U.S. patent application number 14/513981 was filed with the patent office on 2015-01-29 for ophthalmic formulations including selective alpha 1 antagonists.
The applicant listed for this patent is Ocularis Pharma, LLC. Invention is credited to Gerald Horn.
Application Number | 20150031705 14/513981 |
Document ID | / |
Family ID | 35510257 |
Filed Date | 2015-01-29 |
United States Patent
Application |
20150031705 |
Kind Code |
A1 |
Horn; Gerald |
January 29, 2015 |
OPHTHALMIC FORMULATIONS INCLUDING SELECTIVE ALPHA 1 ANTAGONISTS
Abstract
Ophthalmic formulations are provided. The ophthalmic
formulations include one or more active agents that act to optimize
pupil light reflex while minimizing, or effectively eliminating,
any undesired eye redness in response to application thereof. The
active agents include, for example, alpha 1 antagonists, such as
alpha 1a selective antagonists.
Inventors: |
Horn; Gerald; (Deerfield,
IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Ocularis Pharma, LLC |
North Riverside |
IL |
US |
|
|
Family ID: |
35510257 |
Appl. No.: |
14/513981 |
Filed: |
October 14, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10867144 |
Jun 14, 2004 |
8889112 |
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14513981 |
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09854414 |
May 10, 2001 |
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10867144 |
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09710758 |
Nov 8, 2000 |
6420407 |
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09854414 |
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09705526 |
Nov 3, 2000 |
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09710758 |
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09675988 |
Sep 29, 2000 |
6730065 |
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09705526 |
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09662945 |
Sep 15, 2000 |
6291498 |
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09675988 |
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60154893 |
Sep 20, 1999 |
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60154033 |
Sep 16, 1999 |
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Current U.S.
Class: |
514/252.17 ;
514/253.04; 514/280; 514/400; 514/651; 514/663 |
Current CPC
Class: |
A61K 31/517 20130101;
A61K 31/66 20130101; A61K 31/4164 20130101; A61K 31/00 20130101;
A61K 31/475 20130101; A61P 27/06 20180101; A61P 27/04 20180101;
A61K 31/138 20130101; A61K 31/138 20130101; A61K 31/133 20130101;
A61K 31/417 20130101; A61K 45/06 20130101; A61K 31/66 20130101;
A61K 31/18 20130101; A61K 31/417 20130101; A61K 31/551 20130101;
A61K 31/475 20130101; A61K 31/496 20130101; A61K 31/18 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K
2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A61K 31/4168 20130101; A61K 2300/00 20130101; A61K 31/517 20130101;
A61P 27/02 20180101; A61K 31/4375 20130101; A61K 31/166 20130101;
A61K 31/4745 20130101; A61K 31/496 20130101; A61K 9/0048 20130101;
A61K 31/4164 20130101; A61K 31/166 20130101; A61K 31/551 20130101;
A61P 43/00 20180101; A61K 2300/00 20130101 |
Class at
Publication: |
514/252.17 ;
514/400; 514/651; 514/253.04; 514/280; 514/663 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 31/138 20060101 A61K031/138; A61K 31/133 20060101
A61K031/133; A61K 31/496 20060101 A61K031/496; A61K 31/4375
20060101 A61K031/4375; A61K 31/417 20060101 A61K031/417; A61K
31/517 20060101 A61K031/517 |
Claims
1. An ophthalmic formulation in an emulsified form for topical
administration, the ophthalmic formulation comprising: a sterile
aqueous carrier including an ophthalmic artificial tear solution,
and a therapeutically effective amount of an alpha 1 antagonist
that selectively effects an iris alpha adrenergic receptor over a
vascular alpha adrenergic receptor for optimizing a pupil diameter
in a reduced light while minimizing eye redness, wherein the alpha
1 antagonist is selected from the group consisting of sulfonamides
including tamsulosin; uracils including A-131701, fiduloxasin,
Ro-70-004, urapidil and 5-methyl urapidil; piperidines including
4-oxospiro benzopyran-2,4-piperidine; arylpiperazines including
RWJ-38063, RWJ-68141, RWJ-68157, RWJ-69736, Ro-70-004, REC 15/2739,
SB216469, urapidil and 5-methyl urapidil; dihydropyridines
including SNAP 5089 and niguldipine; aminobenzodioxanes including
WB 4101; dihydroindoles including RS 17053; n-alkylated saccharins;
and derivatives thereof.
2. The ophthalmic formulation of claim 1, wherein the alpha 1
antagonist is selective for an iris dilator smooth muscle alpha
adrenergic receptor.
3. The ophthalmic formulation of claim 2, wherein the alpha 1
antagonist effectively reduces activity of the iris dilator smooth
muscle.
4. The ophthalmic formulation of claim 3, wherein the alpha 1
antagonist reduces activity of the iris dilator muscle effectively
without constriction of an iris sphincter muscle.
5. The ophthalmic formulation of claim 1, wherein the alpha 1
antagonist is selective for an alpha 1a adrenergic receptor over an
alpha 1b adrenergic receptor.
6. The ophthalmic formulation of claim 1, wherein the ophthalmic
formulation is in an eye dropper.
7. The ophthalmic formulation of claim 1, wherein the ophthalmic
artificial tear solution includes hydroxypropyl methylcellulose in
an amount of about 0.2% to 1.5% by weight of the ophthalmic
artificial tear solution.
8. The ophthalmic formulation of claim 1, wherein the pupil
diameter is 6 mm or greater.
9. The ophthalmic formulation of claim 1, wherein the pupil
diameter is optimized to 6 mm or less.
10. The ophthalmic formulation of claim 1, wherein the pupil
diameter ranges from about 3 mm to about 5 mm.
11. The ophthalmic formulation of claim 1, wherein the ophthalmic
formulation does not affect a pupil diameter at about 2 mm or less
in a bright light.
12. The ophthalmic formulation of claim 1, wherein a pupil diameter
is optimized by reduction by about 1 mm or more.
13. The ophthalmic formulation of claim 1, wherein a pupil diameter
is optimized by reduction by about 20% or more.
14. The ophthalmic formulation of claim 1, wherein the ophthalmic
formulation reduces an adverse visual effect.
15. The ophthalmic formulation of claim 14, wherein the adverse
visual effect is at least one of a perceived light scattering, a
reduced contrast sensitivity and a reduced acuity.
16. The ophthalmic formulation of claim 14, wherein the adverse
visual effect is due to at least one of an imperfect aspheric
peripheral corneal curvature; a higher order aberration of the eye
selected from the group consisting of a coma, a secondary
astigmatism, a spherical aberration, a trifoil, a quadrafoil, and a
tetrafoil; an uncorrected spherocylindrical correction contributed
to by peripheral zones of a cornea; and combinations thereof.
17. The ophthalmic formulation of claim 1, wherein the ophthalmic
formulation promotes corneal absorption over vascular effect via a
chemical modulation of a vascular tissue.
18. The ophthalmic formulation of claim 17, wherein the chemical
modulation includes a temporary shielding or binding to a
conjunctiva of the eye.
19. The ophthalmic formulation of claim 17, wherein the chemical
modulation increases corneal absorption without effect on vascular
absorption.
20. The ophthalmic formulation of claim 17, wherein the chemical
modulation occurs through exposure to one or more substances
selected from the group consisting of a bioflavonoid, vitamin A,
and substances derived from fruits and vegetables in order to
reduce capillary permeability, including herbal extracts including
aescin.
21. The ophthalmic formulation of claim 17, wherein the chemical
modulation occurs through use of one or more substances selected
from the group consisting of a bioflavonoids, vitamin A, substances
derived from fruits and vegetables in order to reduce capillary
permeability, herbal extracts including aescin demulcents, horse
chestnut extracts, a substance containing mucilage, azone, a
collagen corneal shield, a cyclodextrin including a charged
cyclodextrin and a sulfated cyclodextrin, a bioadhesive polymer, a
microsphere, a chitosan, a captisol; and combinations thereof.
22. The ophthalmic formulation of claim 1, wherein the ophthalmic
formulation protects a mucous membrane of the eye from chemical
irritants, to soothe the eye and/or to reduce redness, burning,
stinging, or dryness by a method selected from the group of binding
a protective layer to the mucous membrane of the eye and the
conjunctiva; by reducing a capillary permeability of the eye and
increasing a venous tone by using bioflavonoids; and combinations
thereof.
23. The ophthalmic formulation of claim 1, wherein the ophthalmic
formulation increases chemical absorption via one or more carrier
particles selected from the group consisting of nanoparticles
including liposomes and emulsions, dendrimers, and buckeyballs.
24. A method of modulating pupil dilation, the method comprising:
administering to an eye of an individual an ophthalmic formulation
in an emulsified form comprising a sterile aqueous carrier
including an ophthalmic artificial tear solution, and a
therapeutically effective amount of an alpha 1 antagonist that
selectively effects an iris alpha adrenergic receptor over a
vascular alpha adrenergic receptor; and allowing the ophthalmic
formulation to remain in contact with the eye for a period of time
in a reduced light where a dilator muscle of the eye receives
greater stimulation in absence of the ophthalmic formulation and
eye redness is minimized, wherein the alpha 1 antagonist is
selected from the group consisting of sulfonamides including
tamsulosin; uracils including A-131701, fiduloxasin, Ro-70-004,
urapidil and 5-methyl urapidil; piperidines including 4-oxospiro
benzopyran-2,4-piperidine; arylpiperazines including RWJ-38063,
RWJ-68141, RWJ-68157, RWJ-69736, Ro-70-004, REC 15/2739, SB216469,
urapidil and 5-methyl urapidil; dihydropyridines including SNAP
5089 and niguldipine; aminobenzodioxanes including WB 4101;
dihydroindoles including RS 17053; n-alkylated saccharins; and
derivatives thereof.
25. A method of administering an ophthalmic formulation comprising
a sterile aqueous carrier including an ophthalmic artificial tear
solution to an eye of an individual comprising administering a
therapeutically effective amount of an alpha 1 antagonist within
the ophthalmic formulation that selectively effects an iris alpha
adrenergic receptor over a vascular alpha adrenergic receptor
wherein the ophthalmic formulation optimizes a pupil diameter while
effectively minimizing eye redness, wherein the alpha 1 antagonist
is selected from the group consisting of sulfonamides including
tamsulosin; uracils including A-131701, fiduloxasin, Ro-70-004,
urapidil and 5-methyl urapidil; piperidines including 4-oxospiro
benzopyran-2,4-piperidine; arylpiperazines including RWJ-38063,
RWJ-68141, RWJ-68157, RWJ-69736, Ro-70-004, REC 15/2739, SB216469,
urapidil and 5-methyl urapidil; dihydropyridines including SNAP
5089 and niguldipine; aminobenzodioxanes including WB 4101;
dihydroindoles including RS 17053; n-alkylated saccharins; and
derivatives thereof.
