Note: Descriptions are shown in the official language in which they were submitted.
CA 02616531 2008-01-23
Sterile, Drop-forming, Multiphase, Emulsifier-free Ophthalmic Preparation
The invention relates to a sterile, drop-forming, multiphase, emulsifier-free
ophthalmic
preparation, in particular a gel preparation. The ophthalmic preparation can
be used, for
example, as artificial tear liquid and for the treatment of "dry eye".
Use of aqueous preparations for the treatment of disorders related to
irritated or inflamed eyes,
in particular of dry eyes, keratoconjunctivitis sicca, is known in the state
of the art. These
preparations are usually present in the form of fluids, gels, creams, or
ointments.
It is disadvantageous that ingredients are often added to solutions, which
elicit
hypersensitivity, lead to irritations, or cause sensitization to or
incompatibility with the
ingredients. It is also known that aqueous solutions often cause itching,
burning, or other
unpleasant side effects upon contact with the eye.
Furthermore, preparations, in particular in the form of gels, creams, or
ointments, have the
disadvantage that application by patients already suffering from a painful
irritation of the eye
is additionally unpleasant. Moreover, the distribution of these preparations
in or on the eye
must often be supported by rubbing, an event which causes additional
sensations of pain in the
patient.
Also, two-phase emulsions are known in the state of the art. However, their
stability inter alia
depends on their viscosity. Thus, emulsions become unstable, if, for example,
a hydrophobic
phase that is finely dispersed in a hydrophilic phase aggregates. This event
limits the stability
during storing of the emulsions and is slower the more viscous the hydrophilic
phase of the
emulsion is.
In order to provide sufficient stability of emulsions, emulsifiers are usually
employed.
However, emulsifiers can also cause allergic reactions or reactions that are
based on
hypersensitivity of the patient.
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An emulsifier-free preparation is for example disclosed in EP 0817610.
However, this
preparation has the disadvantage that it exhibits a very high viscosity. Thus,
the application of
the preparation is unpleasant for the patient and supporting the distribution
of the
composition, for example, by rubbing on the eye causes an additional pain
sensation.
It is an objective of the present invention to provide a preparation which
overcomes at least
one of the aforementioned disadvantages of the state of the art. In
particular, it is an objective
of the present invention to provide a preparation which is suitable for
application on dry eye.
The objective is solved by a sterile, drop-forming, multiphase, emulsifier-
free ophthalmic
preparation, in particular a gel preparation, comprising at least one liquid
aqueous phase and
at least one liquid hydrophobic phase. This preparation comprises at least one
phosphate salt
and has a viscosity in the range of - 200 mPa=s to < 2000 mPa=s. Preferably,
suitable
phosphate salts are water -soluble, according to the present invention.
Advantageous embodiments of the sterile, drop-forming, multiphase, emulsifier-
free
ophthalmic preparation according to the present invention are mentioned in the
dependent
claims.
"Emulsifier-free," as referred to in the present invention, means that the
preparation comprises
only ingredients which are not emulsifiers within the meaning of the present
invention. In
particular, the preparation according to the present invention can comprise
substances selected
from the group comprising water-soluble phosphate salts, preferably sodium
monohydrogen
phosphate dodecahydrate, Na?HPO4 x 12 H20, polyacrylic acid, polymers of
acrylic acid
derivatives, preferably carbomer, triglycerides, preferably mid chain
triglycerides, a vitamin A
component, preferably vitamin A palmitate, vitamin E, sorbitol, sodium
hydroxide,
preservatives such as cetrimide, benzododecinium chloride, benzalkonium
chloride or
thiomersal and/or water, whereby these substances are not emulsifiers in the
sense of the
present invention. In accordance with the present invention, the preparation
can further
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comprise substances selected from the group comprising glycerol and/or
alexidine, whereby
these substances are not emulsifiers in the sense of the present invention.
"Emulsifiers" according to the present invention are interface-active
substances which are
able to decrease the interfacial tension between the oil phase and the aqueous
phase by
accumulating at the interface between these two phases. This is made possible
by the
amphiphilic molecular structure of the emulsifier, which possesses at least
one polar
(hydrophilic) group and at least one non-polar (lipophilic) group. Thus, they
are soluble in the
hydrophilic as well as in the lipophilic phase. The part which is more soluble
in the
corresponding phase extends into this phase and thereby lowers the interfacial
tension
between both phases.
A preferred embodiment is a preparation, in particular gel preparation,
comprising at least one
liquid aqueous phase and at least one liquid hydrophobic phase, wherein this
preparation
comprises at least one preferably water-soluble phosphate salt and has a
viscosity in the range
of _ 200 mPa=s to < 2000 mPa=s, wherein this preparation either does not
contain any further
emulsifiers or only in an amount such that the aforementioned substances do
not exhibit
emulsifying effects.
Another preferred embodiment is a preparation, in particular gel preparation,
comprising at
least one liquid aqueous phase and at least one liquid hydrophobic phase,
wherein this
preparation comprises at least a preferably water-soluble phosphate salt and
has a viscosity in
the range of _> 200 mPa=s to < 2000 mPa=s; it also comprises substances
selected from the
group comprising polyacrylic acid, preferably carbomer, mid-chain
triglycerides, sodium
monohydrogen phosphate dodecahydrate, Na2HPO4 x 12 H20, sorbitol, sodium
hydroxide and
water, wherein this preparation either does not contain any further
emulsifiers or in an amount
such that the aforementioned substances do not exhibit emulsifying effects.
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A still more preferred embodiment is a preparation, in particular gel
preparation, comprising
at least one liquid aqueous phase and at least one liquid hydrophobic phase,
wherein this
preparation comprises at least a preferably water-soluble phosphate salt and
has a viscosity in
the range of _ 200 mPa=s to < 2000 mPa=s, wherein it also comprises substances
selected from
the group comprising polyacrylic acid, preferably carbomer, preferably mid-
chain
triglycerides, sodium monohydrogen phosphate dodecahydrate, Na2HPO4 x 12 H20,
sorbitol,
sodium hydroxide, water and, optionally, a vitamin A component, preferably
vitamin A
palmitate, vitamin E and/or preservatives, preferably cetrimide, wherein this
preparation either
does not contain any further emulsifiers or in an amount such that the
aforementioned
substances do not exhibit emulsifying effects.
