U.S. patent application number 11/109115 was filed with the patent office on 2005-09-15 for use of neurotrophic factor stimulators for the treatment of ophthalmic neurodegenerative diseases.
Invention is credited to Pang, Iok-hou.
Application Number | 20050203121 11/109115 |
Document ID | / |
Family ID | 34635968 |
Filed Date | 2005-09-15 |
United States Patent
Application |
20050203121 |
Kind Code |
A1 |
Pang, Iok-hou |
September 15, 2005 |
Use of neurotrophic factor stimulators for the treatment of
ophthalmic neurodegenerative diseases
Abstract
Compositions and methods for the treatment of retina and optic
nerve head neuropathy are disclosed. The compositions and methods
are particularly directed to the use of neurotrophic factor
stimulators, such as AIT-082 (neotrofin), in the treatment of
glaucomatous neuropathy.
Inventors: |
Pang, Iok-hou; (Grand
Prairie, TX) |
Correspondence
Address: |
ALCON RESEARCH, LTD.
R&D COUNSEL, Q-148
6201 SOUTH FREEWAY
FORT WORTH
TX
76134-2099
US
|
Family ID: |
34635968 |
Appl. No.: |
11/109115 |
Filed: |
April 19, 2005 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
11109115 |
Apr 19, 2005 |
|
|
|
09856987 |
May 25, 2001 |
|
|
|
6906077 |
|
|
|
|
09856987 |
May 25, 2001 |
|
|
|
PCT/US99/28385 |
Dec 1, 1999 |
|
|
|
60110983 |
Dec 3, 1998 |
|
|
|
Current U.S.
Class: |
514/301 ;
514/320 |
Current CPC
Class: |
A61K 31/52 20130101;
Y10S 514/912 20130101 |
Class at
Publication: |
514/301 ;
514/320 |
International
Class: |
A61K 031/4743; A61K
031/454 |
Claims
I claim:
1. A composition for the treatment of retina or optic nerve head
neuropathy comprising an effective amount of one or more
neurotrophic factor stimulator(s) and a pharmaceutically acceptable
vehicle.
2. A composition according to claim 1, wherein the neurotrophic
factor stimulator is selected from the group consisting of AIT-082
(neotrofin), idebenone, ONO-2506, CB-1093, NS521
((1-(1-butyl)-4-(2-oxo-1-benzimidazol- one) piperidine, SS-701,
KT-711 and clenbuterol.
3. A composition according to claim 2, wherein the neurotrophic
factor stimulator is AIT-082 (neotrofin).
4. A composition according to claim 1, wherein the composition is
an oral formulation.
5. A composition according to claim 1, wherein the composition is a
topical ophthalmic, or intraocular formulation.
6. A composition according to claim 3, wherein the composition is
an oral formulation.
7. A composition according to claim 3, wherein the composition is a
topical ophthalmic, or intraocular formulation.
8. A method for the treatment of retina or optic nerve head
neuropathy which comprises administering to a mammal a composition
comprising an effective amount of one or more neurotrophic factor
stimulator(s) and a pharmaceutically acceptable vehicle.
9. A method according to claim 8, wherein the neurotrophic factor
stimulator is selected from the group consisting of: AIT-082
(neotrofin), idebenone, ONO-2506, CB-1093, NS521
((1-(1-butyl)-4-(2-oxo-1-benzimidazol- one) piperidine, SS-701,
KT-711 and clenbuterol.
10. A method according to claim 9, wherein the neurotrophic factor
stimulator is AIT-082 (neotrofin).
11. A method according to claim 8, wherein the composition is an
oral formulation.
12. A method according to claim 8, wherein the composition is a
topical ophthalmic, or intraocular formulation.
13. A method according to claim 10, wherein the composition is an
oral formulation.
14. A method according to claim 10, wherein the composition is a
topical ophthalmic, or intraocular formulation.
Description
[0001] This application claims continuation from U.S. Ser. No.
09/856,987 filed May 25, 2001: which claims priority from
PCT/US99/28385 filed Dec. 1, 1999; which claims priority from U.S.
Ser. No. 60/110,983 filed Dec. 3, 1998.
[0002] The present invention relates to the use of neurotrophic
factor stimulators to treat ophthalmic neurodegenerative
diseases.
