Note: Descriptions are shown in the official language in which they were submitted.
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W O 98/1~280 - PCT/SE97/01606
~EW CO M Bn~ATION
Field of the Invention
The present invention provides a new combination of ph~rm~re~ltic~lly active substances
which is of use in the tre~tment of respiratory disorders, particularly asthma.
Background to the Invention
Despite recent advances in the awareness of asthma and the introduction of powerful and
effective anti-asthma drugs, asthma remains a poorly understood and frequently poorly
o treated (1i~e~ce There have been recent advances in the treatment of the disease which
result from the recognition that asthma is a chronic infl~mm~tory ~ e~e Therapy is now
aimed at both controlling the symptoms and reducing the infl~mm~tion The symptoms
include uncontrolled airway infl~mm~tiQn which may lead to mllcos~ damage and
structural changes possibly leading to irreversible n~l~ lg of the airways and fibrosis of
the lungs.
The ~y~ Lollls may be controlled by ~2-adrenoreceptor agonists such as salbutamol,
s~lmet~rol, terbutaline and formoterol. Forrnoterol is advantageous because the duration of
its effect is long; it has a fast onset time and because it gives few nocturnal w~k~nin~
Prophylactic therapy is typically provided by steroids such as beclomethasone
diprup~ionate, fluticasone propionate and budesonide. Of these budesonide is
advantageous because it may be given in a high inhaled dose (up to 2 mg daily) with very
low systemic effects. Long term clinical studies in adults and children have shown that
2s inhaled budesonide has an excellent safety profile.
Description of the Invention
According to the invention there is provided a composition comprising, in an ~lmixhlre:
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(a) a first active ingredient which is formoterol, a ph~rm~ceutically acceptable salt or
solvate of formoterol, or a solvate of such a salt; and
(b) a second active ingredient which is budesonide;
wherein the molar ratio of the first active ingredient to the second active ingredient is from
s 1:30 to 1:36, preferably about 1:32.5.
According to the invention there is filr~er provided a kit comprising:
(i) a vessel cont~inin~ the first active ingredient,
(ii) a vessel co,.l~ g the second active ingredient; and
lO (iii) instructions for the sequential or sepaldle ~riminictration of the first and second active
ingredients to a patient in need thereof;
wherein the molar ratio of the first active ingredient to the second active ingredient is from
1:30 to 1:36, preferably about 1:32.5.
s A patient suffering from a ~ ory disorder such as asthma can be treated by
5~rimini~t~rin~ via inh~tion a composition according to the invention. Alternatively such a
patient can be treated by ~timini~tering via inhalation, sequentially or separately:
(i) a dose of the first active ingredient; and
(ii) a dose of the second active ingredient;
20 wh~,~ehl the molar ratio of the first active ingredient to the second active ingredient is from
1:30 to 1:36, preferably about 1:32.5.
It has been found that the combination of active ingredients according to the invention is
advantageous because it gives a significantly improved anti-infl~mm~tory effect compared
2S to known tre~tment~ Tnt~ tional patent publication no. WO 93/1 1773 discloses a
combination of budesonide and formoterol having a wide weight ratio range. The closest
example of a combination disclosed in this doc-~ment to the system of the invention has a
weight ratio of forrnoterol fumarate dihydrate to budesonide of 0.06:1, i.e. a molar ratio of
1:16.3. The combination of active ingredients according to the invention gives surprisingly
30 better results when used to treat patients suffering from asthma compared to this known
combination.
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The first and second active ingredients of the kit can be ~lm;nict~red sequentially or
separately to treat rei,~i~dtory disorders. By sequential is meant that the first and second
active ingredients are ~-1mini~tered one irnmediately after the other. They still have the
s desired effect if they are iq~rninictered separately but less than about 12 hours apart,
preferably less than about 2 hours apart, more preferably less than about 30 minlltes apart.
Preferably the first active ingredient is ~-lminietered to provide a daily dose of from 10 to
250nmol (preferably from 15 to 120nmol) and the second active ingredient is ?~1minigtered
o to provide a daily dose offrom 0.1 to lO~Lmol (preferably 0.2 to S,umol) or from 39 to
4300~g ofthe second active ingredient (preferably from 86 to 215011g), subject to the
molar ratio of the first active ingredient to the second active ingredient being within the
range of from 1 :30 to I :36.