The substances, which can be contained in the preparation according to the
present invention,
in particular water-soluble phosphate salts, polyacrylic acid, polymeric
acrylic acid
derivatives, preferably carbomer, triglycerides, a vitamin A component,
vitamin E, sorbitol,
sodium hydroxide, preservatives such as cetrimide, benzododecinium chloride,
benzalkonium
chloride or thiomersal or water, are preferably used in amounts, so that the
aforementioned
substances do not exhibit emulsifying effects. Furthermore, the composition
according to the
present invention can comprise the substances glycerol and/or alexidine, which
are also used
in amounts so that the aforementioned substances do not exhibit emulsifying
effects.
Surprisingly, it turned out that the preparation according to the present
invention, in particular
a gel preparation, can be formulated such that it is stable in a viscosity
range of < 2000 mPa=s.
This is surprising for a person skilled in the art, particularly for an
emulsion of such low
viscosity comprising a hydrophilic (for example, aqueous) phase and a
hydrophobic phase,
since they usually become rapidly unstable and separate from each other.
A particular advantage of these substances arises from the fact that the
stability of the
preparation can be achieved without the addition of emulsifiers. This provides
an
improvement in tolerance of the preparation according to the present
invention.
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Particularly, the use of phosphate salts allows the adjustment of low ranges
of viscosity of the
present invention. A specific advantage of the preparation of the present
invention is achieved
by using the phosphate salt, whereby an emulsifier-free preparation having low
viscosity can
be provided.
In particular it is advantageous that a preparation having low viscosity
considerably improves
the application for the patient. Preferably, a drop-forming preparation can be
provided, which
can be better distributed on the cornea of the eye, due to the low viscosity,
and which irritates
the eye less by an additional mechanical aid for distribution. It is of
significant advantage that
the preparation with low viscosity of the present invention only causes a low
foreign body
sensation on the eye and provides a more pleasant tolerance for the patient
during application.
In preferred embodiments of the ophthalmic preparation, the composition has a
viscosity in
the range of _ 300 mPa=s to <_ 1800 mPa=s, preferably in the range of _ 400
mPa=s to _ 1500
mPa=s, preferably in the range of _ 500 mPa=s to <_ 1400 mPa=s, more
preferably in the range
of _ 600 mPa=s to <_ 1350 mPa=s, most preferably in the range of _ 650 mPa=s
to _ 1300
mPa=s.
The sterile drop-forming ophthalmic preparation comprises preferably at least
one water-
soluble phosphate salt. Suitable water-soluble phosphate salts are preferably
selected from the
group comprising alkali phosphate salts, alkaline-earth phosphate salts,
ammonium phosphate
salts, mono- or dihydrogenphosphates thereof and/or mixtures thereof.
Preferably suitable are
water-soluble phosphate salts, selected from the group comprising sodium
dihydrogen
phosphate, sodium monohydrogen phosphate, potassium dihydrogen phosphate,
potassium
monohydrogen phosphate and/or mixtures thereof. Most preferably sodium
monohydrogen
phosphate is used.
Preferably, the hydrate compounds can be water-soluble phosphate salts,
preferably hydrate
compounds selected from the group comprising hydrate compounds of alkali
phosphate salts,
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alkaline-earth phosphate salts, ammonium phosphate salts, mono- or
dihydrogenphosphates
thereof and/or mixtures thereof, especially preferred are hydrate compounds
selected from the
group comprising hydrate compounds of sodium dihydrogen phosphate, sodium
monohydrogen phosphate, potassium dihydrogen phosphate, potassium monohydrogen
phosphate and/or mixtures thereof. Preferably, NaZHPO4 x n HZO with n = 2, 7
or 12 or
NaH2PO4 x n H20 with n = 1 or 2 is used.
An especially preferred phosphate salt is sodium monohydrogen phosphate
dodecahydrate,
NaZHPO4 x 12 H20. The use of a possible designation such as sodium
monohydrogen
phosphate dodecahydrate in the sense of this invention also includes
appropriate designations
such as disodium hydrogen phosphate dodecahydrate or disodium phosphate
dodecahydrate
for the corresponding substance.
Preferably, a suitable proportion of water-soluble phosphate salt is in the
range of _ 0.01 wt.-
% to <_ 5.0 wt.-%, preferably in the range of _ 0.05 wt.-% to <_ 0.5 wt.-%,
more preferably in
the range of _ 0.08 wt.-% to <_ 0.2 wt.-%, based on the total weight of the
preparation. In most
preferred embodiments the preparation comprises about 0.1 wt.-% of the water-
soluble
phosphate salt, based on the total weight of the preparation. The amount as
specified herein
refers to the appropriate hydrate compound, unless indicated otherwise.
As a lower limit, a minimum proportion of 0.01 wt.-% of NaZHPO4 x 12 H20 based
on the
total weight of the preparation has been shown to be suitable. A proportion of
Na2HPO4 x 12
H20 in the range of _ 0.01 wt.-% to <_ 5.0 wt.-%, based on the total weight of
the preparation
has been shown to be suitable. Preferably, a proportion of Na2HPO4 x 12 H20 in
the range of
_ 0.05 wt.-% to <_ 0.5 wt.-%, more preferably in the range of _ 0.08 wt.-% to
<_ 0.2 wt.-%,
based on the total weight of the preparation is used. In especially preferred
embodiments, the
preparation comprises about 0.1 wt.-% NaZHPO4 x 12 H20, based on the total
weight of the
preparation.
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A further surprising effect of the preparation of the present invention is
that the preparation is
comparable to the three-phase composition of the natural tear film in the eye,
mucin layer,
aqueous phase and lipid layer, when applied to the eye and can replace the
natural tear film. In
particular, this is provided in favourable way independent from the phase of
the natural tear
film which is either present in amounts that are too small or is missing
altogether.
