U.S. patent application number 11/585400 was filed with the patent office on 2007-05-10 for treatment of ophthalmic disorders using urea and urea derivatives.
This patent application is currently assigned to Vitreo-Retinal Technologies, Inc.. Invention is credited to David Castillejos, Vicken H. Karageozian, John Park.
Application Number | 20070105950 11/585400 |
Document ID | / |
Family ID | 38004643 |
Filed Date | 2007-05-10 |
United States Patent
Application |
20070105950 |
Kind Code |
A1 |
Karageozian; Vicken H. ; et
al. |
May 10, 2007 |
Treatment of ophthalmic disorders using urea and urea
derivatives
Abstract
Methods for treating disorders of the eye and/or disorders of a
nerve in a human or veterinary patient by delivering to the patient
a therapeutically effective amount of a compound selected from the
group of; urea, urea derivatives, thiourea, thiourea derivatives,
guanidine, guanidine derivatives and compounds having General
Formula I as set forth herein. For ophthalmic applications, the
compound may be delivered by intravitreal injection such that the
compound causes vitreal liquefaction, posterior vitreoretinal
detachment and other affects.
Inventors: |
Karageozian; Vicken H.;
(Laguna Beach, CA) ; Castillejos; David; (Chula
Vista, CA) ; Park; John; (Santa Ana, CA) |
Correspondence
Address: |
Robert D. Buyan;Stout, Uxa, Buyan & Mullins, LLP
Suite 300
4 Venture
Irvine
CA
92618
US
|
Assignee: |
Vitreo-Retinal Technologies,
Inc.
Irvine
CA
|
Family ID: |
38004643 |
Appl. No.: |
11/585400 |
Filed: |
October 23, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10367614 |
Feb 13, 2003 |
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11585400 |
Oct 23, 2006 |
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10215680 |
Aug 9, 2002 |
7008960 |
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11585400 |
Oct 23, 2006 |
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09517798 |
Mar 2, 2000 |
6462071 |
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10215680 |
Aug 9, 2002 |
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60357347 |
Feb 13, 2002 |
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60357574 |
Feb 15, 2002 |
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Current U.S.
Class: |
514/469 ;
514/580; 514/585; 514/595 |
Current CPC
Class: |
A61P 9/10 20180101; A61K
31/155 20130101; A61K 31/40 20130101; A61K 31/343 20130101; A61P
27/02 20180101; A61K 31/17 20130101; A61K 31/17 20130101; A61K
2300/00 20130101; A61K 31/40 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/469 ;
514/580; 514/585; 514/595 |
International
Class: |
A61K 31/343 20060101
A61K031/343; A61K 31/17 20060101 A61K031/17 |
Claims
1-28. (canceled)
29. A method for treating optic neuropathy or optic nerve damage in
a human or animal subject, said method comprising the step of:
intravitreally injecting a therapeutically effective an
substantially non-toxic amount of a preparation containing an
organic acid in combination with at least one agent selected from
the group consisting of: urea; urea derivatives; thiourea; thiourea
derivatives; guanidine; guanidine derivatives; and, compounds
having the general formula: ##STR4## wherein R is hydrogen, C1-C8
alkyl, C3-C8 cycloalkyl, C1-C6 alkylphenyl or hydroxyl protecting
group; R1 and R2 are each independently hydrogen, C1-C6 alkyl,
C3-C8 cycloalky, C2-C6 alkynyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6
alkenyl, --S(O)q(C1-C6 alkenyl) or ##STR5## wherein A is --CH2--,
--O--, --S--, --S(O)-- or --S(O)2--: W1 and W2 are each
independently hydrogen, halo, hydroxyl, C1-C4 alkyl, C1-C4 alkoxy,
C1-C4 alkylthio, C2-C4 alkenyl, or, C2-C4 alkynyl; R3 is hydrogen,
C1-C8 alkyl, C3-C8 cycloalkyl, or, C1-C6 alkylphenyl; X is O, S, or
NR4; R4 is hydrogen, C1-C6 alkyl, C1-C4 alkylphenyl or, C1-C6
alkoxy; R5 is hydrogen, C3-C8 cycloalkyl or C1-C8 alkyl; Y is
selected from ##STR6## wherein Z1 and Z2 are each independently
hydrogen, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy, hydroxyl,
C2-C4 alkenyl, C2-C6 alkyl, C1-C6 alkythio, halo, trifluoromethyl
or --NR6R7; R6 and R7 are each independently hydrogen, C3-C8
cycloalkyl, C1-C6 alkyl, C1-C4 alkylphenyl; n is 1 to 6 all
inclusive; m and p are each independently 0 to 6 inclusive and q is
0, 1 or 2; and pharmaceutical salts thereof.
30. A method according to claim 29 wherein the organic acid
comprises citric acid.
31. A method according to claim 30 wherein the preparation has the
formulation: TABLE-US-00006 Ingredient Quantity Urea 0.01%-30.0% by
weight Citric Acid 0.00001%-1.0% by weight Sodium Chloride
0.05%-3.6% by weight Sterile water for Injection USP Q.S 100% by
weight
32. A method according to claim 29, 30 or 31 wherein the
preparation contains urea in a concentration of from about 0.003 mg
urea per 50 .mu.l to about 15 mg urea per 50 .mu.l.
33. A method according to claim 32 wherein the concentration of
urea is from 0.005 mg urea per 50 .mu.l to 7.5 mg urea per 50
.mu.l.
34. A method according to claim 29, 30 or 31 wherein the
preparation contains citric acid in a concentration of from about
0.00001% to about 1.0%.
35. A method according to claim 34 wherein the concentration of
citric acid is from 0.00007% to 0.007%.
36. A method according to claim 29, 30 or 31 wherein the
preparation contains sodium chloride in a concentration of 0.05% to
3.6%.
37. A method according to claim 36 wherein the concentration of
sodium chloride is between 0.9% and 1.8%.
38. A method according to claim 29 wherein the preparation
contains: urea in an amount between about 0.005 mg per 50 .mu.l to
7.5 mg per 50 .mu.l; citric acid in an amount between 0.00007% and
0.007%; and sodium chloride in an amount from 0.9% to about
1.8%.
