Note: Descriptions are shown in the official language in which they were submitted.
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TITLE OF THE INVENTION
METHOD FOR OPTIMIZING RETINAL AND OPTIC NERVE
HEALTH
BACKGROUND OF THE INVENTION
Glaucoma is a degenerative disease of the eye wherein the
intraocular pressure is too high to permit normal eye function. As a
result, damage may occur to the optic nerve head and result in
irreversible loss of visual function. If untreated, glaucoma may
eventually lead to blindness. Ocular hypertension, i.e., the condition of
elevated intraocular pressure without optic nerve head damage or
characteristic glaucomatous visual field defects, is now believed by the
majority of ophthalmologists to represent merely the earliest phase in
the onset of glaucoma. Normal tension glaucoma is the condition where
there is no elevated intraocular pressure.
Additionally, evidence suggests that glaucoma may have a
vascular component, possibly vasospastic. New scientific technologies
allow us to look more at the back of the eye and evaluate glaucoma from
a circulatory, metabolic and hematological angle, therefore, being better
able to determine the cause of the disease.
In order to be able to see, light enters through the cornea
and the lens; penetrates the back of the eye through the retina; passes the
ganglion cells and bipolar cells; then goes down to the outer plexiform
layers through the synaptic vesicle, the inner fiber, the nucleus, the
outer fibers, the terminal bars, the cilium and finally reaches the
photoreceptors which can be considered the instant film processing of
the visual light beam. After the light beam has been processed in the
photoreceptor disks, it passes back through the cilium, the ellipsoid,
myoid, Mueller cells, outer fiber, nucleus, inner fiber, synaptic vesicle,
the other plexiform layer, inner nuclear layer, the bipolar cells, the
inner plexiform layer, finally reaching the ganglion cells where it is
processed into an axon signal. After it reaches the ganglion cells, the
signal is transported through the optic nerve fibers to the brain where it
is assessed and compounded by the visual brain lobes to form the visual
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picture. It is believed that the uninterrupted signal carried by the retina,
the optic nerve head and the optic nerve fibers is the most crucial aspect
to create the visual picture and adequate blood flow which nurtures
tissue and therefore assures axon flow. Glaucoma is seen as the
progressive loss of optic nerve axons which leads to an interrupted
signal flow, therefore, the result is visual field damage which leads over
longer periods of time to blindness.
Recently, a topically effective carbonic anhydrase inhibitor
has become available for clinical use in treating glaucoma and ocular
to hypertension. (S,S)-(-)-5,6-Dihydro-4-ethylamino-6-methyl-4H-
thieno[2,3-b]thiopyran-2-sulfonamide-7,7-dioxide hydrochloride
(dorzolamide HCl; MK507) is the active ingredient in TRUSOPTTM
which is prescribed for the treatment of elevated intraocular pressure in
ocular hypertension, open-angle glaucoma and pseudo-exfoliative
glaucoma. TRUSOPT~ Ophthalmic Solution is applied as an isotonic,
buffered, slightly viscous, aqueous solution of dorzolamide HCl. Each
ml of TRUSOPT~ 2% contains 20 mg dorzolamide (22.3mg
dorzolamide HCl). When used as monotherapy, the dose is one drop of
TRUSOPT~ Ophthalmic Solution in the conjunctiva! sac of each
affected eye three times daily.
SUMMARY OF THE INVENTION
The present invention is directed to a method for increasing
retinal and optic nerve head blood velocity in a patient in need thereof
by topical application of a composition comprising a hypotonic solution
of xanthan gum and a topical carbonic anhydrase inhibitor.
The present invention is also directed to a method for
maximizing the health of the optic nerve and retina by topical
application of a composition comprising a hypotonic solution of xanthan
gum and a topical carbonic anhydrase inhibitor.
The present invention is also directed to a method for
treating normal tension glaucoma by topical application of a
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composition comprising a hypotonic solution of xanthan gum and a
topical carbonic anhydrase inhibitor.
Particularly, the invention relates to a method for
increasing retinal and optic nerve head blood velocity by topical
application of a composition comprising a topical carbonic anhydrase
inhibitor(TCAI) such as those which are described in U.S. Patent Nos.
