Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
CA 02761740 2011-11-10
1
Phosphate-free pharmaceutical composition for the treatment of
glaucoma
The invention relates to a phosphate-free pharmaceutical composition
which comprises at least one FP prostanoid receptor agonist and/or at
least one prostamide receptor agonist and also citrate salts and/or citric
acid.
Glaucomas which are also termed green star can lead to a loss of retinal
ganglion cells and optic nerve fibres up to complete blinding because of
increased intraocular pressure. The pressure building up intraocularly
can be attributed to an impairment in the outflow of aqueous humour
from the anterior chamber and the posterior chamber of the eye.
Normally, the aqueous humour secreted by the ciliary body epithelium
leaves the eye via the uveoscleral and the trabecular outflow.
There are used for the therapy of glaucoma, for example
parasympathomimetic agents, such as for example pilocarpine, or
sympathomimetic agents, such as for example dipivefrin.
Betablockers are also used to reduce the intraocular pressure, such as
timolol, and carbonic anhydrase inhibitors, such as dorzolamide, which
effect throttling of the inflow or a reduction in the production of the
aqueous humour in the chamber.
CA 02761740 2011-11-10
2
Also prostaglandin analogues, such as latanoprost, tafluprost and
travoprost, and also the prostamide bimatoprost have been used for
several years in the therapy of glaucomas.
The therapy of glaucoma generally involves a long-term treatment.
The use of at least one calcium chelating agent and at least one
ophthalmological viscosity regulator for the production of a phosphate-
free pharmaceutical composition for the treatment and/or prevention of
epithelial defects in the cornea and/or conjunctiva of the eye is known
from PCT/ EP2006 / 011053 .
It has now emerged that, with long-term treatments of glaucoma
patients by topical application of conventional eye drops or eye sprays
on the eye surface, the result can be an impairment in visual capacity
due to clouding of the cornea. This clouding of the cornea can be
caused by inclusions and/or deposits of poorly soluble calcium
phosphates which are included or deposited in or on the cornea and
also the conjunctiva of the eye. This degeneration of the cornea of the
eye is also termed corneal band degeneration or band keratopathy.
Even slight inclusions and/or deposits of poorly soluble calcium
phosphates in or on the cornea of the eye lead to massively increased
sensitivity to bright light which can be attributed to light scattering
effected on the inclusions or deposits of calcium phosphate(s) or of
poorly soluble calcium compounds. In particular night vision is greatly
impaired as a result.
There is therefore a requirement for a pharmaceutical composition
which enables long-term treatment of glaucoma without the previously
mentioned side-effects.
The object underlying the invention is achieved by providing a
phosphate-free pharmaceutical composition, the phosphate-free
CA 02761740 2011-11-10
3
pharmaceutical composition comprising at least one FP prostanoid
receptor agonist and/or at least one prostamide receptor agonist and
also citrate salts and/or citric acid.
Preferred developments are indicated in the sub-claims 2 to 18.
The object underlying the invention is achieved furthermore by the use
of the phosphate-free composition according to the invention for the
production of a medicine for the therapy and/or prevention of
glaucoma.
There are understood by an FP prostanoid receptor, receptors to which
prostaglandin F2alpha analogues and/or prostaglandin F2alpha binds.
There are understood according to the invention by the term FP
prostanoid receptor, also FP receptors to which prostaglandin F2alpha
bind. The FP receptors concern G-protein-coupled receptors, the
endogenous physiological activator of which is prostaglandin F2alpha. In
the case of stimulation of the FP prostanoid receptor, the result is an
increase in the outflow of aqueous humour from the chamber, in
particular via the uveoscleral route.
In addition to stimulation of the FP prostanoid receptor, an outflow of
aqueous humour from the interior of the eye can also be effected by
stimulation of the prostamide receptor. The prostamides concern
prostaglandin F2aipha- l-amides. Without wishing to be bound to one
theory, it is assumed that prostamide binds to the prostamide receptor
and/or the prostanoid receptor and leads to outflow of the aqueous
humour from the interior of the eye, in particular via the uveoscleral
route.
The inventors have now established surprisingly that topical application
of at least one FP prostanoid receptor agonist and/or at least one
0
CA 02761740 2011-11-10
4
prostamide receptor agonist in combination with citrate salts and/or
citric acid enables a completely surprising long-term treatment of the
eye without the undesired side-effects of calcification or furring up of
the cornea and/or the conjunctiva of the eye thereby occurring.
Citrates, i.e. salts of citric acid, and citric acid act inter alia as calcium
chelating agent. Since the pharmaceutical composition according to the
invention is phosphate-free, no additional phosphate is applied to the
surface of the eye, on the one hand. On the other hand, calcium ions,
in particular Ca2+ ions, are complexed by the citric acid or the citrates
so that formation of poorly soluble calcium phosphates and/or calcium
compounds is counteracted or their formation is preferably prevented.
Conventionally, eye drops or eye solutions are preferably phosphate-
buffered since the phosphate buffer is a very stable buffer system with
very good buffer capacity which is in particular very stable in storage.
