoate.
Examples 16 to 19
Analogous to Examples 9 to 12. Instead of hydrochloric acid, citric acid is
exclusively
used to adjust the pH.
Examples 20 to 30
The ingredients and amounts are analogous to Examples 9 to 19.
Instead of water, a mixture of water (10 vol.%) and ethanol (90 vol.%) is
used.
Budesonide is present in solution.
Other Examples
Analogously to Examples 9 to 30 described above, the same amount of
flunisolide,
beclomethasone dipropionate or fluticasone is used instead of budesonide. In
the
case of fluticasone, lecithin is preferably added instead of sorbitan
trioleate in the
case of the suspension formulation. The steroids are formulation as a
suspension if
the solvent used is water on its own. In the case of a mixture of water and
ethanol the
steroid may be in solution.
Example 31
Epinastine: 0.2 g
EDTA: 25 mg
Tiotropium bromide monohydrate: 29 mg,
0.1 N hydrochloric acid to adjust the pH to 3.0,
water ad 100 ml.
