Note: Descriptions are shown in the official language in which they were submitted.
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Op Ml IO 1NG F N E
TIMCZLOI, AP,g~~ICAsBLE IN THE FORM OF DROPg
The present invention relates to an ophthalmic gel preparation applicable in
the femi of drops,
containing tirnolol and the free form of diclofenamlde. Furdurmore, the
present invention
relates to the use of a gel preparation applicable in the form of drops,
containing timotol and
the free form of diclofenamide for treatment of ocular hypertension and ocular
circulation
disorders and for treatment of primary and xcondary open-angle glaucoma
Glaucoma is a degecierative disease of the eye which is chamctezlzed by damage
bo the optic
nerve due to elevated intraocular pressure, so there may be a loss in the
field of vision. If left
untreated, glaucoma may lead to blindness. Furthermore, it has recently beets
assumed that
one of the reasons for the developrncnt of glaucoma is a disturbance in
microcirculation in the
optical vessels in addition to th.e elevated intraacular pressure, which has
traditionally been
diagnosed as the typical symptom of glaucoma.
A number of active ingr~ients with which the intraoeular pressure can 6e
lowered and thus
the glaucoma can be treated are known in the state of the art. These include,
for example,
beta-receptor blockers such as timolol and carboanhydrase inhibitors
diclafenatnide,
dorzolamide, brinz~olamidc and latatwprost, a prostaglandin derivative.
In particular, it hes long been known that diclofenamide (INN: 4,5-
dichlorobenzene-1,3-
disulfonarnide) can be used to lower intraocuiar pressure. In this method, the
free form of
diclofenamide is administered almost exclusively systemically in the state of
the art; although
this does effectively lower intraoeuler pressure, ii is associated with
considerable negative
side. effects such as states of confusion, gastrointestinal disorders,
tingling and a feeling of
drowsiness. $ecause of these oonsidctable adverse effects, patietlts are not
very willing to
take such carboanhydrase inhibitors administered systemically. ThlS 15 known
as low
compliance.
Since carboar~hydrase is a multifunctional eruyrne that is expressed in
various tissues in the
human body and also because of the known adverse effects, tt~re have been
attempts to
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administer carboanhydrase inhibitors topically, i.e., directly in the eye, to
thereby lower
intraocular pressure without the side effects mentioned above.
European Patent EP 033 042 H 1 teaches the use of various carboanhydrase
inhibitors in the
form aftheir alkali metal salts for producing ophthalmic inserts and
solutions. The use of
carboanhydrase inhibitors in the farm of their alkali metal salts ensures that
the active
ingredients are present is dissolved form in tha ophthalmic preparations.
This is necessary because according to the teaching of this patent, topical
administration of
the $~ee form of diclofenamide does not lower intraocular pressure.
European Patent OI4 642 B1 discloszs the use of timolol and carboanhydrase
inhibitors in the
form of their alkali metal salts for producing ophthalmic inserts and
solutions far topical use.
The carboanhydrase inhibitors also include dielofenamide. In this patent
application,
reference is also made explicitly to the fact that the carboanlaydrase
inhibitors must be in the
farm of their alkali metal salts in order to be soluble. For the reasons given
above, it is not
considered advisable to use the free acid fonts of diclofenarnide with or
without timolol. The
use of aphthalrnic solutions containing diclofenaraidc ire the form of a
dissolved alkali metal
salts is in principle associated with disadvantages.
To dissolve the alkali metal salts of dielofenamide, the solutions must have a
high pI3 value
(plGi > 8). When solutions (or insects) with such a high pH are used
repeatedly, as is necessary
for glaucoma patients, serious adverse effects may occur, such as considerable
eye irritation
or even corneal damage.
In addition, the use of ophthalmic solutions is associated in principle with
disad4~antages.
although topical use is advantageous per se. ThIS is due to the fact that
usually only approx,
% of the active ingredients reach the eye directly, while the remainder is
transported
through tlxe Iacrimal duct into the nose, where it is absorbed thxough the
mucous membranes.