Citric acid or citric salts, after solution in an aqueous medium,
preferably in water, likewise form a stable buffer system with adequate
buffer capacity although the buffer capacity is weaker in comparison
with a phosphate buffer. The pH value of the pharmaceutical
composition according to the invention is preferably in a physiological
range, preferably in a range of pH 5.5 to 8.5, preferably 5.8 to 7.8,
further preferred of 6.0 to 7.2. The pH value is possibly adjusted by the
addition of acid or alkaline solution, preferably 0.1 N HCl or 0.1 N
NaOH.
Both citric acid, primary, secondary and/or tertiary citrates can be used
for the production of the citrate buffer. There are used as citrates,
preferably alkali metal citrates, further preferred sodium citrates.
Preferably, citric acid, sodium citrate, disodium citrate and/or
trisodium citrate are used. The citrate buffer is present preferably in a
CA 02761740 2011-11-10
concentration of 5 mmol/l to 100 mmol/l, further preferred of 10
mmol/l to 50 mmol/l.
According to an extremely preferred embodiment, the phosphate-free
pharmaceutical composition is also calcium ion-free. Calcium ion-free
in the sense of the invention means that the phosphate-free
pharmaceutical composition comprises less than 0.3 mmol/1 calcium
ions, preferably less than 0.1 mmol/1 calcium ions and in particular
preferably no calcium ions.
There is understood by phosphate-free, in the sense of the invention,
that the pharmaceutical composition comprises less than 7 mmol/l
phosphate ions, preferably less than 3 mmol/l phosphate ions,
particularly preferred less than 1 mmol/l phosphate ions and most
particularly preferred no phosphate ions.
There are understood by the term "phosphate ions", in the sense of the
invention, in particular PO43-, HP042- and/or H2PO4-.
The phosphate-free pharmaceutical composition according to the
invention, because of the absence of phosphate ions and because of the
presence of citrate salts and/or citric acid, prevents the formation of
calcium-phosphate complexes and/or calcium-phosphate compounds
and/or other poorly soluble calcium compounds in the eye, which can
lead to deposition or inclusion on or in the cornea and/or the
conjunctiva of the eye and consequently to a significant restriction in
visual capacity due to light scattering on the calcium-phosphate
complexes and/or calcium-phosphate compounds and/or other poorly
soluble calcium compounds. There are understood by poorly soluble
calcium compounds, in particular compounds which form deposits
and/or inclusions in the cornea.
CA 02761740 2011-11-10
6
The citrate salts and/or citric acid complex calcium ions also
physiologically present in the eye and hence counteract the production
of poorly soluble calcium compounds which can lead to deposits or
inclusions in the cornea and/or conjunctiva of the eye.
The phosphate-free pharmaceutical composition according to the
invention prevents or reduces calcification in the cornea and/or in the
conjunctiva of the eye.
Furthermore, the citrate salts and/or citric acid or the citrate buffer
produced therefrom surprisingly also have the effect of promoting
wound-healing. Hence, the phosphate-free pharmaceutical composition
according to the invention assists regeneration of any defects of the eye
surface which are caused for example by preservatives and/or an
inadequate tear film, in particular the corneal surface and/or
conjunctiva of the eye.
It has been shown that citric acid or the citrates, because of their
complexing properties, in particular due to the complexing of calcium
ions, effect improved penetration of the FP prostanoids or prostamides
from the epithelial side in and through the cornea. It is suspected that
because of the complexing of calcium ions, the result is changes in the
intracellular matrix material of the cornea. It is suspected that these
changes effect loosening of the tight junctions which are also termed
Zonula occludens. The loosening of the tight junctions makes it
possible then that the relatively hydrophobic FP prostanoids or
prostamides can reach the eye interior more easily in and through the
cornea.
The use of citric acid or citrates in combination with FP prostanoid(s)
and/or prostamide(s) leads therefore to a surprising synergistic effect.
On the one hand, citric acid and/or citrates counteract a previously
damaged cornea, for example because of the syndrome of dry eye,
CA 02761740 2011-11-10
7
frequently occurring in elderly patients, and/or by using preservative-
containing eye drops, due to the properties which promote wound-
healing. On the other hand, the citric acid and/or the citrates, because
of loosening the tight junctions due to the complexing of calcium ions,
effect improved absorption of the FP prostanoids or prostamides into
the eye. As a result, the dwell time of the FP prostanoids or
prostamides on the cornea which is required for absorption of the FP
prostanoids and/or prostamides is reduced on the one hand. As a
result, in particular also the possibility of washing out of the FP
prostanoids and/or prostamides from the eye surface, caused by the
natural tear flow of the eye, is reduced and hence the bioavailability of
the FP prostanoids or prostamides in the interior of the eye is increased.
The improved absorption of the FP prostanoids or prostamides makes it
possible to reduce the concentration of the quantity of FP prostanoids
or prostamides to be applied to the cornea.
