U.S. patent application number 11/444337 was filed with the patent office on 2007-12-06 for use of a steroid prodrug for the treatment of disease of the posterior segment of the eye.
Invention is credited to Gregory Lambert, Laura Rabinovich-Guilatt.
Application Number | 20070281914 11/444337 |
Document ID | / |
Family ID | 39712456 |
Filed Date | 2007-12-06 |
United States Patent
Application |
20070281914 |
Kind Code |
A1 |
Rabinovich-Guilatt; Laura ;
et al. |
December 6, 2007 |
Use of a steroid prodrug for the treatment of disease of the
posterior segment of the eye
Abstract
Use of a composition comprising at least one prodrug of a
steroid, preferably of a corticosteroid, for the preparation of an
ophthalmic composition intended for the treatment of an ocular
condition or disease of a human being or an animal.
Inventors: |
Rabinovich-Guilatt; Laura;
(Paris, FR) ; Lambert; Gregory; (Chatenay-Malabry,
FR) |
Correspondence
Address: |
YOUNG & THOMPSON
745 SOUTH 23RD STREET, 2ND FLOOR
ARLINGTON
VA
22202
US
|
Family ID: |
39712456 |
Appl. No.: |
11/444337 |
Filed: |
June 1, 2006 |
Current U.S.
Class: |
514/176 ;
514/179 |
Current CPC
Class: |
A61P 27/00 20180101;
A61K 31/4745 20130101; A61K 48/00 20130101; A61K 9/0014 20130101;
A61P 27/02 20180101; A61K 47/543 20170801; A61P 43/00 20180101;
A61K 9/0048 20130101; A61K 31/573 20130101; A61P 31/04 20180101;
A61P 31/12 20180101 |
Class at
Publication: |
514/176 ;
514/179 |
International
Class: |
A61K 31/58 20060101
A61K031/58; A61K 31/573 20060101 A61K031/573 |
Claims
1. A method for the treatment of an ocular condition or disease of
a human being or an animal, comprising administering to said human
or animal in need thereof at least one prodrug of a steroid in the
form of a medicament or ophthalmic composition said medicament or
ophthalmic composition being administered by invasive means,
preferably by intraocular injection.
2. The method according to the claim 1, wherein the prodrug is a
long chain ester of steroid, preferably of corticosteroid, said
ester group comprising an alkyl group of more than 10 carbons
preferentially of more than 14 carbons, even more preferentially of
16 carbons.
3. The method according to claim 1, wherein the steroid is selected
from the group consisting of alclometasone dipropionate,
amcinonide, amcinafel, amcinafide, beclamethasone, betamethasone,
betamethasone dipropionate, betamethasone valerate, clobetasone
propionate, chloroprednisone, clocortelone, Cortisol, cortisone,
cortodoxone, difluorosone diacetate, descinolone, desonide,
defluprednate, dihydroxycortisone, desoximetasone, dexamethasone,
deflazacort, diflorasone, diflorasone diacetate, dichlorisone,
esters of betamethasone, fluazacort, flucetonide, flucloronide,
fludrotisone, fluorocortisone, flumethasone, flunisolide,
fluocinonide, fluocinolone, fluocinolone acetonide, flucortolone,
fluperolone, fluprednisolone, fluroandrenolone acetonide,
fluocinolone acetonide, flurandrenolide, fluorametholone,
fluticasone propionate, hydrocortisone, hydrocortisone butyrate,
hydrocortisone valerate, hydrocortamate, loteprendol, medrysone,
meprednisone, methylprednisone, methylprednisolone, mometasone
furoate, paramethasone, paramethasone acetate, prednisone,
prednisolone, prednidone, triamcinolone acetonide, triamcinolone
hexacatonide, and triamcinolone, salts, derivatives, and a mixture
thereof.
4. The method according to claim 1, wherein the steroid is selected
from the group consisting of cortisone, dexamethasone,
fluocinolone, hydrocortisone, methylprednisolone, prednisolone,
prednisone, and triamcinolone.
5. The method according to claim 1, wherein the prodrug is
dexamethasone palmitate.
6. The method according to claim 1, wherein the prodrug is
comprised in the composition in an amount of about 0.01% to about
10% w/w preferably about 0.5% to about 3% w/w, more preferably
about 2% w/w or about 1% w/w of the composition.
7. The method according to claim 1, wherein said prodrug is in
combination with any ophthalmically acceptable excipient or
carrier, or within an implant.
8. The method according to claim 7, wherein the carrier is selected
from a ophthalmic acceptable oil, phospholipid vesicles or
oil-in-water emulsion or water-in-oil emulsion or any other
suitable carrier.
