Note: Descriptions are shown in the official language in which they were submitted.
W093/06856 2 ~ 2 0 ~1 i O pcr/Au92/oos41
TREATING OPHTHALMIC FIBROSIS USING INTERFERON-ALPHA
Technical Field
The present invention relates to the use of topical interferon-a for the treatment of
various forms of fibrosis in and around the eye arising from various ophthalmic diseases
s and procedures. Specifically the invention relates to alleviation of corneal scarring after
laser photoablative refractive keratectomy (PRK). It also relates to the alleviation of
posterior (lens) capsular opacification after extracapsular cataract surgery with lens
implant; the alleviation of wound scarring following glaucoma filtration surgery.
Interferon-a may also be used to coat the lens implant prior to or during implantation. lt
10 may also possibly be injected into the eye during eye surgery for inhibiting posterior
capsule opacification after cataract surgery and in addition may be injected into the
vitreous body to prevent retinal fibrosis and proliferative vitreo-retinopathy, and injected
subconjunctivally to inhibit fibrosis and scarring following glaucoma filtration surgery.
Background Art
In the field of ophthalmic surgery, it is known to use excimer laser photoablative
refractive keratectomy to sculpt the cornea of the eye in order to relieve refractive errors
(e.g. myopia) and a number of corneal conditions and diseases. Specifically, the 193nm
argon fluoride excimer laser is able to discrete1y remove corneal tissue by photoablation
without thermal damage to surrounding tissue.
20 Of major concern is the acdvation of the stromal keratocytes when a wound is
made to the stroma. As is well known, the basic response of wounded tissue is to repair
*e defect and therefore the ophthalmic surgeon when using *is teclLnique is confronted
wi* alteration to the biochemistry, morphologic features~ and tissue function
~ unpredictability brought about by the wound itself and ~the healing phenomenon.
- 2s Therefore, even though excimer laser ablation of cornea1 tissue appears to ~e an
efficient method of removing tissue with minimal damage to adjacent arças, nevertheless
the healing pro~ess does not always lead to the preserva~on of transparent corneal tissue.
Previous methods of overcoming this problem have been: application of topical
steroids such as prednisolone, prednisolone acetate, prednisolone sodium phosphate,
30 fluoromethalone, fluoromethalone acetate, hydromesterone, dexamethasone, and
dexamethasone alcohol. Other compounds tested have been idoxuridine, collagen cross-
iinkage inhibitors and mitomycin (: .
It is an object of this invention to ameliorate the known disadvantages of present
techniques when dealing with the wound repair mechanism fiollowing photoablative35 refractive keratectomy.
Interfe~ons are a heterogeneous group of proteins that can inhibit many aspects of
~- the fibrotic response. Originally identified by their well known ability to interfere wieh
; ~ the p oduction of viral RNA and protein, they also exert anticellular activities generally
~ ~ considered to be inhibitory, which maybe due to their ability to inhibit the c-myc proto-
WO 93/06856 pcr/Aus2~oo54l
2~9~ 2
oncogene. Type I interferon (viral interferon, interferon-a and -~) is produced in
response to viral infection, and type II (immune interferon, interferon-~) in response to
specific antigens or mitogens. Of the different classes, a-interferon is secreted by
leukocytes, ~ by fibroblasts and ~ by stimulated Iymphocytes. lnterferons,
s particularly interferon-a, have been successfully used in humans for twenty years for the
treatment of systemic malignancy.
Considerable interest has recently been shown in the potential of interferon as a
treatment for such fibrotic diseases as systemic sclerosis, pulmonary fibrosis and keloid.
Fib~oblasts are stimulated to produce interferons by many cytokines that mediate wound
10 healing, such as interleukin-l-(IL-1), platelet derived growth factor (PDGF) and tumour
necrosis factor (TNF). Interferons inhibit fibroblast chemotaxis and proliferation as well
as collagen production, the latter syner~istically with TNF-a. lntraperitoneallyimplanted foreign bodies in mice suffered less encapsulation in the presence of
interferon- y, the capsules having a reduced collagen content. Pibroblast
5 glycosaminoglycan production is inhibited by interferon-a, while collagenase production
is increased. This deactivation of activated fibroblasts can persist for a long time after a
brief exposure to interferon. Of the different types of interferon, the a- and ,B
subclasses exhibit a broader antifibrotic spectrum.