The above-mentioned FP prostanoids concern in particular latanoprost,
travoprost and/or tafluprost, and the above-mentioned prostamides
concern in particular bimatoprost.
This synergistic effect of citric acid or citrates in conjunction with FP
prostanoids or prostamides is unexpected. As a result, irritation to the
eye surface is reduced or avoided.
The invention also relates to the use of FP prostanoids, in particular
latanoprost, travoprost and/or tafluprost, and/or prostamide, in
particular bimatoprost, in combination with citric acid and/or citrate
for the provision of an increased concentration of the mentioned active
substance/ substances in the aqueous humour of the eye, in the iris
and/or in the ciliary body.
It has therefore emerged surprisingly that the phosphate-free
pharmaceutical composition for the eye, according to the invention, is
CA 02761740 2011-11-10
8
tolerated very well, in particular causes no substantial irritation to the
eye or to the eye surface.
The FP prostanoid receptor agonist and/or the prostamide receptor
agonist are preferably used in a concentration in a range of 0.00001%
by weight to 0.05% by weight, further preferred of 0.00005% by weight
to 0.01% by weight, even further preferred of 0.0001% by weight to
0.005% by weight, respectively relative to the total weight of the
composition.
The phosphate-free pharmaceutical composition according to the
invention enables a reduction in the intraocular pressure in a range of
20 to 40%, normally in a range of 20 to 30%, relative to the intraocular
pressure before application.
The frequency of application of the phosphate-free pharmaceutical
composition according to the invention is effected as a function of the
individual requirement or the severity of the glaucoma. Thus in the
case of eye drops, 1 to 3 drops per eye, preferably once daily, can be
sufficient. In the case of severe glaucoma disease, also more drops, for
example up to 16 drops, also several times daily, can be applied per eye.
According to a further preferred embodiment, the at least one FP
prostanoid receptor agonist and/or the at least one prostamide receptor
agonist concern compounds with the structural formula (I) or (II):
CA 02761740 2011-11-10
9
0 0
x x
HO HO
AMY AMY
i
HO H6
wherein
X stands for, independently of each other, OR3 or NR1R2, wherein R1,
R2, R3 stand for, independently of each other, H, unbranched or
branched alkyl radical with 1 to 8 carbon atoms, preferably 2 to 6
carbon atoms, unbranched or branched OH/substituted alkyl radical
with 1 to 8 carbon atoms, preferably 2 to 6 carbon atoms;
A stands for, independently of each other, CHOH, C=O or CF2;
Y stands for, independently of each other,
unbranched or branched alkyl radical with 1 to 10 carbon atoms,
preferably 3 to 8 carbon atoms,
or for unbranched or branched alkylaryl radical with 6 to 12 carbon
atoms, preferably with 7 to 10 carbon atoms, aryl preferably being
phenyl,
or for trifluoromethyl-substituted alkylaryl radical with 7 to 12 carbon
atoms, preferably with 8 to 9 carbon atoms, aryl preferably being
phenyl,
or for
*4CH2 j-CH3
k
wherein k stands for a whole number from 0 to 9, preferably 2 to 7,
CA 02761740 2011-11-10
or for 4 C H 2+,Q
"4CH2 m \ / CZ3
or
wherein m stands for a whole number from 0 to 6, preferably 2 to 4 and
wherein Z stands for H or F,
or for
4CH2*, 0 0
CZ3
or
wherein n stands for a whole number from 0 to 4, preferably 1 to 3 and
wherein Z stands for H or F.
The above-indicated FP prostanoid receptor agonists or prostamide
receptor agonists can also be present as pharmaceutical acceptable
salts and/or esters.
According to a preferred embodiment of the invention, the FP
prostanoid receptor agonist is selected from the group which consists of
prostaglandin, prostaglandin analogue and mixtures thereof.
According to a preferred development of the invention, the
prostaglandin concerns prostaglandin F2alpha with the structural
formula (III). The prostaglandin F2alpha is also termed dinoprost:
CA 02761740 2011-11-10
11
0
OH
HO
HO 6H
(III)
Prostaglandin F2alpha or dinoprost can also be present as
pharmaceutically acceptable ester, for example as alkyl ester with an
alkyl radical of 1 to 6 carbon atoms. Preferably, the alky ester concerns
an ethyl ester or isopropyl ester. The isopropyl ester has proved to be
very suitable.
According to a further preferred embodiment, the prostaglandin
analogue concerns a prostaglandin F2alpha analogue.
According to a further preferred embodiment, the prostaglandin F2alpha
analogue is selected from the group which consists of latanoprost
(structural formula (IV)), tafluprost (structural formula (V)), travoprost
(structural formula (VI)), unoprostone (structural formula (VII)), and
mixtures and also their pharmaceutically acceptable salts and esters
thereof.