As a result of this reduced et~'tcicncy of absorption of the active ingredient
directly in the eye,
patients must use these preparations repeatedly, which in turn leads to
reduced patient
Compliance.
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There are known ophthalmic inserts, which are pieced under the eyelid, but
patients usually
perceive these inserts as being unpleasant. Problems with the elevated pH
naturally also
remain when carboanhydrase lnltibitors are used in the form of their alkali
metal salts.
International Patent Application WO O 1ISZ812 A 1 proposes for the first time
the use of the
free acid form of diclofenamide in the foam of a suspension gel for topical
application in the
eye. The advantage of the suspension gel is that the high viscosity of the gel
ensures a longer
dwell time of a<xive ingredient in the eye. Therefore, this overcomes the
baste disadvantages
of solutions, such as the fact that the active ingredients are washed out
rapidly and are
transported through the vitreous chamber channel into the nose, where they are
absorbed
through the nasal mucosa.
Due to the reduced absorption tbrouEtt the nasal mueosa, the number and
severity of systemic
adverse effects are also reduced. Contrary to the teaching of the state of the
art, it has been
demonstrated through WO OII52812 A 1 that when the Eros acid of diclofenamide
is
incorporated into the suspension gel, it is capable of lowering intraocular
pressure when
administered topically to the eye. Since the &ee acid of dielofcnamide is
used, the high pH
values which are used for dissolving the alkali metal salts of diclofenamide
are no longer
necessary. The pH values of the suspension gel era instead in the range of pH
7 to pH 7.5,
which permits good tolerability of the suspension geI.
Despite these positive properties of such suspension gels, there is still a
demand for effective
ophthalmic solutions andlor solutiorrlike preparations in the sense of
preparations having a
lawer viscosity, because a high viscosity and the resulting long dwell time of
suspension gels
in the eye of younger patients such as children in particular is frequently
perceived as
annoying. There is thus a great demand for effective ophthalmic solutions or
solution-like
preparations for treatment of glaucoma, such that these pt~eparations combine
the advantages
of suspension gels with the advantages ox solutions_ Tn particular, there is a
dernand for
ophthalmic preparations which also contain tirnolol In addition to
diclofenamide because an
efficient antihypertensive effect should be achievable through the combination
of the twa
active ingredients.
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Known ophthalmic solutions containing the free form of dielof~amide have the
basic
disadvantage that diclofenamide is not in dissolved form but instead is
present in suspension
form and therefore the substance settles out with a longer storage time. Such
preparations may
be used only if the patient shakes tflem well before use. if the patient
forgets to do so, this
results in using ineffective solutions. The disadvantages of such preparations
are obvious.
The object of the present invention is to make available ophthalmic
compositions having a
solution-like character, such that these compositions contain diclofenamide in
its free form in
combination with timolol and overcome the known disadvantages of prior art
ophthalmic
compositions containing diclofenamide. In particular, one object of the
present invention is to
make available solution-like ophtiaalnuc compositions containing dielofenamide
in its frc;c
form, such that the ophthalmic coraposition is suitable for topical
application and the solution-
like composition combines the advaatages of suspension gels with the
advantages of
solutions. In addition" aaother object of the present invention is to make
available solution-
like ophthalmic compositions which contain diclofenamide in its free form,
whereby the
ophthalmic compositions should be capable of reducing intraocular pressure
through topical
application in glaucoma patients. Another object of the present invention is
to make available
solution-like ophthalmic eornpositions containing diclofenamide in its free
form, whereby the
diclofen$mide essentially does not settle out even after prolonged xtorage
time.
the features of the independent main claim serve to solve these and other
problems, as
derived from the description.
Advantageous embodiments of this invention are defined by the features of the
dependent
subciaims.
The present invention solves the problems mentioned above by providing an
ophthalmic
composition for treatment of glaucoma in the form of a gel prepatation
applicable in the form
of drops, comprising the free form of diclofenatnide, timolol, gel-forming
agent(s), agents)
for adjusting the pH, water sad optionally other conventional additives.