Preferably, the multiphase preparation comprises the aqueous phase as
continuous phase and
the liquid hydrophobic phase, preferably a liquid oil phase, as droplets
dispersed therein,
preferably in the form of finely dispersed droplets. The preparation is
preferably at least
biphasic; in preferred embodiments it can also be triphasic. Furthermore, the
preparation
preferably comprises a polymeric gel-forming component in the aqueous phase.
Accordingly,
the preparation of the present invention preferably comprises a biphasic, a
liquid aqueous
phase and a liquid hydrophobic phase comprising carrier liquid or a gel base.
The aqueous phase of the preparation is preferably formed so that the
preparation has a
significant water proportion. Preferably, the composition comprises a water
proportion in the
range of _ 60 wt.-% to <_ 98 wt.-%, based on the total weight of the
preparation, preferably in
the range of _ 90 wt.-% to <_ 96 wt.-%, especially preferred the preparation
comprises about
94 wt.-% to <_ 95 wt.-% of water. Preferably, water for injection purposes is
used.
In preferred embodiments, the aqueous phase of the preparation can reproduce
the aqueous
phase of the natural tear film, which moisturizes the cornea and provides a
cleaning and
protecting function.
Advantageously, the ophthalmic preparation of the present invention is
particularly well
tolerated. It is of further advantage that the ophthalmic preparation of the
present invention
leads to no or only a very small irritation or unpleasantness during
application to the eye. This
provides a significant advantage since application to the eye often leads to a
very unpleasant
"burning" sensation in the eye.
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Preferably, the preparation further comprises at least one polymeric gel-
forming component,
in particular a polyacrylic acid and/or a polymeric acrylic acid derivative.
Preferred
polyacrylic acids have, for example, a molecular weight in the range of
approximately 3 to 5
million Dalton. Especially preferred polyacrylic acids or polymeric acrylic
acid derivatives
are crosslinked polymers of acrylic acids that go by the name of carbomer
under INCI
designation, preferably hydrophobic modified crosslinked polymers of acrylic
acids. Preferred
carbomers are available under the trade name Carbopol , for example, from the
company
Noveon Inc. Especially preferred carbomers are homopolymers of acrylic acid,
for example,
Carbopol -homopolymers, especially preferred Carbopol 980 NF is used, even
more
preferred is Carbopol 940 NF. The terms polyacrylic acid and polymeric acrylic
acid are
synonymously used in the sense of this application.
Preferably, the ophthalmic preparation comprises the polymeric gel-forming
component,
preferably polyacrylic acid and/or a polymeric acrylic acid derivative, in
particular preferably
a carbomer, in the range of _ 0.1 wt.-% to <_ 3 wt.-%, based on the total
weight of the
preparation, preferably in the range of _ 0.1 wt.-% to _ 1 wt.-%, especially
preferred in the
range of _ 0.15 wt.-% to <_ 0.5 wt.-%, most preferably at about 0.2 wt.-%.
In preferred embodiments, the preparation further comprises an ophthalmic
and/or
ophthalmologic acceptable, organic oil. In these embodiments the ophthalmic
acceptable
organic oil forms the liquid hydrophobic phase of the preparation of the
present invention.
Suitable liquid hydrophobic oil components are, for example, fatty acid
derivatives such as
fatty acid esters, triglycerides and phthalic acid esters. Preferably the
ophthalmic acceptable,
organic oil of the preparation has as the ophthalmic acceptable organic oil
mid-chain
triglycerides, especially preferred triglycerides formed of at least 80 wt.-%,
based on the total
weight of the fatty acids, preferably at least 90 wt.-% and even more
preferably at least 95
wt.-% of, preferably, Cg-C12-fatty acids, preferably Cg-Clo-fatty acids.
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Especially preferred, the preparation has saturated mid-chain triglycerides.
Also preferred are
triglycerides formed of at least 80 wt.-%, preferably at least 90 wt.-% more
preferably at least
95 wt.-%, based on the total weight of the fatty acids of saturated C8- and C
i o-fatty acids.
Especially preferred are caprylic-capric acid-triglycerides, which are
mixtures of esterified
saturated C8 and Cio fatty acids.
Suitable triglycerides are available in the form of synthetic, half-synthetic
or natural oils, like
olive oil, palm oil, almond oil, coconut oil or mixtures thereof. Preferred
triglycerides are
available from coconut oil. Such mid-chain triglycerides are prepared, for
example, from the
oil of the endosperms of Cocos nucifera L., preferably from the solid dried
part, or Elasis
guineensis Jacq.. Additional preferred suitable triglycerides, preferably mid-
chain
triglycerides are neutral oils, for example, available under the trade name
Myritol 318. In
particular, mid-chain triglycerides are preferred, as described in the
European Dispensatory,
European Pharmacopoeia 5.0, 01/2005:0868, p. 2623, Triglycerida saturata
media. Preferably,
the acidic component comprises a mixture with a proportion of at least 90 wt.-
%, preferably at
least 94 wt.-%, more preferably at least 95 wt.-%, based on the total weight
of the fatty acids
of n-octanoic acid and n-decanoic acid.
An advantage of the preferred mid-chain triglycerides on the basis of a
mixture formed from
saturated C8 and CIO-fatty acids, preferably caprylic-capric acid
triglycerides, is that the
saturated fatty acids provide an improved stability of the lipid film and,
thus, a surprisingly
improved extended retention period of the preparation in the eye.
Advantageously, the mid-chain triglycerides can inhibit the evaporation of the
aqueous
component and prevent a too rapid running off of the tear film or the
preparation.
Preferably, the sterile, drop-forming, ophthalmic preparation comprises an
ophthalmic and/or
ophthalmologic acceptable organic oil, preferably selected from the group of
fatty acid
derivatives, comprising fatty acid esters, triglycerides and/or phthalic acid
esters, especially
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preferred mid-chain triglycerides in the range of ? 0.5 wt.-% to <_ 10 wt.-%,
based on the total
weight of the preparation, preferably in the range of _ 0.6 wt.-% to <_ 5wt.-
%, especially
preferred in the range of _ 0.8 wt.- % to _ 2 wt.-%, most preferably at about
1 wt.-%. In
especially preferred embodiments, the sterile, drop-forming, ophthalmic
preparation
comprises caprylic-capric acid triglyceride or triglycerides formed of at
least 80 wt.-%,
preferably at least 90 wt.-%, more preferably at least 95 wt.-%, based on the
total weight of
the fatty acids of saturated C8 and CIo fatty acids in the range of >_ 0.5 wt.-
% to <_ 10 wt.-%,
based on the total weight of the preparation, preferably in the range of _>
0.6 wt.- % to <_ 5 wt.-
%, more preferably in the range of _ 0.8 wt.-% to <_ 2 wt.-%, and especially
preferred at about
1 wt.-%.