CA 02761740 2011-11-10
12
Latanoprost: o
HO
HO
OH
(IV)
Tafluprost:
o
HO
O \
HO F F
(V)
Travoprost:
o
o
HO
HO O \ CF,
OH
(VI)
CA 02761740 2011-11-10
13
Unoprostone
0
OH
HO
HO
O
(VII)
Unoprostone can also be present as alkyl ester. According to a
preferred embodiment, this hereby concerns an ethyl- or isopropyl
ester.
According to a further variant of the invention, the prostaglandin F2aipha
analogue is a 15-keto-prostaglandin F2a1pha analogue and is preferably
selected from the group which consists of 15-keto-latanoprost, 15-keto-
travoprost and mixtures and also their pharmaceutically acceptable
salts and esters thereof. In this variant, the OH group on the Cis in the
prostaglandin F2aipha analogue is replaced by a keto group.
Prostaglandin F2alpha can be present, according to a variant of the
invention, as amide or else as a pharmaceutically acceptable salt
thereof. The pharmaceutically acceptable salt can for example be a
chloride, acetate, sulphate or mixed salts thereof etc. The
prostaglandin F2aipha amide is also termed prostamide.
According to a preferred embodiment, the prostamide receptor agonist
is prostamide or a prostamide analogue.
Preferably, the prostamide is prostaglandin F2alpha amide and has the
following structural formula (VIII):
'= CA 02761740 2011-11-10
14
0
N
HO RZ
HO
UH
(VIII)
wherein Ri and R2 stand for, independently of each other, hydrogen,
alkyl or hydroxyalkyl with 1 to 8 carbon atoms, preferably 2 to 4 carbon
atoms.
The substituents R1 and R2 are preferably, independently of each other,
hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, n-
pentyl, n-hexyl, n-heptyl or n-octyl. According to a further preferred
embodiment, the above-mentioned preferred alkyl groups are
substituted with at least one OH group. Preferably the OH group is
disposed terminally, i.e. at the end of the alkyl group situated far away
from the nitrogen.
According to a further preferred embodiment, R2 is hydrogen and Ri is
alkyl or hydroxyalkyl with 1 to 8 carbon atoms, preferably with 2 to 4
carbon atoms. R1 is thereby preferably methyl, ethyl, n-propyl,
isopropyl, n-butyl, sec.-butyl, n-pentyl, n-hexyl, n-heptyl or n-octyl.
According to a further preferred embodiment, the above-mentioned
preferred alkyl groups are substituted with at least one OH group.
Preferably, the OH group is disposed terminally, i.e. at the end of the
alkyl group R1 situated far away from the nitrogen.
The substituted amide can thereby be present respectively also as a
pharmaceutically acceptable salt or acceptable ester thereof. The
pharmaceutically acceptable salt can be for example a chloride, acetate,
sulphate, or mixed salts thereof etc.
CA 02761740 2011-11-10
According to a further preferred embodiment, the
prostaglandin F2alpha amide concerns bimatoprost (structural formula
(IX)) or prostaglandin F2alpha-l-ethanol amide (structural formula X)) or
the pharmaceutically acceptable salts or esters thereof.
O o
OH
/
HO H HO
HO = HO
OH OH
Bimatoprost Prostaglandin F2alpha- l -ethanol amide
(IX) (X)
According to a further variant of the invention, the
prostaglandin F2alpha amide analogue is a 15-keto-prostaglandin F2a1pha
amide analogue and is selected preferably from the group which
consists of 15-keto-bimatoprost, 15-keto-prostaglandin F2alpha-1-ethanol
amide and mixtures and also their pharmaceutically acceptable salts
and esters thereof. In this variant, the OH group on the C15 in the
prostaglandin F2aipha amide analogue is replaced by a keto group.
According to a preferred development, the phosphate-free
pharmaceutical composition according to the invention comprises at
least one ophthalmologically tolerable viscosity regulator.
There are termed viscosity regulators in the sense of the invention,
substances which have a viscosity-increasing effect.
In the sense of the invention, there is understood by
"ophthalmologically tolerable", in particular that no irritations to the eye
and possibly no impairments in visual capacity occur.
= CA 02761740 2011-11-10
16
Preferably, the viscosity regulator has a viscoeleastic behaviour. There
is understood by a viscoelastic behaviour according to the invention
that the viscosity changes under the influence of compressive, tensile,
thrust and/or shear stresses. For particular preference, the phosphate-
free pharmaceutical composition according to the invention has the
behaviour of a non-Newtonian liquid as a result of the viscosity
regulator.
The viscosity is preferably in a range of 2 to 1,000 mPa=s, further
preferred in a range of 2 to 500 mPa=s, particularly preferred in a range
to 2 to 100 mPa= s.
The viscosity-increasing effect has the extremely advantageous effect
that the phosphate-free pharmaceutical composition applied to the eye
surface has an increased dwell time and flows off the eye surface again
more slowly. The non-Newtonian flow behaviour of the viscosity
regulator produces a property which is excellent for application to the
eye, namely that the viscosity reduces with increasing shearing rate.