BACKGROUND OF THE INVENTION
[0003] Primary open-angle glaucoma (POAG) is a progressive disease
leading to optic nerve damage and, ultimately, loss of vision. The
cause of this disease has been the subject of extensive studies for
many years, but is still not fully understood. Glaucoma results in
the neuronal degeneration of the retina and optic nerve head. Even
with aggressive medical care and surgical treatment, the disease
generally persists causing a gradual loss of retinal neurons
(retinal ganglion cells ("RGCs")), a decline of visual function,
and ultimately blindness (Van Buskirk et al., Predicted outcome
from hypotensive therapy for glaucomatous optic neuropathy, Am. J.
Ophthalmol., volume 25, pages 636-640 (1993); Schumer et al., The
nerve of glaucoma!, Arch. Ophthalmol., volume 112, pages 37-44
(1994)).
[0004] Several theories have been proposed to elucidate the
etiology of glaucoma. One theory suggests that excessive
intraocular pressure (in some cases coupled with genetic defects on
the optic nerve head, RGC or the optic nerve) disrupts the normal
axonal transport along the optic nerve, eventually leading to RGC
injury.
[0005] Disturbance of axonal transport of the optic nerve hinders
traffic of intracellular molecules between the RGC cell soma and
its terminal. Among the intracellular molecules of importance are
neurotrophic factors. Neurotrophic factors are peptide molecules
which stimulate or otherwise maintain growth of neural tissue. The
transport of neurotrophic factors from the brain to the cell body
of RGCs is essential to the survival of the RGCs. Deprivation of
neurotrophic factors can induce apoptosis of neurons (Raff et al.,
Programmed cell death and the control of cell survival: lessons
from the nervous system, Science, volume 262, pages 695-700
(1993)).
[0006] Deprivation of neurotrophic factors appears to be a cause of
glaucoma-induced RGC apoptosis, as such causal link is supported by
a great deal of experimental evidence (see, generally, Anderson et
al., Effect of intraocular pressure on rapid axoplasmic transport
in monkey optic nerve, Invest. Ophthalmol., volume 13, pages
771-783 (1974); Quigley et al., The dynamics and location of axonal
transport blockade by acute intraocular pressure elevation in
primate optic nerve, Invest. Ophthalmol., volume 15, pages 606-616
(1976); Mansour-Robaey et al., Effects of ocular injury and
administration of brain-derived neurotrophic factor on survival and
regrowth of axotomized retinal ganglion cells, Proc. Natl. Acad.
Sci. USA, volume 91, pages 1632-1636 (1994); Meyer-Franke et al.,
Characterization of the signaling interactions that promote the
survival and growth of developing retinal ganglion cells in
culture, Neuron, volume 15, pages 805-819 (1995); and Cui et al.,
NT-4/5 reduces naturally occurring retinal ganglion cell death in
neonatal rats, Neuroreport, volume 5, pages 1882-1884 (1994)). Such
trophic factors include neurotrophins and other cytokines.
[0007] The neurotrophin ("NT") family of peptides include nerve
growth factor (NGF), brain-derived neurotrophic factor (BDNF),
NT-3, NT-4/5 and NT-6. They act by binding to neuron surface
receptors, such as TrkA, TrkB, TrkC and p75NTR. The Trk receptors
are tyrosine kinases. TrkA is selective for NGF, TrkB is selective
for both BDNF and NT-4/5, whereas TrkC is selective for NT-3. After
binding, the NT-receptor complex is internalized and transported
via the axon to the soma. These receptors undergo ligand-induced
phosphorylation and dimerization, and activate a cascade of Ras
protein-mediated signal transduction events that affect multiple
vital functions of the neuron (Lewin et al., Physiology of the
neurotrophins, Ann. Rev. Neurosci., volume 19, pages 289-317
(1997); Segal et al., Intracellular signaling pathways activated by
neurotrophic factors, Ann. Rev. Neurosci., volume 19, pages 463489
(1996); Ebadi et al., Neurotrophins and their receptors in nerve
injury and repair, Neurochem Int., volume 30, pages 347-374 (1997);
Kaplan et al., Signal transduction by the neurotrophin receptors,
Curr. Opin. Cell Biol., volume 9, pages 213-221 (1997)). Thus,
these receptors play a fundamental role in the regulation of
survival and differentiation of developing neurons and contribute
to the maintenance of neuronal machinery in adult life.