39. A method according to claim 29 wherein the preparation has a pH
from about 4.0 to about 9.0.
40. A method according to claim 29 wherein the preparation has a pH
of is less than 7.0.
41. A method according to claim 40 wherein the preparation has a pH
in the range of 4.0 to 6.5.
42. A method according to any of claims 29, 30 or 31 wherein the
preparation further comprises one or more buffers.
43. A method according to claim 42 wherein the preparation contains
at least one buffer selected from the group consisting of phosphate
buffers, acetate, and glycine.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of U.S. Provisional
Application Ser. No. 60/357,347, filed Feb. 13, 2002, and U.S.
Provisional Application Ser. No. 60/357,574, filed Feb. 15, 2002.
This application is also a continuation-in-part application of U.S.
application Ser. No. 10/215,680, filed Aug. 9, 2002, which is a
continuation application of U.S. application Ser. No. 09/517,798,
filed Mar. 2, 2000, now U.S. Pat. No. 6,462,071. The contents of
all the foregoing patent applications are hereby incorporated by
reference in their entireties.
FIELD OF THE INVENTION
[0002] This invention relates generally to the use of stabilized
aqueous solutions of urea or urea derivatives for administration to
the eyes of humans or other mammals. Urea and urea derivatives
liquefy the vitreous humor and induce a posterior vitreous
detachment thereby separating the cortical vitreous from the inner
limiting lamina of the retina. The strong attachment of the
cortical vitreous to the inner limiting lamina of the retina
creates traction on the retina which results in rhegmatogenous
retinal tears, idiopathic macular holes as well as cystoid macular
edema. This separation of the cortical vitreous from the inner
limiting lamina of the retina by urea or urea derivatives
eliminates the vitreoretinal traction which allows the non surgical
re-attachment of the retinal tear(s), the closure of the macular
hole, and the resolution of cystoid macular edema.
BACKGROUND OF THE INVENTION
A. Anatomy of the Human Eye
[0003] In human beings, the anatomy of the eye includes a "vitreous
body" which occupies approximately four fifths of the cavity of the
eyeball, behind the lens. The vitreous body is formed of gelatinous
material, known as the vitreous humor. Typically, the vitreous
humor of a normal human eye contains approximately 99% water along
with 1% macromolecules including: collagen, hyaluronic acid,
soluble glycoproteins, sugars and other low molecular weight
metabolites.
[0004] The retina is essentially a layer of nervous tissue formed
on the inner posterior surface of the eyeball. The retina is
surrounded by a layer of cells known as the choroid layer. The
retina may be divided into a) an optic portion which participates
in the visual mechanism, and b) a non-optic portion which does not
participate in the visual mechanism. The optic portion of the
retina contains the rods and cones, which are the effectual organs
of vision. A number of arteries and veins enter the retina at its
center, and splay outwardly to provide blood circulation to the
retina. The posterior portion of the vitreous body is in direct
contact with the retina. Networks of fibrillar strands extend from
the retina and permeate or insert into the vitreous body so as to
attach the vitreous body to the retina. (Sebag, J. Graefe's Arch.
Clin. Exp. Ophthalmol. 225, 89-93; 1987)
B. The Causes, Treatments and Clinical Sequelae of Rhegmatogenous
Retinal Tears, Macular Holes and Cystoid Macular Edema
[0005] Diabetic retinopathy, trauma, and other ophthalmological
disorders sometimes result in rupture or leakage of retinal blood
vessels with resultant bleeding into the vitreous humor of the eye
(i.e., "intravitreal hemorrhage"). Such intravitreal hemorrhage
typically manifests as clouding or opacification of the vitreous
humor.
[0006] The human vitreous gel undergoes progressive liquefaction
with age. After the age of 40 years, there is a steady increase in
observed liquefied vitreous associated with a decrease in vitreous
gel volume so that by the age 80 years more than half of the
vitreous is liquefied (McLeod, D, et al. Trans. Ophthal. Soc. UK,
1997; 97:225-231). Light microscopic studies of whole human
vitreous have demonstrated that vitreous liquefaction initially
occurs in pockets, which then coalesce (Sebag. J, et al. Invest.
Ophthalmol. Vis. Sci. 1989; 30: 1867-1871). These processes
eventually result in rhegmatogenous posterior vitreous detachment
(PVD). PVD is usually a sudden event during which liquefied
vitreous from the center of the vitreous body bursts through a hole
in the posterior vitreous cortex and then dissects the residual
cortical gel away from the inner limiting lamina of the retina
(Larsson, L. et al. Graefe's Arch. Clin. Exp. Opthalmol. 1985; 223:
92-95). The residual vitreous gel then collapses forward to occupy
an anterior position in the vitreous cavity. This process may
induce a tear in the retina which, in the presence of residual
vitreoretinal traction around the break, can result in
rhegmatogenous retinal detachment (McLeod, D. et al. Trans. Opthal.
Soc. UK 1997; 97: 225-231). Vitreoretinal traction may also result
in macular hole formation and it has been suggested that some forms
of cystoid macular edema are due to vitreoretinal traction during
incomplete PVD (Sebag, J. et al. Survey Opthalmol. 1984; 28:
493-498). In cases where the rhegmatogenous PVD is accompanied by a
retinal tear or detachment, it is important that such retinal tear
or detachment be promptly diagnosed and surgically repaired.
Failure to promptly diagnose and repair the retinal tear or
detachment may allow photoreceptor cells of the retina, in the
region of the tear or detachment, to die. Such death of the
photoreceptor cells of the retina may result in loss of vision.
Furthermore, allowing the retinal detachment to remain un-repaired
for such extended period of time may result in further intravitreal
hemorrhage and/or the formation of fibrous tissue at the site of
the hemorrhage. Such formation of fibrous tissue may result in the
formation of an undesirable fibrous attachment between the vitreous
body and the retina.