Description
CROSS REFERENCES TO RELATED APPLICATIONS
[0001] The present application is a divisional of U.S. application
Ser. No. 10/867,144, filed on Jun. 14, 2004; which is a
continuation-in-part of U.S. application Ser. No. 09/854,414 filed
on May 10, 2001; which is a continuation-in-part of earlier filed
U.S. application Ser. No. 09/710,758 filed Nov. 8, 2000 that issued
as U.S. Pat. No. 6,420,407 on Jul. 16, 2002; which is a
continuation-in-part of earlier filed U.S. application Ser. No.
09/705,526 filed Nov. 3, 2000, now abandoned; which is a
continuation-in-part of earlier filed U.S. application Ser. No.
09/675,988 filed Sep. 29, 2000 that issued as U.S. Pat. No.
6,730,065 on May 4, 2004; which is a continuation-in-part of
earlier filed U.S. application Ser. No. 09/662,945 filed Sep. 15,
2000 that issued as U.S. Pat. No. 6,291,498 on Sep. 18, 2001 which
claims priority to provisional patent applications serial nos.
60/154,893 filed Sep. 20, 1999 and 60/154,033 filed Sep. 16, 1999,
both now expired; all of which applications are incorporated herein
by reference and to which application is claimed priority under the
appropriate section of Title 35 of the U.S.C.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to compositions formulated for
administration to an eye. More specifically, the present invention
relates to compositions formulated and administered to a human eye
to improve vision, such as to reduce excessive pupil dilation in a
reduced light including absent lighting conditions.
[0003] While it is generally known that pupil size varies in its
diameter in a reduced light between individuals from 3 mm to 9 mm,
little attention has been paid to the effect of this difference on
vision, such as on night vision, vision in dim light and the like.
However, individuals with large pupils suffer from much more light
scatter, glare, halo, and related aberrant focus of light rays that
can make function under certain conditions of lighting very
difficult as disclosed in U.S. Pat. No. 6,515,006. This is due to
the fact that the eye must focus through as much as nine times more
corneal surface area in dim light conditions as compared to bright
light conditions.
[0004] As the corneal curvature becomes increasingly imperfect as a
function of distance from the corneal center, a greater degree of
undesirable light scattering occurs the larger the corneal surface
area is through which light is allowed to focus. This is
particularly relevant to night vision and vision in any dimly lit
environment, where the ideal surface area required for sufficient
light entry is far exceeded due to genetic factors related to the
light reflex common to many individuals. It therefore is desirable
to minimize this excessive pupil response to a reduced light in
such individuals.
[0005] The pupillary dilation that occurs in a reduced light
including complete darkness allows increased light to enter the
eye. However, a pupil size of about 3 mm to about 4 mm is the
maximum size needed for this purpose, allowing 9 to 16 times more
light to enter as compared to a 1 mm pupil in bright illumination.
The mean pupil size in several studies of normal populations has
been shown to be much larger, namely, about 6.1 mm. More recent
studies using recently available technology for mapping optical
imperfections known as higher order aberrations (HOA's, such as
spherical aberration, coma, secondary astigmatism, trefoil, and the
like) demonstrate a strong correlation between the increase in
pupil size in darkness above 4 mm and the degree of HOA's to which
the eye is exposed.
[0006] Further, individuals with increased optical refractive
error, individuals with only partial correction of their refractive
error, such as soft contact lens wearers with uncorrected
astigmatism, individuals with excessive higher order aberrations,
and individuals with previous refractive surgery with optical zones
much smaller than their mesopic or scotopic pupil, refractive
surgery with other induced higher order aberrations, and the like
have still greater reduction in their quality of vision and/or
contrast sensitivity (e.g., visual acuity in a reduced light), and
an even more dramatic need for a reduced pupil light reflex
response to reduced illumination. Laser vision correction in
particular has added new quality of vision difficulties for many of
these individuals. Exposing the retina to light focusing from as
much as nine times more surface area than is necessary essentially
magnifies every variation in curvature from the ideal. For example,
a normal healthy population of individuals selected only for
nearsightedness and/or astigmatism demonstrates over a 20%
incidence of difficulty with night vision and night driving, as
documented by the FDA for approval of recent laser vision
correction machines.
[0007] In general, direct acting miotic agents, such as
pilocarpine, have been used in an effort to decrease pupil size.
However, pilocarpine causes brow ache, ciliary muscle contraction
and pseudo myopia, excessive dimness when first applied since the
pupil size is usually reduced to less than 2 mm, and redness. Its
miotic effect is believed to last only a few hours, and it has a
known, though remote, risk of retinal detachment. This is probably
related to the pull on the retina from stimulated ciliary muscle
contraction. In addition to pilocarpine, the use of certain
sulfamoyl-substituted phenethylamine derivatives to reverse
drug-induced mydriasis (e.g., dilation of the pupil caused by the
administration of a drug) are disclosed in U.S. Pat. No.
5,288,759.
[0008] In general, alpha 1 antagonists are known to have propensity
to reverse pupillary dilation with cyloplegic agents, and hence it
might be inferred reduce the pupil light reflex. But, at the same
time, the alpha 1 antagonists are by their intrinsic nature known
to cause dilation of conjunctival and/or scleral vessels. This can
cause undesirable redness to the eye. Of these, phentolamine has
been demonstrated to have one of the best profiles with respect to
pupil light reflex reduction and minimal induction of vascular
dilation, and thus is useful for the purpose of reducing the pupil
light reflex when applied as in topical eye medication disclosed in
U.S. Pat. No. 6,515,006.
[0009] Another medication used to reverse pupillary dilation and
studied for its effect on pupil size is dapiprazole, an alpha 1
adrenergic receptor blocking agent. Dapiprazole is 5,6,7,8
tetrahydro-3-[2-(4-o,tolyl-1-piperazinyl)ethyl]-8-triazolo[4,3-a]pyridine
hydrochloride. In general, it is available in a 0.5% solution to
partially counteract, or reverse, the dilation effect of
phenylephrine, an adrenergic dilating agent, and the dilating and
accommodation loss caused by tropicamide. However, dapiprozole is
known to produce substantial increased redness and conjunctival
chemosis (e.g., swelling) upon instillation. Further, it has been
demonstrated that dapiprazole is not as effective with respect to
reducing pupil size in dim light in clinical application as
compared to, for example, phentolamine and phenoxybenzamine as
disclosed in U.S. Pat. No. 6,515,006 when used topically for this
purpose. Because of its side effects the commercial use of
dapiprazole is indicated for sporadic use, such as the reversal of
iatrogenic mydriasis, and not for repeat, regular, or chronic
use.
[0010] In general, the receptors that mediate pupil dilation are
located within the smooth muscle of the iris and are commonly
referred to as adrenergic receptors. The adrenergic receptors can
be further classified as alpha 1 or alpha 2 receptors. In the iris
dilator muscle, adrenergic receptors that mediate pupil dilation
are alpha 1 receptors. This classification can be further
subdivided into alpha 1 receptor types specific to smooth muscle
(which can vary for different organ systems), and frequently
different receptor alpha 1 subclassification for vascular alpha 1
adrenergic receptors.
[0011] In the human bladder, for example, alpha 1a receptors
mediate bladder contraction, while alpha 1b receptors are present
in vascular tissue. Tamsulosin represents a somewhat preferential
alpha 1a selective antagonist, which when administered orally
reduces bladder spasm with a reduced effect on blood pressure as
compared to known medications that include nonselective alpha
antagonists. In addition to tamsulosin, other compounds or agents,
such as KMD 3213, WB-4101, and 5-methyl urapidil, have an even
greater specificity for alpha 1a selectivity. For example, KMD 3213
is being studied clinically to treat bladder spasticity due to its
reduced effect on vascular tissue and lower incidence of
hypotension (low blood pressure) than found with nonselective alpha
1a antagonists that have been used (such as doxazosin).
[0012] A need therefore exists to provide improved ophthalmic
compositions that can effectively modulate the pupil light reflex
in a reduced light to a more optimal range limit of dilation, to
eliminate extraneous light and eliminate higher order aberrations
in such lighting, thereby enhancing vision and to do so without
inducing vascular effects in the eye, such as redness.
SUMMARY OF THE INVENTION
[0013] The present invention relates to ophthalmic formulations. In
general, the ophthalmic formulations can act to reduce excessive
pupil dilation, particularly in a reduced light including absent
lighting. In an embodiment, the compositions include an alpha 1
antagonist. Preferably, the compositions include a sub-class of
alpha 1 antagonists that includes selective alpha 1 antagonists.
This class of compounds can preferentially effect iris alpha
adrenergic receptors over vascular alpha adrenergic receptors. In
this regard, the selective alpha 1 antagonists can effectively act
to reduce the pupil light reflex of an eye in a reduced light while
minimizing dilation of conjunctival and/or scleral vessels. Thus,
an undesirable redness response and/or chemosis can be effectively
eliminated when the selective alpha 1 antagonist is applied to the
eye, such as in a topical manner. Compounds selectively
antagonizing the alpha 1 iris dilator smooth muscle and not the
vascular tissues of the eye are ideal for the purpose of enhancing
reduced light vision.
[0014] To this end, in an embodiment, the present invention
provides an ophthalmic formulation. The ophthalmic formulation
includes a therapeutically effective amount of a compound that
selectively effects an iris alpha adrenergic receptor over a
vascular alpha adrenergic receptor to optimize a pupil diameter in
a reduced light while minimizing eye redness.
[0015] In an embodiment, the compound is selective for an iris
dilator smooth muscle alpha adrenergic receptor.
[0016] In an embodiment, the compound effectively reduces activity
of the iris dilator smooth muscle.
[0017] In an embodiment, the compound reduces activity of the iris
dilator muscle effectively without effecting an iris sphincter
muscle.
[0018] In an embodiment, the compound includes an alpha 1
antagonist.
[0019] In an embodiment, the alpha 1 antagonist is selective for an
alpha 1a adrenergic receptor over an alpha 1b adrenergic
receptor.
[0020] In an embodiment, the alpha 1 antagonist includes
sulfonamides including tamsulosin; uracils including A-131701,
fiduloxasin, Ro-70-004, urapidil and 5-methyl urapidil; piperidines
including 4-oxospiro benzopyran-2,4-piperidine; arylpiperazines
including RWJ-38063, RWJ-68141, RWJ-68157, RWJ-69736, Ro-70-004,
REC 15/2739, SB216469, urapidil and 5-methyl urapidil;
dihydropyridines including SNAP 5089 and niguldipine;
aminobenzodioxanes including WB 4101; dihydroindoles including RS
17053 and KMD-3213, n-alkylated saccharins, and derivatives
thereof.
