COMPOSITIONS TOPIQUES POUR LA RE-EPITHELISATION DANS LE CAS DE DEFAUTS EPITHELIAUX PERSISTANTS

TOPICAL COMPOSITIONS FOR RE-EPITHELIAZATION OF PERSISTENT EPITHELIAL DEFECTS

Abrégé anglais

Persistent epithelial defects are effectively treated by topically applying a
gelatinous composition containing either aminocaproic acid
or tranexamic acid to the eye. In vivo results demonstrate improved healing of
the epithelium and basement membrane complex. The
gelatinous composition is prepared by a process that ensures sterility and
proper pH conditions throughout the gel.

Revendications

-7-
CLAIMS:
1. The use of tranexamic acid for the manufacture of a gel formulation to be
administered to a patient's cornea for the treatment of a persistent
epithelial
defect.
2. The use of claim 1, wherein the formulation comprises 1-10 % by weight of
tranexamic acid, less than 10 % by weight of a gel-forming polymer compound,
less that 10 % by weight of a preservative or bacteriocidal agent, and water.
3. The use of claim 2, wherein the formulation comprises 0.05-0.25 % by weight
of
a preservative or bacteriocidal agent.
4. The use of claim 2 or 3, wherein the formulation comprises 0.5-5 % by
weight of
gel forming polymer compound carboxypolymethylene.
5. The use of claim 1, wherein the formulation comprises about 5 % by weight
of
tranexamic acid.
6. The use of claim 1, wherein the gel formulation has a viscosity in the
range of
about 26,500 cps to 1,580,000 cps.
7. The use of claim 2, wherein said formulation is suitable for multiple
administrations over a period of time sufficient to heal said persistent
epithelial
defect.
8. The use of ~- aminocaproic acid for the manufacture of a gel formulation to
be
administered to a patient's cornea for the treatment of a persistent
epithelial
defect.
9. The use of claim 8, wherein the formulation comprises 10-60 % by weight of
aminocaproic acid, less than 10 % by weight of a gel-forming polymer
compound, less than 10% by weight of a preservative or bacteriocidal agent,
and
water.
10. The use of claim 9, wherein the formulation comprises 0.05-0.25 % by
weight of
a preservative or bacteriocidal agent.

-8-
11. The use of claim 9 or 10, wherein the formulation comprises 0.5-5 % by
weight
of gel forming polymer compound carboxypolymethylene.
12. The use of claim 8, wherein the formulation comprises about 30 % by weight
of
aminocaproic acid.
13. The use of claim 8, wherein the gel formulation has a viscosity in the
range of
55,500 cps to 1,620,000 cps.
14. The use of claim 8, wherein the formulation is suitable for multiple
administrations over a period of time sufficient to heal said persistent
epithelial
defect.

Description

CA 02161652 2005-10-25
WO 94/25058 PCT/US94/04470
TOPICAL COMPOSITIONS FOR
RE-EPITHELIALIZATION OF
PERSISTENT EPITHELIAL DEFECTS
DESCRIPTION
BACKGROUND OF THE INVENTION
Field of the Invention
The present invention generally relates to a topical
composition applied to the eye for the treatment of persistent
epithelial defects (PEDs).
Description of the Prior Art
E-Aminocaproic acid (ACA) and tranexamic acid (TA) are
antifibrinolytic agents. Both drugs have been used in the
treatment of traumatic hyphaema in the eye. The impetus for
using these drugs to treat this disorder is the presumption that
hemorrhages occur as a result of clot breakdown by fibrinolysis.
The drugs have been administered orally to patients and
experiments have been conducted with topically applied
compositions containing the drugs.
Use of aminocaproic acid has been described in the
following references:
- Lowey et al. "Systemic aminocaproic acid reduces
f brinolysis in aqueous humor." Arch. Ophthalmol. 1987
Feb 105(2):272-6.
- Allingham et al. "Topically applied aminocaproic acid
concentrates in the aqueous humor of the rabbit in
therapeutic levels." Arch. Ophthalmol. 1987 Oct; 10 I
1421-3.
- Allingham et al. "Topical aminocaproic acid significantly
reduces the incidence of secondary hemorrhage in
traumatic hyphema in the rabbit model." Arch.
Ophthalmol. 1988 Oct; 106(10): 1436-8.
- Ehlers et al. "Factors affecting therapeutic concentration
of topical aminocaproic acid in traumatic hyphema."
Invest. Ophthalmol. Vis. Sci. 1990 Nov; 31(11):2389-94.