4,797,413, 4,386,098, 4,416,890, 4,426,388, 5,378,703, 5,240,923 and
5,153,192; and the like. Particularly preferred topical carbonic
anhydrase inhibitors is the class of compounds of the structural formula
to (I):
z
T ~~SO,NH2
WAw ~S
(I)
an individual diastereomer, an individual enantiomer or mixture
thereof, or an ophthalmologically acceptable salt thereof, wherein:
A is carbon or nitrogen, preferably carbon;
Z is -NHR or -OR, preferably -NHR;
R is C,_6alkyl, either straight or branched chain, preferably CZ_4alkyl
such as ethyl, propyl or isobutyl;
R' is
(a) hydrogen,
(b) C, _3alkyl, preferably methyl, ethyl or n-propyl, or
(c) C,_4alkoxy-C,_4alkyl, preferably 3-methoxypropyl or
ethoxymethyl; and
X is -S(O)S- or -C(O)-, preferably -S(O)2-.
The carbon atoms to which Z and R' are bonded may be
chiral. When named according to absolute configuration, e.g., (R, S) or
(S,S), the first letter represents the chirality the carbon atom to which Z
is bonded and the second letter represents the chirality of A when A is
carbon. The carbonic anhydrase inhibitors of this invention accordingly
may be used as diastereomeric mixtures or single enantiomers or as
racemic mixtures. More preferred carbonic anhydrase inhibitors are
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dorzolamide, brinzolamide, acetazolamide, metazolamide described in
U.S. Patent Nos., 4,797,413, 4,386,098, 4,416,890, 4,426,388,
5,378,703, 5,240,923 and 5,153,192; and the like . Dorzolamide, which
has recently been approved under the trademark, T~USOPT~, is the
first topically effective CAI for clinical use.
More particularly, the invention relates to a method for
increasing retinal and optic nerve head blood velocity by topical
application of a composition wherein the topical carbonic anhydrase
inhibitor is (S,S)-(-)-5,6-dihydro-4-ethylamino-6-methyl-4H-thieno[2,3-
b]thiopyran-2-sulphonamide-7,7-dioxide, or an ophthalmologically
acceptable salt thereof or 2H-thieno[3,2-a]-1,2-thiazine-6-sulfonamide-4-
(ethylamino)-3,4-dihydro-2-(3-methoxypropyl)-1,1-dioxide or an
ophthalmologically acceptable salt thereof. Other aspects of the
invention will become apparent upon review of the complete
application.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to a method for increasing
retinal and optic nerve head blood velocity by topical application of a
composition comprising a hypotonic solution of xanthan gum and a
topical carbonic anhydrase inhibitor. It is also directed to a method for
treating normal tension glaucoma by topical application of a
composition comprising a hypotonic solution of xanthan gum and a
topical carbonic anhydrase inhibitor.
The present invention is based upon the finding that CAIs
can preserve or benefit vision by increasing both retinal and optic nerve
head blood flow velocity. The increase in blood flow velocities was
attained without any change in retinal vessel width which might have
been the expected reason for the increase in flow velocity.
Research was done using TRUSOPT~, as the carbonic
anhydrase inhibitor. It is a known compound useful as a carbonic
anhydrase inhibitor and for the reduction of intraocular pressure as is
described in U.S. Pat. No. 4,797,413.
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In the compositions of the present invention the
concentration of xanthan gum comprises about 0.1 to 2% (w/w),
preferably 0.4 to 0.7% (w/w). Particularly preferred is KELTROLTM T
xanthan gum from Monsanto Performance Materials.
Xanthan gum is a high molecular weight polysaccharide
gum obtainable from the aerobic fermentation of a carbohydrate with
bacteria of the genus Xanthomonas, especially Xanthomonas campestris.
Each xanthan gum repeat unit contains five sugar residues: two glucose,
two mannose and one glucuronic acid. The polymer backbone consists
of four (3-D-glucose units linked at the 1 and 4 positions. Trisaccharide
side chains on alternating anhydroglucose units distinguish xanthan gum
from cellulose. Each side chain comprises a glucuronic acid residue
between two mannose units. At most of the terminal mannose units is a
pyruvate moiety.
Xanthan gum solutions are pseudoplastic. In other words,
when shear stress is increased, the viscosity is progressively reduced.