After application of the phosphate-free pharmaceutical composition with
the viscosity regulator on the surface of the eye, a shear stress is
applied to the phosphate-free pharmaceutical composition via blinking
of the eyelid, as a result of which the initially increased viscosity is
reduced. Due to blinking of the eyelid, the viscosity is reduced so that a
uniform film forms on the surface of the eye. After blinking, the
viscosity increases so that the film on the eye surface adheres well and
runs off only slowly, as a result of which the dwell time of the
phosphate-free composition according to the invention on the eye
surface is increased.
Because of the increased dwell time on the eye surface, the
bioavailability of the at least one FP prostanoid receptor agonist and/or
of the at least one prostamide receptor agonist can be increased since
= CA 02761740 2011-11-10
17
rapid outflow of the at least one FP prostanoid receptor agonist and/or
of the at least one prostamide receptor agonist is prevented and
therefore the period of time available for absorption of the active
substances is lengthened.
Preferably, the viscosity regulator acts at the same time as sliding aid
and lubricant on the eye. The sliding and lubricating effect is
advantageous in particular when the eye surface, in particular the
cornea, has already suffered damage, in particular epithelium lesions.
Hence the use of a viscosity regulator is advantageous in particular
when an epithelium lesion has already been effected because of long-
term therapy with conventional pharmaceutical compositions.
According to a preferred embodiment, the quantity of viscosity regulator
is approx. 0.005% by weight up to approx. 5% by weight, preferably
approx. 0.01% by weight up to approx. 1% by weight, respectively
relative to the total weight of the phosphate-free pharmaceutical
composition.
According to a preferred development of the invention, the
ophthalmologically tolerable viscosity regulator is selected from the
group which consists of chondroitin sulphate, polyacrylamide,
polyacrylic acid, polyacrylic resins, polyethylene glycol, cellulose
derivatives, polysaccharides, polyvinyl pyrrolidone, hyaluronic acid,
hyaluronates, derivatives thereof and mixtures thereof.
Hyaluronic acid and the salts thereof, the hyaluronates, have proved to
be very suitable.
Hyaluronic acid is a component of the vitreous body of the eye and in
this respect does not represent a foreign compound to the human
organism. For this reason, hyaluronic acid is very readily tolerated
from an immunological point of view. Furthermore, hyaluronic acid or
CA 02761740 2011-11-10
18
hyaluronate has a structural similarity to mucin. Mucin forms the
lowermost layer of the three-layer tear film and ensures optimum
wetting of the corneal and conjunctival epithelia.
Furthermore, hyaluronic acid has an excellent property for application
to the eye, namely that the viscosity decreases with an increase in the
shearing rate. Hyaluronic acid hence has a non-Newtonian flow
behaviour.
Hyaluronic acid or the salts thereof, hyaluronates or in particular
sodium hyaluronate, has or have excellent optical properties so that no
impairment in the visual capacity results in the patients who are
treated.
Hyaluronic acid or hyaluronate can be isolated from the vitreous body
of the eyes of cattle or else also from cockscombs. Furthermore,
hyaluronic acid or hyaluronate can be produced also in strains of
bacteria with pharmaceutical quality. For example potassium-,
sodium- and/or magnesium hyaluronate can be used as salts of
hyaluronic acid. Sodium hyaluronate is particularly preferred.
Aqueous sodium hyaluronate solutions and/or hyaluronic acid are
exceptionally suitable, on the basis of these physical properties, as
sliding aid and lubricant with a good adhesive effect and extended dwell
time on the conjunctival and corneal epithelia without impairing visual
performance.
According to a further embodiment, hyaluronic acid and/or hyaluronate
has a molecular weight which is in a range of 50,000 to 10,000,000
dalton, preferably of approx. 250,000 to 5,000,000. The molecular
weight of hyaluronic acid or hyaluronate is particularly preferably
50,000 to 4,000,000 dalton. For exceptional preference, the hyaluronic
acid or hyaluronate has a molecular weight of approx. 1,500,000 to
CA 02761740 2011-11-10
19
3,500,000 dalton. Hyaluronic acid and/or hyaluronate are used
preferably in a concentration of 0.01 to 1.0% by weight, further
preferred of 0.05 to 0.8% by weight, particularly preferred of 0.08 to
0.4% by weight, respectively relative to the total weight of the
phosphate-free pharmaceutical composition.
The high molecular weight of hyaluronic acid or of the hyaluronate
used, such as for example sodium hyaluronate, effects high
viscoelasticity at a low concentration. In the solution, the molecular
chains are present in a random arrangement in the manner of a tangle.
Under the influence of the shear forces exerted by movement of the
eyelid, the macromolecules align themselves approximately parallel.
This change in the three-dimensional structure under the influence of
shear forces must be crucial for the excellent viscoelastic properties.
According to a further preferred embodiment, the pharmaceutical
composition comprises phosphate-free pharmaceutical auxiliary
substances which are selected from the group which consists of
inorganic buffer substances, organic buffer substances, inorganic salts,
organic salts, solvents, solubility aids, solubility promoters, salt
formers, viscosity and consistency regulators, gelatinising agents,
emulsifiers, solubilisers, wetting agents, expansion aids, antioxidants,
preservatives, filling and carrier substances, osmolarity regulators and
also mixtures thereof.