[0008] In the retina, mRNA of both TrkA and TrkB has been observed
in RGCs, dopaminergic amacrine cells and the optic nerve ("ON").
Their expression was shown to be highly regulated during neuronal
development (see, Jelsma et al., Different forms of the
neurotrophin receptor trkb mRNA predominate in rat retina and optic
nerve, J. Neurobiol., volume 24, pages 1207-1214 (1993); Rickman et
al., Expression of the protooncogene, trk, receptors in the
developing rat retina, Vis. Neurosci., volume 12, pages 215-222
(1995); Ugolini et al., TrkA, TrkB and p75 mRNA expression is
developmentally regulated in the rat retina, Brain Res, volume 704,
pages 121-124 (1995); Cellerino et al., Brain-derived neurotrophic
factor/neurotrophin-4 receptor TrkB is localized on ganglion cells
and dopaminergics amacrine cells in the vertebrate retina, J. Comp.
Neurol., volume 386, pages 149-160 (1997)). The TrkB
receptor-selective ligands, BDNF and NT-4/5, have been shown to be
efficacious for the protection of RGCs. Numerous studies have shown
that these NTs not only improve the survival and neurite outgrowth
of RGCs in culture, but also significantly reduce axotomy-induced
in vivo damage of the ON and RGCs, as well as stimulate the growth
of axonal branches from regenerating RGCs (see, generally, the
Anderson et al.; Quigley et al.; Mansour-Robaey et al.;
Meyer-Franke et al.; and Cui et al. publications cited above). For
example, a single intravitreal injection of 5 .mu.g of BDNF
prevented the death of the axotomized RGCs when administered during
the first five days after injury (Mansour-Robaey et al., above). In
contrast with the loss of nearly half of the axotomized RGCs in the
untreated retinas, virtually all RGCs were present one week after a
single injection of BDNF on Day 0. Messenger RNA expression of BDNF
was significantly elevated in the rat RGC layer after ON injury
(Gao et al., Elevated mRNA expression of brain-derived neurotrophic
factor in retinal ganglion cell layer after optic nerve injury,
Invest. Ophthalmol. Vis. Sci., volume 38, pages 1840-1847 (1997)),
further suggesting the potential importance of this NT in retinal
recovery.
[0009] In addition to these protective effects against mechanical
damage at the retina and/or ON, neurotrophins may also be
protective against other forms of neuronal insult. By a yet unknown
mechanism (but possibly a suppression of the apoptosis cascade),
BDNF protects CNS neurons from glutamate neurotoxicity (Lindholm et
al., Brain-derived neurotrophic factor is a survival factor for
cultured rat cerebellar granule neurons and protects them against
glutamate-induced neurotoxicity, Eur. J. Neurosci., volume 5, pages
1455-1464 (1993)); and it has been effective in vivo in preventing
ischemic cell death in the rat retina (Unoki et al., Protection of
the rat retina from ischemic injury by brain-derived neurotrophic
factor, ciliary neurotrophic factor, and basic fibroblast growth
factor, Invest. Ophthalmol. Vis. Sci., volume 35, pages 907-915
(1994)), and hippocampus (Beck et al., Brain-derived neurotrophic
factor protects against ischemic cell damage in the rat
hippocampus, J. Cereb. Blood Flow Metab., volume 14, pages 689-692
(1994)).
[0010] Ciliary neurotrophic factor (CNTF) is another trophic factor
that supports survival of neurons. It is part of a cytokine family
structurally unrelated to neurotrophins. Both CNTF and its receptor
are expressed by the Mller glia during retinal neurogenesis and
differentiation (Kirsch et al., Evidence for multiple, local
functions of ciliary neurotrophic factor (CNTF) in retinal
development: expression of CNTF and its receptors and in vitro
effects on target cells, J. Neurochem., volume 68, pages 979-990
(1997). It may also be useful in preventing glaucomatous
neuropathy, since it prevents lesion-induced death of RGCs (Mey et
al., Intravitreal injections of neurotrophic factors support the
survival of axotomized retinal ganglion cells in adult rats in
vivo, Brain Res., volume 602, pages 304-317 (1993)) and ON axonal
degeneration, albeit less effective than BDNF (Weibel et al.,
Brain-derived neurotrophic factor (BDNF) prevents lession-induced
axonal die-back in young rat optic nerve, Brain Res., volume 679,
pages 249-254 (1995)).