Preferred embodiments of the preparation of the present invention, in
particular on the basis of
gels, with amounts of gel-forming agents in the aqueous phase in the range of
_ 0.1 wt.-% to
3 wt.-%, based on the total weight of the preparation, in particular about 0.2
wt.-%, comprise
a mid-chain triglyceride in the range of ? 0.5 wt.-% to <_ 10 wt.-%, in
particular about 1 wt.-%
mid-chain triglyceride.
A further specific advantage of the preparation is provided by the fact that
the preparation can
comprise a corresponding amount of triglycerides without using emulsifiers
simultaneously.
This has the significant advantage that proportions of remaining natural tear
liquid of the eye,
which may still be present, are not destroyed by an emulsifier.
Preferably the triglycerides in the preparation of the present invention are
present in the form
of finely dispersed droplets. Without being bound to a certain theory, it is
assumed that the
presence of triglycerides in the preparation of the present invention in the
form of finely
dispersed droplets provides a surprising stability, even over extended storage
times without
adding emulsifiers.
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Another advantage of the preparation is achieved by the fact that the
preparation, in particular
in the form of single dose units, is very stable even without preservatives
and not only under
the conditions of moderate climate (21 C, 45% r. h., relative humidity) or
Mediterranean
subtropical climate (25 C, 40% r. h.), but also under very hot and moist
climatic conditions,
for example at 25 C, 60% r. h., at 30 C, 70% r. h. or at 40 C, 75% r. h., and
shows small or
only slight changes regarding pH value, osmolality, viscosity and appearance
for at least three
months, preferably six months, more preferably nine months, even more
preferably twelve
months, further preferred 18 months, most preferably 26 months.
The preparation of the present invention cannot preferably comprise drugs or
pharmaceutically active agents such as antiviral agents, steroidal and
nonsteroidal anti-
inflammatory compounds or corticosteroids, antibiotics, antimycotics,
anaesthetics, anti-
inflammatory agents or anti-allergic agents. Pharmaceutically active agents in
the sense of the
invention do not include vitamin A and vitamin E, in particular.
In preferred embodiments, the preparation of the present invention can further
comprise at
least one ophthalmic active agent, for example a vitamin A component,
preferably vitamin A-
palmitate. Beyond the use of vitamins, such as vitamin A and/or vitamin E,
there are
preferably no pharmaceutically active components in the preparation of the
present invention.
The particularly preferred content of vitamin A palmitate is about 1000 I.E.
vitamin A
palmitate per gram preparation, whereby preferably an additional 20% extra
stability amount
is used. Preferred suitable vitamin A palmitate has 1 million I.E. per gram
vitamin A palmitate
and comprises preferably butylated hydroxyanisole and/or butylated
hydroxytoluene as
stabilisers. Preferably, the content of a vitamin A component, in particular
vitamin A
palmitate is in the range of _ 0.05 wt.-% to _ 0.5 wt.-%, preferably in the
range of _ 0.08 wt.-
% to 5 0.2 wt.-%, especially preferred at about 0.1 wt.-%, with consideration
of the extra
stability amount of about 0.12 wt.-%, based on the total weight of the
preparation.
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Particularly preferred, the vitamin A component is used in combination with an
antioxidant
such as vitamin E. The Vitamin A component is preferably stabilized with at
least one
antioxidant, preferably vitamin E, more preferably D,L-a-tocopherole.
Especially preferred, a
small content of antioxidant is used for stabilization, preferably vitamin E,
more preferably
D,L-a-tocopherole, for example, in the range of _ 0.002 wt.-% to _< 0.01 wt.-
%, preferably in
the range of >_ 0.006 wt.- % to <_ 0.008 wt.-%, based on the total weight of
the preparation.
Another advantage is that an active agent such as a vitamin A component, which
is suspended
or dissolved in the oil phase, can be dispersed more uniformly. The
wettability of objects
applied to the cornea, such as contact lenses or front lenses of ophthalmic
devices, is thereby
improved.
In preferred embodiments the preparation comprises one or more agents for
adjusting the
isotonicity, preferably multivalent alcohols such as dextrose, glycerol,
propylene glycol,
sorbitol or mannitol, preferably the preparation comprises sorbitol.
Preferably, the preparation has one or more agents for adjusting the
isotonicity in an amount,
which is sufficient to provide the preparation isotonically with natural tear
liquid. In preferred
embodiments, the preparation comprises isotonicity agents, preferably sorbitol
in the range of
_ 0.5 wt.-% to <_ 10 wt.-%, based on the total weight of the preparation,
preferably in the
range of _ I wt.-% to <_ 5 wt.-%, especially preferred at about 4 wt.-%. In
further preferred
embodiments the preparation comprises isotonicity agents, preferably sorbitol
in the range of
_ 3.5 wt.-% to <_ 4 wt.-%, preferably in the range of _ 3.6 wt.-% to <_ 3.7
wt.-%, based on the
total weight of the preparation. In particular, the preparation can comprise
sorbitol in the
range of _ 3.6 wt.-% to <_ 3.7 wt.-%, more preferably at about 3.666 wt.-%,
based on the total
weight of the preparation, if the preparation comprises also glycerol.
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In preferred embodiments the preparation has an osmolality in the range of _
100 mosmol/kg
to <_ 500 mosmol/kg, preferably in the range of _ 200 mosmol/kg to <_ 300
mosmol/kg,
especially preferred in the range of ? 220 mosmol/kg to <_ 260 mosmol/kg.
Preferably the pH value of the ophthalmic preparation is adjusted with acids
and/or bases,
preferably with boric acid and/or sodium hydroxide solution, wherein the use
of a 2 to 3 %
solution of sodium hydroxide in water is particularly preferred.