[0021] In an embodiment, the ophthalmic formulation is orally
administered.
[0022] In an embodiment, the ophthalmic formulation is administered
in a topical manner.
[0023] In an embodiment, the ophthalmic formulation is administered
from an eye dropper that contains the ophthalmic formulation.
[0024] In an embodiment, the ophthalmic formulation is administered
from a contact lens on which the ophthalmic formulation is
applied.
[0025] In an embodiment, the resultant pupil diameter ranges from
about 6 mm or less.
[0026] In an embodiment, the resultant pupil diameter ranges from
about 3 mm to about 5 mm.
[0027] In an embodiment, the resultant pupil diameter ranges from
about 2.75 mm to about 4.0 mm.
[0028] In an embodiment, the pupil diameter at about 2 mm or less
in a bright light is not effected.
[0029] In an embodiment, the pupil diameter is reduced by about 1
mm or more.
[0030] In an embodiment, a pupil area is reduced by about 20% or
more.
[0031] In an embodiment, the compound further promotes corneal
absorption over vascular effect via chemical modulation of a
vascular tissue.
[0032] In another embodiment, the present invention provides a
method of modulating pupil dilation. The method includes
administering to an eye of an individual a formulation comprising a
therapeutically effective amount of a compound that selectively
effects an iris alpha adrenergic receptor over a vascular alpha
adrenergic receptor; and allowing the formulation to remain in
contact with the eye for a period of time in a reduced light where
a dilator muscle of the eye receives greater stimulation in absence
of the formulation.
[0033] In an embodiment, the formulation is administered in an
amount so as to provide an optimized pupil diameter of about 6 mm
or less.
[0034] In an embodiment, the optimized pupil diameter ranges from
about 3 mm to about 5 mm.
[0035] In an embodiment, the optimized pupil diameter ranges from
about 2.75 mm to about 4 mm.
[0036] In an embodiment, the optimized pupil diameter at about 2 mm
or less in a bright light is not effected.
[0037] In an embodiment, a pupil diameter is reduced by about 1 mm
or more to optimize pupil diameter.
[0038] In an embodiment, a pupil area is reduced by about 20% or
more to optimize pupil diameter.
[0039] In an embodiment, the formulation is administered in an
amount so as to reduce an adverse visual effect.
[0040] In an embodiment, the adverse visual effect is due to at
least one of a perceived light scattering, a reduced contrast
sensitivity and a reduced acuity.
[0041] In an embodiment, the adverse visual effect is due to an
imperfect aspheric peripheral corneal curvature.
[0042] In an embodiment, the adverse visual effect is due to a
higher order aberration of the eye, such as a coma, a secondary
astigmatism, a spherical aberration, a trifoil, a quadrafoil, and a
tetrafoil.
[0043] In an embodiment, the adverse visual effect is due to an
uncorrected spherocylindrical correction contributed to by
peripheral zones of a cornea.
[0044] In an embodiment, the compound includes an alpha 1a
selective antagonist.
[0045] In an embodiment, the alpha 1a selective antagonist includes
sulfonamides including tamsulosin; uracils including A-131701,
fiduloxasin, Ro-70-004, urapidil and 5-methyl urapidil; piperidines
including 4-oxospiro benzopyran-2,4-piperidine; arylpiperazines
including RWJ-38063, RWJ-68141, RWJ-68157, RWJ-69736, Ro-70-004,
REC 15/2739, SB216469, urapidil and 5-methyl urapidil;
dihydropyridines including SNAP 5089 and niguldipine;
aminobenzodioxanes including WB 4101; dihydroindoles including RS
17053 and KMD-3213; n-alkylated saccharins; and derivatives
thereof.
[0046] In yet another embodiment, the present invention provides a
method of administering a formulation to an eye of an individual.
The method includes administering a therapeutically effective
amount of a compound within the formulation that selectively
effects an iris alpha adrenergic receptor over a vascular alpha
adrenergic receptor wherein the compound optimizes a pupil diameter
while effectively minimizing eye redness.
[0047] In an embodiment, the formulation further promotes corneal
absorption over vascular effect via a chemical modulation of a
vascular tissue.
[0048] In an embodiment, the chemical modulation includes a
temporary shielding or binding to a conjunctiva of the eye.
[0049] In an embodiment, the chemical modulation increases corneal
absorption without effect on vascular absorption.
[0050] In an embodiment, the chemical modulation increases corneal
absorption while decreasing vascular absorption.
[0051] In an embodiment, the chemical modulation occurs through
exposure to one or more substances selected from the group
consisting of a bioflavonoid, vitamin A, and substances derived
from fruits and vegetables in order to reduce capillary
permeability, including herbal extracts including aescin.
[0052] In an embodiment, the chemical modulation occurs through use
of one or more substances selected from the group consisting of
demulcents, herbal extracts, horse chestnut extracts, and a
substance containing mucilage.
[0053] In an embodiment, a mucous membrane of the eye is protected
from chemical irritants, to soothe the eye and/or to reduce
redness, burning, stinging, or dryness by binding a protective
layer to the mucous membrane of the eye and the conjunctiva.
[0054] In an embodiment, a mucous membrane of the eye is protected
from chemical irritants, to soothe the eye and/or to reduce
redness, burning, stinging, or dryness by reducing a capillary
permeability of the eye and increasing a venous tone by using
bioflavonoids.
[0055] In an embodiment, the chemical modulation occurs through a
chemical modulator selected from the group consisting of an azone,
a collagen corneal shield, a cyclodextrin including a charged
cyclodextrin and a sulfated cyclodextrin, a bioadhesive polymer, a
microsphere, a chitosan, a captisol and derivatives thereof.
[0056] In an embodiment, the chemical absorption is increased via
one or more carrier particles selected from the group consisting of
nanoparticles including liposomes and emulsions, dendrimers, and
buckeyballs.
[0057] In an embodiment, the pupil diameter is optimized to about 6
mm or less.
[0058] In an embodiment, the pupil diameter is optimized to about
3.0 mm to about 5.0 mm in size.
[0059] In an embodiment, the pupil diameter is optimized to about
2.75 mm to about 4.0 mm.
[0060] In an embodiment, the pupil diameter at about 2 mm or less
in a bright light is not effected.
[0061] In an embodiment, the pupil diameter is reduced by about 1
mm or more to optimize pupil diameter.
[0062] In an embodiment, the pupil diameter is optimized by
reducing a pupil area by about 20%.
[0063] In an embodiment, the compound includes an alpha 1a
selective antagonist that acts as a sole active ingredient to
optimize pupil diameter.
[0064] An ophthalmic formulation of the present invention in an
embodiment preferably obtains two simultaneous effects (a) reducing
the amount of dilation the eye would normally undergo in a reduced
light; and (b) reducing eye redness. Reducing normal dilation can
be obtained by administering a compound which interferes with the
normal stimulation of muscles which cause dilation. This can be
done, for example, with an alpha 1 antagonist which may also cause
redness, though if the alpha 1 antagonist is preferentially
selective for the iris smooth muscle this will be lessened.
However, redness may be reduced using an alpha 1 agonist. The
antagonist and agonist will, in general, counteract each other. The
present invention provides a particularly preferred formulation of
(a) an alpha 1 antagonist which is an imidazoline, preferably
phentolamine; and (b) an alpha 1 agonist which is either
tetrahydrozoline and specifically tetrahydrozoline hcl; or other
alpha agonists such as oxymetazoline, naphzoline or the like. While
some of these compounds may slightly increase pupil size when used
in the absence of an alpha antagonist this effect can be prevented
in the presence of an alpha antagonist. Formulations of the
invention provide preferred combinations of alpha-1-antagonists and
alpha-1-agonists which reduce both dilation and redness. As
previously discussed, a selective alpha 1 antagonist, such as
tamsulosin or KMD 3213, can be used on its own to reduce pupil
reflex while, at the same time, providing minimal, if any, eye
redness according to another preferred embodiment of the present
invention.
[0065] A formulation for optimizing pupil size in dim lighting
conditions is disclosed according to an embodiment of the present
invention. The formulation is preferably a solution of the type
used in an artificial tear formulation having dissolved therein a
therapeutically effective amount of a compound characterized by its
ability to reduce dilation of the eye, particularly in dim light.
The compound generally interferes with a natural biochemical
reaction which results in the stimulation of the dilator muscles of
the eye. In an embodiment, the formulation preferably includes a
compound which reduces eye redness, e.g. tetrahydrazoline,
oxymetazoline, naphzoline or the like. The compound which has the
ability to disrupt endogenous compounds which stimulate dilator
muscles of the eye may be an alpha 1 antagonist which belongs to a
class of compounds which includes imidazolines such as phentolamine
and tolamine. As previously discussed, the present invention also
provides a single active component that can effectively reduce
pupil light reflex to optimize vision while, at the same time,
provide minimal, or effectively eliminate, redness to the eye upon
application thereof, such as in a topical medication. In an
embodiment, the single active component includes a selective alpha
1 antagonist, such as a selective alpha 1a antagonist.
[0066] A method of optimizing pupil diameter is disclosed wherein
the pupil diameter in reduced light is effected so that it is not
more than about 4 mm to about 5 mm, or about two to five times its
diameter size in day light. The method encompasses administering a
therapeutically effective amount of an alpha 1 antagonist, such as
a selective alpha 1 antagonist, to an eye of a person in need
thereof. The optimized pupil diameter in reduced light may be no
more than about 5 mm, and the pupil diameter in bright light may be
constricted no more than about 2 mm or even as small as about 1 mm.
Further, the optimized pupil diameter in reduced light may be
between and including about 3 mm and about 5 mm, preferably about 3
mm to about 4 mm and may vary with different patients. Actual
results with human patient's are shown in the Examples as described
below. A reduction of pupillary size of 1 mm or greater compared to
whatever an individual's normal pupil size is in reduced light,
however, is sufficient to establish a clinically useful effect
pursuant to an embodiment.
[0067] The results show that alpha-1-antagonists can reduce
dilation but that some alpha-1-antagonists also cause significant
redness of the eye. In an embodiment, the reduction in dilation is
about 1.0 mm or greater. The formulations and methodologies of the
present invention provide reduced pupil diameter with effectively
no redness or acceptable levels of redness. This can be achieved
with the use of an alpha 1 selective antagonist acting as a sole
active ingredient pursuant to an embodiment of the present
invention. In an embodiment, the amount of pupil area can be
effectively reduced by about 20% or greater thereby enhancing
vision.