The inorganic buffer substances are selected preferably from the group
consisting of boric acid, sodium hydroxide, sodium borate, sodium
carbonate, hydrochloric acid, sodium hydrogen carbonate and mixtures
thereof.
The organic buffer substances are selected preferably from the group
which consists of acetic acid, sodium acetate, potassium hydrogen
phthalate, succinic acid, maleic acid, trometamol and mixtures thereof.
CA 02761740 2011-11-10
The inorganic salts are selected preferably from the group which
consists of common salt, potassium chloride, aluminium hydroxide,
ammonium hydroxide, ammonium chloride, ammonium sulphate,
calcium chloride and mixtures thereof.
The organic salts are selected preferably from the group which consists
of salts of succinic acid, salts of maleic acid, salts of acetic acid and
mixtures thereof.
The emulsifiers, solubilisers, wetting agents and expansion agents are
selected preferably from the group which consists of poloxamer,
phospholipids, lecithin, alkali soaps, for example sodium palmitate,
alkali sulphates, for example sodium lauryl sulphate, macrogols, for
example polyethylene glycols, macrogol stearates, polysorbates,
macrogol glycerol monostearates, propylene glycols, glycerine,
cyclodextrines and mixtures thereof.
The antioxidants are selected preferably from the group which consists
of ascorbic acid, butyl hydroxytoluene, alpha-tocopherol and their salts
and esters and mixtures thereof.
The osmolality regulators are selected preferably from the group which
consists of sorbitol, glucose, glycerine, polyethylene glycol, fructose and
mixtures thereof.
There can be used as solvent, for example water, monovalent alcohols,
paraffins, triglycerides, oils or mixtures thereof.
According to a development, the phosphate-free composition according
to the invention can also comprise solubilisers, detergents and/or
emulsifiers in order further to improve the solubility of the at least one
hydrophobic FP prostanoid receptor agonist and/or prostamide receptor
CA 02761740 2011-11-10
21
agonist. In order to avoid undesired irritation to the eye, as little
quantities as possible of solubilisers, detergents, and/or emulsifiers are
added, according to a preferred variant.
Preferably, the pharmaceutical composition according to the invention
is formulated to be free of preservatives. In order to avoid undesired
irritation to the eye, no preservatives, in particular no benzalkonium
chloride, are added to the pharmaceutical composition according to the
invention, according to a preferred variant.
Furthermore, it is preferred according to the invention that the
phosphate-free pharmaceutical composition is present in the form of a
solution, of drops, a spray, a suspension, emulsion, a gel, an ointment,
paste, a powder, powder, granulate or a tablet.
The phosphate-free pharmaceutical composition is preferably an
ophthalmic agent, further preferred an ophthalmic agent for topical
application.
In the provision of the phosphate-free pharmaceutical composition in
the form of eye ointments or eye gels, this is prepared for example in
Vaseline or paraffin with and without the addition of an emulsifier, such
as for example cholesterin, wool wax, wool wax alcohols, cetyl alcohol
etc.
According to a preferred embodiment, the phosphate-free
pharmaceutical composition is present in the form of a, preferably
aqueous, solution so that this can be applied for example in the form of
eye drops or an eye spray on the surface of the eye.
In one embodiment, the osmolarity of the phosphate-free
pharmaceutical composition according to the invention is at 100 to 900
mOsm/l.
CA 02761740 2011-11-10
22
The preferably aqueous solutions are thereby isotonic solutions
according to a preferred embodiment, relative to tear fluid. In the case
of isotonic solutions, the osmolarity is preferably at 200 to 350
mOsm/l, preferably at 300 mOsm/l. According to a further preferred
embodiment, the phosphate-free pharmaceutical composition according
to the invention is hypoosmolar. In this case, the osmolarity can be for
example approx. 160 - 180 mOsm/l. A hypoosmolar solution is used in
particular when an abnormally high osmolarity of a tear film must be
compensated for in the case of a patient with dry eyes. As a function of
the symptoms to be treated, a hypertonic solution can also be
advantageous. The pharmaceutical composition can thereby also have
a particularly high osmolarity of 700 to 900 mOsm/l.
For the isotonisation of the aqueous solution, preferably sodium
chloride, boric acid, sorbitol, glycerine, etc. are used.
The phosphate-free composition according to the invention is also
suitable for the production of a combination preparation, the FP
prostanoid(s) and/or prostamide(s) being present together with one or
more further active substances. Hence, the present invention also
relates to a pharmaceutical composition in the form of a combination
preparation in which, in addition to FP prostanoid and/or prostamide,
at least one further active substance or at least two further active
substances are present.