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It has surprisingly been found that by adding timolol to a suspension gel
containitag the free
form of diclofenatnide, the viscosity of the suspension gel is reduced to such
an extent that a
gel suitable For drops is formed and is significantly more fluid than the
suspension gel
containing only diclofenamide in free form, but the diclofenamide essentially
does not settle
out. This surprising change it1 physical properties of the suspension gel due
to the addition of
a second active in~dient makes it possible to produce effective ophthalmic gel
preparations
applicable in the form of drops, containing timolol and diclofenamide in free
farm.
According to this invention, a gel preparation applicable is the form ofdrops
is understood to
mean that the inventive ophthalmic preparation is so free-flowing that it can
be administered
as drops from the storage container with no problem by applying slight
pressure, if necessary,
Such gel preparations are ideal for treatment of elevated intraocular pressure
in glaucoma
patients because a greater reduction in intraocular pressure is achieved
through the
combination of the two active ingredients than would be the case with one
active ingredient
alone. Surprisingly, the antihyprrtensive effect of the two active ingredients
on intraocular
pressure is also synergistic, i.e., the intraocular pressure-reducing effect
of the combination of
the two active ingredients is greater than would be expected by adding the
values for the
individual active ingredleats. Due to the fact that diclpfenamide in its free
form is used in
these preparations, this eliminates the elevated pH values which occur when
alkali metal salts
of diclofenanude are dissolved. The pH values of the inventive preparations
vary between 6.5
and 7.7, preferably between 7 and 7.5, especially preferably around T.2 and
also especially
preferably around 7.3. These pH values ensure that the inventive gel
preparations applicable
in the form of drops will not cause eye irritation.
Due to the fact that th.e inventive gel preparations applicable in the form of
drops can be usod
topically in the eye, this also eliminates the adverse effects Such as those
which occur due to
systemic use of the free acid of diclofenamide.
The reduction in viscosity (in comparison with the corresponding formulation
without
timolol) achieved by the addition of the second active ingredient results in
the invective gel
preparatipns applicable in the form of drops having a viscosity which f rst is
so low that the
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preparations are perceived by the patient as being pleasant in the eye and not
annoying
because of their solution-like properties, while on the other hand, because of
the residual gel
properties still present, there is a longer dwell time of the active
ingredients in the eye and
thus there is greater absorption of the active ingredients in the eyes. Thus
with the inventive
gel preparations, transport to and absorption through the nasal mucosa arc
reduced and the
systetnie adverse effects are also reduced accordingly.
Heeause of the gel-like character, the active ingredients are not washed out
through the
chamber channel as rapidly as they would be with pure solutions. Therefore, a
larger amount
of active ingredient is absorbed in the eye. Since the preparations also
contain two active
ingredients which are synergistic in effect, the inventive gel preparations
applicable in the
form of drops containing timolol and the free form of diclofenamide are
ideally suitable far
lowering intraocular prrssure in glaucoma patients when applied topically.
They thus ideally
combine the properties of ophthalmic soltttlons and ophthalmic suspension
gels.
The inventive Qphthalmic gel preparations applicable in the form of drops also
have the
advantage that although they have a comparatively low viscosity and
diClofenamide is used in
the free form, there is no significant sedimentation of the diclofenamide.
This plxysical effect,
which is achieved by adding timolol and was also unexpected, yields the
inventive gel
preparations that are applicable in the form of drops and do not have to be
shaken before use
or need oni5° be shaken less vigorously. A.c a rule, even bringing the
container holding the
inventive gel preparation that is applicable in the form of drops close to the
eye is su~cienc to
stir up any residues of free diclofenanude which might Gave settled out after
prolonged
standing. As a rule, the inventive gel preparations applicable in the form of
drops need not be
shaken vigorously. ?his ensures that patients who have forgotten to shake the
container will
nevertheless be administering eve solutions to tht eye area.
Formulating ophthalmic compositions containing timolol and the free fonm of
diclofenamide
as gel preparations applicable in the form of drops according to the present
invention yields
highly effective and well-tolerated therapeutic agents for treatment of
primary and secondary
open-angle glaucoma and ocular hypertension.