[0068] In accordance with the method of the present invention, in
an embodiment, an application device such an eyedropper is utilized
in order to apply a therapeutically effective amount of an alpha 1
antagonist to the eye of a patient which is preferably the eye of a
human patient and more preferably a substantially unmedicated human
eye. Thereafter, the formulation is allowed to effect the pupil of
the eye and contract the pupil so that the pupil does not expand
above a level which is two to five times the diameter of dilation
when the eye of the patient is present in bright light in an
embodiment. Accordingly, another aspect of the present invention is
a formulation comprised of an aqueous solution having an alpha 1
antagonist such as an imidazoline, an alpha 1 selective antagonist,
and the like, present therein wherein the formulation is present in
an eyedropper. As used herein, the term "eyedropper" includes any
suitable type of eyedropper including, for example, plastic
form/fill/seal containers that are squeezed to produce drops.
[0069] The present invention, in an embodiment, is also directed to
a method for optimizing pupil diameter in a reduced light by
minimizing its dilatation in response to less light, comprising
administering a therapeutically effective amount of an alpha 1
antagonist, such as an alpha 1 selective antagonist, to an eye of a
person in need thereof. In this method, dilatation of the pupil
diameter in a reduced light may be minimized in response to less
light compared with bright light, and the method may not induce
ciliary muscle contraction.
[0070] In the method of the present invention in an embodiment, the
patient may suffer from excessively large pupils in a reduced
light, and the patient may suffer from poor quality of vision, and
the patient may be undergoing medication that results in dilation
of the pupil diameter. Alternatively, the pupil diameter of the
patient may be naturally excessively dilated as a result of an
excessive genetically programmed response to dimming of light. In
addition, the patient may use nutritional supplements or
stimulants, or require use of oral medications, that as a side
effect increase the pupil diameter in a reduced light, such as
caffeine, antihistamines and products containing stimulants such as
ephedra or other epinephrine like compounds.
[0071] The present invention in an embodiment includes a treatment
method wherein the eye drop formulation of the present invention is
administered to the eye(s) of a human patient each night before
going to sleep. The formulation remains effective for about 20
hours and as such is required to be administered once a day, such
as when administered each morning, according to an embodiment of
the present invention.
[0072] The method of the present invention in an embodiment may be
carried out by directly instilling onto the eye an eye drop
formulation of the present invention according to an embodiment.
Optionally, the alpha 1 antagonist may be administered by
contacting a contact lens, and the contact lens applied to the eye
pursuant to an embodiment. As a soft contact lens has a varied
water content often ranging from about 40% to 70%, an aqueous
soluble compound is easily applied when in this reservoir, with the
advantage of prolonged exposure to corneal absorption. In the
method of the present invention, the used alpha 1 antagonist
preferably may belong to a class of compounds referred to as
imidazolines and particularly to phentolamine according to an
embodiment. As previously discussed, an alpha 1 selective
antagonist, such as tamsulosin, or KMD-3213, can be used as a
single active component of the ophthalmic formulation according to
an embodiment.
[0073] The present invention in an embodiment is directed to a
method for reducing pupil diameter in a reduced light in cases
where dilation of the pupil is excessive, such as about 6 mm or
greater. However, reducing dilation even from about 8 mm to less
than about 7 mm can improve visual function for an individual with
about 8 mm pupils in a reduced light. As a result, the pupil area
can be effectively reduced to enhance vision. In an embodiment, the
pupil area is reduced about 20% or greater. Administering a
formulation of the present invention does not induce ciliary
contraction or undesirable pseudomyopia that may result from taking
certain medications like pilocarpine. Formulations disclosed herein
reverse mydriasis (i.e., dilation) which results after the
administration of parasympatholytic agents. Formulations of the
invention are also effective on agents paralyzing accommodation
such as 1% cyclogyl, which can then be used for more complete
cycloplegia and accurate prelaser refractive measurement.
[0074] The present invention recognizes that alpha 1 antagonists
which are typically used for treatment of high blood pressure,
treatment of pheochromocytoma, migraines, bladder spasm, prostate
enlargement, sexual dysfunction and the like can be formulated and
used in reducing pupil diameter in a reduced light, thereby
enhancing pupil light reflex.
[0075] The present invention provides an ophthalmic composition
which achieves the combined requirements of reduced redness and
pupil diameter optimization.
[0076] Alpha adrenergic receptor antagonists function to block
alpha 1 receptor mediated contraction of arterial and venous smooth
muscle. Alpha-2 adrenergic receptors are involved in suppressing
sympathetic output, increasing vagal tone, facilitating platelet
aggregation, inhibiting the release of norepinephrine and
regulating metabolic effects. Alpha adrenergic antagonists have a
wide spectrum of pharmacological specificities and are chemically
heterogeneous. See, for example, Goodman & Gillman's "The
Pharmacological Basis of Therapeutics" (Ninth Edition) at pages
225-232 in particular.
[0077] The chemical classes of alpha-1-antagonists include, for
example, alkylating agents, imidazolines, piperazinyl quinazolines,
indoles and the like. Many have both alpha 1 and alpha-2 receptor
antagonist activity. The indoles provide alpha-2 activity and are
not believed to be clinically useful in reducing pupil
dilation.
[0078] Alkylating agents provide effectiveness for reversing
pharmacologic mydriasis, but are only modestly effective for
minimizing pupillary dilation. However, these compounds produce
unacceptably high levels of eye redness with severe blood vessel
dilation causing fluid leakage and swelling of the conjunctiva
known as chemosis. The best use is in veterinary medicine to
reverse cyclopegia in animal eyes.
[0079] The piperazinyl quinazolines, such as prazosin and
dapiprazole, have a modest effect on pupil diameter in dim light.
However, they are believed to be less clinically effective as
compared to imidazolines, with prazosin more effective than
dapiprazole, which is believed to have minimal if any clinically
significant effect. Dapiprazole also causes unacceptably high
levels of eye redness with severe blood vessel dilation, thereby
causing fluid leakage and swelling of the conjunctiva (chemosis). A
longer lasting, more potent piperazinyl quinazoline may be
clinically effective, but its side effects shortcomings would have
to be overcome.
[0080] Phentolamine is not as strong an alpha 1 receptor antagonist
as prazosin. However, imidazolines such as phentolamine have other
related properties beyond alpha 1 antagonism. Further, any alpha
antagonist which by its structure preferentially effects iris
smooth muscle more or vascular tissue less will have improved
clinical efficacy to the extent the iris and vascular alpha 1
adrenergic receptors vary in an individual. This difference may
account for the varying relationship between conventional
understanding of potency, which is often related to the
cardiovascular effects, and the ophthalmic derivation of the
present invention.
[0081] Other properties include blocking receptors for 5-HT,
release of histamine from mast cells, and blockage of K+ channels.
Imidazolines provide long lasting reduction in pupil dilation
without causing unacceptably high levels of redness. Used at night
before sleep they produce about 20 hours of effect; used on arising
they are generally effective for about 24 hours as the patient is
generally sleeping during the last few hours, i.e., sleeping during
hours 20-24 after administration pursuant to an embodiment of the
present invention.
[0082] As previously discussed, the present invention provides an
ophthalmic formulation that includes a single active component that
is selective for iris alpha receptors as compared to vascular alpha
receptors. This provides effective reduction in pupil size in a
reduced light while, at the same time, causing minimal, if any,
redness in response to application thereof to the eye, such as in a
topical manner. In an embodiment, the single active component
includes a selective alpha 1 antagonist.
[0083] The compounds that are selective for iris alpha receptors as
compared to vascular alpha receptors can include a variety of
different and suitable compounds. For example, classes of compounds
and specific types of compounds can include sulfonamides including
tamsulosin; uracils including A-131701, fiduloxasin, Ro-70-004,
urapidil and 5-methyl urapidil; piperidines including 4-oxospiro
benzopyran-2,4-piperidine; arylpiperazines including RWJ-38063,
RWJ-68141, RWJ-68157, RWJ-69736, Ro-70-004, REC 15/2739, SB216469,
urapidil and 5-methyl urapidil; dihydropyridines including SNAP
5089 and niguldipine; aminobenzodioxanes including WB 4101;
dihydroindoles including RS 17053 and KMD-3213, n-alkylated
saccharins, derivatives thereof, and the like.
[0084] An aspect of the present invention is an ophthalmic
formulation comprised of an aqueous solvent and an alpha 1
antagonist, such as an imidazoline or an alpha 1 selective
antagonist, in an embodiment. The aqueous solvent may, in its
simplest form, be water but is preferably a solvent that includes
an ophthalmic artificial tear solution. The alpha 1 antagonist in
an embodiment is preferably present in a relatively low
concentration, such as less than about 1% concentration. For
example, the alpha 1 antagonist may be present in an amount in the
range of about 0.01 milligram per cubic centimeter of aqueous
solvent to about 50 milligram per cubic centimeter of solvent.
Another aspect of the present invention in an embodiment is the
formulation contained within an application device such as a
conventional or improved eyedropper of the type described herein.
Alternatively, a mucin or mucinous agent may be used to bind
preferentially to the conjunctival surface and minimize vascular
absorption while corneal absorption of the active ingredient is
thereby occurring with little adverse effect. Similarly, a
demulcent may be used for this protective purpose. -Demulcent herbs
have the effect of acting as a protective barrier on irritated or
inflamed tissue. When they are used on the skin, demulcents are
called emollients. The experience of demulcency cannot always be
explained pharmacologically. They contain complex polysaccharide
molecules of mucilage that have the property of becoming slimy and
gummy when in contact with water. This may offer protection to the
conjunctiva of the eye when applied topically, and minimize
absorption of the active ingredient alpha 1 antagonist by the
conjunctiva.
[0085] An aspect of the present invention in an embodiment is an
ophthalmic formulation that includes an imidazoline in an
artificial tear carrier.
[0086] Another aspect of the present invention in an embodiment is
a method of treatment whereby an imidazoline is applied to a human
eye in an amount sufficient to reduce pupil dilation.
[0087] Yet another aspect of the present invention in an embodiment
is a formulation that includes an alpha-1-antagonist (e.g.,
phentolamine) and an alpha-1-agonist (e.g., tetrahydrazoline).
[0088] An advantage of the present invention is to treat patients
who have been subjected to laser surgery and have developed a range
of different vision problems as a result of excessive dilation of
their pupils relative to the effective size of their laser surgery
created optical zone.
[0089] Another advantage of the present invention is that the
ophthalmic formulations can be formulated in a manner which is
readily administered to the eye to obtain a desired effect.
[0090] Yet another advantage of the present invention is to provide
an ophthalmic formulation with a single active component that can
effectively optimize pupil light reflex to improve vision while, at
the same time, provide minimal, if any, redness to the eye upon
application thereof.
[0091] Additional features and advantages of the present invention
are described in, and will be apparent from, the following Detailed
Description of the Invention and the figures.
BRIEF DESCRIPTION OF THE FIGURES
[0092] FIG. 1 schematically illustrates an eyedropper apparatus
according to an embodiment of the present invention.