Upon reduction of the shear, total viscosity is recovered almost
instantaneously. This behaviour results from the high-molecular-weight
molecule which forms complex molecular aggregates through hydrogen
bonds and polymer entanglement. Also, this highly ordered network of
entangled, stiff molecules accounts for the high viscosity observed at
low shear rates. Shear thinning results from disaggregation of this
network and alignment of individual polymer molecules in the direction
of shear force. However, when the shearing ceases, aggregates re-form
rapidly. As a result of its helical conformation, xanthan gum viscosity
is relatively insensitive to temperature changes below the transition
temperatures and to differences in ionic strength and pH. Xanthan gum
solutions do not therefore have any liquid-gel phase transition
properties, hence xanthan gum is not suitable for use in the formulation
of in situ gelling solutions.
The results of the present invention suggest that the high
degree of pseudoplasticity, which is independent of concentration,
appears to be important in contributing to the unusual ocular penetration
properties of the hypotonic formulation of xanthan gum.
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Xanthan gum is commercially available, for example, under
the tradename KELTROLT"' from Monsanto Performance Materials, a
unit of Monsanto Company, St. Louis, MO 63167, USA.
Following administration of the composition to the
conjunctival sac of a patient's eye, there is no liquid-gel phase transition.
The advantageous enhancement in ocular bioavailability of the topical
carbonic anhydrase inhibitor is achieved through the unique
combination of the properties of the hypotonic solution of xanthan gum.
The topical carbonic anhydrase inhibitors of use in the
present invention include those compounds described in U.S. Patent Nos.
4,797,413, 4,386,098, 4,416,890, 4,426,388, 5,378,703, 5,240,923 and
5,153,192; and the like. Preferred topical carbonic anhydrase inhibitors
are the class of compounds of the structural formula (I):
z
~~SO~TH~
A
R'~ ~X S (I)
an individual diastereomer, an individual enantiomer or mixture
thereof, or an ophthalmologically acceptable salt thereof, wherein:
A is carbon or nitrogen, preferably carbon;
Z is -NHR or -OR, preferably -NHR;
R is C, _6alkyl, either straight or branched chain, preferably CZ_4alkyl
such as ethyl, propyl or isobutyl;
R' is
(a) hydrogen,
(b) C,_~alkyl, preferably methyl, ethyl or n-propyl, or
(c) C,_4alkoxy-C,_4alkyl, preferably 3-methoxypropyl or
ethoxymethyl; and
X is -S(O)S- or -C(O)-, preferably -S(O)S-.
The carbon atoms to which Z and R' are bonded may be
chiral. When named according to absolute configuration, e.g., (R,S) or
(S, S), the first letter represents the chirality the carbon atom to which Z
is bonded and the second letter represents the chirality of A when A is
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carbon. The carbonic anhydrase inhibitors of this invention accordingly
may be used as diastereomeric mixtures or single enantiomers or as
racemic mixtures.
Preferred topical carbonic anhydrase inhibitors for use in
the present invention are compounds of formula (I), above, wherein A
is carbon; and wherein R is -CH~CH~ and R' is -CH3; or R is
-CHZCH2CH~ and R' is -CH~CH2CH~OCH3; or R is -CH~CH3 and R' is
-CH2CH2CH3; or R is -CH2CH~(CH3)~ and R' is hydrogen; or R is
-CH~CH~ and R' is -CH~OCH~CH3; and carbons 4 and 6 of the topical
carbonic anhydrase inhibitor both have S absolute stereochemical
configuration.
More preferred carbonic anhydrase inhibitors are
dorzolamide, brinzolamide, acetazolamide, metazolamide described in
U.S. Patent Nos., 4,797,413, 4,386,098, 4,416,890, 4,426,388,
5,378,703, 5,240,923 and 5,153,192; and the like . Dorzolamide, which
has recently been approved under the trademark, TRUSOPT ~z , is the
first topically effective CAI for clinical use.
Most preferred topical carbonic anhydrase inhibitors are
(S,S)-(-)-5,6-dihydro-4-ethylamino-6-methyl-4H-thieno[2,3-
b]thiopyran-2-sulphonamide-7,7-dioxide, or an ophthalmologically
acceptable salt thereof and 2H-thieno[3,2-a]-1,2-thiazine-6-sulfonamide-
4-(ethylamino)-3,4-dihydro-2-(3-methoxypropyl)-l,l-dioxide or an
ophthalmologically acceptable salt thereof.
A particularly preferred topical carbonic anhydrase
inhibitor is dorzolamide, especially as its hydrochloride salt.