The sterile, drop-forming, ophthalmic preparation comprises preferably sodium
hydroxide,
preferably in the range of _ 0.02 wt.-% to <_ 1 wt.-%, based on the total
weight of the
preparation, further preferred in the range of _ 0.05 wt.-% to <_ 0.1 wt.-%,
especially preferred
in the range of _ 0.06 wt.-% to _ 0.07 wt.-%. These values refer to the solid
sodium
hydroxide, unless indicated otherwise. In especially preferred embodiments the
preparation
without preservatives comprises about 0.0665 wt.-% sodium hydroxide, based on
the total
weight of the preparation, and a preparation which comprises preservatives
comprises
preferably about 0.06333 wt.-% sodium hydroxide, based on the total weight of
the
preparation.
In preferred embodiments, the ophthalmic preparation comprises substances
selected from the
group comprising polyacrylic acid, polymeric acrylic acid derivatives,
preferably carbomer,
triglycerides, preferably mid-chain triglycerides, water-soluble phosphate
salts, preferably
Na2HPO4 x 12 H20, sorbitol, sodium hydroxide and/or water. In particularly
preferred
embodiments, the ophthalmic preparation comprises 0.2 wt.-% polymeric acrylic
acid,
preferably carbomer, 4.0 wt.-% sorbitol, 0.1 wt.-% Na2HPO4 x 12 H20, 0.0665
wt.-% sodium
hydroxide and/or 1.0 wt.-% mid-chain triglycerides as well as ad 100 wt.-%
water, based on
the total weight of the preparation.
In further preferred embodiments, the ophthalmic preparation comprises
substances selected
from the group comprising polyacrylic acid, polymeric acryl acid derivatives,
in particular
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carbomers, triglycerides, in particular mid-chain triglycerides, water-soluble
phosphate salts,
in particular NazHPO4 x 12 H20, a vitamin A component, preferably vitamin A
palmitate,
vitamin E, preferably D,L-a-tocopherole, sorbitol, sodium hydroxide and/or
water. In further
especially preferred embodiments the ophthalmic preparation comprises 0.2 wt.-
% polymeric
acrylic acid, preferably carbomer, 4.0 wt.-% sorbitol, 0.1 wt.-% Na2HPO4 x 12
H20, 0.0665
wt.-% sodium hydroxide, 0.12 wt.-% vitamin A palmitate, 0.006 wt.-% vitamin E,
preferably
D,L-a-tocopherole and/or 1.0 wt.-% mid-chain triglycerides as well as ad 100
wt.-% water,
based on the total weight of the preparation.
In advantageous embodiments, the preparation has a pH value in the range of >_
6 to <_ 8,
preferably in the range of _ 6,5 to <_ 7,5. In particularly advantageous
embodiments, the
preparation has a pH value in the range of _ 6.8 to <_ 7.2.
The preparation of the present invention can further comprise components, for
example,
preservatives, preferably selected from the group comprising cetrimide,
benzododecinium
chloride, benzalkonium chloride and/or thiomersal. Preferably the
preservatives are selected
from the group comprising cetrimide and/or alexidine. Preferably the
preparation comprises
preservatives, preferably selected from the group comprising cetrimide,
benzododecinium
chloride, benzalkonium chloride and/or thiomersal in the range of _ 0.001 wt.-
% to <_ 0.05 wt.-
%, based on the total weight of the preparation, more preferably in the range
of _ 0.005 wt.-%
to <_ 0.01 wt.-%.
"Cetrimide" is the common name for N-cetyl-N,N,N-trimethyl-ammonium bromide,
"benzododecinium chloride" for N-benzyl-N-dodecyl-N,N-dimethyl-ammonium
chloride,
"benzalkonium chloride" for benzyllauryldimethylammonium chloride, and
"thiomersal" for
the sodium salt of 2-(ethylmercurythio)-benzoate.
In preferred embodiments, the preparation comprises 0.01 wt.-% cetrimide
and/or
benzododecinium chloride, based on the total weight of the preparation. In
further preferred
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embodiments, the preparation comprises 0.01 wt.-% benzalkonium chloride, based
on the
total weight of the preparation. In particularly preferred embodiments, the
preparation is free
of preservatives.
The preparation of the present invention can comprise alexidine as further
substance,
preferably alexidine hydrochloride, preferably the preparation of the present
invention can
comprise about 3 ppm of alexidine=2HCI, based on the total weight of the
preparation.
Alexidine is not an emulsifier in the sense of the present invention, or
alexidine is comprised
in amounts such that the substance does not exhibit an emulsifying effect.
As a further substance the preparation of the present invention can comprise
glycerol, also
designated as glycerine, for example, in an amount of about 0.2 wt.-%, based
on the total
weight of the preparation. Glycerine is not an emulsifier in the sense of the
present invention,
or glycerine is comprised in amounts such that the substance does not exhibit
an emulsifying
effect.
Preferably, the preparation can comprise glycerol in the range of _ 0.01 wt.-%
to _ 1.0 wt.-%,
based on the total weight of the preparation, preferably in the range of >_
0.lwt.-% to <_ 0.5
wt.-%, especially preferred in the range of >_ 0.2 wt.-% to S 0.3 wt.-%. The
preparation can
comprise glycerol in the form of 100 % glycerol or 85 % glycerol, which is
preferably a
mixture with water. In preferred embodiments, the preparation can comprise 0.2
wt.-%
glycerol (100 %) or 0.23 5 wt.-% glycerol (85 %).
In preferred embodiments, the ophthalmic preparation comprises substances
selected from the
group comprising polyacrylic acid, polymeric acrylic acid derivatives,
preferably carbomers,
triglycerides, preferably mid-chain triglycerides, water-soluble phosphate
salts, preferably
NaZHPO4 x 12 H20, a vitamin A component, preferably vitamin A palmitate,
vitamin E,
preferably D,L-a-tocopherol, sorbitol, sodium hydroxide, preservatives,
preferably cetrimide,
benzododecinium chloride, benzalkonium chloride or alexidine, glycerol and/or
water.
