U.S. patent application number 10/487122 was filed with the patent office on 2004-10-28 for use of non-feminizing estrogens as retinoprotective agents for the treatment of glaucoma.
Invention is credited to Clark, Abbot F, Pang, Iok-Hou.
Application Number | 20040214806 10/487122 |
Document ID | / |
Family ID | 33300135 |
Filed Date | 2004-10-28 |
United States Patent
Application |
20040214806 |
Kind Code |
A1 |
Pang, Iok-Hou ; et
al. |
October 28, 2004 |
Use of non-feminizing estrogens as retinoprotective agents for the
treatment of glaucoma
Abstract
The invention provides pharmaceutical compositions containing
non-feminizing estrogen and methods of using these compositions to
prevent or ameliorate retinal and optic nerve damage associated
with glaucoma.
Inventors: |
Pang, Iok-Hou; (Grand
Prairie, TX) ; Clark, Abbot F; (Arlington,
TX) |
Correspondence
Address: |
Barry L Copeland
Alcon Research
6201 South Freeway
Fort Worth
TX
76134-2099
US
|
Family ID: |
33300135 |
Appl. No.: |
10/487122 |
Filed: |
February 19, 2004 |
PCT Filed: |
September 3, 2002 |
PCT NO: |
PCT/US02/27969 |
Current U.S.
Class: |
514/182 |
Current CPC
Class: |
A61K 31/56 20130101 |
Class at
Publication: |
514/182 |
International
Class: |
A61K 031/56 |
Claims
We claim:
1. A method for treating glaucoma-related retina or optic nerve
damage in a patient, said method comprising administering to a
patient in need thereof a therapeutically effective amount of a
composition comprising at least one non-feminizing estrogen
compound or an analog thereof.
2. The method of claim 1, wherein said glaucoma is primary open
angled glaucoma.
3. The method of claim 1, wherein said glaucoma is normal-tension
glaucoma (also known as low-tension glaucoma).
4. The method of claim 1, wherein said non-feminizing estrogen
compound is a polycyclic compound comprising at least a first ring
and a second ring and having a terminal phenolic group wherein said
polycyclic compound has a molecular mass of less than 1000
Daltons.
5. The method of claim 1, wherein said non-feminizing estrogen
compound is selected from the group consisting of estratriene-3-ol,
3,17.alpha.-estradiol, estrone, estriol, and their analogs.
6. The method of claim 1, wherein said non-feminizing estrogen is
administered concurrently or sequentially with one or more
IOP-lowering pharmaceutical agents.
7. The method of claim 1, wherein said non-feminizing estrogen is
administered concurrently or sequentially with one or more
IOP-lowering surgical procedures.
8. The method of claim 1, wherein said non-feminizing estrogen is
administered concurrently or sequentially with one or more
retinoprotective agents.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to the field of glaucoma. More
specifically, the invention provides a method to protect
glaucomatous retinopathy using compositions comprising at least one
non-feminizing estrogen.
[0003] 2. Description of the Related Art
[0004] "Glaucomas" are a group of debilitating eye diseases that
are the leading cause of preventable blindness in the United States
and other developed nations. Primary Open Angle Glaucoma (POAG) is
the most common form of glaucoma. The disease is characterized by
the degeneration of the trabecular meshwork (TM), leading to
obstruction of the normal ability of aqueous humor to leave the eye
without closure of the space (e.g., the "angle") between the iris
and cornea (Langham (1979); Segawa (1979); Rohen (1983)). A
characteristic of such obstruction in this disease is an increased
intraocular pressure (IOP), resulting in progressive visual loss
and blindness if not treated appropriately and in a timely fashion.
The disease is estimated to affect between 0.4% and 3.3% of all
adults over 40 years old (Leske et al. (1994, 1997, 2001);
Bengtsson (1989); Strong (1992)). Moreover, the prevalence of the
disease rises with age to over 6% of those 75 years or older
(Strong (1992)).
[0005] Another form of POAG, normal-tension glaucoma, is
characterized by a severe optic neuropathy in the absence of
abnormally high IOP. Patients with normal-tension glaucoma have
pressures within the normal range, albeit often in the high normal
range (Tanna & Jampel (2000)).
[0006] Because increased IOP is a readily measurable characteristic
of glaucoma, the diagnosis of the disease is largely based on an
increase in IOP which is generally estimated by tonometry (Strong
(1992); Greve & Chisholm (1993)). Unfortunately, as is evident
from normal-tension glaucoma, glaucomatous retinopathy and optic
nerve damage can occur in the absence of abnormally high IOP
(Yamamoto & Kitazawa (1998); Tanna & Jampel (2000)).