The concentration of TCAI in the present invention is about
0.05 to 5% (w/w), usually about 0.5 to 3% (w/w), and is administered
once or twice daily, to each affected eye.
The novel method of this invention comprises the topical
ocular administration of about 0.025 to 5 mg per day, preferably about
0.25 to 3 mg per day, of the topical carbonic anhydrase inhibitor to each
eye.
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8 As a unit dosage, between 0.025 and 2.5 mg, preferably
between 0.25 and 1.5 mg, of the topical carbonic anhydrase inhibitor is
applied to each eye.
Conventional ophthalmic solutions are usually prepared as
isotonic solutions using tonicity adjusting agents such as potassium
chloride, sodium chloride, mannitol, dextrose and glycerin. An isotonic
solution will have a freezing point depression of approximately -
0.54°C.
Tonicity may also be measured by the osmolality of the solution, an
isotonic solution having an osmolality of about 290 milliosmoles per
kilogram (mOs/kg).
It is a characteristic of the ophthalmic compositions of the
present invention that they are hypotonic solutions, with a freezing point
depression between about -0.28°C and -0.4°C, and preferably
between
about -0.31 °C and -0.37°C.
Alternatively, the hypotonicity of the ophthalmic solutions
of the present invention is between about I50 and 215 mOs/kg, and
preferably between 170 and 200 mOs/kg.
According to a further aspect of the present invention,
there is provided a novel method for increasing retinal and optic nerve
head blood velocity by topical application of a composition comprising a
hypotonic solution of xanthan gum, a therapeutically effective amount of
a topical carbonic anhydrase inhibitor and a therapeutically effective
amount of a ~3-adrenergic receptor blocking agent. Suitable
(3-adrenergic receptor blocking agents include betaxolol, bufetolol,
carteolol, levobunolol, metipranolol, and timolol, or an
ophthalmologically acceptable salt thereof. A particularly preferred
~3-adrenergic receptor blocking agent is timolol maleate.
Such compositions preferably comprise about 0.05 to 5%
{w/w) of the topical carbonic anhydrase inhibitor, usually about 0.5 to
3% (w/w), and about 0.01 to 1% (w/w) of the 13-adrenergic receptor
blocking agent, preferably about 0.1 to 0.5% (w/w) to be administered
once or twice a day to each affected eye.
Thus, a further novel method of this invention comprises
the topical ocular administration of about 0.025 to 5 mg per day,
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preferably about 0.25 to 3 mg per day, of the topical carbonic -
anhydrase inhibitor and about 0.005 to 1 mg per day, preferably about
0.05 to 0.5 mg per day, of the 13-adrenergic receptor blocking agent to
each eye.
As a unit dosage, between 0.005 and 0.5 mg of the 13-
adrenergic receptor blocking agent, and preferably between 0.05 and
0.25 mg of the f3-adrenergic receptor blocking agent, is applied to each
eye.
The pH of the composition ranges from about 5.0 to about
7.5, preferably about 5.5 to about 7Ø
Suitable subjects for the administration of the formulation
of the present invention include primates, man and other animals,
particularly man and domesticated animals such as cats and dogs.
The pharmaceutical preparation may contain non-toxic
auxiliary substances such as antibacterial components which are non-
injurious in use, for example, thimerosal, benzalkonium chloride,
methyl and propyl paraben, benzyldodecinium bromide, benzyl alcohol,
or phenylethanol; buffering ingredients such as sodium chloride, sodium
borate, sodium acetate, sodium citrate, or gluconate buffers; and other
conventional ingredients such as sorbitan monolaurate, triethanolamine,
polyoxyethylene sorbitan monopalmitylate, ethylenediamine tetraacetic
acid, and the like.
The following examples of ophthalmic compositions are
given by way of illustration.
EXAMPLE 1
SOLUTION COMPOSITION A B
(S,S)-(-)-5,6-Dihydro-4-ethylamino-6-2.226% 2.226%
methyl-4H-thieno[2,3-b]thiopyran-2-
sulfonamide-7,7-dioxide
monohydrochloride
Xanthan Gum 0.5 % 0.7 %
Sodium Chloride 0.2% 0.2%
_g_
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Benzalkonium Chloride 0.0075% 0.0075%
Sodium hydroxide QS pH 5.6 pH 5.6
Purified Water QS 100% 100%
The active compound, sodium chloride and benzalkonium
chloride were dissolved in water for injection. The pH of the
composition was adjusted to 5.6 by addition of 0.2 N sodium hydroxide
solution, and water for injection was added until the weight of
composition was equal to 75 parts of the final weight (Example lA) or
65 parts of the final weight (Example 1B). The composition was
sterilised by filtration, and the solution flushed with sterile nitrogen.