CA 02616531 2008-01-23
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In still more preferred embodiments, the ophthalmic preparation comprises
substances
selected from the group comprising polyacrylic acid, polymeric acrylic acid
derivatives, in
particular carbomers, triglycerides, in particular mid-chain triglycerides,
water-soluble
phosphate salts, in particular Na2HPO4 x 12 H20, sorbitol, sodium hydroxide,
glycerol and/or
water. In further especially preferred embodiments, the ophthalmic preparation
comprises 0.2
wt.-% polymeric acrylic acid, preferably carbomer, 3.666 wt.-% sorbitol, 0.1
wt.-% Na2HPO4
x 12 H20, 0.063 wt.-% sodium hydroxide, 0.235 wt.-% glycerol (85 %) or 0.2 wt.-
% of
glycerol (100%) and/or 1.0 wt.-% mid-chain triglycerides as well as ad 100 wt.-
% water,
based on the total weight of the preparation.
In still further preferred embodiments, the ophthalmic preparation comprises
substances
selected from the group comprising polyacrylic acid, polymeric acrylic acid
derivatives, in
particular carbomers, triglycerides, in particular mid-chain triglycerides,
water-soluble
phosphate salts, in particular Na2HPO4 x 12 H20, a vitamin A component,
preferably vitamin
A palmitate, vitamin E, in particular D,L-a-tocopherol, sorbitol, sodium
hydroxide, glycerol
and/or water. In further especially preferred embodiments, the ophthalmic
preparation
comprises 0.2 wt.-% polymeric acrylic acid, preferably carbomer, 3.666 wt.-%
sorbitol, 0.1
wt.-% Na2HPO4 x 12 H20, 0.063 wt.-% sodium hydroxide, 0.12 wt.-% vitamin A
palmitate,
0.006 wt.-% vitamin E, preferably D,L-a-tocopherol, 0.235 wt.-% glycerol (85
%) or 0.2 wt.-
% glycerol (100 %) and/or 1.0 wt.-% mid-chain triglycerides as well as ad 100
wt.-% water,
based on the total weight of the preparation.
In further preferred embodiments, the ophthalmic preparation comprises
substances selected
from the group comprising polyacrylic acid, polymeric acrylic acid
derivatives, preferably
carbomer, triglycerides, preferably mid-chain triglycerides, water-soluble
phosphate salts,
preferably Na2HPO4 x 12 H20, a preservative, preferably cetrimide, sorbitol,
sodium
hydroxide and/or water. In further particularly preferred embodiments, the
ophthalmic
preparation comprises 0.2 wt.-% polymeric acrylic acid, preferably carbomer,
4.0 wt.-%
sorbitol, 0.1 wt.-% Na2HPO4 x 12 H20, 0.06333 wt.-% sodium hydroxide, 0.1 wt.-
%
CA 02616531 2008-01-23
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cetrimide and/or 1.0 wt.-% mid-chain triglycerides as well as ad 100 wt.-%
water, based on
the total weight of the preparation. In especially preferred embodiments, the
ophthalmic
preparation comprises 0.2 wt.-% polymeric acrylic acid, preferably carbomer,
4.0 wt.-%
sorbitol, 0.1 wt.-% Na2HPO4 x 12 H20, 0.06333 wt.-% sodium hydroxide, 0.01 wt.-
%
cetrimide and/or 1.0 wt.-% mid-chain triglycerides as well as ad 100 wt.-%
water, based on
the total weight of the preparation.
In further preferred embodiments, the ophthalmic preparation comprises
substances selected
from the group comprising polyacrylic acid, polymeric acrylic acid
derivatives, preferably
carbomers, triglycerides, preferably mid-chain triglycerides, water-soluble
phosphate salts,
preferably Na2HPO4 x 12 H20, a vitamin A component, preferably vitamin A
palmitate,
vitamin E, preferably D,L-a-tocopherol, sorbitol, sodium hydroxide,
preservatives, preferably
cetrimide or benzododecinium chloride and/or water. In further preferred
embodiments, the
ophthalmic preparation comprises 0.2 wt.-% polymeric acrylic acid, preferably
carbomer, 4.0
wt.-% sorbitol, 0.1 wt.-% Na2HPO4 x 12 H20, 0.06333 wt.-% sodium hydroxide,
0.1 wt.-%
cetrimide, 0.12 wt.-% vitamin A palmitate, 0.006 wt.-% vitamin E, preferably
D,L-a-
tocopherol and/or 1.0 wt.-% mid-chain triglycerides as well as ad 100 wt.-%
water, based on
the total weight of the preparation. In still further preferred embodiments,
the ophthalmic
preparation comprises 0.2 wt.-% polymeric acrylic acid, preferably carbomer,
4.0 wt.-%
sorbitol, 0.1 wt.-% NaZHPO4 x 12 H20, 0.06333 wt.-% sodium hydroxide, 0.01 wt.-
%
cetrimide, 0.12 wt.-% vitamin A palmitate, 0.006 wt.-% vitamin E, preferably
D,L-a-
tocopherol and/or 1.0 wt.-% mid-chain triglycerides as well as ad 100 wt.-%
water, based on
the total weight of the preparation.
In still more preferred embodiments, the ophthalmic preparation comprises
substances
selected from the group comprising polyacrylic acid, polymeric acrylic acid
derivatives,
preferably carbomers, triglycerides, preferably mid-chain triglycerides, water-
soluble
phosphate salts, preferably Na2HPO4 x 12 H20, glycerol, sorbitol, sodium
hydroxide,
preservatives, preferably cetrimide or benzalkonium chloride and/or water. In
still further
CA 02616531 2008-01-23
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preferred embodiments, the ophthalmic preparation comprises 0.2 wt.-%
polymeric acrylic
acid, preferably carbomer, 3.666 wt.-% sorbitol, 0.1 wt.-% Na2HPO4 x 12 H20,
0.063 wt.-%
sodium hydroxide, 0.01 wt.-% cetrimide or 0.01 wt.-% benzalkonium chloride,
0.2 wt.-%
glycerol (100 %) or 0.235 wt.-% glycerol (85 %) and/or 1.0 wt.-% mid-chain
triglycerides as
well as ad 100 wt.-% water, based on the total weight of the preparation.