[0093] FIG. 2 schematically illustrates an eyedropper apparatus
according to another embodiment of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0094] The present invention relates to ophthalmic formulations. In
general, the ophthalmic formulations can effectively act to reduce
excessive pupil dilation, particularly in a reduced light including
absent lighting.
[0095] In an embodiment, the ophthalmic formulations of the present
invention antagonistically effect the alpha 1 adrenergic receptors
of the iris over the conjunctival vessels. When light illumination
is reduced, reduced pupil dilation results compared to the genetic
predisposition of the treated subject. A pupil dilation in a
reduced light from about 3 mm to about 5 mm is preferred, as
compared to a pupil dilation from about 1 mm to about 2 mm in a
bright light. This can provide from about two to about sixteen
times more pupil surface area in a reduced light as compared to
pupil surface area in a bright light. Since the mean pupil in a
reduced light is about 6 mm within a range from about 3 mm to about
9 mm, many individuals can obtain a more ideal pupil size under a
reduced light, such as mesopic or scotopic conditions, that is
closer to about 3 mm to about 4 mm using a selective alpha
antagonist in an ophthalmic formulation according to an embodiment
of the present invention.
[0096] The degree of optical imperfections in a subject's eye will
determine the magnitude of improved quality of night vision.
However, such imperfections are exceedingly common. For example, a
range of about 25% to about 40% of subjects questioned about their
quality of night vision prior to undergoing laser vision correction
in FDA monitored and controlled studies indicate poor night vision
and/or glare, halo, and difficulty driving at night before
undergoing laser vision correction.
[0097] In an embodiment, the ophthalmic compositions include an
alpha 1 antagonist. Preferably, the compositions include a
sub-class of alpha 1 antagonists that include selective alpha 1
antagonists also referred to herein as alpha 1 selective
antagonists or the like. This class of compounds can preferentially
effect iris alpha adrenergic receptors over vascular alpha
adrenergic receptors in a reduced light as previously discussed. In
this regard, the selective alpha 1 antagonists can effectively act
to reduce the pupil light reflex in a reduced light of an eye while
minimizing dilation of conjunctival and/or scleral vessels, thus
effectively eliminating an undesirable redness response to a
therapeutic amount of the selective alpha 1 antagonist applied to
the eye, such as in a topical manner.
Characteristics of the Eye
[0098] It is well known that pupillary dilation in a reduced light
is a teleologic adaption to allow more light to enter our eyes.
Along with adaptions on the retina to scotopic, or night vision,
this allows increased useful acuity over a very large range of dim
light situations. It is also well known that only very small
pupillary openings are consistent with a large field of vision, as
occurs for example in bright sunlight with about 1 mm pupillary
openings. Less well known is the dramatic range that exists among
human beings of the degree to which pupils will dilate in a reduced
light, ranging from maximal dilation in complete darkness of as
little as about 3 mm in some individuals to as high as about 9 mm
in others. This difference is part of the genetic makeup of an
individual. In this regard, a pupil at about 3 mm in size provides
sufficient added light in a reduced light relative to a pupil size
of about 1 mm to about 2 mm in daylight. What is less well known is
that unless a pupil in darkness is less than about 3 mm, there is
no perceived increase in darkness. It is therefore this range in
pupil size of about 3 to about 4 mm that is the ideal pupil size in
darkness according to an embodiment of the present invention.
Larger pupils in a reduced light can allow more extraneous light
increasing light scatter. This reduces contrast, reduces acuity,
and causes glare and halo effect in some cases, with little or no
clinical benefit.
[0099] When living in literal total darkness, there may have been a
very slight advantage for our evolutionary ancestors to have larger
pupil diameters in a reduced light. However, but whatever advantage
was conferred has been lost once several advances in civilization
resulted in illumination; including, for example, artificial means
of background lighting, neon lights to allow signs to be more
easily read, fluorescent light with its weighted blue more highly
scattering component, point sources of light caused by car
headlights, traffic lights and the like. These light sources are
visible at optimal quality when sufficient corneal diameter exists
to allow light to enter, such as a pupil size at about 3 mm, but
not an excessive pupil size, as less corneal diameter is used to
refract light, as less light scatter is induced than pupils at
about 5 mm to about 6 mm or larger in size. Optimized pupil size in
a reduced light according to an embodiment of the present invention
ranges from about 2 millimeters (mm) to about 6 mm, preferably
about 3 mm to about 5 mm, and more preferably about 3 mm to about 4
mm.
[0100] In an embodiment, the formulations of the present invention
can selectively reduce pupil size by about 1 mm or greater. This
effectively equates to a reduction in pupil area of about 20% or
greater. As previously discussed, the present invention
contemplates the use of a single active agent, preferably an alpha
1a selective antagonist that can optimize pupil light reflex while
minimizing, if not eliminating, redness.
[0101] The peripheral corneal curvature in many people is not in
perfect curvature alignment with that of the central cornea. In
individuals with small to moderate pupils in a reduced light, the
pupil acts as a filter so that the peripheral cornea in these cases
is not a factor. But, for larger pupils in a reduced light,
peripheral corneas may be either too steep or too flat in many
cases relative to the central curvature, causing spherical
aberration. These corneas are technically referred to as either
prolate or oblate when imperfect. The eye drops of the present
invention in an embodiment clinically eliminate the adverse effects
of virtually all such spherical aberration, as the peripheral
corneal curvature outside of a central optical zone at about 4 mm
to about 5 mm in size are filtered by the treated smaller pupil in
reduced light and the extraneous light focused by the spherical
aberration is eliminated.
[0102] Pupils at about 3 mm in size are sufficiently large to allow
sufficient light to enter the eye in scotopic situations or other
reduced light environments, yet provide excellent filters to
minimize light scatter of ambient artificial light and/or point
sources of light. Pupils at about 9 mm in size, on the other hand,
utilizing nine times more corneal surface area than a 3 mm pupil,
can induce considerable light scatter of point sources, neon
lights, and fluorescent blue light. While the current state of the
art within the ophthalmic and optometric professions does not
generally recognize this distinction, and wherein refractive
surgery standard of care does not generally recognize a distinction
in pupil diameter in dim light as a predictive factor in outcome,
use of the novel pharmacologic method of the present invention has
demonstrated this to be so in clinical use.
[0103] As shown below, Tables 1 and 2 demonstrate the results of a
study of several different alpha adrenergic antagonists on several
patients, with different parameters being measured. The results
show that several alpha adrenergic antagonists reduced dilation
when applied to a human eye. However, only the imidazolines obtain
the desired reduction in dilation without causing excessive redness
of the eye. In addition, the present invention in an embodiment
provides a sub-class of alpha antagonists that can act as a sole
active component in an ophthalmic medication to effectively reduce
pupil light reflex while providing minimal, if any, redness
response upon application thereof to the eye. In an embodiment, the
sub-class of alpha antagonists includes alpha 1 selective
antagonists, including alpha 1a selective antagonists, such as
tamsulosin.
[0104] Refractive optical aids, such as glasses or contact lenses,
increase the degree of light scatter in scotopic situations by
adding optical elements that are imperfect in that they have
surfaces that scatter light. Refractive surgery on the cornea,
whereby a change in contour is induced by surgical means that can
include incision (RK), laser ablation (Lasik, PRK), or prosthesis
(e.g., plastic segments inserted into the cornea) also adds
imperfections that increase the degree of light scatter in scotopic
conditions. The variables of pupil size in reduced light and
refractive optics adding to light scatter has created circumstances
in which individuals have quality of vision difficulty navigating
in scotopic situations as a result of glare, halo, and related
distortions at night or in dimly lit environments of any kind.
[0105] The present invention in an embodiment is particularly
useful in treating patients who have been subjected to various
types of refractive surgery as described above. Because such
surgery can increase the degree of light scatter, the
administration of the formulation of the present invention can
modulate this effect by contracting the pupil. Thus, the present
invention includes carrying out refractive surgery on a patient and
thereafter administering a formulation according to an embodiment
to the patient over time as needed, such as to maintain the pupil
size at about 2 mm to about 5 mm, preferably about 3 mm to about 5
mm and more preferably about 3 mm to about 4 mm. The formulation of
the present invention in an embodiment may be administered
periodically on a daily basis, such as once daily, twice daily, or
as needed, and particularly, administered in situations where the
patient is subjected to a reduced light.
[0106] The term "reduced light" or other like terms as used herein,
such as "dim light" and the like, refers to a light environment
wherein the pupils of the patient are dilated to a substantially
maximum amount. This includes an environment absent of light.
Alternatively, the term "bright light" or other like term is used
herein to describe a surrounding light environment wherein the
pupil of the patient's eye is contracted maximally, such as dilated
to a minimum amount. The term "bright light" suggests lighting
derived from, for example, indoor lighting, the outdoor lighting,
mid-day lighting, no cloud lighting, and the like. An aspect of the
present invention is that the formulation in an embodiment can
limit pupil dilation to about two to about twenty-five times pupil
area in reduced light as compared to the pupil area which would
occur in bright light.
[0107] In an embodiment, the method of the present invention
utilizes a novel pharmacologic mechanism of optimizing pupil size
by reducing pupil size in dim light. Conventional teaching of eye
specialists has been to use constricting agents of the pupil, such
as acetylcholine or cholinesterase inhibitors to reduce pupil size.
Using dilute concentrations of such agents, it is possible to
constrict the pupil and create improved viewing for affected
individuals in scotopic environments. However, undesirable side
effects of such medications, including excessive constriction
initially causing severe dimming, brow ache, generalized pain,
redness, and induced blurring secondary to ciliary accommodation,
severely limits the value of these classes of pharmacologic agents.
Retinal detachment is a known rare complication of its use.
Pharmaceutically Active Component
[0108] The pharmacologic method of the present invention in an
embodiment utilizes a class of compounds known as alpha 1
antagonists to inhibit pupillary dilation in reduced light, such as
under scotopic conditions preferentially over constriction of the
pupil, thus affecting the dilator muscles of the iris
preferentially, and has effectively no clinically significant
effect on the ciliary muscle responsible for accommodation. This
class of compounds has been used to treat hypertension, prevent
bladder spasmodic contractions and improve urinary outflow, and
treat prostate enlargement.
[0109] A significant feature of the present invention in an
embodiment is to employ a particular class of alpha antagonists,
particularly imidazolines to allow improvement in vision quality in
a reduced light effectively without causing either excessive
redness or negative clinical effects in normal lighting conditions.
Additionally, another feature of the present invention is to
reverse the effects of parasympatholytics more effectively than
dapiprazole.