Then a clarified, steam sterilised concentrate of 2% xanthan gum was
added to the solution of drug and the obtained solution was homogenised
by stirring. The solution was aseptically subdivided into sterile vials
and sealed.
EXAMPLE 2
SOLUTION COMPOSITION
(S,S)-(-)-5,6-Dihydro-4-ethylamino-6-0.88%
(n-propyl)-4H-thieno[2,3-b)thiopyran-
2-sulfonamide-7,7-dioxide
monohydrochloride
Xanthan Gum 0.5 %
Sodium Citrate 0.147%
Hydrochloric Acid QS pH 5.0
Sorbitol 1.5 %
Benzalkonium Chloride 0.0075%
Purified Water QS 100%
The active compound, sodium citrate, benzalkonium
chloride and sorbitol are dissolved in water for injection. The pH of the
composition is adjusted to pH 5.0 by addition of hydrochloric acid, and
water for injection is added until the weight of the composition is equal
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to 75 parts of the final weight. The composition is sterilised by
filtration, flushing with sterile nitrogen. Then a clarified, steam
sterilised concentrate of 2% xanthan gum is added to the solution of the
drug and the obtained solution is homogenised by stirring. The solution
is aseptically subdivided into sterile vials and sealed.
EXAMPLE 3
SOLUTION COMPOSITION
()-5,6-dihydro-4-[(2- 1.662%
methylpropyl)amino]-4H-thieno[2,3-
b]thiopyran-2-sulfonamide-7,7-dioxide
monohydrochloride
Xanthan Gum 0.5 %
Sodium Citrate 0.22%
Sodium Hydroxide QS pH 5.6
Mannitol 0.50%
Benzalkonium Chloride 0.0075%
Purified Water QS 100%
The active compound, sodium citrate, benzalkonium
chloride and mannitol are dissolved in water for injection. The pH of
the composition is adjusted to pH 5.6 by addition of sodium hydroxide,
and water for injection is added until the weight of the composition was
equal to 75 parts of the final weight. The composition is sterilised by
filtration, flushing with sterile nitrogen. Then a clarified, steam
sterilised concentrate of 2% xanthan gum is added to the solution of the
drug and the obtained solution is homogenised by stirring. The solution
is aseptically subdivided into sterile vials and sealed.
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EXAMPLE 4
SOLUTION COMPOSITION
(S, S)-(-)-5,6-dihydro-4-ethylamino-6-1.6695%
methyl-4H-thieno[2,3-b]thiopyran-2-
sulfonamide-7,7-dioxide
monohydrochloride
Xanthan Gum 0.7%
Sodium Chloride 0.25%
Sodium Hydroxide QS pH 5.8
Benzalkonium Chloride 0.0075%
Purified Water QS 100%
The active compound, sodium chloride and benzalkonium
chloride were dissolved in water for injection. The pH of the
composition was adjusted to pH 5.8 by addition of sodium hydroxide,
and water for injection was added until the weight of the composition
was equal to 65 parts of the final weight. The composition was
sterilised by filtration, flushing with sterile nitrogen. Then a clarified,
steam sterilised concentrate of 2% xanthan gum was added to the
solution of the drug and the obtained solution was homogenised by
stirring. The solution was aseptically subdivided into sterile vials and
sealed.
EXAMPLE S
SOLUTION COMPOSITION
(S, S)-(-)-5,6-dihydro-4-ethylamino-6- 1.113 %
methyl-4H-thieno[2,3-b]thiopyran-2-
sulfonamide-7,7-dioxide
monohydrochloride
Xanthan Gum 0.7%
Sodium Hydroxide QS pH 6.0
Sodium Chloride 0.32%
_ 1~ _
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Benzalkonium Chloride 0.0075%
Purified Water QS 100%
The active compound, sodium chloride and benzalkonium
chloride were dissolved in water for injection. The pH of the
composition was adjusted to pH 6.0 by addition of sodium hydroxide,
and water for injection was added until the weight of the composition
was equal to 65 parts of the final weight. The composition was
sterilised by filtration, flushing with sterile nitrogen. Then a clarified,
steam sterilised concentrate of 2% xanthan gum was added to the
solution of the drug and the obtained solution was homogenised by
stirring. The solution was aseptically subdivided into sterile vials and
sealed.