Conversely, ocular hypertension does not always lead directly to
retina or optic nerve damage. Approximately 5 million Americans
have elevated IOP without optic nerve damage or visual field loss.
Because the relationship between pressure and optic nerve and
retina damage is not necessarily direct, high IOP is now considered
to be only a risk factor rather than an essential disease
characteristic. For this reason, additional methods, such as direct
examination of the optic disk and determination of the extent of a
patient's visual field loss are often conducted to improve the
accuracy of diagnosis (Greve & Chisholm (1993)). Also for the
same reason, the ultimate goal of glaucoma treatment is to preserve
vision by protecting against the pathological changes in the retina
and optic nerve.
[0007] Current glaucoma therapy is directed to lowering IOP. A
variety of therapeutic agents have been proposed as having the
ability to reduce elevated IOP. These therapies lower IOP, but they
do not directly address the pathogenic mechanisms occurring at the
retina and optic nerve, and the disease continues to progress.
Moreover, many of these agents are often associated with untoward
effects. There is currently no generally accepted therapeutic
method to manage glaucomatous retinopathy and optic neuropathy.
Agents offering retinoprotection properties would be desirable.
SUMMARY OF THE INVENTION
[0008] The present invention overcomes these and other drawbacks of
the prior art by providing compositions comprising at least one
non-feminizing estrogen or its analogs and methods for their use in
the treatment of glaucomatous retinopathy. In particular, the
invention provides methods for retinoprotection by administering to
a patient in need thereof a therapeutically effective amount of a
composition including at least one non-feminizing estrogen compound
or an analog thereof. As used herein, the phrase "non-feminizing
estrogen compound" refers to compounds having very little or no
feminizing, or sex-related, activity.
[0009] It is contemplated that virtually any non-feminizing
estrogen compound will be useful in the methods of the invention.
Typically, the non-feminizing estrogen compound for use in the
methods of the invention will be polycyclic compounds having a
terminal phenolic group, in a structure containing at least a
second ring, having a molecular mass of less than 1000 Daltons.
Examples of such compounds include, but are not limited to,
estratriene-3-ol, 3,17.alpha.-estradiol, estrone, estriol, and
their analogs. Most preferably, the non-feminizing estrogen
compound is estratriene-3-ol.
DETAILED DESCRIPTION PREFERRED EMBODIMENTS
[0010] Incidence of ocular hypertension and primary open angle
glaucoma is known to increase during menopause (Qureshi (1996);
Worda & Sator (2000)), which may be related to the sudden
decrease of circulating concentration of estrogen in
post-menopausal women. Administration of estrogen together with
progestin was shown to lower IOP (Meyer et al. (1966); Caramazza et
al. (1968); Treister & Mannor (1970); Sator et al. (1998)).
Treister and Mannor also observed the IOP-lowering effect with
estrogen administration alone (1970). The estrogen-induced
reduction in IOP correlates with an increase in outflow facility of
aqueous humor. However, independent of the IOP-lowering effect,
estrogens have been demonstrated to be protective against various
insults in the brain (Cyr et al. (2000); Emilien et al. (2000);
Granholm (2000); Green et al. (2000); Henderson (1997); McMillan
& Dorsa (1999); Monk & Brodaty (2000); Simpkins et al.
(2000); Woolly (1999)). Estrogen receptor (Kobayashi et al. (1998);
Ogueta et al. (1999); Wickham et al. (2000)) and an
estrogen-binding protein (Rao (1998)) have been found in the
retina. It is likely that estrogen receptor is involved in
vision-affecting conditions in the retina. The present inventors
contemplate for the first time that estrogens are useful in the
prevention, treatment or reduction of retina and optic nerve
damages associated with glaucoma independent of their effects on
IOP.
[0011] Classical estrogens or their metabolites are not practical
as therapeutic agents for the treatment of retinal diseases because
their feminizing effects are not acceptable to many patients.
Non-feminizing estrogen compounds are estrogen-related compounds
having substantially no sex-related effect on the subject. Simpkins
et al. (U.S. Pat. No. 6,197,833; U.S. Pat. No. 5,877,169; U.S. Pat.
No. 5,843,934 all incorporated herein by reference) discuss the use
of such compounds for treatment of patients with a number of
degenerative conditions or conditions resulting from ischemic
damage in the brain. Simpkins et al. do not discuss the use of the
compounds for the treatment of eye-related diseases.