In yet further preferred embodiments, the ophthalmic preparation comprises
substances
selected from the group comprising polyacrylic acid, polymeric acrylic acid
derivatives,
preferably carbomers, triglycerides, preferably mid-chain triglycerides, water-
soluble
phosphate salts, preferably Na2HPO4 x 12 H20, glycerol, sorbitol, sodium
hydroxide,
preservatives, preferably alexidine and/or water. In other preferred
embodiments, the
ophthalmic preparation comprises 0.2 wt.-% polymeric acrylic acid, preferably
carbomer,
3.666 wt.-% sorbitol, 0.1 wt.-% Na2HPO4 x 12 H20, 0.063 wt.-% sodium
hydroxide, 0.0003
wt.-% alexidine HC1, 0.2 wt.- % glycerol (100%) or 0.235 wt.-% glycerol (85 %)
and/or 1.0
wt.-% mid-chain triglycerides as well as ad 100 wt.-% water, based on the
total weight of the
preparation.
In particularly preferred embodiments, the ophthalmic preparation comprises
the following
substances, based on the total weight of the preparation:
a. 0.2 wt.-% polymeric acrylic acid;
b. 4.0 wt.-% sorbitol;
c. 0.1 wt.-% Na2HPO4 x 12 H20;
d. 0.0665 wt.-% sodium hydroxide;
e. 1.0 wt.-% mid-chain triglycerides;
f ad 100 wt.-% water.
Unless indicated otherwise, the amount of the respective substances contained
in the
preparation are selected such that the total amount of the respective
substances does not
exceed 100 wt.-%, based on the total weight of the preparation.
CA 02616531 2008-01-23
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Within the meaning of this invention the term "substance" describes substances
which are in
the preparation, in particular those selected from the group comprising
polymeric acrylic acid,
polymeric acrylic acid derivatives, carbomer, sorbitol, water-soluble
phosphate salt,
preferably Na2HPO4 x 12 H20, sodium hydroxide, mid-chain triglycerides,
preservatives,
preferably cetrimide, vitamin A component, preferably vitamin A palmitate,
vitamin E,
preferably D,L-a-tocopherol, glycerol and/or water.
In further preferred embodiments the ophthalmic preparation comprises the
following
substances, based on the total weight of the preparation:
a. 0.2 wt.-% polymeric acrylic acid;
b. 4.0 wt.-% sorbitol;
c. 0.1 wt.-% Na2HPO4 x 12 H20;
d. 0.06333 wt.-% sodium hydroxide;
e. 1.0 wt.-% mid-chain triglycerides;
f. 0.1 wt.-% cetrimide;
g. ad 100 wt.-% water.
In still further preferred embodiments, the ophthalmic preparation comprises
the following
substances, based on the total weight of the preparation:
a. 0.2 wt.-% polymeric acrylic acid;
b. 4.0 wt.-% sorbitol;
c. 0.1 wt.-% Na2HPO4 x 12 H20;
d. 0.06333 wt.-% sodium hydroxide;
e. 1.0 wt.-% mid-chain triglycerides;
f. 0.1 wt.-% cetrimide;
g. 0.12 wt.-% vitamin A palmitate;
h. 0.006 wt.-% D,L-a-tocopherol;
i. ad 100 wt.-% water.
CA 02616531 2008-01-23
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In other preferred embodiments, the ophthalmic preparation comprises the
following
substances, based on the total weight of the preparation:
a. 0.2 wt.-% polymeric acrylic acid;
b. 4.0 wt.-% sorbitol;
c. 0.1 wt.-% Na2HPO4 x 12 H20;
d. 0.06333 wt.-% sodium hydroxide;
e. 1.0 wt.-% mid-chain triglycerides;
f. 0.01 wt.-% cetrimide;
g. ad 100 wt.-% water.
In still further preferred embodiments, the ophthalmic preparation comprises
the following
substances, based on the total weight of the preparation:
a. 0.2 wt.-% polymeric acrylic acid;
b. 4.0 wt.-% sorbitol;
c. 0.1 wt.-% Na2HPO4 x 12 H20;
d. 0.06333 wt.-% sodium hydroxide;
e. 1.0 wt.-% mid-chain triglycerides;
f. 0.01 wt.-% cetrimide;
g. 0.12 wt.-% vitamin A palmitate;
h. 0.006 wt.-% D,L-a-tocopherol;
i. ad 100 wt.-% water
In yet preferred embodiments, the ophthalmic preparation comprises the
following substances,
based on the total weight of the preparation:
a. 0.2 wt.-% polymeric acrylic acid;
b. 3.666 wt.-% sorbitol;
c. 0.1 wt.-% Na2HPO4 x 12 H20;
d. 0.063 wt.-% sodium hydroxide;
e. 1.0 wt.-% mid-chain triglycerides;
CA 02616531 2008-01-23
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f. 0.01 wt.-% benzalkonium chloride;
g. 0.2 wt.-% glycerol (100 %), or 0.235 wt.-% glycerol (85 %);
h. ad 100 wt.-% water.
In other preferred embodiments, the ophthalmic preparation comprises the
following
substances, based on the total weight of the preparation:
a. 0.2 wt.-% polymeric acrylic acid;
b. 3.666 wt.-% sorbitol;
c. 0.1 wt.-% Na2HPO4 x 12 H-)O;
d. 0.063 wt.-% sodium hydroxide;
e. 1.0 wt.-% mid-chain triglycerides;
f. 0.0003 wt.-% alexidine HCI;
g. 0.2 wt.-% glycerol (100 %), or 0.235 wt.-% glycerol (85 %);
h. ad 100 wt.-% water.
In yet further preferred embodiments, the ophthalmic preparation comprises the
following
substances, based on the total weight of the preparation:
a. 0.2 wt.-% polymeric acrylic acid;
b. 3.666 wt.-% sorbitol;
c. 0.1 wt.-% Na2HPO4 x 12 H?O;
d. 0.063 wt.-% sodium hydroxide;
e. 1.0 wt.-% mid-chain triglycerides;
f. 0.2 wt.-% glycerol (100 %), or 0.235 wt.-% glycerol (85 %);
g. ad 100 wt% water.