[0007] The typical surgical procedure used for repair of retinal
tears or detachment requires that the surgeon be able to look
through the vitreous humor, to visualize the damaged region of the
retina (i.e., "transvitreous viewing of the retina"). When
intravitreal hemorrhage has occurred, the presence of the
hemorrhagic blood within the vitreous can cause the vitreous to
become so cloudy that the surgeon is prevented from visualizing the
retina through the vitreous. Such hemorrhagic clouding of the
vitreous can take .about.12 months or longer to clear sufficiently
to permit trans-vitreal viewing of the retina.
[0008] The term Pneumatic Retinopexy was used by Hilton and
Grizzard (Hilton, G. F. et al. Ophthalmology 1986; 93: 626-641) as
a designation for a nonincisional retinal detachment operation
consisting of an intravitreal injection of an expandable gas with
cryotherapy and/or photocoagulation of the retinal break(s).
Patient positioning oriented the gas bubble to close the retinal
break(s), allowing spontaneous resorption of the subretinal fluid.
Other authors have reported the complications of subretinal gas
(McDonald, H. R. et al. Opthalmology, 1987; 94: 319-326), new
retinal break formation (Poliner, L. S. et al. Ophthalmology, 1987;
94: 315-318), macular detachment (Yeo, J. H. et al. Arch.
Opthalmol. 1986; 104: 1161-1163) and possible lower success rate in
aphakic and pseudophakic eyes (Chen, J. C. et al. Ophthalmology,
1988; 95: 601-608).
[0009] Pneumatic Retinopexy is a method of retinal detachment
repair which uses cryopexy or photocoagulation in combination with
intravitreal gas injection to effect an internal tamponade of
retinal breaks. Extension of existing retinal detachments with
migration of subretinal fluid into the macula has been reported
after pneumatic Retinopexy (Yeo, J. H. et al. Arch. Ophthalmol.
1986; 104: 1161-1163). The present report documents the occurrence
of new retinal tears with associated retinal detachment in
previously uninvolved quadrants in 20% of the patients within 2-4
weeks of pneumatic Retinopexy (Poliner, L. S. et al. Opthalmology,
1987; 94: 315-318). In these patients the original retinal
detachments completely resolved. New retinal tears and associated
detachments then developed opposite the original break with
vitreous condensation and traction in previously uninvolved
quadrants.
[0010] The majority of macular holes are "idiopathic" because they
occur in eyes that have no previous ocular pathology. Macular holes
can form immediately after blunt trauma. Besides trauma, other
ocular problems have been associated with macular hole formation,
including cystoid macular edema, epiretinal membranes,
vitreomacular traction syndrome, rhegmatogenous retinal tears,
hypertensive retinopathy, and proliferative diabetic retinopathy
(Aaberg, T. M. Survey Opthalmol. 1970; 15: 139-162).
[0011] The hallmark complaint of idiopathic macular hole formation
is painless central vision distortion or blur of acute or subacute
nature. Central visual acuity is initially diminished only mildly;
however, as the macular hole progresses over weeks to months, the
visual acuity usually deteriorates, then stabilizes around the
20/200 to 20/800 level, and a macular hole diameter of 500
.mu.m.
[0012] Examples of substances which have been purported to cause
vitreal liquefaction and/or posterior vitreous detachment, or
disinsertion are found in the U.S. Pat. Nos. 4,820,516 (Sawyer),
5,292,509 (Hageman), and 5,866,120 (Karageozian et al.).
[0013] There exists a need in the prior art for the elucidation and
development of new materials and methods for accelerating the
liquefaction of the vitreous and the induction of posterior
vitreous detachment, or disinsertion of the vitreous.
C. Prior Therapeutic Applications of Urea and Urea Derivatives.
[0014] U.S. Pat. Nos. 5,470,881 (Charlton et al.), 5,629,344
(Charlton et al.) have described the topical application to the
cornea or the "surface" of the eye of urea and/or urea derivatives
to treat ocular conditions such as dryness, non-infectious
keratitis, irregularities of the corneal or conjunctival
epithelium, ocular scarring and "subjective irritations" of the
eye. It is important to note that the urea formulations that have
been described in the above mentioned patents utilize formulations
which are non-aqueous in nature. These formulations contain
hydrophobic non-aqueous systems like white petrolatum, mineral oil,
and anhydrous liquid lanolin. Some of the formulations described
are aqueous in nature; however, in place of urea the authors
suggest the use of urea derivatives like ureidopropionic acid, or
allantoin.
[0015] In the past, some aqueous urea preparations were reported to
hydrolyze, thus producing ammonia as a byproduct. Ammonia is toxic
to the eye when applied topically, and is even more toxic when
applied intravitreally. Thus,
[0016] Urea is a small molecule having a molecular weight of 60.06.
Urea is somewhat basic, the pH of a 10% water solution is 7.2. Urea
is very soluble in water, ethanol, methanol and glycerol; however,
it is practically insoluble in chloroform or ether. Urea is
colorless to white, prismatic crystals or white crystalline powder
which stored under dry conditions is stable at room temperature.
Aqueous urea solutions freshly prepared are clear, colorless and
odorless. However, aqueous urea solutions gradually degrade and
develop an odor of ammonia.
[0017] Urea is a product of the metabolism of proteins in the human
body, it is excreted in human urine in average amounts of 30
gm/day. Urea has been widely used in medicine. Urea Solution for
Injection has been an Official Monograph in the United States
Pharmacopoeia/National Formulary (USP 24, 2000, pp.1730), for over
40 years. Urea for injection (intravenous) had been a US Food and
Drug approved product for over 20 years. The Urea product was
registered and sold in the United States by Abbot Pharmaceutical
Co. in 1961, under the trade name of Ureaphil. The Physicians' Desk
Referance (PDR, Edition 1961, Medical Economics Publishing) lists
the Urea for injection 1961 through 1979. References indicate that
Urea for Injection was also registered and sold in numerous
International countries as an osmotic diuretic for the reduction of
intracranial pressure as well as for the reduction of intraocular
pressure in subjects with Glaucoma. (Tartar, R. C. et al. American
Journal of Opthalmology: 52:323-331; 1961). In addition, urea has
been used intravenously to treat painful crisis of sickle-cell
disease. (McCurdy, P. R. I. V. "Urea treatment of the painful
crisis of Sickle Cell Disease" New England Journal of Medicine.