The present inventors have recently demonstrated that interferon-a inhibits foetal
20 calf serum and platelet derived growth factor induced proliferation of human tenon's
capsule fibroblasts in vitro. They suggest that interferons may prove to be of benefit in
the treatment of fibrosis following PRK in particularj and of ocular fibrosis in general.
Disclosure of the Invention
According to a first form of this invention, there is provided a method for the
2s treatment of corneal scar~ing in a patient requiring such treatment, comprlsing
adn~inistering to the cornea of said patient an effective amount of interferon-oc or a
pharmaceutical compositivn for the treatment of corneal scarring in a patient comprisîng
interfer~n-a together with a phanna~utically acceptable carrier7 diluent and/or
excipient.
30 According to a second form of this invention, there is provided a method for
inhibiting opacificatios~. of the posterior c~psule after extracapsular ca~ract surgery, in a
patient requiring such treatment, comprising administering to the lens capsule of said
patient an effective amount of interferon-(x or a pharmaceutical composition for this
method comprising interferon-a together with a pharmaceutically acceptable carrier,
35 diluent and/or excipient.
According to a third form of this invention, there is provided a method for
inhibiting wound fibrosis and scarring after glaucoma filtration surgery, in a patient
requiring such treatment, comprising administering to the subconjunctival space of said
patient an effe~tive amount of interferon-a or a pharrnaceutical composition for this
WO 93/06856 ~ ~ 2 ~ 9 ~ ~ pcr/Aug2/oos41
method comprising interferon-o~ together with a pharmaceutically accepeable carrier,
diluent and/or excipient.
According to a fourth form of this invention, therç is provided a method for
inhibiting formation of pre-retinal membranes and proliferative vitreo-retinopathy
5 following retinal detachment surgery and/or vitrectomy, following traumat and as a
result of retinal vascular disease (including diabetes, thalassaemia and retinal vein
occlusion) in a patient requiring such treatment, comprising administering to the vitreous
body or retina of said patient an effective amount of interferon-a or a pharrnaceutical
composition for this method comprising interferon-oc together with a pharmaceutically
lo acceptable carrier, diluent and/or excipient.
Interferon-a 2A, interferon-a 2B or interferon-a 2C or any other type of
interferon-a may be used in this invention.
The invention also provides novel protein formulations in which the carrier or
diluent is a bioerodable polymer, e.g. a polymer ester (polyanhydrine), which may be a
15 copolymer of sebacic acid and bis paracarboxyphenoxybutane; or a poly(ortho) ester.
The method of this invention inhibits the scarring response following a variety of
corneal procedures such as photoablative refractive keratectomy; lamellar keratoplasty;
lamellar keratectomy; epikeratoplasty; removal of pterygium and keratomileusis.
Typically, the patient on whom the methods of this invention are used i~ a human.
20 However, the methods would also be able to be used on other mammals. r
The methods of this invention may also inhibit scarring after chemical damage toconjunctiva and cornea and may also prevent scarring in pathological conditions such as
ocular pemphigoid and StevensJohnson's syndrome, Simplex & Zoster keratitis. It may
also inhibit fibrosis in thyroid eye disease, orbital psuedo-tumour and ocular myositis.
25 Preparation of topical composition drops are made up from Intron A powder
(Schering-Plough) or Roferon-A (Roche) to a solution of 1 x 106 IU/mL.
Formulation of Intron A is as follows:
a- 2b interferon solution
Dibasic sodium phosphate, anhydrous, USP
30 Monosodium phosphate, monohydrate, USP
Glycine, ph. eur.
Human albumin solution, ph. eur.
Water for injection, ph. eur.
Drops base may be hypromellose or polyvinyl alcohol for dilution to 106 IU/mL.
3~ The composition of the present invention may be administered topically as a
solution, ointment, or within a collagen shield or similar dissolving corneal contact
protective dressing containing conventional, non-toxic, pharmaceutically acceptable
carriers, diluents and/or excipients as desired, or by direct injection.