[0011] Thus, neurotrophic factors play an ameliorative role in
glaucomatous retinopathy, and retinal degeneration in general.
These trophic factors, however, are peptide molecules, and are
therefore difficult to exploit pharmaceutically due to
bioavailability problems generally resident in the pharmaceutical
administration of peptides. What are needed, therefore, are
non-peptide molecules which stimulate neurotrophic activity in
compromised retinal tissues, without the bioavailability problems
attendant to the natural peptides.
[0012] Several neurotrophic factor stimulators have been reported
in the scientific literature, for example, AIT-082 (Graul &
Castaner, AIT-082, Drugs of the Future, volume 22, pages 945-947
(1997)), idebenone (Nabeshima et al., Oral administration of NGF
synthesis stimulators recovers reduced brain NGF content in aged
rats and cognitive dysfunction in basal-forebrain-lesioned rats,
Gerontology, volume 40, supplement 2, pages 46-56 (1994)), ONO-2506
(Matsui et al., Protective effects of ONO-2506 on neurological
deficits and brain infarct volume following 1 week of permanent
occlusion of middle cerebral artery in rats, Society for Neurosci.
Abstracts, volume 24, page 254 (1998)), NS521 (Gronborg et al.,
Neuroprotection by a novel compound, NS521, Society for Neurosci.
Abstracts, volume 24, page 1551 (1998)), CB-1093 (Aimone et al.,
The 1.alpha.,25(OH).sub.2D.sub.3 analog CB-1093 induces nerve
growth factor in non-human primate brain, Society for Neurosci.
Abstracts, volume 24, page 292, (1998)) and Clenbuterol (Culmsee et
al., NGF antisense oligonucleotide blocks protective effects of
clenbuterol against glutamate-induced excitotoxicity in vitro and
focal cerebral ischemia in vivo, Society for Neurosci. Abstracts,
volume 24, page 295 (1998)). However, nowhere in the art has it
been disclosed or suggested to use neurotrophic factor stimulators
to treat glaucoma or other ophthalmic neuropathies.
SUMMARY OF THE INVENTION
[0013] The present invention is directed to compositions and
methods for treating glaucomatous neuropathy and retinal
degenerative diseases. The compositions and methods comprise
neurotrophic factor stimulators for the treatment of compromised or
at risk retinal or optic nerve head tissue.
[0014] The neurotrophic factor stimulators are compounds which
stimulate the production or activity of retinal neurotrophic
factors. The stimulation of neurotrophic factors in the eye
ameliorates the conditions of glaucomatous neuropathy and other
retinal and optic nerve head degenerative diseases.
[0015] Preferred compositions and methods are directed to the
neurotrophic factor stimulators, AIT-082 (neotrofin) and
idebenone.
DETAILED DESCRIPTION OF THE INVENTION
[0016] The present invention is directed to compositions and
methods for treating glaucomatous neuropathy and other retinal or
optic nerve head degenerative diseases. The compositions comprise
one or more neurotrophic stimulator(s) in a pharmaceutically
acceptable vehicle.
[0017] As used herein, "neurotrophic factor stimulators" refer to
those compounds which increase the in situ production or activity
of neurotrophic factors in the retina. As used herein,
"neurotrophic factor" refers to NGF, BDNF, NT-3, NT-4/5, NT-6, CNTF
or other trophic factors which prevent, treat or ameliorate retinal
neuropathy. Examples of neurotrophic factor stimulators include:
AIT-082 (neotrofin), idebenone, ONO-2506, CB-1093, NS521
((1-(1-butyl)-4-(2-oxo-1-benzimidazolone)piperid- ine) SS-701,
KT-711 and clenbuterol. The most preferred neurotrophin stimulator
of the present invention is AIT-082 (neotrofin). The preceding
molecules may be obtained commercially or may be synthesized by
methods known to those skilled in the art. 1
EXAMPLE 1
[0018] The following example demonstrates the protective efficacy
of a neurotrophic factor stimulator (propentofylline) against
retinal cell insult.
[0019] Retinal Ganglion Cell Survival Assay:
[0020] Techniques for the isolation and culture of RGCs were
adapted from those reported by Takahashi N. et al., Rat retinal
ganglion cells in culture. Exp. Eye Res. volume 53, pages 565-572
(1991). The procedure involved the retrograde labeling of ganglion
cells by injecting a fluorescent dye, Di-I, into the superior
colliculi. Two to 4 days later, retina cells were dissociated.