285: 992-994; 1971).
[0018] Urea has been used topically as a dermatological active
ingredient in the treatment of Psoriasis, ichthyosis, atopic
dermatitis and removal of excess keratin from dry skin. (Remington.
"The Science and Practice of Pharmacy" 19 Edition, Chapter 62, pp.
1041-1042, 1995).
SUMMARY OF THE INVENTION
[0019] In accordance with the present invention, urea, a urea
derivative, thiourea, a thiourea derivative, guanidine, a guanidine
derivative or a compound having General Formula I (below) is
administered intravitreally to liquefy the vitreous humor and
induce a posterior vitreous detachment thereby facilitating
separation of the cortical vitreous from the inner limiting lamina
of the retina. The strong attachment of the cortical vitreous to
the inner limiting lamina of the retina creates traction on the
retina, which results in rhegmatogenous retinal tears, idiopathic
macular holes as well as cystoid macular edema. This separation of
the cortical vitreous from the inner limiting lamina of the retina
by urea or urea derivatives eliminates the vitreoretinal traction
which allows the non surgical re-attachment of the retinal tear(s),
the closure of the macular hole, and the resolution of cystoid
macular edema, among other things. In addition, the occurrence of
new retinal tears with associated retinal detachment in pneumatic
Retinopexy patients are completely eliminated. The compounds in
addition to urea, thiourea, guanidine and derivatives thereof,
other compounds useable to carry out the methods of the present
invention have the General Formula I, as follows: ##STR1##
Wherein:
[0020] R is hydrogen, C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8
cycloalkyl, C.sub.1-C.sub.6 alkylphenyl or hydroxyl protecting
group;
[0021] R.sup.1 and R.sup.2 are each independently hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalky, C.sub.2-C.sub.6
alkynyl, C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkenyl, --S(O)q(C.sub.1-C.sub.6 alkenyl) or
##STR2## Wherein A is --CH.sub.2--, --O--, --S--, --S(O)-- or
--S(O).sub.2--: W.sup.1 and W.sup.2 are each independently
hydrogen, halo, hydroxyl, C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy, C.sub.1-C.sub.4 alkylthio, C.sub.2-C.sub.4 alkenyl, or,
C.sub.2-C.sub.4 alkynyl;
[0022] R.sup.3 is hydrogen, C.sub.1-C.sub.8 alkyl, C.sub.3-C.sub.8
cycloalkyl, or, C.sub.1-C.sub.6alkylphenyl;
[0023] X is O, S, or NR.sub.4;
[0024] R.sup.4 is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkylphenyl or, C.sub.1-C.sub.6 alkoxy;
[0025] R.sup.5 is hydrogen, C.sub.3-C.sub.8 cycloalkyl or
C.sub.1-C.sub.8 alkyl;
[0026] Y is ##STR3##
[0027] Wherein Z.sup.1 and Z.sup.2 are each independently hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.6
alkoxy, hydroxyl, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkythio, halo, trifluoromethyl or
--NR.sup.6R.sup.7;
R.sup.6 and R.sup.7 are each independently hydrogen,
C.sub.3-C.sub.8 cycloalkyl, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.4
alkylphenyl;
n is 1 to 6 all inclusive;
m and p are each independently 0 to 6, both inclusive;
q is 0, 1 or 2; and pharmaceutical salts thereof.
[0028] Further in accordance with the present invention, there are
provided methods for treating various ophthalmological disorders in
human or veterinary patients by administering to the patient a
therapeutically effective amount of urea, a urea derivative,
thiourea, a thiourea derivative, guanidine, a guanidine derivative
or a compound having General Formula I. The compound may be
injected directly into the vitreous body of the eye (i.e.,
intravitreal injection) or may be administered by any other route
that causes distribution of a therapeutically effective amount of
the compound to the vitreous body. The compound may be administered
for the purpose of treating specific ocular diseases or conditions
associated with increased intraocular pressure and alterations of
the vitreous humor. In one embodiment, the formulations induce a
posterior vitreous detachment from the retina thereby separating
the cortical vitreous from the inner limiting lamina of the retina.
This separation of the cortical vitreous from the inner limiting
lamina of the retina by urea or urea derivatives eliminates the
vitreoretinal traction which allows the non surgical re-attachment
of the retinal tear(s), the closure of the macular hole, and the
resolution of cystoid macular edema, among other things. In
addition, the occurrence of new retinal tears with associated
retinal detachment in pneumatic Retinopexy patients are completely
eliminated.
[0029] Still further in accordance with the present invention,
there are provided methods for treating rubeosis and/or neovascular
glaucoma. Rubeosis is a term that describes abnormal blood vessel
growth on the iris and the structures in the front of the eye which
are normally devoid of visible blood vessels. Typically, rubeosis
results from retinal ischemia in patients who suffer from diabetic
retinopathy or vein occlusion. Because the retina is deprived of
normal blood flow, the body causes these abnormal blood vessels to
form as a compensatory mechanism to supply oxygen to the eye.
Unfortunately, the formation of these abnormal vessels often
results in obstruction of the angle and/or trabecular meshwork
through which aqueous fluid drains from the front of the eye. This
causes an elevation in intraocular pressure or "neovascular
glaucoma" and a resultant loss of peripheral vision. The present
invention provides a treatment of rubeosis by administration to the
vitreous body of the affected eye an amount of a) urea, a urea
derivative, thiourea, a thiourea derivative, guanidine, a guanidine
derivative or a compound having General Formula I, b) a
nonsteroidal antiinflamatory agent (e.g., ketoralac, diclofenac,
etc.) or c) the combination of i) urea, a urea derivative,
thiourea, a thiourea derivative, guanidine, a guanidine derivative
or a compound having General Formula I and ii) a nonsteroidal
antiinflamatory agent (e.g., ketoralac, diclofenac, etc.)
sufficient to lessen or prevent the neovascularization of the iris
and/or other structures in the front of the eye.