Suitable physiologically acceptable salts of formoterol include acid addition salts derived
from inorganic and organic acids, for example the chloride, bromide, sl-lph~te, phosphate,
maleate, rulll~dLe, tartrate, citrate, ben7n~te, 4-methoxyben7-~te, 2- or 4-hydroxyben70~qt~,
4-chloroben7O~te p-tol-l~n(?s-llphonate, methanesulphonate, ascorbate, acetate, succinate,
lactate, glu~LLd~e, gluconate, tricarballylate, hydroxyn~phth~lene-carboxylate or oleate salts
or solvates thereof. l~e first active ingredient is preferably formoterol fumarate, especially
the dihydrate.
When the first active ingredient is formoterol fumarate dihydrate, the preferred daily dose
of the first active ingredient is from 4 to l OO~lg, more preferably from 6 to 50~g (subject to
the molar ratio of the first actlve ingredient to the second active ingredient being within the
range of from 1 :30 to 1 :36).
Most preferably the composition or kit of the invention comprises 6~g of formoterol
ruul~dle dihydrate and 200~1g of budesonide, or 4.5~Lg of formoterol fumarate dihydrate
and 160~1g of budesonide, either of ~vhich is ~-lmini~t~red up to four times a day.
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tPrn~tively the composition or kit of the invention comprises 12,ug of formoterol
fumarate dihydrate and 400~1g of budesonide, or 9,ug of formoterol fumarate dihydrate and
320,ug of budesonide, either of which is arlminict~red once or twice a day.
s Preferably the active ingredient(s~ are used in ~lmixtllre with one or more
ph~rm~entically acceptable additives, ~ nt~ or carriers, preferably in an amount of from
50~1g to 25mg per dose, more preferably in an amount of from 50~1g to l Omg, most
preferably in an amount of from l 00 to 2000,ug. Examples of suitable diluents or carriers
include 1~rtose, dextran, m~nnitol and glucose. Preferably lactose is used, especially as the
10 monohydrate.
It should be understood that where reference is made to the amounts of each active
ingredient that these are metered amounts. When the active ingredients are ~minietered,
the amount of each ingredient inhaled by the patient can differ from the metered amount,
e.g. due to retention of the active ingredient in the inhalation device. Furthermore when
the active ingredients are fo~m~ te~l sep~ualely~ the ~rlminict~red arnourlt of each is not
nec~s~ri1y reduced proportionately. Thus the ~-lmini~t~red ratio of the active ingredients
could differ from the metered ratio. Preferably the ~lmini~t~red ratio is within the metered
ratio specified above.
One or more of the active ingredients used in the invention is preferably in the forrn of a
dry powder, more preferably a finely divided, e.g. a micronised, dry powder, e.g. having a
mass median diameter of less than l0~1m, for exarnple from I to 5~m, most preferably an
agglomerated micronised dry powder. As an alternative to agglomeration the finely
2S divided active ingredients may be in the form of an ordered mixture with the one or more
ph~ ceutically acceptable additives, diluents or carriers. An ordered mixture is the
combination of finely divided active ingredient with coarse particles of ph~ eutically
acceptable additive, diluent or carrier. The ingredients used in the invention can be
obtained in these ~L.,rel~ed forms using methods known to those of skill in the art.
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s
According to the invention there is further provided the use of a composition or kit
according to the invention in the manufacture of a medicament for use in the tr~tment of a
hdl~ly disorder, e.g. ~ethm~ The invention also provides the use of budesonide or of
formoterol in the m~nllf~cture of a kit or of a composition according to the invention for
use in the tre~tment of a ~e;~uhcLLoly disorder, e.g. ~cthm~
~clmini~tration may be by inh~l~t;on orally or intr~n~lly. The ingredients are preferably
adapted to be ~iminictered from a dry powder inhaler, a ~lc;,~ul;sed metered dose inhaler,
or a nebuliser.
When the ingredients of the composition or kit are adapted to be ~mini~t~red from a
pre;,~lllised inhaler, they are preferably in micronised form. They are dissolved or,
preferably, suspended in a liquid propellant ~ Lu~t. The propellants which can be used
include chlorofluorocarbons, hydrocarbons or hydrofluoro~lk~n~c Especially plerell..d
propellants are P 1 34a (tetrafluoroethane) and P227 (h~La~luolupr(,~le) each of which
may be used alone or in combination. They are optionally used in combination with one or
more other propellants and/or one or more s-lrf~-~t~nt~ and/or one or more other excipients,
for example ethanol, a lubricant, an anti-oxidant and/or a stabilising agent.