Cultured RGCs were identified by sufficient Di-I fluorescence to be
observed visually using a fluorescent microscope.
[0021] Neonatal, Sprague-Dawley rats, 2-5 days old, were
anesthetized by hypothermia, after which, a 2 mm midline opening
was made in the scalp just caudal to the traverse sinus. The tip of
the injection needle (30 gauge) was inserted 6 mm below the top of
the skull, and a 5 .mu.l Di-I solution, containing 3 mg/ml Di-I
(1,1'-dioctadecyl-3,3',3',3'-tetramethy- lindo-carbocyanine
perchlorate (Molecular Probes, Eugene, Oreg.) in 90% ethanol and
10% dimethylsulfoxide, was injected. The wound was then covered
with a drop of Flexible Collodion (Amend Drug & Chemical Co.,
Irvington, N.J.). Rats were returned to their mother after warming
and recovery from anesthesia.
[0022] Two to 4 days after Di-I injection, rats were anesthetized
by hypothermia and sacrificed by decapitation. Their eyes were
enucleated and placed in Dulbecco's modified Eagle's medium:
Nutrient mixture F12 (1:1; DMEM/F12, Gibco Co., Grand Island,
N.Y.). The retina from each eye was detached and isolated. Retinal
cells were dissociated by combining 12 retinae with 5 ml of papain
solution, containing 10 mg papain (34 units/ml; Sigma Chemical Co.,
St Louis, Mo.), 2 mg DL-cysteine (3.3 mM; Sigma, St. Louis, Mo.)
and 2 mg bovine serum albumin (0.4 mg/ml; Sigma) in 5 ml of
DMEM/F12, for 25 min at 37.degree. C., then washed 3 times with 5
ml RGC medium (DMEM (Gibco), supplemented with 10% fetal bovine
serum (Hyclone, Logan, Utah.), 4 mM glutamine (Gibco), 100 units/ml
penicillin and 100 .mu.g/ml streptomycin (Sigma). Additional RGC
medium was added to the retinal pieces to a final total volume of
40 ml. Retinal pieces were triturated by passing through a
disposable pipette several times until cells were dispersed. Cell
suspension (1.5 ml; containing approximately 4.5.times.10.sup.6
cells) was placed into each of the poly-D-lysine coated glass
bottom culture dishes. The cells were cultured for 3 days in 95%
air/5% CO.sub.2 at 37.degree. C.
[0023] Fetal calf serum was removed from the culture medium 3 days
after the cells were isolated with or without various therapeutic
agents. Three days later, the cells were observed with a
fluorescent microscope at 200.times. magnification, and
Di-I-labeled fluorescent cells in 20 microscopic fields were
counted and averaged. The results are illustrated in Table 1,
below:
1TABLE 1 Effects of a neurotrophic factor stimulator on RGC
survival Cultured with Serum Agent RGC Survival (%) Yes None 100.0
.+-. 4.9* No None 46.4 .+-. 5.6 No BDNF (5 .mu.M) + Forskolin 79.9
.+-. 5.4* (10 ng/ml) No Propentofylline (100 .mu.M) 96.9 .+-. 4.8*
Note: RGC survival in the presence of serum defines 100%. All
values are expressed as mean and SEM (n = 6). *represented p <
0.05 versus the no-serum, no-drug group by one-way ANOVA then
Dunnett's test.
[0024] Table 1 illustrates that the survival of RGCs was greater in
the presence of fetal calf serum (and the endogenous neurotrophic
factors contained in the serum). The neurotrophic factor, BDNF, in
the presence of forskolin, appeared to protect against such insult
(i.e., removal of the fetal calf serum). Similarly,
propentofylline, which is known to stimulate the production of
nerve growth factor in cultured astrocytes (Shinoda et al.,
Stimulation of nerve growth factor synthesis/secretion by
propentofylline in cultured mouse astroglial cells, Biochem.
Pharmacol., volume 39, pages 1813-1816 (1990)) and in aged rat
brain in vivo (Nabeshima et al., Impairment of learning and memory
and the accessory symptom in aged rat as senile dementia model:
oral administration of propentofylline produces recovery of reduced
NGF content in the brain of aged rats, Jpn. J. Psychol. Pharmacol.,
volume 13, pages 89-95 (1993)), also protected the cells against
the serum deprivation-induced cell death. These data indicate that
compounds that stimulate neurotrophic factor production or increase
their activity may protect retinal cells, especially RGCs, against
injury induced by deprivation of neurotrophic factors.