[0030] Still further in accordance with the present invention,
there are provided methods for protecting nerves from damage or for
treating damaged nerves to cause regeneration and/or restoration of
some impulse transmission through the nerve, by administering or
contacting with the affected nerve a therapeutic amount of urea, a
urea derivative, thiourea, a thiourea derivative, guanidine, a
guanidine derivative or a compound having General Formula 1. This
method may be used to treat or prevent damage or diminished sensory
and/or motor impulse transmission in any nerve, including optic
nerves, central nerves (e.g., brain and spinal chord) and
peripheral nerves. For this application the compound may be
administered by any suitable route including intravitreal
injection(to treat or prevent damage to the optic nerve), injection
or delivery into the affected nerve, intrathecal, intracranial or
intraventricular injection (to treat or prevent damage to central
nerves of the brain or spinal chord) or injection or implantation
next to or in proximity to the affected nerve.
[0031] Still further aspects and elements of the present invention
will become apparent to those of skill in the art upon reading and
understanding of the following detailed description and
examples.
DETAILED DESCRIPTION
[0032] The preferred route of administration of the formulations
and/or compositions disclosed herein is by intravitreal injection,
whereby an aqueous solution of urea, thiourea, guanidine, a
derivative of urea, thiourea or guanidine or a compound having
General Formula I as shown above is injected directly into the
vitreous body located within the posterior chamber of the eye.
Alternatively, however, a vitreous liquefying and PVD inducing
amount of such compound may be administered by any other suitable
route of administration (e.g., topically, etc.) which results in
sufficient distribution of the compound(s) to the vitreous body in
sufficient amount to cause the desired vitreous liquefaction and
posterior vitreous detachment effect.
[0033] The preferred injectable aqueous solution of stabilized urea
may contain, certain inactive ingredients which cause the solution
to be substantially hypotonic, isotonic, or hypertonic and of a pH
range of 4.5-9.0 which is non toxic for injection into the eye.
Such solution of stabilized urea for injection may be in glass
vials or pre-filled syringes maintained at room temperature or
refrigerated temperature, ready for use. In addition such solutions
of stabilized urea may be initially lyophilized to a dry state and
thereafter, may be reconstituted prior to use.
[0034] Urea employed in the invention method can be obtained
99.0-100.5% purity from several Manufacturers of fine
chemicals.
[0035] The present invention provides stabilized aqueous urea
solutions which comprise a) urea (or a urea derivative), b) sodium
chloride, c) citric acid and d) water. One specific example of such
a solution is shown in Table I, as follows: TABLE-US-00001 TABLE I
Stabilized Urea Formulation Ingredient Quantity Urea 0.01%-30.0% by
weight Citric Acid 0.00001%-1.0% by weight Sodium Chloride
0.05%-3.6% by weight Sterile water for Injection USP Q.S 100% by
weight
[0036] In the stabilized aqueous urea solutions of the present
invention, the urea concentration is typically in a range of about
0.003 mg per 50 .mu.l to about 15 mg per 50 .mu.l. In one
embodiment, urea is provided in the formulation or composition in
an amount between 0.005 mg per 50 .mu.l to 7.5 mg per 50 .mu.l.
Citric acid is typically provided in a range between about 0.00001%
to 1.0%, and in one embodiment, the citric acid is present in an
amount between 0.00007% to 0.007%. Sodium chloride is typically
provided in the formulation or composition in an amount between
0.05% to 3.6%, and in one embodiment, sodium chloride is provided
in an amount between 0.9% and 1.8%. In a preferred embodiment, the
composition comprises a combination of urea in an amount between
about 0.005 mg per 50 .mu.l to 7.5 mg per 50 .mu.l, between
0.00007% and 0.007% citric acid, and between 0.9% to about 1.8%
sodium chloride. The formulations disclosed herein may have a pH
from about 4.0 to about 9.0, and in a preferred embodiment, the pH
is less than 7.0, for example, in a range of 4.0 to 6.5. The
formulations may also contain one or more buffers, such as,
phosphate buffers, acetate, and/or glycine.
[0037] These formulation ingredients are typically initially
dissolved in sterile water, sterile filtered and subsequently
dispensed as a solution into glass or plastic vials or glass or
plastic syringes. In addition the solution could be lyophilized to
a dry composition. Thus, the pharmaceutical formulations are either
liquid formulations, lyophilized formulations, and/or sterile
powders. The formulations may be stored in prefilled syringes, in
glass vials, and may be stored at room temperature, refrigerated
temperature, and frozen temperatures in a sealed condition with
little degradation over prolonged periods of time, for example over
one year, and in certain embodiments, over three years.
[0038] Tables II-IV below show specific examples of stabilized urea
preparations that are within the general formulation set forth in
the foregoing Table I. TABLE-US-00002 TABLE II Ingredient Quantity
Urea USP/NF 1.50% Citric Acid USP/NF 0.0007% Sodium Chloride USP/NF
0.9% Sterile Water for Inj. USP Q.S 100%
[0039] TABLE-US-00003 TABLE III Ingredient Quantity Urea USP/NF
1.50% Sodium Chloride USP/NF 0.9% Sterile Water for Inj. USP Q.S
100%
[0040] TABLE-US-00004 TABLE IV Ingredient Quantity Urea USP/NF
1.50% Sterile Water for Inj. USP Q.S 100%
[0041] As described in the following examples, the formulations of
a stabilized aqueous solution of urea set forth in Table I, II, III
and Table IV may be injected directly into the vitreous of the eye
at dosage levels which bring about desirable therapeutic effects,
including but not necessarily limited to the vitreous liquefaction
and PVD induction effect of the present invention, without causing
significant toxicity to the eye or associated anatomical
structures. Among other things, and for example, the amount of urea
present in the formulations may be provided in amounts to enhance
the therapeutic effects mediated by one or more therapeutic agents.