CA 02161652 2005-10-25
WO 94/25058 1A PCT/US94/04470
SUMMARY OF THE INVENTION
It is an object of this invention to provide a topical
composition useful in the treatment of PEDs.
According to the invention, it has been discovered that
topically applied ACA improves healing of the epithelium and
basement membrane complex. Similar results can be achieved
with topical formulations which include TA.
DETAILED DESCRIPTION OF THE PREFERRED
EMBODIMENTS OF THE INVENTION
After corneal abrasion, PEDs may occur due to the failure
of regenerating epithelium to adhere to the underlying stroma.
ACA inhibits activation of plasmin which metabolizes

WO 94/25058 2 j~ j%5z 2 PCT/US94/044706
fibronectin, a glycoprotein that anchors ocular epithelium to the
stroma. TA has similar effects.
PEDs were induced in experimental animals to
demonstrate that topical formulations containing ACA
improves the healing of the epithelium and basement
membrane complex. To induce PEDs, filter paper disks saturated
with 4N NaOH were placed for 2 min. on corneas of
anesthetized rabbits. Seven days later, the majority of the
corneas had areas denuded of epithelium.
Treatment began seven days after PED induction. Either
30% ACA or the vehide (4% carboxypolymethylene powder)
alone was administered topically three times daily. Rabbits were
treated 5, 11, 16, or 19 days. As a control, another group received
no ACA or vehide. Assessment with fluorescein staining
indicated that PEDs in rabbits treated with ACA for 19 days were
50% smaller than those from rabbits treated with vehicle alone.
After 15 days, 100% of the control (untreated) rabbits had PEDs.
Rabbits which received ACA had more pronounced healing
during the first weak of treatment with even greater healing
observed after 11 days of treatment.
Frozen sections, stained immunofluorescently for
fibronectin, appeared to qualitatively contain more adherent
fibronectin. Transmission and scanning electron microscopy
showed more disrupted, thinner and vacuolated epithelium in
untreated controls compared to ACA treated eyes. Light
microscopy showed more continuous adherent epithelium after
ACA treatment.
The study demonstrates that topical treatment of PEDs
with ACA promotes reepithelialization. Based on the similar
modes of action, the same results should be achieved with
topically applied TA.
Topically applied ophthalmic gel formulations within the
practice of this invention indude either 10-60 wt% ACA or 1-10
wt% TA. A suitable ophthalmic gel formulation containing 30%

WO 94/25058 3 2161652 PCT/US94/04470
ACA within the scope of this invention can have the following
ingredients: 30 grams ACA, 100 milligrams ethylenediamine
tetraacetic acid (EDTA), 2 grams of carboxypolymethylene
powder (available from BF Goodrich Co.), and 100 ml of sterile
water. A suitable ophthalmic gel formulation containing 5% TA
within the scope of this invention can have the following
ingredients: 5 grams TA, 100 milligrams EDTA, 2 grams of
carboxypolymethylene powder, and 100 ml of sterile water. The
concentration of carboxypolymethylene powder can vary, but the
topical formulation generally performs best when this
component is within the range of approximately 0.5% to 5% by
weight. The viscosity of the gel formulation with ACA is in the
range of 55,500 cps to 1,620,000 cps and with TA is in the range of
26,500 cps to 1,580,000 cps. Other gelatin forming polymer
compounds may also be employed within the practice of this
invention and should generally be present at less than 10% by
weight. Other bacteriocidal agents or preservatives besides
EDTA can be used within the practice of this invention and
these agents or preservatives are typically used at levels less than
1% by weight and optimally ranges between 0.05% and 0.25% by
weight.
The ophthalmic gel formulation is prepared according to a
procedure that ensures suitable pH conditions within the gel,
optimum ACA solubility and gel consistency, and sterility in the
resulting product. First, the carboxypolymethylene powder is
added to 25 ml of sterile water in an autoclavable container.
Second, the pH of the carboxypolymethylene/sterile water
mixture is then adjusted to approximately 2.5 by titration with
HCI. Other sterilized acid solutions may also be used for this
purpose. Achieving a low pH in the preparation process at this
point is needed since it will prevent the carboxypolymethylene
from forming a thick gel and makes both subsequent combining
with ACA or TA and sterilization of the gel possible. Third, the
carboxypolymethylene mixture is autoclaved to achieve sterility.
Suitable autoclaving conditions include 250'F for 30 minutes;
however, the time and temperature for autodaving can be