[0012] Estrogen occurs in at least two isomeric forms, including
.alpha. estrogen and .beta. estrogen. .beta. estrogens are
pleotrophic molecules with many biological activities. Clinical
uses include treatment of osteoporosis, symptoms of menopause and
fertility control. In comparison to .beta. estrogen, .alpha.
estrogen is typically believed to be at least 100-1000 times less
potent in estrogenic activity. Numerous examples have been reported
in the literature that show that the biological effects of .beta.
estrogen are not shared by the .alpha. isomer. In fact, in the art,
.alpha. estrogen is typically used as a negative control for .beta.
estradiol.
[0013] Simpkins et al. (U.S. Pat. No. 5,843,934, herein
incorporated by reference) showed the .alpha. estrogen has a
comparable activity to that of .beta. estrogen for neuroprotection.
This activity provides .alpha. estrogen with a number of advantages
over .beta. estrogen in the treatment of degenerative diseases,
trauma and aging related to the central nervous system. These
advantages arise in situations which require treatment of males
where the development of female traits is to be avoided and the
treatment of females where the subject has increased susceptibility
to endometrial, breast and cervical cancer. The present inventors
show for the first time that non-feminizing estrogens are useful in
the treatment of glaucomatous retinopathy.
[0014] U.S. Pat. No. 5,521,168 discusses the use of estrogen
metabolites for lowering of intraocular pressure. The compounds
disclosed in this patent are estrogen metabolites, some of which
may not have sex-related pharmacological actions. However, U.S.
Pat. No. 5,521,168 does not discuss the use of these estrogen
metabolites or any non-feminizing estrogens in the treatment of
glaucoma-related retina and optic nerve damages.
[0015] It is contemplated that virtually any non-feminizing
estrogen compound will be useful in the methods of the invention.
Typically, the non-feminizing estrogen compound for use in the
methods of the invention will be a polycyclic compound having a
terminal phenolic group, in a structure containing at least a
second ring, having a molecular mass of less than 1000 Daltons.
Examples of such compounds include, but are not limited to,
estratriene-3-ol, 3,17.alpha.-estradiol, estrone, estriol, and
their analogs. Most preferably, the non-feminizing estrogen
compound is estratriene-3-ol.
EXAMPLES
[0016] The following examples are included to demonstrate preferred
embodiments of the invention. It should be appreciated by those of
skill in the art that the techniques disclosed in the examples
which follow represent techniques discovered by the inventors to
function well in the practice of the invention, and thus can be
considered to constitute preferred modes for its practice. However,
those of skill in the art should, in light of the present
disclosure, appreciate that many changes can be made in the
specific embodiments which are disclosed and still obtain a like or
similar result without departing from the spirit and scope of the
invention.
[0017] The compositions of the present invention comprise one or
more non-feminizing estrogens and a pharmaceutically acceptable
vehicle. As used herein, the term "pharmaceutically acceptable
vehicle" refers to any formulation which is acceptable, i.e., safe
and provides the appropriate delivery for the desired route of
administration, of an effective amount of one or more
non-feminizing estrogens. The compositions of the present invention
may be administered in a variety of different ways including
systemically (e.g., oral administration, intramuscular injection,
subcutaneous injection, intravenous injection, transdermal
administration and transmucosal administration), topically and by
intraocular injection, intraocular perfusion, periocular injection
or retrobulbar (sub-tenon) injection.
[0018] The exact dosage of the non-feminizing estrogen(s) will
vary, but will be determined by skilled clinicians in the art.
Various factors affecting the dosage amount include the actual
disease to be treated, the severity of condition, the health of the
patient, the potency and specific efficacy of the non-feminizing
estrogen, and so on. The amount dosed, however, will be in an
effective to prevent, treat or ameliorate an ocular disease or
disorder, e.g., those described herein; such an amount is referred
herein as an "effective amount." In general, the daily dosage of
non-feminizing estrogens will range between about 0.001 and 100
milligrams per kilogram body weight per day (mg/kg/day), and
preferably between about 0.01 and 5.0 mg/kg/day.
[0019] The non-feminizing estrogens of the present invention may be
contained in various types of ophthalmic compositions, in
accordance with formulation techniques known to those skilled in
the art. For example, the compounds may be included in solutions,
suspensions and other dosage forms adapted for topical,
intravitreal or intracameral use.