According to a preferred development of the invention, the
pharmaceutical composition according to the invention can comprise, in
addition to FP prostanoid(s) (FP prostanoid receptor agonist(s)) and/or
prostamide(s) (prostamide receptor agonist(s)), also beta blockers,
carbonic anhydrase inhibitors, sympathomimetic agents,
parasympathomimetic agents or mixtures thereof.
CA 02761740 2011-11-10
23
The above-mentioned FP prostanoids concern in particular latanoprost,
travoprost and/or tafluprost, and the above-mentioned prostamides
concern in particular bimatoprost which can be present respectively
with the previously mentioned active substances as active substance
combination according to the invention.
In particular timolol, betaxolol, carteolol, levobunolol and also their
salts and/or esters or mixtures thereof have proved to be very suitable
as betablockers.
Timolol is used preferably in the form of timolol hydrogen maleate.
In particular dorzolamide, brinzolamide, acetazolamide and also their
salts and/or esters or mixtures thereof have proved to be very suitable
as carbonic anhydrase inhibitors.
Dorzolamide is used preferably in the form of the hydrochloride
(dorzolamide HCl).
In particular brimonidine, apraclonidine (Iopidine), acetazolamide and
also their salts and/or esters or mixtures thereof have proved to be very
suitable as sympathomimetic agents.
Brimonidine is used preferably as tartrate salt (brimonidine[(R,R)-
tartrate], e.g. Alphagan.
Pilocarpine and also its salts and/or esters or mixtures thereof have
proved to be very suitable as a parasympathomimetic agent.
Pilocarpine is used preferably in the form of pilocarpine nitrate.
CA 02761740 2011-11-10
24
According to a preferred variant of the invention, the active substance
combination comprises FP prostanoid and timolol or prostamide and
timolol:
- latanoprost and timolol
- travoprost and timolol
- tafluprost and timolol
- bimatoprost and timolol
According to a preferred variant of the invention, the active substance
combination comprises FP prostanoid and timolol or prostamide and
dorzolamide:
- latanoprost and dorzolamide
- travoprost and dorzolamide
- tafluprost and dorzolamide
- bimatoprost and dorzolamide
The above active substance combinations can of course comprise
auxiliary substances, such as for example inorganic buffer substances,
organic buffer substances, inorganic salts, organic salts, emulsifiers,
solubilisers, wetting agents, expansion agents, antioxidants, osmolality
regulators, etc. or mixtures thereof. The phosphate-free pharmaceutical
composition according to the invention can be used in the therapy
and/or prevention of glaucoma.
In particular, the phosphate-free pharmaceutical composition according
to the invention is suitable for the production of a medicine for the
therapy and/or prevention of glaucoma.
The pharmaceutical composition according to the invention is preferably
present in a storage and dosage system. Preferably, it thereby concerns
a multidose container or multidose system. The COMOD system of
I
CA 02761740 2011-11-10
= 25
the company Ursapharm, SaarbrUcken, Germany has proved to be very
suitable for this purpose.
According to a preferred variant, the container in which the
pharmaceutical composition according to the invention is stored
consists up to at least 75% by weight of polyethylene, preferably approx.
78 to 94% by weight of polyethylene, respectively relative to the total
weight of the container. The remainder up to 100% by weight is
preferably an alkene or polyalkene which is different from polyethylene.
According to a further preferred variant, the container in which the
pharmaceutical composition according to the invention is stored
consists up to at least 75% by weight of polypropylene, preferably
approx. 78 to 94% by weight of polypropylene, respectively relative to
the total weight of the container. The remainder up to 100% by weight
is preferably an alkene or polyalkene which is different from
polypropylene.
According to a further preferred variant, the container consists of glass.
The invention is explained subsequently with reference to examples
without being restricted thereto.