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The inventive preperatiatu arc also capable of t~educing disturbances in
ocular
microcirculation such as those which are presumed to be an additional cause of
glaucoma.
The inventive gel preparations applicable is the form of drops have a
viscosity between 2 and
4000 mPa~s (tnillipascal seconds), between S and 250D mPa~s, preferably
between 10 and
2000 ~rtPa~s and especially preferably between 12 and 100 tnPa~s, and even
more preferably
between 15 and Ir)0 m~'a~s.
The viscosity of the inventive geI composition applicable in the form of drops
is preferably
adjusted so that the cozlta~ct time in the eye amounts to at least ~ min
(minutes st least
15 min, preferably at least ~0 min, also preferably at feast 60 min and even
more preferably at
least 90 min, u~ particular preferably at least 2 h (hours, most preferably at
!cast 4 h and also
must preferably at least 6 to 8 h_ ..
The confisct time is underswod to be the period of time measured from
application of the
inventive gei preps~ration applicable in the form of drops until the time the
preparation has
been completely washed out of the eye together with the lacrimal fluid. Those
skilled in the
art are aware of how the contact times of gel preparations applicable in the
form of drops oan
be determined. For example, one possibility is to mix a gel containing
Carbopol with
fluorescein. The gel is applied to the conjunctiva! sac and then the
fluorescence of the labeled
gel thus administered is observed in a reflected-Iight microscope with split
lighting.
The active ingredient content of the inventive suspension gels is 0.1 to 10
wt9'ro diclofenamide,
preferably 0. I to 5 wt°lo, more preferably 0.5 to 3 wt%, even more
preferably from 2 to 5 wt%
and most preferably between 3 and S wt°h of the free aci d of
diciofenamide.
With aspect to timolol as the free base, the active ingredient conteztt of the
inventive gel
preparations applicable iri the form of drops is between 0.1 and 1.5 wt9~,
preferably between
0.2 and 1 wt°lo, even more preferably between 0.25 and D_?5
wt°lo and most preferably
between 0.25 and 0.5 wt°1n.
If timoiot is used as a salt, the amounts are to be adjusted accordingly.
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The inventive gel formulation comprising timolol and the free form of
diclofenarnide is
tolerated very well even over a prolonged period of administration, i.e., them
are usually tto
adverse effects in the eye such as bmnirlg and itching.
Amounts given in weight, unless otherr~rise indicated, are always based on the
total
composition of the inventive gel composition applicable in the form of drops.
To produce the inventive suspension gels, the free form of diclofenamide must
usually be
micrn~-~i~xd. This micrnnizing is performed according to the conventional
state-of the-art
methods, e.g., by milling in various types of mills, triturating and
screening.
The micronized particles for use in inventive ophthalmic compositions
preferably have
particle sizes of less than 90 ltm, preferably less then 50 pm, especially
preferably less than
25 um.
Tirnolol may be used in the form of the free base, or also in the form of its
pharmaceutically
usable derivatives, salts and the like which have the same effect. When
reference is made to
timolol, this includes not only the base but especially preferably the
hydrogen maleate salt of
timolol.
Before further processing to yield the gel applicable in the form of drops,
the mieronized
diclafenamide is preferably sterilized. According to this invention, all
polymer compounds
suitable for producing stable suspension gals may be used as gel-forming
agents. In particular
the gel-~orming agemt is selected from the group consisting of polyacrylic
acid, cellulose
ether, polyvinyl alcohol and polysaccharides, which may be of either synthetic
or natural
origin.
The use of hydrogels based on polyacrylic acid andlor cellulose ether is
especially preferned_
Polyacrylic acid gels, in particular those based on csrbomers of the Carbopol~
type available
commercially from B.h. Goodrich are especially preferred. The use of Carbopol~
980 NF as
a gel-forming agent in the inventive gel preparations applicable in the form
of drops is
particularly preferred.