The preparation of the present invention is advantageously prepared aseptic
without any
problems and is well tolerated. The preparation of the sterile composition of
the present
invention, in particular gel composition, is preferably carried out in a multi-
step method. In
CA 02616531 2008-01-23
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particular, at least one water-soluble phosphate salt is added to the aqueous
phase of the
composition of the present invention.
It is apparent that the ophthalmic preparation is preferably sterile for use.
Sterile substances
are, therefore, either used under sterile conditions or the preparation is
sterilized after the
incorporation of these substances.
In a preferred method of production of a preparation of the present invention,
a suspension of
the polymeric acrylic acid or the polymeric acrylic acid derivative, in
particular a carbomer, is
prepared, preferably under aseptic conditions. To this suspension, a sterile-
filtered solution of
the isotonicity agent, preferably sorbitol, also comprising sodium
monohydrogen phosphate
dodecahydrate or other phosphate salts, and if necessary a preservative, is
then added. Here,
preferably sterile-filtered nitrogen or compressed air as pressure gas is
used. After thoroughly
mixing, the carboxyl groups of the polyacrylic acid component are neutralized
by adding a
suitable base (preferably sterile 2% to 3% sodium hydroxide solution), the gel-
forming of the
polyacrylic acid component is then induced and the mixture is stirred
preferably until
homogeneity of the gel is achieved.
To the prepared sterile hydrogel, the hydrophobe liquid phase, preferably the
mid-chain
triglyceride component is then added under aseptic conditions. Preferably, the
mid-chain
triglyceride is dispersed homogeneously into the continuous aqueous phase, in
particular the
sterile hydrogel.
Preferably, it is stirred until complete homogenization is achieved. The
dimension of the so
prepared droplets of the hydrophobic liquid phase, or oil drops, in the
dispersion has a
maximum size of about 100 m. Afterwards, the sterile preparation can be
converted in the
usual manner.
CA 02616531 2008-01-23
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In the production method of a preparation of the present invention an active
agent such as
vitamin A palmitate can also be added to the so prepared sterile gel.
Preferably, the active
agent is added under aseptic conditions and mixed homogeneously. Preferably,
the vitamin A
component and the very small amount of antioxidant, which is preferably
present, are
dissolved in the hydrophobic phase and then filtered sterilely. The sterile,
hydrophobic, active
agent-containing phase is then incorporated into the gel under agitation.
It is especially advantageous that the ophthalmic preparation of the present
invention is useful
for preparing a cosmetic and/or pharmaceutical preparation for the treatment
of diseases or
conditions of the eye or of the organs or tissue surrounding the eye or
connected therewith, in
particular of dry eye.
Due to the advantageous substances of the preparation, it can be used for the
treatment of
diseases or conditions of the eye or the organs or tissues surrounding the eye
or connected
therewith, in particular in the form of a gel preparation. In particular, the
preparation is
suitable for relieving discomfort related to dry eye and/or for the
symptomatic treatment of
dry eye.
In particular, the preservative-free ophthalmic preparation of the present
invention is
advantageously suitable for the long-term application of dry eye. Due to the
advantageous
substances of the ophthalmic preparation, the preservative-free ophthalmic
preparation can
especially be safely reapplied and used, for example, as a tear replacement
agent.
Surprisingly, it was found that within a few minutes after application of the
preparation,
significant improvement of disorders, such as feeling of dryness in the eye as
well as burning,
itching, redness, or swelling can be achieved. It is of particular advantage
that these disorders
are continuously relieved by the preparation of the present invention.
CA 02616531 2008-01-23
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For application, the preparation of the present invention is preferably filled
up in suitable
containers, which are preferably formed such that the content can be applied
onto the eye, for
example in dropping bottles, in particular in containers well known under the
designation
Ophtiole , advantageously based on polyethylene, preferably HDPE (polyethylene
of high
density, high density polyethylene) or LDPE (polyethylene of low density, low
density
polyethylene).
In preferred embodiments of the ophthalmic preparation, the preparation is
contained in a
single-dose unit, preferably in a single-dose container, for example, known
under the
designation single-dose-Ophtiole , preferably based on LDPE. In particularly
preferred
embodiments of the ophthalmic preparation, the preparation is present in the
form of a gel
preparation in a single-dose container free of preservatives.
In further preferred embodiments of the sterile, drop-forming, multiphase,
emulsifier-free
ophthalmic preparation, the preparation is contained in a multi-dose unit, for
example a multi-
dose container. In especially preferred embodiments of the ophthalmic
preparation, the
preparation is preferably present in the form of a gel preparation in a multi-
dose container free
of preservatives.
A multi-dose unit contains a larger quantity of the sterile, drop-forming,
multiphase,
emulsifier-free ophthalmic preparation, for example several doses. Thus, it is
advantageously
possible that, for example, a multiple dose can be contained in one container.
The viscosity was determined by the cone/plate-method ("Platte-Kegel-
Verfahren") with a
rheometer of the type DV-III+ by the company Brookfield using a CP51-spindle
at 5 U/rpm at
20 C. Viscosity data refers to the viscosity of the composition prior to
application on the eye,
unless indicated otherwise.
CA 02616531 2008-01-23
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The following embodiment example serves to explain the invention and does not
represent
any restriction.
Example 1
Eye gel comprising, based on 100 kg:
- 0.2 kg polymeric acrylic acid* ~;
- 4.0 kg sorbitol;
- 0.1 kg Na2HPO4 x 12 H20;
- 0.0665 kg sodium hydroxide;
- 1 kg mid-chain triglycerides*2;
- ad 100 kg water.
For example available under the trade name Carbopol 980 NF from the company
Noveon
Inc.
*2 For example available under the trade name Myritol 318 .
The preparation has a viscosity of 781 mPa=s, determined by the cone/plate-
method ("Platte-
Kegel-Verfahren") with a rheometer of the type DV-III+ by the company
Brookfield using a
CP51-spindle at 5 U/min, at 20 C, a pH value of 7,0 and an osmolality of 261
mosmol/kg.