Examples
Example 1)
bimatoprost 0.3 mg
polyvinyl pyrrolidone (Kollidon) 20.0 mg
citric acid 0.05 mg
sodium citrate x 2 H2O 8.5 mg
sorbite 33 mg
water for injection purposes (f. I.) ad 1.0 ml
= CA 02761740 2011-11-10
= 26
adjusted to pH 7.4 with 0.1 N NaOH
Example 2)
bimatoprost 0.3 mg
hyaluronic acid, Na salt (MW: 2-3.106Da) 0.1 mg
citric acid 0.05 mg
sodium citrate x 2 H2O 8.5 mg
sorbite 33 mg
water f. I. ad 1.0 ml
adjusted to pH 7.4 with 0.1 N NaOH
Example 3)
travoprost 0.04 mg
hyaluronic acid, Na salt (MW: 2-3.106Da) 0.1 mg
sorbite 30 mg
sodium citrate x 2 H2O 15 mg
citric acid 0.65 mg
water f. I. ad 1.0 ml
adjusted to pH 6.0 with 0.1 N HC1
Example 4)
latanoprost 0.05 mg
hyaluronic acid, Na salt (MW: 2-3.106Da) 0.1 mg
sorbite 30 mg
sodium citrate x 2 H2O 15 mg
citric acid 0.65 mg
water f. I. ad 1.0 ml
CA 02761740 2011-11-10
27
adjusted to pH 6.0 with 0.1 N HC1
Example 5)
latanoprost 0.05 mg
polyvinyl pyrrolidone (Kollidon) 20.0 mg
sodium citrate x 2 H2O 7.5 mg
citric acid 0.2 mg
sodium chloride 6.0 mg
water f. I. ad 1.0 ml
adjusted to pH 6.0 with 0.1 N HCl
Example 6)
tafluprost 0.015 mg
polyvinyl pyrrolidone (Kollidon) 20.0 mg
sodium citrate x 2 H2O 7.5 mg
citric acid 0.2 mg
sodium chloride 6.0 mg
water f. I. ad 1.0 ml
adjusted to pH 6.0 with 0.1 N HCl
Example 7)
tafluprost 0.05 mg
hyaluronic acid, Na salt (MW: 2-3.106Da) 1.0 mg
sodium citrate x 2 H2O 7.5 mg
citric acid 0.2 mg
sodium chloride 6.0 mg
water f. I. ad 1.0 ml
CA 02761740 2011-11-10
28
adjusted to pH 6.0 with 0.1 N HCl
Example 8)
latanoprost 0.05 mg
sodium chloride 6.0 mg
sodium citrate x 2 H2O 10.0 mg
citric acid 0.2 mg
water f. I. ad 1.0 ml
adjusted to pH 6.0 with 0.1 N HCl
Example 9)
latanoprost 0.05 mg
sodium chloride 6.0 mg
sodium citrate x 2 H2O 10.0 mg
citric acid 0.2 mg
water f. I. ad 1.0 ml
adjusted to pH 6.0 with 0.1 N HCl
Example 10)
latanoprost 0.05 mg
sodium chloride 6.0 mg
sodium citrate x 2 H2O 10.0 mg
citric acid 0.2 mg
water f. I. ad 1.0 ml
adjusted to pH 6.0 with 0.1 N HCl
== CA 02761740 2011-11-10
29
Example 11)
bimatoprost 0.3 mg
timolol 2.5 mg
hyaluronic acid, Na salt (MW: 2-3.106Da) 0.1 mg
citric acid 0.05 mg
sodium citrate x 2 H2O 8.5 mg
sorbite 33 mg
water f. I. ad 1.0 ml
adjusted to pH 7.4 with 0.1 N NaOH
Example 12)
bimatoprost 0.3 mg
dorzolamide 10 mg
hyaluronic acid, Na salt (MW: 2-3.106Da) 0.1 mg
citric acid 0.05 mg
sodium citrate x 2 H2O 8.5 mg
sorbite 33 mg
water f. I. ad 1.0 ml
adjusted to pH 7.4 with 0.1 N NaOH
Example 13)
travoprost 0.04 mg
timolol 2.5 mg
hyaluronic acid, Na salt (MW: 2-3.106Da) 0.1 mg
sorbite 30 mg
sodium citrate x 2 H2O 15 mg
citric acid 0.65 mg
water f. I. ad 1.0 ml
CA 02761740 2011-11-10
adjusted to pH 6.0 with 0.1 N HC1
Example 14)
travoprost 0.04 mg
dorzolamide 10 mg
hyaluronic acid, Na salt (MW: 2-3.106Da) 0.1 mg
sorbite 30 mg
sodium citrate x 2 H2O 15 mg
citric acid 0.65 mg
water f. I. ad 1.0 ml
adjusted to pH 6.0 with 0.1 N HCl
Example 15)
latanoprost 0.05 mg
timolol 2.5 mg
hyaluronic acid, Na salt (MW: 2-3.106Da) 0.1 mg
sorbite 30 mg
sodium citrate x 2 H2O 15 mg
citric acid 0.65 mg
water f. I. ad 1.0 ml
adjusted to pH 6.0 with 0.1 N HC1
Example 16)
latanoprost 0.05 mg
dorzolamide 10 mg
hyaluronic acid, Na salt (MW: 2-3.106Da) 0.1 mg
sorbite 30 mg
CA 02761740 2011-11-10
31
sodium citrate x 2 H2O 15 mg
citric acid 0.65 mg
water f. I. ad 1.0 ml
adjusted to pH 6.0 with 0.1 N HCl
Example 17)
tafluprost 0.05 mg
timolol 2.5 mg
hyaluronic acid, Na salt (MW: 2-3.106Da) 1.0 mg
sodium citrate x 2 H2O 7.5 mg
citric acid 0.2 mg
sodium chloride 6.0 mg
water f. I. ad 1.0 ml
adjusted to pH 6.0 with 0.1 N HCl
Example 18)
tafluprost 0.05 mg
dorzolamide 10 mg
hyaluronic acid, Na salt (MW: 2-3.106Da) 1.0 mg
sodium citrate x 2 H2O 7.5 mg
citric acid 0.2 mg
sodium chloride 6.0 mg
water f. I. ad 1.0 ml
adjusted to pH 6.0 with 0.1 N HC1