EXAMPLE 6
SOLUTION COMPOSITION
(S, S)-(-)-5,6-dihydro-4-ethylamino-6-1.113 %
methyl-4H-thieno[2,3-b]thiopyran-2-
sulfonamide-7,7-dioxide
monohydrochloride
Xanthan Gum 0.7 %
Sodium Hydroxide QS pH 6.5
Sodium Chloride 0.32%
BenzaIkonium Chloride 0.0075%
Purified Water QS 100%
The active compound, sodium chloride and benzalkonium
chloride were dissolved in water for injection. The pH of the
composition was adjusted to pH 6.5 by addition of sodium hydroxide,
and water for injection was added until the weight of the composition
was equal to 65 parts of the final weight. The composition was
sterilised by filtration, flushing with sterile nitrogen. Then a clarified,
steam sterilised concentrate of 2% xanthan gum was added to the
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solution of the drug and the obtained solution was homogenised by
stirring. The solution was aseptically subdivided into sterile vials and
sealed.
EXAMPLE 7
SOLUTION COMPOSITION
(S, S)-(-)-5,6-dihydro-4-ethylamino-6- 2.226%
methyl-4H-thieno[2,3-b]thiopyran-2-
sulfonamide-7,7-dioxide
monohydrochloride
(S)-(-}-1-(ter-t-butylamino)-3-[(4- 0,684%
morpholino-1,2,5-thiadiazol-3-yl)oxy]-2-
propanol maleate
Xanthan Gum 0.5 %
Sodium Chloride 0.15%
Sodium Hydroxide QS pH 5.6
Benzalkonium Chloride 0.0075%
Purified Water QS 100%
The active compounds, sodium chloride and benzalkonium
chloride are dissolved in water for injection. The pH of the composition
is adjusted to pH 5.6 by addition of sodium hydroxide, and water for
injection is added until the weight of the composition was equal to 75
parts of the final weight. The composition is sterilised by filtration,
flushing with sterile nitrogen. Then a clarified, steam sterilised
concentrate of 2% xanthan gum is added to the solution of the drug and
the obtained solution is homogenised by stirring. The solution is
aseptically subdivided into sterile vials and sealed.
RESULTS
Concentrations of 2% dorzolamide(TRUSOPT~} or 2%
dorzolamide in hypotonic xanthan gum formulation were measured by
HPLC in various fluids and tissues of pigmented rabbit eye at 1, 2, 4 and
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8 hours after dosing. The instillation of the 2% dorzolamide in
hypotonic xanthan gum formulation resulted in, for example
approximately 2.8-fold higher concentration of dorzolamide in the
aqueous humor and iris-ciliary body at 2 hours than the 2%
dorzolamide . Likewise, the retinal, choroidal and scleral
concentrations were approximately 2.2-fold higher at 2 hours.
Moreover, the concentration of dorzolamide in the red blood cell and
plasma were very similar after dosing with either the 2% dorzolamide
(TRUSOPT~) or 2% dorzolamide in hypotonic xanthan gum
formulations. This suggests that the penetration of dorzolamide into the
anterior and posterior portions of the eye is enhanced by the instillation
of dorzolamide in the hypotonic xanthan gum formulation and is
independent of drug concentrations in the blood.
The claimed use of the compound to increase retinal and
optic nerve head blood flow velocity has been the subject of a study to
determine whether TRUSOPT~ drops compared to placebo drops had a
significant effect on retinal and optic nerve head blood flow velocity in
healthy subjects.
In the study, normal, healthy subjects were randomly
assigned to receive placebo or 2.0%TRUSOPT~ drops to both eyes in a
double masked clinical trial. Intraocular pressure and scanning laser
video fluorescin angiography were evaluated at baseline and 120
minutes following application. Subjects treated with TRUSOPT~
exhibited an accelerated arteriovenous passage time as well as an
increase in optic nerve head velocity. Additionally, the expected
decrease in intraocular pressure was found.
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