[0110] In addition to imidazolines, the present invention in an
embodiment provides an ophthalmic formulation that includes a sole
active ingredient derived from a sub-class of alpha 1 antagonists,
preferably, alpha 1 selective antagonists, such as alpha 1a
selective antagonists. This sub-class of alpha 1 antagonists can
preferentially act on the iris alpha adrenergic receptors over
vascular alpha adrenergic receptors. This provides effective
reduction in pupil light reflex for improved vision while, at the
same time, providing minimal, if any, redness response upon
application thereof. The present invention contemplates the use of
any suitable type and amount of alpha 1 selective antagonist, such
as sulfonamides including tamsulosin; uracils including A-131701
(ABBOT), fiduloxasin (ABBOTT), Ro-70-004, urapidil and 5-methyl
urapidil; piperidines including 4-oxospiro
benzopyran-2,4-piperidine; arylpiperazines including RWJ-38063
(R.W. Johnson Research Institute), RWJ-68141 (R.W. Johnson Research
Institute), RWJ-68157 (R.W. Johnson Research Institute), RWJ-69736
(R.W. Johnson Research Institute), Ro-70-004, REC 15/2739,
SB216469, urapidil and 5-methyl urapidil; dihydropyridines
including SNAP 5089 and niguldipine; aminobenzodioxanes including
WB 4101; dihydroindoles including RS 17053 and KMD-3213 (KISSEI
PHARMACEUTICAL, Co. Ltd.); and n-alkylated saccharins; and
derivatives thereof. RS 17053 is generally known and not limited to
having a chemical name of
(N-[2-(2-cyclopropylmethoxyphenoxyl)ethyl]-5-chloro-.alpha.,.alph-
a.-dimethyl-1H-indole-3-ethanamine) or other suitably known
chemical name, such as
N-[2-(2-cyclopropylmethoxyphenoxyl)ethyl]-5-chloro-alpha,
alpha-dimethyl-1H-indole-3-ethanamine hydrochloride and KMD-3213 is
the active ingredient in commercially-available RAPAFLO.RTM.
(silodosin) and generally known and not limited to having a
chemical name of
1-(3-Hydroxypropyl)-5-[(2R)-2-({2-[2-(2,2,2-trifluoroethoxyl)phenoxy]ethy-
l}amino)propyl]-2,3-dihydro-1H-indole-7-carboxamide or other
suitably known chemical name, such as
(-)-(R)-1-(3-hydroxypropyl)-5-[2-[[2-[2-(2,2,2-trifluoroethoxyl)phenoxy]e-
thyl]amino]propyl]indoline-7-carboxamide and
1-(3-hydroxypropyl)-5-(2-(2-(2-(2,2,2
trifluoroethoxy)phenoxy)ethylamino)propyl)indoline-7-carboxamide.
[0111] A formulation of the present invention in an embodiment can
be used to optimize pupil size to obtain enhanced vision acuity in
reduced light by reducing the pupil diameter effectively, without
causing a clinically significant reduction in pupil size in bright
light, particularly when the pupil size does not need to be reduced
to some extent as required under reduced light.
[0112] Formulations of the present invention in an embodiment
include two active compounds. The first active compound is an
antagonist which blocks the effect of an endogenous compound which
stimulates a dilator muscle of a human eye. In an embodiment, the
antagonist is an alpha 1 antagonist, such as a nonselective alpha 1
antagonist including phenoxybenzamine and phentolamine. The second
active compound is an agonist which (a) does not substantially
interfere with antagonists and thus allows for iris dilation to be
blocked and (b) prevents or reduces redness. The first active
compound is preferably an imidazoline, more preferably
phentolamine. The second active compound is preferably
tetrahydrazolene, more preferably tetrahydrazolene hcl,
oxymetazoline, naphzoline or other redness reducer.
[0113] In another embodiment, the formulation of the present
application includes a single active component that can act to
reduce pupil size in a reduced light while minimizing, or
effectively eliminating, an undesirable redness response to
application thereof, such as in a topical manner. Preferably, the
single active component includes an alpha selective antagonist,
such as an alpha 1 selective antagonist including alpha 1a
selective antagonists, such as tamsulosin or the like as previously
discussed.
[0114] According to the present invention in an embodiment, the
optimized pupil diameter in reduced light is no more than about two
to five times greater than that in bright light.
[0115] Thus, it will be understood by those skilled in the art
reading this disclosure that the formulation of the present
invention in an embodiment decreases the difference between the
diameter of pupil dilation in reduced light and the diameter of
pupil dilation in bright light. This is done by decreasing the
amount of dilation the human eye will undergo when exposed to
reduced light.
[0116] While the ophthalmic composition of the present invention in
an embodiment can be used to optimize pupil size under any
circumstances, the composition of the present invention is
administered to the eye of an individual to reduce naturally
occurring pupillary dilation in reduced light, especially in
situations where the dilation is sufficiently excessive so as to
have a measurable effect on vision acuity. The composition of the
invention can be used also to counteract pupil dilatation caused by
medication according to an embodiment.
[0117] As used herein, the term "active agent" or other like terms
including, for example, active component, is a pharmaceutically
acceptable compound which when applied to the eye acts on an iris
smooth muscle dilator. More preferably, the active agent is of a
particular class of alpha 1 antagonists, such as imidazolines,
including phentolamine, alpha 1 selective antagonists including
tamsulosin and the like.
[0118] Imidazolines are compounds having the following general
structural formula:
##STR00001##
[0119] wherein x is any positively charged moiety and is preferably
H, Ca, Na, Mg or an amine in preferably H, and R is an alkyl or
substituted alkyl containing 1 to 18 carbons wherein the
substitutions are preferably OH and N, and wherein R is
preferably
##STR00002##
[0120] wherein R.sup.1 is a lower alkyl containing 1 to 6 carbons
and may be a straight chain, branched or cyclical alkyl and is
preferably --CH3 and X.sup.1, is a positively charged moiety and
preferably --H and R.sup.2 is an alkyl containing 1 to 6 carbons
and is preferably --CH.sub.2--.
[0121] Alpha 1 antagonists are currently used to treat
pheochromocytoma, a condition in which alpha receptor stimulants,
such as epinephrine and norepinephrine, are released throughout the
body in extremely high concentration.
[0122] Examples of alpha 1 antagonist are disclosed within issued
U.S. Pat. No. 6,046,207 issued Apr. 4, 2000. Other examples are
disclosed within U.S. Pat. Nos. 5,891,882 and 5,792,767. The above
cited three U.S. patents are incorporated herein by reference to
disclose alpha 1 antagonist. Further, publications cited in these
patents are incorporated herein by reference in order to disclose
and describe therapeutically effective compounds which can be
formulated and used in connection with the present invention when
used in appropriate ophthalmic formulations and applied directly to
the eye of a patient to effect pupil dilation.
[0123] Those skilled in the art reading this disclosure will
recognize that an active compound can be any pharmaceutically
acceptable compound which disrupts (i.e., blocks the biochemical
interactions or reactions) endogenous compounds which stimulate
dilator muscles of a human eye. Compounds other than
alpha-1-antagonists can be tested as described here and it will be
noted (as shown in the results of Table 1) that not all alpha
1-antagonists provide pharmaceutically acceptable results (when
applied alone) even when endogenous compounds which stimulate
dilator muscles of a human eye are blocked and dilation is reduced.
For example, phenoxybenzamine (an alpha-1-antagonist) will reduce
dilation but causes an unacceptably high level of redness in the
treated eye when applied as the only active compound. As previously
discussed, the present invention in an embodiment includes a
sub-class of alpha 1 antagonist, such as alpha 1 selective
antagonists that can preferentially act on the iris alpha
adrenergic receptors over the vascular alpha adrenergic receptors
and thus can be effectively utilized as a sole active agent to
improve vision according to an embodiment of the present
invention.
[0124] According to the present invention in an embodiment, an
ophthalmic composition containing an active agent, such as an
imidazoline, an alpha 1 selective antagonist and the like, is
advantageously applied topically to the eye, especially in the form
of a solution, a suspension, an ointment, a gel or coated on or
absorbed into a solid insert or contact lens. Such compositions
include the active ingredient, for example, in a range of from
approximately about 0.01 milligrams per cubic centimeters (cc) of
total formulation to approximately 50 milligrams per cc, preferably
from approximately 0.05 milligrams per cc to approximately 20
milligrams per cc, or more preferably in the range of from
approximately 0.1 milligrams per cc to approximately 10 milligrams
per cc and most preferably in the range of from 1 milligram per cc
to 5 milligrams per cc of total formulation volume. The dose of the
active ingredient may depend on various factors, such as mode of
administration, age and/or the condition of the eye being
treated.
[0125] A preferred concentration of about 1 to about 5 milligrams
of active agent per cc of total formulation volume in an embodiment
may be administered by placing a single drop on a moist soft
contact lens, and inserting the lens for about 15 minutes to about
45 minutes at one time per day. Administered in this manner an
active agent such as imidazoline including phentolamine has a 20-24
hour clinical effectiveness. Phentolamine appears to have
cumulative affect, such that with regular usage administration
every other day (e.g., 48 hours) via the contact lens may be all
that is necessary for some patients. The contact lens dosing allows
for preferential absorption within the cornea, maximizing drop
utilization and minimizing mild redness that may otherwise occur as
well as the remote risk of systemic absorption. The amount of
active agent in an embodiment within 1 drop of topical formulation,
such as less than 0.10 mg, is about 50.times. less than the
clinically recommended dosing for systemic results on the
cardiovascular system. If 10% of the active agent reached systemic
circulation, it would result in 500.times. less than typical
clinical dosage. Using contact lens dosing, this is estimated to be
still less. The drop may be administered in a one to five milligram
per cc concentration directly to the eye as a recommended daily or
BID dosing according to an embodiment of the present invention.
[0126] It should be appreciated that any suitable type of contact
lens can be utilized for formulation administration purposes. In
general, the formulation including the active agent is absorbed by
the contact lens. This can allow a slow release of the active agent
over the corneal surface over time. In an embodiment, the contact
lens has a water content greater than about 10%, preferably ranging
from about 20% to about 80%, more preferably ranging from about 30%
to about 70%.
[0127] An effective active agent for the purpose of the present
invention should limit pupil dilation and not significantly effect
pupillary constriction. Further, the active agent should have
significantly more effect and cause significantly increased
percentage reduction in pupil diameter in patients with large
pupils in reduced light, (e.g., in patients whose reduced light
pupil exceeds their daylight pupil considerably) and much less
effect on pupil diameter in patients who have a more idealized
pupil diameter in reduced light (e.g., in patients where their
reduced light pupil is nearly equal to their daylight pupil) as
shown below, for example, in Table 2.
[0128] There are used for a corresponding ophthalmic composition
customary pharmaceutically acceptable excipients and additives
known to the person skilled in the art, for example those of the
type mentioned below, especially carriers, stabilizers,
solubilizers, tonicity enhancing agents, buffer substances,
preservatives, thickeners, complexing agents and other excipients.