While not wishing to be bound by any particular theory or mechanism
of action, it seems that a therapeutic agent that is
co-administered with a formulation containing urea is more
effectively distributed in the eye to provide a desired therapeutic
effect. In other words, coadministration with urea advantageously
seems to provide enhanced bioavailablity of other therapeutic
agents so that the other therapeutic agents can provide one or more
therapeutic effects. As used herein, the term "coadministered" does
not mean that the urea and the therapeutic agents must be
administered precisely at the same time. Instead, in reference to
the disclosure herein, coadministration refers to the
administration of one or more therapeutic agents, other than urea,
at a time in which the urea has provided a desired therapeutic
effect. Thus, the one or more additional therapeutic agents may be
administered in the same formulation comprising urea, or the
therapeutic agents may be administered shortly before or after the
administration of a formulation containing urea.
[0042] In addition, methods of treating neuropathies have also been
invented by administering a formulation or composition containing
an amount of urea effective to enhance neuronal activity, such as
neurotransmission of one or more neurons. Administration of
urea-containing formulations results in enhanced optic nerve
function in patients who experienced reduced optic nerve
function.
EXAMPLE I
Treatment of Retinal Tears
[0043] Seven male and five female human patients having an average
age of 47 years were observed to have single or multiple retinal
tears, in addition 9 of the 12 patients had macular detachment. All
patients received pneumatic Retinopexy treatment 3 days after
intravitreal injection of 1.5 mg of urea in 50 .mu.l of aqueous
solution prepared according to the formulation set forth in Table
II above. Ophthalmoscopic as well as biomicroscopic examination of
all eyes showed no adverse effects of the intravitreal injection of
the urea solution. Within 3-7 days after urea injection, 11/12
patients had developed PVD, only 1/12 patients had not developed
PVD. Within 90 days of the urea injection that one patient also
developed PVD.
[0044] Within 3 days of treatment 9/12 patients had complete
retinal reattachment and macular attachment, and within 7 days all
12 patients had complete retinal reattachment and macular
attachment. All patients were followed up for a period of 90 days,
none of the patients experienced an occurrence of new retinal tears
with associated retinal detachment.
[0045] It has been reported that, only 3% of patients treated by
Retinopexy without prior urea treatment improved more than 2 lines
of visual acuity (11 letters) at 1 month post Retinopexy and only
7% of the patients improved more than 2 lines of visual acuity (11
letters) at 6 months post Retinopexy. (Tornambe, P. E. et. al.
Opthalmology, 1989; 96: 772-783). In this example, 64% of patients
who received intravitreal urea injection 3 days prior to pneumatic
Retinopexy exhibited an improvement of more than 2 lines of visual
acuity (11 letters), and 64% of the patients showed an improvement
of more than 2 lines of visual acuity (11 letters) at 6 months post
Retinopexy. Also, at 1 month after Retinopexy, the urea-treated
patients exhibited an average improvement in visual acuity of 3.9
lines on the eye chart (20 letters) and at 6 months after the
Retinopexy, the average improvement of visual acuity per
urea-treated patient was 4.2 lines (21 letters). Thus, it is
concluded that a) the urea treatment facilitated re-attachment of
the retinal tears as well as the reattachment of the detached
macula of the patients after administration of formulations
containing urea, b) as a result of the induction of PVD, the
occurrence of new retinal tears with associated retinal detachment
does not occur and c) there was improvement in vision in 64% of the
Retinopexy patients who received urea treatment compared to only 3%
-7% of Retinopexy patients who did not receive urea treatment.
Example II
Treatment of Idiopathic Macular Hole
[0046] A female patient 58 years old was observed to have a 450
.mu.m idiopathic macular hole of 6 months duration. The macular
defect was classified as a stage 3 macular hole, and the patient's
visual acuity was recorded at 20/400 at a baseline time point prior
to urea treatment. The subject was administered a single
intravitreal injection of a formulation containing 1.5 mg of urea
in a 50 .mu.l solution prepared in accordance with the formulation
of Table III above, and within 7 days the patient had a complete
Posterior Vitreous Detachment (PVD). Ophthalmoscopic as well as
Biomicroscopic examination of the patient's eye showed no adverse
effects of the intravitreal injection of the urea solution. Seven
days after the intravitreal urea injection the patient was
administered an intravitreal injection of 0.3 ml of expandable gas
(C.sub.3F.sub.8).
[0047] One week after administration of the gas, the size of the
macular hole had decreased from 450 .mu.m to a smaller size of 200
.mu.m and the patient's vision had improved from a baseline visual
acuity of 20/400 to 20/80. Two weeks post treatment the size of the
macular hole had decreased from 450 .mu.m to a smaller size of 90
.mu.m and the patient's vision had improved from a baseline visual
Acuity of 20/400 to 20/70. Four weeks post treatment the size of
the macular hole had decreased from 450 .mu.m to a smaller size of
60 .mu.m and the patient's vision had improved from a baseline
visual acuity of 20/400 to 20/60.
[0048] Stage 3 macular holes in patients who have not been
administered the formulations disclosed herein do not close by
themselves, the conventional way of treating macular holes is to
perform a vitreous surgery. The surgery of macular holes has
centered around three steps: a) the separation of the posterior
hyaloid from the macula and the posterior pole of the eye; b)
peeling of the perihole tissue; and c) use of long acting gas and
face-down positioning. The risks of vitreous surgery and the
mechanical membrane peeling of the posterior hyaloid by suction may
be traumatic to the optic nerve head or the retina itself, leading
to retinal hemorrhage, damage to the nerve fiber layer, or even
perhaps retinal breaks leading to poor vision.
[0049] By administering the PVD-inducing amount of a compound of
the present invention, the need for vitreous surgery may be
completely eliminated. In this manner, the possible complications
associated with vitreous surgery and resulting poor vision are
avoided. As discussed herein, the compounds of this invention
liquefy the vitreous humor and induce a posterior vitreous
detachment thereby separating the cortical vitreous from the inner
limiting lamina of the retina without the need for mechanical
disruption of the vitreous. This separation of the cortical
vitreous from the inner limiting lamina of the retina eliminates
the vitreoretinal traction and thereby allows for non-surgical
re-attachment of the retinal tear(s) and closure of the macular
hole.