[0020] Aqueous compositions are generally preferred, based on ease
of formulation and physiological compatibility. However, the
non-feminizing estrogens of the present invention may also be
readily incorporated into other types of compositions, such as
suspensions and viscous or semi-viscous gels or other types of
solid or semi-solid compositions for topical or retrobulbar
injection. The ophthalmic compositions of the present invention may
also include various other ingredients, such as buffers,
preservatives, co-solvents and viscosity building agents.
[0021] An appropriate buffer system (e.g., sodium phosphate, sodium
acetate or sodium borate) may be added to prevent pH drift under
storage conditions.
[0022] Topical ophthalmic products are typically packaged in
multi-dose form. Preservatives are thus required to prevent
microbial contamination during use. Suitable preservatives include:
benzalkonium chloride, chlorobutanol, methyl paraben, propyl
paraben, phenylethyl alcohol, edetate disodium, sorbic acid,
polyquaternium-1, or other agents known to those skilled in the
art. Some of these preservatives, however, may be unsuitable for
particular applications, (e.g., benzalkonium chloride may be
unsuitable for intraocular injection). Such preservatives are
typically employed at a level of from 0.001 to 1.0% weight/volume
("% w/v").
[0023] For topical administration of non-feminizing estrogens, the
typical dosage generally will range between about 1-2 two drops
administered to the eye 1-4 times per day of a composition
comprising 0.001 and 5% weight/volume ("w/v"), and preferably
between 0.1 and 1% (w/v) of one or more non-feminizing estrogens.
Solutions, suspensions, ointments, gels, jellies and other dosage
forms adapted for topical administration are preferred.
Additionally, non-feminizing estrogens may be delivered slowly,
over time, to the afflicted tissue of the eye through the use of
contact lenses. This regimen is generally performed by first
soaking the lenses in a non-feminizing estrogen solution, and then
applying the contact lenses to the eye for normal wear.
[0024] The compositions of the present invention are further
illustrated in the following formulation examples, non-feminizing
estrogens of the present invention are represented generically in
the examples as "non-feminizing estrogen."
Example 1
[0025] A Topical Ophthalmic Composition Useful for Treating Retinal
Vascular Diseases:
1 Ingredient Concentration (% w/v) Non-feminizing estrogen 0.1
Dibasic Sodium Phosphate 0.2 HPMC 0.5 Polysorbate 80 0.05
Benzalkonium Chloride 0.01 Sodium Chloride 0.75 Edetate Disodium
0.01 NaOH/HCl q.s., pH 7.4 Purified Water q.s. 100%
Example 2
[0026] A Sterile Intraocular Injection Solution Useful for Treating
Retinal Vascular Diseases:
2 Ingredient Concentration (% w/v) Non-feminizing estrogen 0.05-5.0
Cremophor EL .RTM. 10 Tromethamine 0.12 Mannitol 4.6 Disodium EDTA
0.1 Hydrochloric acid or q.s., pH to 7.4 sodium hydroxide Water for
injection q.s. 100%
Example 3
[0027] A Tablet Formulation Suitable for Oral Administration, and
Useful for Treating Retinal Vascular Diseases:
3 Amount per Tablet Ingredient (mg) Non-feminizing estrogen 200
Cornstarch 50 Lactose 145 Magnesium stearate 5
Example 4
[0028] An Systemic Injectable Solution Useful for Treating Retinal
Vascular Diseases:
4 Ingredient Amount Non-feminizing estrogen 200 mg 0.4 M KH2PO4
solution 2 ml 1 N KOH solution q.s. to pH 7.0 Water for injection
q.s. to 20 ml
[0029] All of the compositions and/or methods disclosed and claimed
herein can be made and executed without undue experimentation in
light of the present disclosure. While the compositions and methods
of this invention have been described in terms of preferred
embodiments, it will be apparent to those of skill in the art that
variations may be applied to the compositions and/or methods and in
the steps or in the sequence of steps of the method described
herein without departing from the concept, spirit and scope of the
invention. More specifically, it will be apparent that certain
agents which are both chemically and structurally related may be
substituted for the agents described herein to achieve similar
results. All such substitutions and modifications apparent to those
skilled in the art are deemed to be within the spirit, scope and
concept of the invention as defined by the appended claims.
[0030] References
[0031] The following references, to the extent that they provide
exemplary procedural or other details supplementary to those set
forth herein, are specifically incorporated herein by
reference.
[0032] United States Patents
[0033] U.S. Pat. No. 5,521,168
[0034] U.S. Pat. No. 5,843,934
[0035] U.S. Pat. No. 5,877,169
[0036] U.S. Pat. No. 6,197,833
[0037] Books
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