Examples of such additives and excipients can be found in U.S. Pat.
Nos. 5,891,913, 5,134,124 and 4,906,613.
[0129] Formulations of the present invention in an embodiment are
prepared, for example by mixing the active agent with the
corresponding excipients and/or additives to form corresponding
ophthalmic compositions. The active agent is preferably
administered in the form of eye drops, the active agent being
conventionally dissolved, for example, in a carrier. The solution
is, where appropriate, adjusted and/or buffered to the desired pH
and, where appropriate, a stabilizer, a solubilizer or a tonicity
enhancing agent is added. Where appropriate, preservatives and/or
other excipients are added to an ophthalmic formulation of the
invention.
[0130] Carriers used in accordance to an embodiment of the present
invention are typically suitable for topical or general
administration, and are for example water, mixtures of water and
water-miscible solvents, such as C1- to C7-alkanols, vegetable oils
or mineral oils including from about 0.5% to about 5% by weight
hydroxyethylcellulose, ethyl oleate, carboxymethylcellulose,
polyvinylpyrrolidone and other non-toxic water-soluble polymers for
ophthalmic uses, such as, for example, cellulose derivatives, such
as methylcellulose, alkali metal salts of carboxymethylcellulose,
hydroxymethylcellulose, hydroxyethylcellulose,
methylhydroxypropylcellulose and hydroxypropylcellulose, acrylates
or methacrylates, such as salts of polyacrylic acid or ethyl
acrylate, polyacrylamides, natural products, such as gelatin,
alginates, pectins, tragacanth, karaya gum, xanthan gum,
carrageenin, agar and acacia, starch-derivatives, such as starch
acetate and hydroxypropyl starch, and also other synthetic
products, such as polyvinyl alcohol, polyvinylpyrrolidone,
polyvinyl methyl ether, polyethylene oxide, preferably cross-linked
polyacrylic acid, such as neutral Carbopol, or mixtures of those
polymers. Preferred carriers include, for example, water, cellulose
derivatives, such as methylcellulose, alkali metal salts of
carboxymethylcellulose, hydroxymethylcellulose,
hydroxyethylcellulose, methylhydroxypropylcellulose and
hydroxypropylcellulose, neutral Carbopol, or mixtures thereof. The
concentration of the carrier ranges, for example, from about 1 to
about 100,000 times the concentration of the active ingredient.
[0131] The solubilizers used for an ophthalmic composition of the
present invention in an embodiment include, for example, tyloxapol,
fatty acid glycerol poly-lower alkylene glycol esters, fatty acid
poly-lower alkylene glycol esters, polyethylene glycols, glycerol
ethers vitamin E and vitamin E derivatives, such as Vitamin E
Tocopherol Polyethylene Glycol 1000 Succinate (TPGS) or mixtures of
those compounds. A specific example of an especially preferred
solubilizer is a reaction product of castor oil and ethylene oxide.
Reaction products of castor oil and ethylene oxide have proved to
be particularly good solubilizers that are tolerated extremely well
by the eye. Another preferred solubilizer is tyloxapol. The
concentration used depends especially on the concentration of the
active ingredient. The amount added is typically sufficient to
solubilize the active ingredient. For example, the concentration of
the solubilizer ranges from about 0.1 to about 5000 times the
concentration of the active ingredient pursuant to an embodiment of
the present invention.
[0132] According to an embodiment of the present invention lower
alkylene means linear or branched alkylene with up to and including
seven carbon atoms. Examples are methylene, ethylene,
1,3-propylene, 1,2-propylene, 1,5-pentylene, 2,5 hexylene,
1,7-heptylene and the like. Lower alkylene is preferably, such as
linear or branched alkylene, with up to and including four carbon
atoms.
[0133] Examples of buffer substances are acetate, ascorbate,
borate, hydrogen carbonate/carbonate, citrate, gluconate, lactate,
phosphate, propionate, perborate TRIS (tromethamine) buffers and
the like. Tromethamine and borate buffer are preferred buffers. The
amount of buffer substance added is, for example, that necessary to
ensure and maintain a physiologically tolerable pH range. The pH
range is typically in the range of from about 5 to about 9,
preferably from about 6 to about 8.2 and more preferably from about
6.8 to about 8.1.
[0134] Tonicity enhancing agents are, for example, ionic compounds,
such as alkali metal or alkaline earth metal halides, such as, for
example, CaCl.sub.2, KBr, KCi, LiCl, NaI, NaBr or NaCl, or boric
acid and the like. Non-ionic tonicity enhancing agents are, for
example, urea, glycerol, sorbitol, mannitol, propylene glycol,
dextrose and the like. For example, sufficient tonicity enhancing
agent is added to impart to the ready-for-use ophthalmic
composition an osmolality of approximately from about 50 mOsmol to
about 1000 mOsmol, preferred from about 100 mOsmol to about 400
mOsmol, more preferred from about 200 mOsmol to about 400 mOsmol
and even more preferred from about 280 mOsmol to about 350 mOsmol.
Examples of preservatives are quaternary ammonium salts, such as
cetrimide, benzalkonium chloride or benzoxonium chloride,
alkyl-mercury salts of thiosalicylic acid, such as, for example,
thimerosal, phenylmercuric nitrate, phenylmercuric acetate or
phenylmercuric borate, parabens, such as, for example,
methylparaben or propylparaben, alcohols, such as, for example,
chlorobutanol, benzyl alcohol or phenyl ethanol, guanidine
derivatives, such as, for example, chlorohexidine or
polyhexamethylene biguanide, or sorbic acid and the like. Preferred
preservatives are cetrimide, benzalkonium chloride, benzoxonium
chloride, parabens and the like. Where appropriate, a sufficient
amount of preservative is added to the ophthalmic composition to
ensure protection against secondary contaminations during use
caused by bacteria and fungi.
[0135] Ophthalmic formulations of the present invention can also
include, for example, non-toxic excipients, such as, for example,
emulsifiers, wetting agents or fillers, such as, for example, the
polyethylene glycols designated 200, 300, 400 and 600, or Carbowax
designated 1000, 1500, 4000, 6000 and 10,000 and the like. Other
excipients that may be used if desired are listed below but they
are not intended to limit in any way the scope of the possible
excipients. They are especially complexing agents, such as
disodium-EDTA or EDTA, antioxidants, such as ascorbic acid,
acetylcysteine, cysteine, sodium hydrogen sulfite,
butyl-hydroxyanisole, butyl-hydroxytoluene or alphatocopherol
acetate; stabilizers, such as a cyclodextrin, thiourea,
thiosorbitol, sodium dioctyl sulfosuccinate or monothioglycerol
vitamin E and vitamin E derivatives, such as Vitamin E Tocopherol
Polyethylene Glycol 1000 Succinate (TPGS); or other excipients,
such as, for example, lauric acid sorbitol ester, triethanol amine
oleate or palmitic acid ester and the like. Preferred excipients
are complexing agents, such as disodium-EDTA and stabilizers, such
as a cyclodextrin and the like. The amount and type of excipient
added is in accordance with the particular requirements and is
generally in the range of from approximately 0.0001% by weight to
approximately 90% by weight.
[0136] In another embodiment of the present invention, the
ophthalmic composition includes a therapeutically effective amount
of an imidazoline such as phentolamine, a carrier, a solubilizer
and another therapeutically effective pharmaceutical agent which
may be, for example, an anti-redness agent such as
tetrahydrazolene, an antibiotic, an antiallergic, an anesthetic, or
another drug.
[0137] A range of different active agents such as imidazolines are
known to those skilled in the art. The present invention is
intended to encompass such compounds and equivalent compounds which
have substantially the same therapeutic effect. Specifically, the
present invention is intended to encompass formulations which
include an aqueous solvent having dissolved therein a
therapeutically effective amount of a compound which compound when
dissolved in the formulation in a low concentration, such as 10% or
less, even as low as 1% or less, and administered to a human
patient's eye will prevent dilation of the eye in dim light to a
level which is about two to five times in diameter the amount of
dilation or less than occurs when the patient is present in bright
light.
[0138] Bioflavonoids, known to reduce capillary permeability, and
demulcents, known to protect mucous membranes, may be used in
conjunction with an alpha 1 antagonist to reduce vascular
permeability increase.
[0139] In an embodiment, the formulations of the present invention
further promote corneal absorption over vascular effect via a
chemical modulation of a vascular tissue. The chemical modulation
provides a temporary shielding or binding to a conjunctiva of the
eye, wherein the chemical modulation increases corneal absorption
without effect on vascular absorption or while decreasing vascular
absorption. The chemical modulation occurs through exposure to one
or more substances, such as a bioflavonoid, vitamin A, and
substances derived from fruits and vegetables in order to reduce
capillary permeability, including herbal extracts including aescin.
In an embodiment, the chemical modulation occurs through a chemical
modulator, such as an azone, a collagen corneal shield, a
cyclodextrin including a charged cyclodextrin and a sulfated
cyclodextrin, a bioadhesive polymer, a microsphere, a chitosan, a
captisol and derivatives. In an embodiment, the chemical absorption
is increased via one or more carrier particles, such as
nanoparticles including liposomes and emulsions, dendrimers,
buckeyballs and the like.
Artificial Tears
[0140] As indicated above a simple formulation of the present
invention according to an embodiment includes an aqueous solvent
which may be sterile water suitable for administration to the eye
having an active agent, such as an imidazoline, an alpha selective
antagonist, and the like, dissolved therein in a low concentration,
e.g., 10% concentration or less as discussed above. However,
preferred formulations of the present invention include the active
agent dissolved in a formulation which is referred to in the art as
an artificial tear formulation. Such artificial tear formulations
are disclosed and described within U.S. Pat. Nos. 5,895,645;
5,627,611; and 5,591,426 as well as patents and publications cited
and referred to in these patents, all of which are intended to be
incorporated herein by reference.
[0141] Artificial tear formulations of the present invention in an
embodiment promote good wettability and spread. Further, the
artificial tear formulations preferably have good retention and
stability on the eye and do not cause significant discomfort to the
user. A preferred artificial tear composition of the present
invention, in an embodiment, includes
[0142] (1) polyvinylpyrrolidone, preferably in the amount of about
0.1 to 5% by weight of said solution;
[0143] (2) benzalkonium chloride, preferably in an amount of about
0.01% to about 0.10% by weight;
[0144] (3) hydroxypropyl methylcellulose, preferably in an amount
of about 0.2% to about 1.5% by weight of said solution; and
[0145] (4) glycerin, preferably in an amount of about 0.2% to about
1.0% by weight of said solution, wherein the composition is an
aqueous solution having isotonic properties.
[0146] Those skilled in the art will recognize that a wide range of
different formulations and artificial tear formulations which can
be utilized in connection with the present invention.