[0025] The methods of the present invention comprise administering
to a human patient one or more neurotrophic factor stimulators for
the treatment of retinal or optic nerve head neuropathy.
[0026] The methods of the present invention are particularly
directed to the use of neurotrophin factor stimulators for the
treatment of glaucoma, and other diseases and disorders of the
outer retina, particularly age related macular degeneration,
retinal ischemia, acute retinopathies associated with trauma,
post-surgical complications, the damage associated with laser
therapy including photodynamic therapy (PDT), and surgical light
induced iatrogenic retinopathy. As used herein, "retina or optic
nerve head neuropathy" refers to any of the foregoing diseases or
other retinal or optic nerve head neurodegenerative diseases.
[0027] The neurotrophic factor stimulators of the present invention
may be contained in various types of pharmaceutical compositions,
in accordance with formulation techniques known to those skilled in
the art. In general, the neurotrophic factor stimulators will be
formulated in solutions or suspensions for topical ophthalmic or
intraocular administration, or as tablets, capsules or solutions
for systemic administration (e.g., oral or intravenous).
[0028] Oral formulations of the neurotrophin stimulators are
preferred due to ease of administration. Oral formulations may be
in liquid or solid form. In general, oral formulations will contain
the active neurotrophin factor stimulator and inert excipients. In
general, solid tablet or capsule dosages will contain various
excipients such as bulking agents, binding agents, time release
coatings, or other agents known to those skilled in the art. Liquid
dosages will contain carriers, buffers, tonicity agents,
solubilizing agents, or other agents known to those skilled in the
art.
[0029] The compositions of the present invention may be
administered intraocularly following traumatic and/or other acute
ischemic events involving the retina and optic nerve head tissues
or prior to or during surgery to prevent ischemic damage or injury.
Compositions useful for intraocular administration will generally
be intraocular injection compositions or surgical irrigating
solutions. Intraocular injection compositions will generally be
comprised of an aqueous solution, e.g., balanced salt irrigating
solutions, discussed below.
[0030] When the neurotrophin factor stimulators are administered
during intraocular surgical procedures, such as through retrobulbar
or periocular injection and intraocular perfusion or injection, the
use of balanced salt irrigating solutions as vehicles are most
preferred. BSS.RTM. Sterile Irrigating Solution and BSS Plus.RTM.
Sterile Intraocular Irrigating Solution (Alcon Laboratories, Inc.,
Fort Worth, Tex., USA) are examples of physiologically balanced
intraocular irrigating solutions. The latter type of solution is
described in U.S. Pat. No. 4,550,022 (Garabedian et al.), the
entire contents of which are incorporated herein by reference.
Retrobulbar and periocular injections are known to those skilled in
the art and are described in numerous publications including, for
example, Ophthalmic Surgery: Principles of Practice, Ed., G. L.
Spaeth, W. B. Sanders Colo., Philadelphia, Pa., U.S.A., pages 85-87
(1990).
[0031] In general, the doses utilized for the above described
purposes will vary, but will be in an effective amount to prevent,
reduce or ameliorate retina or optic nerve head neuropathy. As used
herein, "pharmaceutically effective amount" refers to that amount
of a neurotrophin factor stimulator which prevents, reduces or
ameliorates retina or optic nerve head neuropathy. The neurotrophic
factor stimulators will generally be contained in the topical or
intraocular formulations contemplated herein in an amount of from
about 0.001 to about 10.0% weight/volume ("% w/v"). Preferred
concentrations will range from about 0.1 to about 5.0 % w/v.
Topical formulations will generally be delivered to the eye one to
six times a day, at the discretion of a skilled clinician. Systemic
administration compositions will generally contain about 10-1000 mg
of a neurotrophic factor stimulator, and can be taken 14 times per
day, at the discretion of a skilled clinician.
[0032] As used herein, the term "pharmaceutically acceptable
carrier" refers to any formulation which is safe, and provides the
appropriate delivery of an effective amount of at least one
neurotrophic factor stimulator for the desired route of
administration.
