Note: Descriptions are shown in the official language in which they were submitted.
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PHARMACEU11CAL COMPOSTfIONS COMPRISING MICELLES COMPRISING LIPOPHI1.1C
GLUCOCORTICOS
TEROID AND ONLY ONE SURFACTANT ..
F>ELD OF INVENTION
s The present invention relates to a pharmaceutical composition comprising
micelles in an
aqueous medium, wherein the micelles comprise a lipophilic glucocorticosteroid
and one
and only one pharmaceutically acceptable surfactant The invention further
relates to a
process for the preparation of the pharmaceutical composition and use of the
pharmaceu-
tical composition for the manufacture of a medicament for treating allergic
and/or inflam-
~o matory diseases in the respiratory tract or for treating intestinal
diseases and methods for
treatment of the diseases in a mammal, including man.
BACKGROUND OF THE INVENTION
is Rhinitis and asthma are today effectively treated by the use of
glucocorticosteroids such as
e.g. mometasone furoate, budesonide, and fluticasone propionate. Patent
applications that
can be mentioned in this context are WO 92/I3873 and WO 96/19199 both to Astra
AB of
Sweden.
2o Well-known methods of administering the glucocorticosteroids are by oral
and nasal
inhalation. The glucocorticosteroid compositions are used in the form of
powders in dry
powder inhalers, as solutions or suspensions in pressurized metered dose
inhalers (plVlDIs).
A suspension in water is a user-friendly form of administration as the
solution is easily
accepted by the mucosa. However, in a water suspension the glucocorticosteroid
crystals
2s are in contact with the water which can affect the stability of the
glucocorticosteroid. A
glucocorticosteroid ester may be chemically degraded for example by ester
hydrolysis when
using such a compound. Further, the compositions in the form of suspensions
may be less
stable than solutions e.g. due to sedimentation or precipitation. It is also
easier to admini-
ster a solution accurately in comparison with a suspension.
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US 4,994,439 to California Biotechnology discloses aqueous compositions for
trans-
mucosal membrane administration of protein or peptide drugs wherein the
compositions
comprise the drug in mixtures with at least one bile salt or fusidate or a
derivative thereof
and at least one non-ionic detergent of the formula RO(CHR'CH20)"R, wherein
one R is H
and the other R represents the radical of a saturated or unsaturated cyclic or
acyclic organic
alcohol of 6-40 carbons. The use of a mixture of carrier components results in
the forma-
tion of mixed micelles, exhibiting transport efficiencies across mucous
membranes
comparable to or better than those achieved using bile salts/fusidates alone.
Detergents on
their own are said to be poor absorption promoters.
~o
EP 0179583 Ai to Merck & Co. Inc. discloses a system for enhancing the water
dissolution
rate and solubility of poorly soluble drugs. The compositions of EP 0179583 A1
involve
combining the poorly water-soluble drug with the surfactant in appropriate
ratios and by an
appropriate method that results in the formation of an anhydrous product. The
examples are
~s directed to anhydrous compositions of the antiparasitic agents ivermectin
or abamectin and
a surfactant.
It is an object of the present invention to provide a stable aqueous solution
of a lipophilic
glucocorticosteroid for use as a medicament, especially for treating allergic
and/or inflam
20 oratory diseases in the respiratory tract and also for treating intestinal
diseases such as
inflammatory bowel diseases (IBD), ulcerative colitis and Crohn's disease.
It is a further object of the invention to provide a process for the
preparation of such a
stable solution.
2s
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SUMMARY OF THE INVENTION
According to the invention there is provided a pharmaceutical composition
comprising
micelles in an aqueous medium, wherein the micelles comprise a lipophilic
glucocortico-
steroid and one and only one pharmaceutically acceptable surfactant.
According to a preferred embodiment the composition comprises one and only one
non-
ionic surfactant.
~o According to another preferred embodiment the composition is used for
treating allergic
and/or inflammatory diseases in the respiratory tract.
According to yet another preferred embodiment the composition is used for
treating
intestinal diseases.
is
According to a further aspect of the invention a process for the preparation
of a
pharmaceutical composition comprising micelles in as aqueous medium, wherein
the
micelles comprise a lipophilic glucocorticosteroid and one and only one
pharmaceutically
acceptable surfactant, the process comprising the steps of:
xo a) dissolving the glucocorticosteroid in the surfactant;
b) adding an aqueous medium to the solution from step a) and stirring the
solution.