CA 02161652 2005-10-25
WO 94/25058 PCT%US94/04470 varied significantly. The objective of autoclaving
is to sterilize
the carboxypolymethylene gel vehicle. Other sterilizing
techniques such as radiation exposure may be possible; however,
filter sterilization is not possible with gel formulations. Fourth,
the ACA or TA and EDTA powders are dissolved in the
remaining 75 ml of sterile water. Fifth, filter sterilize the ACA
or TA/EDTA solution into the sterile carboxypolymethylene gel.
This can be done with a final filter of 0.22 microns and serial
filtration may be necessary. ACA cannot be heat sterilized since
it both decomposes and discolors at the temperatures required
for heat sterilization. Filter sterilization should be done
aseptically in a laminar air flow hood. Sixth, adjust the pH of
the gel product to 7.4 by aseptically adding a sterile NaOH
solution or other basic solution. The NaOH solution must
contain the prescribed wt% of ACA or TA to produce a final
product at that level (e.g., 30% ACA in the NaOH is used to
achieve a final ophthalmic gel formulation product with 30%
ACA). As above, the NaOH solution with ACA or TA can be
filter sterilized using a 0.22 micron filter. High performance
liquid chromatography (HPLC) has been performed to confirm
the wt% ACA or TA final concentration. Seventh, prepare unit
doses of the gel for administration to patients. A suitable unit
dose could be prepared by adding 0.2 ml of the gel to each of
several 1 ml Glaspak*syringes where the syringes will be capped
with a sterile tip. The shelf life of the topical ACA or TA
formulation is at least two years.
The gel formulation may be improved by incorporating
ACA or TA into liposomes such as those which may be created
from soya lecithin, phosphatidyl choline, and other compounds.
ACA is very water soluble and could be incorporated into
lecithin liposomes. The size arid shape of the lecithin liposomes
could be adjusted by the addition of water. A particular
advantage which is likely to arise from the incorporation of
ACA or TA in lecithin liposomes is that they may allow for a
sustained release of ACA or TA (e.g., ACA or TA will be released
topically over a longer period of time since the release of ACA or
*Trade-mark

~ WO 94/25058 rJ PCT/US94/04470
2161652
TA will be a function of the time of breakdown for the lecithin
liposomes). Increased concentrations of ACA or TA might be
used with the lecithin liposomes to prolong the usefulness of
the gel.
The formulation technique described above provides a
number of advantages. First, the pH of the gel is adjusted to a
level which is consistent with conditions in plasma and in the
aqueous humor (e.g., pH 7.4). By adding NaOH, the acidity of
ACA or TA is overcome. By first adjusting the gel to an acidic
and flowable form (e.g., adjusting carboxypolymethylene
solution to pH 2.5) and subsequently adding the basic (NaOH)
solution, the formulation process assured that the basic solution
(NaOH) would be evenly distributed in the gel, thereby
achieving a uniform pH throughout the gel. In addition, the
formulation process assured that the ACA was evenly dissolved
and distributed throughout the gel. Precautions were taken not
to dilute the concentration of ACA or TA in the gel by the
addition of base. Second, the solubility and consistency of the gel
formulated according to the seven step process has an optimum
consistency. The solubility and consistency of the gel changes
with the addition of ACA or TA. The consistency of the gel is
very important to an efficacious formulation since, with gels
that are too thin, the product does not remain in contact with
the corneal epithelium, and, with gels that are too thick, the
product does not spread over the corneal epithelium. Third, a
sterilized product is produced in a two part process where the gel
is heat sterilized and the ACA or TA is filter sterilized. In this
way, decomposition of ACA or TA by heat sterilization is
avoided. Moreover, the gel is sterilized by heat since filter
sterilization of a gel is not possible.
Other vehicles and gels do not provide comparable results
to the carboxypolymethylene gels described above. For example,
a gel of similar consistency which was prepared with ethylene
maleic anhydride (EMA) and ACA was found to be toxic.
While the invention has been described in terms of its

WO 94/25058 6 PCT/US94/04474
preferred embodiments, those skilled in the art will recognize
that the invention can be practiced with modification within the
spirit and scope of the appended daims.
-