Example III
Intravitreal Urea Injection as an Adjuvant in Pneumatic
Retinopexy
[0050] The present invention provides a method to reduce
vitreoretinal traction and induce total posterior vitreous
detachment (t-PVD) in subjects with primary regmatogen retinal
detachment (PRRD) susceptible of treatment by pneumatic retinopexy
was practiced by administering a formulation containing urea
formulation set forth in Table II (VRT-1001) to the patients.
[0051] Consecutive patients of both genders with PRRD eligible for
treatment with pneumatic retinopexy where enrolled after informed
consent. A 0.3 ml intravitreal injection of the urea formulation
set forth in Table II (VRT-1001, Vitreoretinal Technologies Inc.,
Irvine, Calif., USA) was administered, and pneumatic retinopexy was
performed the next day, using 0.4 ml of 100% C.sub.3F.sub.8. Argon
laser was applied as soon as possible to seal the retinal tears.
Before, and 1, 7, 15, 30 and 90 days after the procedure, patients
were monitored with biomicroscopy, posterior pole photography and
retinal fluoroscein angiography (FAG), ultrasound (USG), and
electroretinography (ERG). Visual capacity (VC), intraocular
pressure (IOP), location of retinal lesions, vitreal status,
retinal reapplication, complications, or adverse effects were all
recorded. Complete and stable retinal application was considered as
a success after a three month follow up.
[0052] Twelve eyes of 12 patients with PRRD were assessed. The ages
of the patients ranged from between 27 and 60 years (mean
45.8.+-.9.7). 58.3% did not have PVD and 41.7% had partial superior
PVD by USG. After giving the VRT-1001 injection, all eyes presented
t-PVD (75% collapsed and 25% without collapsed). A stable and
complete retinal reapplication after the pneumatic retinopexy was
achieved in all eyes during the follow up. Final VC was 20/40 or
better, in 50% of the eyes (p <0.01). 8.3% maintained their
initial VC. 8.3% had 1 line of improvement and 83.4% improved 2
lines. No change in intraocular pressure (IOP) was observed (mean
13.4.+-.3 mmHg). The ERG was sub-normal, as expected after retinal
detachments, with no evidence of retinal toxicity, showing an
improvement at the end of the study. No alterations were observed
in the FAG. Minor complications occurred and they were resolved
within a few days. No adverse effects were reported.
[0053] The methods disclosed herein demonstrate that formulations
containing urea are useful as an adjuvant in pneumatic retinopexy
to improve the success rate in retinal reapplication.
Example IV
Treatment of Vitreous Hemorrhage
[0054] The formulations and treatments disclosed herein are also
effective to treat vitreous hemorrhage. In this example, seven
human patients were treated for diabetes-related nonclearing
vitreous hemorrhage. Each patient received a single intravitreal
injection of 100 .mu.l of a formulation containing urea. The
formulation used in this example contained 6% urea, 0.9% sodium
chloride, and sterile water for injection (qs 100%).
[0055] All seven patients demonstrated clearance of their vitreous
hemorrhage sufficient to treat the retina with photocoagulation
within 2 to 4 weeks after injection. The rate at which the
hemorrhagic blood cleared from the vitreous appears to have been
significantly accelerated when compared with normal hemorrhage
clearance rates seen in clinical practice.
Example V
Treatment as Adjunct to Vitrectomy
[0056] The treatment solutions disclosed herein may be injected
intravitreally to cause pharmacologic vitreolysis alone or as an
adjunct to a vitrectomy procedure.
[0057] In this example, five human patients requiring pars plana
vitrectomy for various indications were treated one week prior to
vitrectomy with a single intravitreal injection of 100 .mu.l of a
urea in aqueous solution. The formulation contained 6% urea, 0.9%
sodium chloride, and sterile water for injection (qs 100%). All
patients underwent routine vitrectomies 8 to 10 days after the urea
injection. The minimum waiting time between the urea injection and
the vitrectomy procedure is about 1 day to 3 days.
[0058] The patients who received the intravitreal injection of urea
were noted to have complete vitreous liquefaction and collapse by
one week after the injection (i.e., at the time of the virectomy
procedure). Unlike patients who do not receive urea injection prior
to vitrectomy, the vitreous of urea-treated patients in this
example was liquefied to the extent that all or substantially all
vitreous traction on the retina was relieved, thereby allowing the
surgeon to remove the entire vitreous by aspiration with a syringe
system. No vitrectomy cutter was used. Also, in this example, the
administration of the urea-containing formulations resulted in a
70% decrease in surgical time relative to the procedures performed
on patients who did not receive urea.
Example VI
Treatment of Diabetic Retinopathy
[0059] An association between a low incidence of progressive
retinopathy in subjects with vitreous liquefaction and total PVD
(either spontaneous or surgically induced), and a significant risk
of aggressive proliferation of new blood vessels in patients with
only a partial PVD has been well documented, both in diabetics,
(Tagawa, H. et. al. Opthalmology, 1986; 93: 596-601 also Tagawa, H.
et. al. Opthalmology, 1986; 93: 1188-1192) as well as in patients
with central (Hikichi, T. et. al. RETINA, 1995; 15: 29-33) or
branch vein occlusion (Kado, M. et. al. Am J. of Opthalmology,
1988; 105: 20-24). Histopathological observations suggest that the
cortical vitreous can provide a scaffold for retinal
neovascularization in diabetic retinopathy and other
retino-vascular proliferative disorders.
[0060] Therefore the ability to prophylactically liquefy the
vitreous, collapse the scaffold and induce PVD, could provide an
important strategy for diabetic patients in the pre-proliferative
phase to protect them against future retinal or optic disc
neovascularization.
[0061] Injection of urea into the vitreous results in the breakdown
of hyaluronic acid of the vitreous and liquefaction of the vitreous
body within several days. In addition, disinsertion of the
posterior vitreous has been observed in patients by the use of slit
lamp biomicroscopy and in rabbits by specialized histological
techniques after urea treatment.
[0062] A method of treating and/or preventing diabetic retinopathy
includes a step of administering a formulation or composition
containing urea to a patient.