According to yet another aspect of the invention use of a composition
comprising micelles
in an aqueous medium, wherein the micelles comprise a lipophilic
glucocorticosteroid and
is one and only one pharmaceutically acceptable surfactant, for the
manufacture of a
medicament for treating allergic and inflammatory diseases in the respiratory
tract is
obtained.
According to a further aspect of the invention use of a composition comprising
micelles in
so an aqueous medium, wherein the micelles comprise a lipophilic
giucocorticosteroid and
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one and only one pharmaceutically acceptable surfactant for the manufacture of
a medica-
ment for treating intestinal diseases is obtained.
Another aspect of the invention is a method for treatment of allergic and/or
inflammatory
diseases in the respiratory tract of a mammal, including man. The method is
characterized
by administration to the mammal in need of such treatment of an
therapeutically effective
amount of a pharmaceutical composition comprising micelles in an aqueous
medium,
wherein the micelles comprise a lipophilic glucocorticosteroid and one and
only one
pharmaceutically acceptable surfactant.
~o
A last aspect of the invention is a method for treatment of intestinal
diseases in a mammal,
including man. The method is characterized by administration to the mammal in
need of
such treatment of an therapeutically effective amount of a pharmaceutical
composition
comprising micelles in an aqueous medium, wherein the micelles comprise a
lipophilic
a glucocorticosteroid and one and only one pharmaceutically acceptable
surfactant.
DETAILED DESCRIPTION OF THE INVENTION
According to the present invention it was found that lipophilic
glucocorticosteroids and
zo their esters can be incoeporated in micelles formed by a surfactant,
especially a non-ionic
surfactant, in an aqueous medium. According to "Pharmaceutical Dosage Forms;
Disperse
Systems", vol.l, p.315 ff (1988) ed. by FLA. Lieberman et al, micelles are
molecular ' ..
aggregates formed in the solution of a surfactant. Surfactants in a dilute
aqueous solution
exist primarily as monomers, but at higher concentrations a number of
surfactant molecules
zs aggregate to form micelles. Thereby a stable formulation is obtained in
which the lipophilic
glucocorticosteroid/glucocorticosteroid ester is protected and is possible to
be absorbed.
The micelles will act as non-aqueous reservoirs for the lipophilic
glucocorticosteroid and
will positively affect the pharmacolcinetic and deposition of the
glucocorticosteroid
so molecule. The glucocorticosteroid will also be more easy to dose accurately
as well as for
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the patient to administer accurately. For further information of the
expression "lipophiiic"
reference can be made to the above mentioned reference where on p. 155 it is
stated that
"lipophilic drugs may be wetted by oils and semipolar liquids."
The problem with preparation of compositions comprising the lipophilic
glucocortico-
steroids used in the invention in an aqueous medium is that they are very
difficult to
dissolve in water and then to obtain a stable composition. It was found in the
present
invention that by dissolving the lipophilic glucocorticosteroid in a
surfactant, preferably a
non-ionic surfactant, stable compositions can be obtained with the
glucocorticosteroid in
io micellar form.
The inventor of the present invention, has further found that use of the
stable compositions
comprising e.g. rofleponide palmitate incorporated in micelles formed by a
surfactant,
causes less irritation in the lung after oral inhaiation by human patients,
than is experienced
is after oral inhalation of the same surfactant on its own.
The present compositions comprise one and only one surfactant. The surfactant
used in the
present compositions can be non-ionic, zwitterionic, anionic or cationic. It
is, however,
preferred, to use a non-ionic surfactant, since this normally reduces the risk
of side-effects
zo after administration. Examples of non-ionic, zwitterionic, anionic or
cationic surfactants
which may be used in the present invention can be found in Wade and Welter,
Handbook
of Pharmaceutical Excipients, 1994, The Pharmaceutical Press, London.
The non-ionic surfactants used according to the present invention are suitably
selected from
2s poloxamers, e.g. poloxamer 188; poiyoxyethylene alkyl ethers, e.g. poloxyl
10 stearyl
ether, poloxyl 20 stearyl ether; polyoxyethyiene stearates, e.g. polyoxyl 8
stearate, poloxyl
12 stearate; polyoxyethyleneglycol hydroxystearates, e.g.
polyoxyethyleneglycol 12-
hydroxystearates, and polyoxyethylene sorbitan fatty acid esters. A preferred
group of non-
ionic surfactants is polyoxyethylene sorbitan fatty acid esters, e.g.
polyoxyethylene 20
3o sorbitan monolaurate, monopalmitate, monostearate or monooleate also known
as poly-
.. __.