The dosage range of interferon-o~ may be between about 50,000 and 50 x 106 IU
212 0 9 5 0 PCI/AU92/00541
and may be between about I x 106 to 20 x lo6 lU/mL. Preferably the dosage is between
about lx106 and about 10X106 IU/mL. The interferon-o~ may be administered in 50 ~L
drops, four times a day for six weeks; or preferably two times a day for one week.
Interferon-o~ may also be administered two times a day for three days or one drop hourly
5 for three days. This dosage range is applicable to the first, second and third embodiments of the invention.
When applied according to the fourth embodiment the interferon-a is given by
intravitreal injection within the range of 50,000 to 5.0 x 106 IU/0.lmL.
The compositions of this invention may also contain a slow release polymer.
0 The pharmaceutically acceptable carriers, diluents and/or excipients are those well
known in the art of ophthalmic surgery and comprise the following: hydroxyethyl
cellulose, hypromellose, polyvinyl alcohol, gelatin, polyquad, dextran, castor oil or
other vegetable oil e.g. sesame, inert soft white paraffin, liquid paraffin, anhydrous
lanolin, sodium hyalusonate, methyl cellulose, potassium sorbate, polysorbate; or sodium
15 chloride, sodium phosphate, buffers hydrochloric acid bicarbonate, Na citrate (citric
acid) boric acid in purified water. They may also be biodegradable polymer esters
(polyanhydrines) e.g. sebacic acid and bis paracarboxyphenoxybutane, which are
employed in the novel formulations of the invention.
The compositions may also contain preservatives and antiseptics ~uch as:
20 thiomersal, phenyl mercuric acetate, benzylalkonium chloride, disodium edetate, sodium
metabisulfite, polymercuric nitrate, chlorobutol, hyloxapol, povidone, propyl hydroxy
benzoate, methyl hydroxy benzoate.
It is preferable that the composition of this invention be~applied to the corneaimmediately following photoablative refractive keratectomy. As a drop, ointment or
2s collagen shield etc. Where the interferon is applied as a drop, it is preferably to treat the
eye thus, four to eight times a day for up to about 6 weeks.
The comeal response may be modified by the pre-treatment with interferon o~ drops
before PRX. It may also be modified by pre-treatment with steroid drops.
The interferon-a may be prepared from natural sources or may be prepared by
30 recombinant DNA techniques. All of these techniques would be well known to one
skilled in this art.
Best Mode and Other Modes for Carrying Out the Invention
An effective amount of interferon-ol-2b to prevent corneal scarring after
photoablative refractive keratectomy is administered topically to the cornea which has
3~ been subjected to this procedure.
The present invention will now be described with reference to the following
examples which should not be construed as limiting on the scope thereof.
WO 93/06856 2 ~ 2 0 9 ~ ~ PCr/AU92/00541
Example 1
Preparation of interferon a-2B topical composition ::
Preparation of topical composition drops are made up from Intron A powder -~
(Schering-Plough) to a solution of 1 x 106 IU/mL.
Formulation of Intron A is as f~llows: ;
a-2b interferon solution
Dibasic sodium phosphate, anhydrous, USP
Monosodium phosphate, monohydrate, USP
Glycine, ph. eur. ;
0 Human albumin solution, ph. eur.
Water for injection, ph. eur.
The drops base is hypromellose or polyvinyl alcohol for dilution to lo6 IU/ml,.
Example 2
The composition of this invention is applied to the cornea immediately followingls photoablative refractive keratectomy, As a drop, ointment or collagen shield etc. Where
the interferon is applied as a drop, it is preferable to treat the eye thus, four times a day
for up to about 6 weeks.
The corneal response may be modified by the pre-treatment with interferon-a-2b
drops before PRK. It may also be modified by pre-treatment with steroid dr~s. - ~
20 Industrial Applicability ~ -
It should be clear that the method of treatment of this invention will find wide use
in the veterinary and medical fields. ---
The foregoing describes only some embodiments of the present invention and
modifica'dons obvious to those sldlled in the art can be made thereto without departing
25 from the scope of the invention.
References
Gipson IK ~1990) Archives of Opthalmology 108 1539.
Cintron C ~1990) Archives of Opthalmology 108 1540. `
Binder PS (1990) Archives of Opthalmology 108 1541.
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