[0063] Sixty-nine patients with nonproliferative diabetic
retinopathy were each administered a single intravitreal injection
of 50 .mu.l of a urea formulation containing 3% urea, 0.9% sodium
chloride, and sterile water for injection.
[0064] All 69 patients exhibited complete vitreous liquefaction and
collapse within 2-4 weeks after administration of the formulation.
The vitreous liquefaction and vitreous collapse in nonproliferative
diabetic retinopathy patients would inhibit the growth and
proliferation of the blood vessels, and thus inhibit the
progression of diabetic retinopathy. All 69 (of the) patients were
followed for six months following the procedure.
Example VII
Treatment of Retinitis Pigmentosa
[0065] In accordance with the present invention, urea, thiourea,
guanidine and possibly the other compounds of General Formula I
above may provide neuroprotective/neuroregenerative effects. In
this particular example, patients suffering from retinitis
pigmentosa were used to demonstrate the neuroprotective
effects.
[0066] A double masked placebo controlled, randomized, dose
escalation study was done in 32 human patients with retinitis
pigmentosa. All patients were treated with a single intravitreal
injection of 50 .mu.l of a urea-containing formulation. Three
groups of patients received different concentrations of urea. One
group received a formulation containing 1.5% urea, 0.9% sodium
chloride, and sterile water for injection. A second group received
an identical formulation except the formulation contained 3.0%
urea. A third group received an identical formulation except the
formulation contained 6.0% urea. A placebo group received 50 .mu.l
of 0.9% sodium chloride.
[0067] Forty-seven percent of the patient reported an increase of
at least 3 lines of best corrected visual acuity measured by ETDRS
charts, whereas, only 14% of the placebo patients reported an
increase of at least 3 lines of best corrected visual acuity
measured by ETDRS charts.
[0068] The improvement demonstrated by the urea-treated patients
corresponds to an average of 10 degrees of improvement in the
patient's visual field. In this masked, placebo control study the
neuroprotective/neuroregenerative effects of the urea formulation
was demonstrated by a) the increase of visual acuity in 47% of the
treated patients b) the corresponding enlargement or increase in
the visual fields of these same patients. There was no dramatic
increase in the visual field of the placebo control patients.
Example VIII
Treatment of Neuropathies
[0069] In accordance with the present invention, urea, thiourea,
guanidine and possibly the other compounds of General Formula I
above are effective to treat neuropathies (e.g., disorders or
damage to nerves). In this example, 33 non sighted patients with
optic nerve damage caused by trauma and/or glaucoma, with visual
acuity of light perception or no light perception were administered
a urea-containing formulation, as disclosed herein. The study was a
double masked placebo controlled, randomized, dose escalation study
conducted with 33 human patients with optic nerve damage. Patients
were randomized into 5 groups, Group 1 of 5 patients, Group 2 of 4
patients, Group 3 of 8 patients, Group 4 of 8 patients and Group 5
of 8 patients. Each patient received a single intravitreal
injection of 50 .mu.l of an aqueous treatment solution, as follows:
TABLE-US-00005 Group 1 0.9% sodium chloride (control) Group 2 0.2%
by weight Urea Group 3 1.5% by weight urea Group 4 3.0% by weight
Urea Group 5 6.0% by weight Urea
[0070] Forty-three percent of the patients exhibited an increase of
best corrected visual acuity measured by ETDRS charts. In Six
patients the vision improved from No light perception to light
perception, in 2 patients the vision improved from light perception
to count fingers at 12 inches, in 2 patients the vision improved
from no light perception to 20/400 and 20/800 vision and in 2
patients the vision improved from light perception to 20/600 and
20/800 vision. No patients in the placebo group reported any
improvement in best corrected visual acuity as measured by ETDRS
charts.
[0071] In another study, three patients with long standing (6
months or longer) optic nerve damage related to optic nerve tumors
were treated with a single intravitreal injection of 100 .mu.l of a
6% urea containing formulation. All three patient treated reported
a significant improvement in visual acuity after treatment. The
patients' visual acuity improved from an average of Count Fingers
at 12 inches to 20/200.
Example IX
Treatment of Rubeosis
[0072] In accordance with the present invention, urea, thiourea,
guanidine and possibly the other compounds of General Formula I
alone and/or in combination with nonsteroidal antiinflamatory
agents (e.g., ketoralac, diclofenac, flourbiprofen, Ibuprofen etc.)
may be effective in treating rubeosis. In this example, a single
patient suffering from rubeosis received a single intravitreal
injection of 100 .mu.l of an aqueous solution containing 6.0% by
weight urea, 0.9% by weight sodium chloride, and 0.2% by weight
ketoralac in a (and) sterile water for injection (qs 100%). The
patient was followed for 10 weeks.
[0073] The patient was noted to have a dramatic reduction in
neovascularization of the iris as documented by iris fluoroscein
angiography before and after the urea/keterolac injection.
Example X
Treatment of Diabetic Macular Edema
[0074] In accordance with the present invention, urea, thiourea,
guanidine and possibly the other compounds of General Formula I
above may be administered alone and/or in combination with a
nonsteroidal antiinflamatory agent (e.g., ketoralac, diclofenac,
flourbiprofen, ibuprofen, etc.) to treat macular edema. In this
example, a patient with macular edema related to diabetic
retinopathy received a single intravitreal injection of 100 .mu.l
of an aqueous solution containing 6.0% by weight urea, 0.9% by
weight sodium chloride and 0.07% by weight ketoralac in sterile
water for injection (qs 100%). The patient was noted to have a
dramatic improvement in best corrected visual acuity of at least 3
lines by ETDRS measurements during the course of the 8 week
monitoring cycle.
[0075] It will be understood by those of ordinary skill in the art,
that the present invention is not limited to the specific examples
and embodiments described here above. Rather, the present invention
can be practiced using a wide equivalent variation of conditions,
formulations and other parameters, without affecting the scope of
the invention or any embodiment therein.
[0076] Also, all publications cited in this patent application are
expressly incorporated by reference herein in their entirety.
* * * * *