20 When the ingredients of the composition or kit of the invention are adapted to be
~riminict~red via a nebuliser they may be in the form of a nebulised aqueous ~u~ension or
solution, with or without a suitable pH or tonicity adJustment, either as a unit dose or
multidose device.
25 The composition or kit may optionally be ~imini.~t~red as divided doses from 1 to 4, and
preferably once or twice a day.
The invention is illustrated by the following Exarnples which are not intended to limit the
scope of the application. In the Examples micronisation is carried out in a conventional
30 manner such that the particle size range for each component is suitable for ~lminic~tiQn
by inhalation. Turbuhaler is a trademark of Astra AB.
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W O 98115280 PCT/SE97101606
Example I
6 Parts by weight of formoterol fumarate dihydrate was mixed with 794 parts by weight of
lactose monohydrate. The blend was micronised using a high ples~ air jet mill and then
conditioned using the process of EP-A-717 616. 200 Parts by weight of micronised- budesonide was added to the conditioned product by mixing and homogenising with a low
pressure jet mill. The llliiCLlllG was then spheronised using the process of EP-A-72 1 331
and filled into the storage C(J11~ llen:t of a Turbuhaler.
0 Example 2
4.5 Parts by weight of formoterol fumarate dihydrate was mixed with 835 parts by weight
of lactose monohydrate. The blend was micronised using a high pressure air jet mill and
then conditioned using the process of EP-A-7 17 616. 160 Parts by weight of micronised
budesonide was added to the conditioned product by mixing and homogenising with a low
pressure jet mill. The mixture was then spheronised using the process of EP-A-72 1 331
and filled into the storage co~ lent of a Turbuhaler.
I~xample 3
12 Parts by weight of forrnoterol furnarate dihydrate was mixed with 588 parts by weight
of lactose monohydrate. The blend was rnicronised using a high pressure air jet mill and
then conditioned using the process of EP-A-7 17 616. 400 Parts by weight of micronised
budesonide was added to tne conditioned product by mixing and homogenising with a low
~)leSSulc jet mill. The mixture was then spheronised using the process of EP-A-721 331
and filled into the storage COlll~ nent of a Turbuhaler.
Eicample 4
6 Parts by weight of formoterol fumarate dihydrate was mixed with 994 parts by weight of
lactose monohydrate. The blend was micronised using a high pressure air jet rnill and then
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conditioned using the process of EP-A-717 616. The mixture was then spheronised using
the process of EP-A-721 331 and filled into the storage compartment of a Turbuhaler.
200 Parts by weight of micronised budesonide was mixed with 800 parts by weight of
s lactose monohydrate. The blend was micronised using a high ~les~llle air jet mill and then
conditioned using the process of EP-A-717 616. The mixture was then spheronised using
the process of EP-A-721 331 and filled into the storage CO~ u Llllent of a Turbuhaler.
Example S
o 4.5 Parts by weight of formoterol rulll~d~ dihydrate was mixed with 995 parts by weight
of lactose monohydrate. The blend was micronised using a high pressure air jet mill and
then conditioned using the process of EP-A-717 616. The mixture was then spheronised
using the process of EP-A-721 331 and filled into the storage co~ llent of a
Turbuhaler.
160 Parts by weight of micronised budesonide was mixed with 840 parts by weight of
lactose monohydrate. The blend was micronised using a high pressure air jet mill and then
conditioned using the process of EP-A-717 616. The llli~LuL~ was then spheronised using
the process of EP-A-721 331 and filled into the storage colll~ L~llent of a Turbuhaler.
Example 6
12 Parts by weight of formoterol fumarate dihydrate was mixed with 988 parts by weight
of lactose monohydrate. The blend was micronised using a high ~r~,s~uLc air jet mill and
then conditioned using the process of EP-A-717 616. The mixture was then spheronised
using the process of EP-A-721 331 and filled into the storage COlLl~d~ Illlent of a
Turbuhaler.
400 Parts by weight of micronised budesonide was mixed with 600 parts by weight of
lactose monohydrate. The blend was micronised using a high ~L~S~U1G air jet mill and then
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conditioned using the process of EP-A-717 616. The ll~Lule was then spheronised using
the process of EP-A-721 331 and filled into the storage c~m~ Llllc~lL of a Turbuhaler.
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