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sorbate 20, polysorbate 40, polysorbate 60 and polysorbate 80, respectively
Examples of
~.
suitable commercial polysorbates are Tween 20, Tween 40, Tween 60 and Tween
80.
A further preferred group of non-ionic surfactants is polyoxyethylenegiycol 12-
hydroxy-
stearates and an especially preferred compound is polyoxyethyleneglycol 660 12-
hydroxy-
stearate.
In the present invention, lipophilic glucocortieosteroids relate to lipophilic
glucocortico-
steroids per se, as well as their pharmaceutically acceptable solvates,
esters, acetals and
salts, and solvates of any of these.
~o
Examples of glucocorticosteroids which may be used in the present invention
include
betamethasone, fluticasone (e.g. as propionate), budesonide, tipredane,
dexamethasone,
beclomethasone (e.g. as dipropionate), prednisolone, fluocinolone (e.g. as
acetonide),
triamcinolone (e.g. as acetonide), mometasone (e.g. as furoate), rofleponide
(e.g. as
~s palmitate), flumethasone, flunisolide, ciclesonide, deflazacort,
cortivazol, 16a,17a-
butylidenedioxy-6a,9a-difluoro-11 (3,21-dihydroxy-pregna-1,4-diene-3,20-dione;
6oc,9a-
difluoro-11 /3-hydroxy-16a,17a-butylidenedioxy-17(3-methylthio-androsta-4.-ene-
3-one;
16oc,17a-butylidenedioxy-6a,9a-difluoro-11 (3-hydroxy-3-oxo-androsta-1,4-diene-
17~3-
carbothioic acid S-methyl ester; methyl 9a-chloro-6a-fluoro-113-hydroxy-16a-
methyl-3-
20 oxo-17a-propionyloxy-androsta-1,4-diene-17a-carboxylate; 6a,9a-difluoro-l
lei-hydroxy-
16a-methyl-3-oxo-17a-propionyloxy-androsta-1,4-diene-17~i-carbothioic acid S-
(2-oxo-
tetrahydrofuran-3-yl) ester; optionally in their pure isomeric forms (where
such forms w
exist) and/or in the form of their pharmaceutically acceptable solvates,
esters, acetals or
salts, or where applicable solvates of any of these. Suitably, use is made of
mometasone
is furoate, beclomethasone dipropionate or fluticasone propionate or
glucocorticosteroids
with an asymmetric acetal structure, e.g. comprising 16a,17a-butylidenedioxy
group, such
as budesonide or rofleponide or pharmaceutically acceptable solvates, esters,
acetals or
salts, or where applicable, solvates thereof. The most preferred lipophilic
glucocorticosteroid ester is rofleponide palnutate.
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The amount of surfactant used in the composition should be less than 5 % (w/w)
of the
total composition weight. Preferably the amount of surfactant is less than 3 %
(w/w) and
most preferably less than 1 % (w/w) of the total composition weight. The
concentration of
s the surfactant must, however, be higher than the critical micellar
concentration (CMC),
being the lowest concentration at which micelles are formed in an aqueous
medium. The
CMC value-depends primarily upon the temperature and the concentration of
possible
additives. It lies within the competence of the skilled person to determine
the CMC for
each indivi-dual composition and thus prepare suitable micelles according to
the present
io invention.
The amount of the glucocorticosteroid used depends on the field of use. If the
glucocorti-
costeroid is used for treating diseases in the respiratory tract by inhalation
a suitable daily
dose is from 10 to 2400 fig, preferably from 10 to 1600 ~tg. If the
glucocorticosteroid is
~s used for treating intestinal diseases a suitable daily dose is from 400 to
4000 p.g, preferably
from 800 to 3000 ~,g.