[0033] The compositions of the present invention may contain
additional pharmaceutically active agents or may be dosed
concurrently with other pharmaceutical compositions. In particular,
when treating a mammal for the prevention, treatment or
amelioration of glaucomatous retinopathy, the compositions of the
present invention may contain additional "anti-glaucoma" agents or
may be dosed concurrently or sequentially with anti-glaucoma agent
compositions. Examples of anti-glaucoma agents include:
prostaglandins or prostanoids, carbonic anhydrase inhibitors,
beta-adrenergic agonists and antagonists, alpha-adrenergic agonists
or other anti-glaucoma agents known to those skilled in the
art.
EXAMPLE 2
[0034] Topical compositions useful for treating glaucomatous
neuropathy:
2 Component % (w/v) AIT-082 (Neotrofin) 0.1-2.0 Tyloxapol 0.01-0.05
HPMC 0.5 Benzalkonium Chloride 0.01 Sodium Chloride 0.8 Edetate
Disodium 0.01 NaOH/HCl q.s. pH 7.4 Purified Water q.s.
EXAMPLE 3
[0035] A preferred topical composition useful for treating
glaucomatous neuropathy:
3 Component % (w/v) AIT-082 (Neotrofin) 0.5-1.0 Tyloxapol 0.01-0.05
HPMC 0.5 Benzalkonium Chloride 0.01 Sodium Chloride 0.8 Edetate
Disodium 0.01 NaOH/HCl q.s. pH 7.4 Purified Water q.s.
[0036] The above formulation is prepared by first placing a portion
of the purified water into a beaker and heating to 90.degree. C.
The hydroxypropylmethylcellulose (HPMC) is then added to the heated
water and mixed by means of vigorous vortex stirring until all of
the HPMC is dispersed. The resulting mixture is then allowed to
cool while undergoing mixing in order to hydrate the HPMC. The
resulting solution is then sterilized by means of autoclaving in a
vessel having a liquid inlet and a hydrophobic, sterile air vent
filter.
[0037] The sodium chloride and the edetate disodium are then added
to a second portion of the purified water and dissolved. The
benzalkonium chloride is then added to the solution, and the pH of
the solution is adjusted to 7.4 with 0.1M NaOH/HCl. The solution is
then sterilized by means of filtration.
[0038] AIT-082 is sterilized by either dry heat or ethylene oxide.
If ethylene oxide sterilization is selected, aeration for at least
72 hours at 50.degree. C. is necessary. The sterilized compound is
weighed aseptically and placed into a pressurized ballmill
container. The tyloxapol, in sterilized aqueous solution form, is
then added to the ballmill container. Sterilized glass balls are
then added to the container and the contents of the container are
milled aseptically at 225 rpm for 16 hours, or until all particles
are in the range of approximately 5 microns.
[0039] Under aseptic conditions, the micronized drug suspension
formed by means of the preceding step is then poured into the HPMC
solution with mixing. The balliill container and balls contained
therein are then rinsed with a portion of the solution containing
the sodium chloride, the edetate disodium and benzalkonium
chloride. The rinse is then added aseptically to the HPMC solution.
The final volume of the solution is then adjusted with purified
water and, if necessary, the pH of the solution is adjusted to pH
7.4 with NaOH/HCl.
EXAMPLE 4
[0040] Formulation for Oral Administration:
[0041] Tablet:
[0042] 1-1000 mg of a neurotrophic factor stimulator with inactive
ingredients such as starch, lactose and magnesium stearate can be
formulated according to procedures known to those skilled in the
art of tablet formulation.
EXAMPLE 5
[0043] Preferred Formulation for a Topical Ocular Solution:
4 Component % (w/v) AIT-082 (Neotrofin) 0.5-1.0 Benzalkonium
chloride 0.01 HPMC 0.5 Sodium chloride 0.8 Sodium phosphate 0.28
Edetate disodium 0.01 NaOH/HCl q.s. pH 7.2 Purified Water q.s.
EXAMPLE 6
[0044] A Preferred Formulation for Oral Administration:
[0045] Tablet:
[0046] 50-500 mg of AIT-082 (Neotrofin) with inactive ingredients
such as starch, lactose and magnesium stearate can be formulated
according to procedures known to those skilled in the art of tablet
formulation.
[0047] The invention in its broader aspects is not limited to the
specific details shown and described above. Departures may be made
from such details within the scope of the accompanying claims
without departing from the principles of the invention and without
sacrificing its advantages.
* * * * *