Eyedroppers
[0147] Formulations of the present invention can be administered in
a manner generally known to those skilled in the art. In an
embodiment, the formulation is administered using an eyedropper.
The eyedropper can be constructed in any suitable way. For example,
the eyedropper apparatus 10 includes an eyedropper part 12 which
includes a hollow cylindrical barrel 14 having a first end 16 and a
second end 18 and an inner surface as shown in FIG. 1. Further, the
eyedropper 12 includes means for providing suction to draw the
formulation of the invention into the hollow cylindrical barrel.
For example, the eyedropper part 12 includes a suction device 20
that includes a suction member 22 attached to the first end 16 of
the cylindrical barrel 14 such that liquid can be drawn into and
out of the cylindrical barrel 14. The suction member 22 can be made
from any suitable material, such as a rubber material, or other
suitable material that is not reactive with the ophthalmic
formulation. The suction member 22 optionally includes an
attachment part 24 that allows the eyedropper part to be attached
to a container 26 holding the formulation 28 in any suitable way.
In this regard, the eyedropper part can be attached to the
container after use, thus allowing storage of the formulation
within a closed system. The first end 16 of the barrel 14 is
configured to receive the means for providing suction to draw in a
formulation. The second end 18 of the barrel is generally
configured to have a small opening 30 which permits passage of the
formulation and allows drops of the formulation to be metered out
directly onto the patient's eye. The cylindrical barrel 14 is
preferably designed so that it is relatively small and contains
less than about 5 cubic centimeters of formulation and may be
calibrated to allow for ease of measurement if desired.
[0148] It may be desirable to utilize a measured dose eyedropper of
the type described within U.S. Pat. No. 5,514,118 or an illuminated
eyedropper device of the type described in U.S. Pat. No. 5,584,823.
A range of other eye droppers can also be utilized of the type
described within the following U.S. Pat. Nos. 5,059,188; 4,834,727;
4,629,456; and 4,515,295. The patents cited here which disclose
eyedroppers are incorporated herein by reference as are the various
patents and publications cited and discussed within these
patents.
[0149] The eyedropper apparatus can be configured in any suitable
manner as previously discussed. An alternative embodiment is shown
in FIG. 2 where the eyedropper part 40 is an integral part of the
apparatus 42 and thus is not removably attachable from the
apparatus 42 such as the eyedropper part discussed above. As shown
in FIG. 2, the eyedropper apparatus 42 includes a reservoir 44 that
can hold or contain the formulation 46. The reservoir 44 includes
an end 48 in which the eyedropper part 40 is attached thereto. For
example, the eyedropper 42 can include an attachment member 50
positioned between the eyedropper part 40 and the reservoir 44.
This can be utilized to accept a cap (not shown) or other similar
part in order to close the apparatus after use. The eyedropper part
has an opening 52 through which the formulation can be administered
to the patient.
[0150] Examples of the present invention are provided below
according to an embodiment without limitation.
Example 1
[0151] A 5 mg/ml vial of phentolamine was diluted in an artificial
tear formulation to approximately 6.0 cc of solution. The
artificial solution created an effective composition for reducing
the pupillary diameter in reduced light via topical instillation as
an eye drop. This method induces mild conjunctival and episcleral
blood vessels causing very slight, transient redness to the
eye.
Example 2
[0152] The composition of Example 1 is applied as a single drop to
a moist soft contact lens with no excess saline, and the medication
is delivered topically over an optional 15 minute to 2 hour period,
30 minutes preferred, through wear of the soft contact lens after
which time it is removed. This greatly reduces any systemic
absorption of the medication and vasodilation of the vessels, and
minimizes redness as a result, while allowing efficient drop
utilization with the most effective concentrations to reach the
iris dilator muscles and minimize dilation in scotopic conditions.
The loss of muscle tone of these muscles may result in constriction
of the pupil, but not sufficient to cause the dimness from a
pinpoint pupil effect commonly seen with acetylcholine or
cholinesterase inhibitors. Phentolamine has the advantage of
creating a longer lasting effect chemical sympathectomy, reducing
the frequency of application required to maintain effective
scotopic viewing.
[0153] Phentolamine as modified and applied requires a single
instillation per day to render up to 20 to 24 hours of effect.
Phenoxybenzamine formulations ranging from 0.1% to 5% have not been
as effective as phentolamine, and induce much more vasodilation and
congestion. Similarly, prazosin and tolamine at 0.1% to 5% exhibits
slight pupillary reduction in dilation in dim light but appears to
be less effective than phentolamine. Labetalol, a potent beta
adrenergic receptor antagonist, consists of four isomers, two of
which have some alpha 1 antagonist activity. Its S,S and S,R
isomers, and in concentrations of 0.1% to 2%, 0.5% preferred, are
modestly effective. Other alpha 1 antagonists such as tamsulosin,
bunazosin, alfuzonsin, urapidil, ketanserin, and indoramin, in
concentrations of 0.1% to 2%, with 0.5% preferred are believed to
provide clinical effectiveness as well. In particular, it is
believed that alpha 1a selective antagonists, such as tamsulosin,
urapidil and the like, can effectively act as a sole active agent
to optimize pupil light reflex in reduced light while minimizing
redness as previously discussed. Alpha-2 receptor antagonists, such
as found in Yohimbe extract, do not appear to have an effect on
pupil dilation in reduced light.
[0154] Neuroleptic agents such as chlorpromazine, and ergot
alkaloids such as ergotamine have mild alpha 1 receptor antagonist
activity and may exhibit mild effectiveness for the purposes of the
present invention.
TABLE-US-00001 TABLE 1 Effect of Alpha Adrenergic Receptor
Antagonists on Pupil Dilation Effect on Redness Adrenergic pupil
diam. (direct receptors in darkness topical Duration Compound
blocked (mm) instillation) (hrs) Concentration Phentolamine a-1
7.5->4.0 + 20-40 3.3 mg/ml* Phenoxybenzamine a-1 7.5->5.5
++++ .gtoreq.20 5 mg/ml Prazosin a-1, 2 7.5->6 +++ 5-12 5 mg/ml
Dapiprazole a-1, 2 7.5->7 +++ 5-12 5 mg/ml Yohimbe a-2
7.5->7.5 + 0 5 mg/ml Tolamine a-1 7.5->6 + 5-12 5 mg/ml
*applied via soft contact lens with 1-2 gtts applied and placed for
30 minutes before removed
TABLE-US-00002 TABLE 2 Effect of Phentolamine 0.35% on Pupil
Diameter** Bright Bright Dim Light Light Pre Dim Light Light Post
Subject Pre mm mm Post mm mm Comments NF 7.0 3.5 4.0 3.0 Night
vision good pre and post NB 7.5 4.0 4.0 3.0 Had glare, halos, poor
night vision pre: post night = day = exc; glare = 0; halos 70%
reduced; depth perception improved LR 7.5 3.0 4.0 2.5 Had glare,
halo's poor night vision pre: post night much improved, dim light
about same. GH 3.5 3.0 3.0 2.5 Night vision good pre and post LH
4.0 3.0 3.5 2.5 Night vision good pre and post Phentolamine 3.3
mg/cc applied as a single drop to a soft contact lens placed for 30
minutes. Application of drops morning or daytime.
[0155] As shown below, Table 3 demonstrates the results of
administering phentolamine eye drops, an alpha adrenergic
antagonist, to several patients pursuant to an embodiment of the
present invention. The results illustrate the benefit that is
derived from reducing pupil diameter by 1 mm or more and/or pupil
area by 20% or more in dim light conditions pursuant to an
embodiment. In this regard, a significant increase in spherical
aberrations is typically found per each one millimeter of increase
in pupil size diameter above 5 mm. These aberrations generally
increase as a function of severity of the refractive error,
particularly increases in the myopic spherical equivalent of
refractive error. Coma may increase, as well as other higher order
aberrations, as pupil size diameter increases, again especially as
refractive error increases. Thus, a reduction in pupil diameter by
1 mm or more and/or pupil area by 20% or more can effectively act
to improve vision in dim light conditions. As previously discussed,
the present invention contemplates the use of a single active
agent, preferably an alpha 1a selective antagonist, that can
optimize pupil light reflex while minimizing, if not eliminating,
redness.
TABLE-US-00003 TABLE 3 Effect of Phentolamine on Visual Acuity in
Dim Light Pupil Diameter in Dim Light Pupil Pupil Dim Light Pre-
Post- Diameter Area Contrast Subject Drug Drug Change Change Pre-
Post- No. mm mm mm % Drug Drug 1 8.2 7.4 0.8 19% 20/40 20/32 2 7.8
5.9 1.9 43% 20/53 20/50 3 7.7 6.9 0.8 20% 20/29 20/25 4 8.5 7.1 1.4
30% 20/29 20/22 5 7.9 5.9 2.0 44% 20/35 20/20 6 7.8 6.9 0.9 22%
20/32 20/24 7 7.9 7.5 0.4 10% 20/63 20/38 8 8.2 7.1 1.1 25% 20/38
20/21 9 7.9 6.5 1.4 32% 20/32 20/21
[0156] Where a range of values is provided, it is understood that
each intervening value, to the tenth of the unit of the lower limit
unless the context clearly dictates otherwise, between the upper
and lower limit of that range and any other stated or intervening
value in that stated range is encompassed within the invention. The
upper and lower limits of these smaller ranges may independently be
included in the smaller ranges is also encompassed within the
invention, subject to any specifically excluded limit in the stated
range. Where the stated range includes one or both of the limits,
ranges excluding either both of those included limits are also
included in the invention.
[0157] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which this invention belongs. Although
any methods and materials similar or equivalent to those described
herein can also be used in the practice or testing of the present
invention, the preferred methods and materials are now described.
All publications mentioned herein are incorporated herein by
reference to disclose and describe the methods and/or materials in
connection with which the publications are cited.
[0158] It must be noted that as used herein and in the appended
claims, the singular forms "a", "and", and "the" include plural
referents unless the context clearly dictates otherwise. Thus, for
example, reference to "a compound" includes a plurality of such
compounds and reference to "the step" includes reference to one or
more steps and equivalents thereof known to those skilled in the
art, and so forth.
[0159] The publications discussed herein are provided solely for
their disclosure prior to the filing date of the present
application. Nothing herein is to be construed as an admission that
the present invention is not entitled to antedate such publication
by virtue of prior invention. Further, the dates of publication
provided may be different from the actual publication dates which
may need to be independently confirmed. All of the references cited
herein are incorporated by reference in their entirety.
[0160] It should be understood that various changes and
modifications to the presently preferred embodiments described
herein will be apparent to those skilled in the art. Such changes
and modifications can be made without departing from the spirit and
scope of the present invention and without diminishing its intended
advantages. It is therefore intended that such changes and
modifications be covered by the appended claims.
* * * * *