The composition according to the invention may also contain one or more
pharmaceutically
acceptable additives such as buffers and other pH modifiers, antioxidants,
complexing
Zo agents to further increase the stability, viscosity regulating agents and
isotonicity modifying
agents. Compounds used as such agents are compounds generally used in drug
formula-
tions e.g. EDTA for complexing and carboxymethyl cellulose (CMC) for
regulating-
viscosity. As substances for adjusting the isotonicity can be mentioned
glucose, mannitol,
salts, glycerol and propylene-glycol. Preferably alkaline buffers are used
such that the pH
2s of the composition is from 4 to 7. It is, however, preferred to use one or
more antl-
oxidant(s), which may be water-soluble to a smaller or larger degree. Examples
of such
antioxidants include, without limitation, tocopherols, especially a-
tocopherol, and
preferably racemic a-tocopherol, butylhydroxyanisole (BHA),
butylhydroxytoluene (BHT)
and ascorbic acid.
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In order to prepare the aqueous composition according to the present invention
the gluco-
corticosteroid drug has to be dissolved in a first step. It was found in the
present invention
that a stable composition of the glucocorticosteroid is obtained if the
glucocorticosteroid is
dissolved in the surfactant. Then the aqueous medium is added to the
glucocorticosteroid-
s surfactant solution and the mixture is stirred, preferably intensely
stirred, to obtain a stable
and homogeneous solution. Preferably the aqueous medium is of the same
temperature as
the one of the glucocorticosteroid-surfactant solution before it is added to
the solution. If
other pharmaceutically acceptable additives are used they are suitably added
to the aqueous
medium before mixing with the glucocorticosteroid-surfactant solution if they
are water
~o soluble. (3therwise they are added to the surfactant solution. In a
preferred embodiment of
the process glucose is dissolved in the aqueous medium in an isotonic amount.
The surfactant used can be a solid compound at ambient temperature or a more
or less fluid
compound. If a solid surfactant is used it should be heated in order to melt
it in a first step
is of the process. The glucocolticosteroid is then dissolved in the melted
surfactant. This is a
preferred embodiment of the invention.
If the surfactant is fluid enough the glucocorticosteroid can be dissolved
directly in the
surfactant at ambient temperature or it may be suitable to increase the
temperature of the
2o surfactant to more readily dissolve the glucocorticosteroid. Then the water
is added.
A further possibility is to dissolve the surfactant in a conventional organic
solvent, e.g...
ethanol, and then to dissolve the glucocorticosteroid in this solution or vice
versa. The
organic solvent then has to be evaporated before the aqueous medium is added.
It is impor-
ts tart that the organic solvent is removed from the composition otherwise the
composition
will have a stinging effect in the nose of the patient if the composition is
used for the
manufacture of a medicament for treating allergic and/or inflammatory diseases
in the
respiratory tract.
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Optionally the composition according to the invention can be made sterile in a
conven-
tional manner, e.g. by using dry heat, steam or irradiation.
The composition according to the invention is used for the manufacture of a
medicament
for treating allergic and/or inflammatory diseases in the respiratory tract.
The composition
can then be administered via the upper and lower respiratory tract, including
nasal or oral
inhalation. The composition according to the invention can be used in common
devices for
aqueous solutions for nasal and oral inhalation e.g. in a spray pump or in a
nebulizer. For
administration by nebulisation reference is made to "Medication Nebulizer
Performance",
io Chest 110(2), (1996), pp. 498-505. The composition according to the
invention is also used
for the manufacture of a medicament for treating intestinal diseases such as
inflammatory
bowel diseases (IBD), ulcerative colitis and Crohn's disease. The compositions
can then be
administered by rectal administration.
a The invention also relates to a method for treatment of allergic and/or
inflammatory
diseases in the respiratory tract of a mammal, including man. The composition
according to
the invention is administered in a therapeutically effective amount to the
mammal in need
of such a treatment, preferably by nasal or oral inhalation.
2o The invention also relates to a method of treatment of intestinal diseases
in a mammal,
including man. The composition according to the invention is administered in a
therapeu-
tically effective amount to the mammal in need of such a treatment, preferably
by rectal
administration.
2s The invention will now be illustrated by the following non-limiting
example:
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EXAMPLE
Manufacturing of rofleponide palmitate in micellar solution.
5 g Solutol~ HS 15 (polyethyleneglycol 660 12-hydroxystearate) manufactured by
BASF of
Germany is melted in a beaker at 35°C-40°C. 100 mg rofleponide
paimitate is added to the
melt and dissolved.
An isotonic solution of 25 g glucose in 495 g water is heated to 35-
40°C and added to the
~o melt using intense stirring. A clear solution containing 0.2 mg rofleponide
palmitate/ml is
obtained.
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