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In preferred embodiments of the inventive gel preparations applicable in the
form of drops,
polyacrylic acid gels such as Carbopol~, in particular Carbopol~7 980 NF with
a
concentration of >0 to 10 wt%, preferably 4.01 wt% to 5 wt°l°,
even more preferably
0.05 wt% to I vet°!°, more preferably 0.1 wt% to 0.5
wt°lo and most preferably 0.2 wt°!° to
O.A wt% are included.
To prevent any contamination of the gel during application, the inventive
ophthalmic
compositions may be preserved by adding a preservative. Suitatble
preservatives include all
the substances with which those skilled in the art are very familiar and which
are suitable for
use in the eye, for example, benzyl alcohol, benzalkonium chloride or other
quaternary
annmoniutn compounds, chlothelcidine diacetate or digluconatc, thiotncrsaI,
etc. Use of
benzododecinium salts, in particular benzododecinium chloride, is especially
preferred. A
benzododecinium chloride content of 0.003 wt% to 0.05 v~t%, preferably 0.01
wt%, is
preferred.
As another additive, preferably sorbitol is used in the inventive
compositions. In p1'efdred
embodiments of the inventive diclofettunide gel preparations applicable in the
form of drops,
sorbitol is present in an amount of 0 to 10 wt°.'o, preferably 2 wt% to
8 wt%, especially
preferably 3 wt°~° to 6 wt% and most preferably between 3,5 wt%
and 4.5 wt°to.
Instead of sorbitol, gIy.,erol, mannitol andlor dextrose, for example, tray
also be used.
Mineral acids and bases are preferably used to adjust the pH of the inventive
gel preparations
applicable in the form of drops. Use of sodium hydroxide and/or hydrochloric
acid is
especially preferred. The pH of the inventive ophthalmic compositions is
preferably between
pH 6.5 and pH ?.7, especially between pH 7.0 and p)~-17_S and most preferably
between pH
?.2 and pH and pH 7.3.
The inventive gel preparations applicable in the form of drops are produced by
the usual state-
of the-art methods, First, the so-called basic gel or matrix is produced with
all ingredients
except for diclofenamide_ The basic gel is sterile and already has the desired
low viscosity.
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The micronized active ingredient diclofenamide is sterilized and added to this
sterile
suspension geI matrix. Then it is prepared to yield a campletely uniform
distribution of the
suspended diclofenamide particles-
The following exarttples are used to present especially preferred embodiments
of the present
invention. They are by no means to be interpreted restricti~~ely.
Exam~sles 1 through 4:
Four gel preparations applicable in the form of drops containing diclofenamide
in the free
form inn concentrations of 3 to 5 wt°lo and timolol in concentrations
of 0.25 to 0.5 wt% were
prepared. Timolol was used in the form of the hydrogen maleate salt. The
compositions of the
individual examples are summarized in the following mbIe. All the percentage
t~mounts arc
understood to be percent by weight (wt%) baqed on the total composition. The
suspension
gels producad in this way have the physical properties shown in Table 2.
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Ta le 1:
Ingredients Exampla 1 Example 2 Example 3 Example 4
D~cIofen~tllide 3 5 3 3
(%)
Timoiol (!) 4.S 0.5 0.25 0.25
Timalol hydrogen 0.683 0.683 0,342 0.3x2
maleate (f)
Carbomer (CarbopolQO0.2 0.2 0.2 0.4
980 NFL
(%)
B~nxoaoaeci~i,~ o.oi 0.01 0.01 0.01
~rloria~ (ai)
Sorbit4l 3.75 4.00 4.48 4.25
Sodium hydroxide 0.146 0.146 0.112 0_2
(%}
Water for injectionto 100 to 100 to 100 to 100
purposes
(%)
r,
Properties Example 1 Example 2 Example 3 Example 4
(strong) (weak)
pl-I value 7.2 7.z ?.z 7.2
Osrnolality 275 - 295 270 - 290 290 - 310 295 - 305
(mOsmollkg)
Viscosity (ml'~a~s) 10 - 30 2 - I S 50 - 80 1400 - 1900