9. The method according to claim 8 wherein the oil phase comprises
at least about 1, at least about 5, at least about 10, at least
about 20, at least about 30 or at least about 40 weight percent of
the composition/emulsion, preferably 10% of the emulsion.
10. The method according to claim 1 wherein the administrated
prodrug will gradually release through its hydrolysis by endogenous
enzymes in situ, to generate therapeutic levels of the active
drug.
11. The method according to claim 1, wherein said prodrug is
administered through one intraocular injection every one, two or
six months.
12. The method according to claim 1, wherein the amount of the
composition of the invention administered is such that, after one
month, the molar ratio drug/prodrug in the retina or in the choroid
is equal or less than 1, preferentially of 0.5, more preferentially
of 0.1.
13. The method according to claim 1, wherein the disease is a
condition or disease of the interior of the eye, preferably of the
back of the eye.
14. The method according to claim 13, characterized in that said
diseases are: uveitis, macular edema, macular degeneration, retinal
detachment, ocular tumors, bacterial, fungal but viral infections,
multifocal choroiditis, diabetic retinopathy, proliferative
vitreoretinopathy (PVR), sympathetic opthalmia, Vogt
Koyanagi-Harada (VKH) syndrome, histoplasmosis, uveal diffusion,
and vascular occlusion.
15. The method according to claim 1, wherein the composition
further comprises an active agent selected from cyclosporine,
anti-VEGF, and/or an antibiotic.
16. The method according to claim 1, wherein the composition
comprises dexamethasone palmitate and at least one active agent
selected from the group consisting of cyclosporine, anti-VEGF, and
an antibiotic.
Description
[0001] The present invention relates to the field of the treatment
of the ophthalmic diseases, in particular of the intraocular
diseases of a human being or an animal, by at least one steroid,
and in particular by at least one corticosteroid.
[0002] The invention particularly focuses on ophthalmic
compositions or devices, preferably ophthalmic emulsions,
comprising at least one steroid, preferably a corticosteroid. The
invention also relates to the administration of such ophthalmic
compositions, and in particular to their administration
intraocularly. The invention relates also to the controlled release
of therapeutic active agents, in particular of corticosteroids
intraocularly, in particular in the posterior segment of the
eye.
[0003] A posterior ocular condition is a disease which primarily
affects a posterior ocular site such as choroid or sclera,
vitreous, vitreous chamber, retina, optic nerve, and blood vessels
and nerves which vascularize or innervate a posterior ocular
site
[0004] Steroids are already largely used to treat ophthalmic
diseases affecting the posterior chamber of the eye, in particular
central retinal vein occlusion (CRVO), branch retinal vein
occlusion (BRVO), choroidal macular edema (CME), diabetic macular
edema (DME), diabetic macular retinopathy, uveitis, and age related
macular degeneration (ARMD). These treatments generally imply their
systemic administration, causing known side effects, which are
significant, regarding the ophthalmic diseases to treat. These side
effects singularly decrease the interest of the treatment of these
ophthalmic diseases by systemic administration of steroids.
[0005] Other modes of administration, topic, suprachoroidal,
subconjunctival, retrobulbar, and intravitreal were searched.
Regarding topical application, dexamethasone penetration into the
vitreous humour after repeated topical application is negligible
(less than 2 ng/ml after 1 drop of 0.1% dexamethasone phosphate
drops hourly for 10 hours) (Weijtens, Ophthalmology, 2002). In
comparison, serum and vitreous levels of 60 and 5 ng/ml
respectively are observed following a single oral administration of
7.5 mg dexamethasone (Weijtens, Am J Ophthalmol, 1998).
[0006] It was also shown that the subretinals concentrations of
dexamethasone after subconjunctival or peribulbar injection were
120 and 13-fold more elevated than after oral administration
(Weijtens et al Ophthalmology, 2000). The local intraocular
administration is thus highly preferred.
[0007] However, the injection of steroids in significant amounts in
the eye, implies a sudden and massive increase in their
concentration in all ocular structures, and can also lead to
undesirable and consequent local ocular side effects, in particular
a significant increase in the intraocular pressure possibly leading
to the development of glaucoma, or to the appearance or the
development of cataracts.
[0008] It was notably noticed that the presence of corticosteroids
in the anterior segment of the eye was in particular related to the
appearance of these side effects, and was thus undesirable.
[0009] The need to administrate the corticosteroids the most
locally possible, therefore selectively in the disease site, in
effective quantities, was then clear.
[0010] The effectiveness of the treatment is in particular related
to the presence of the active compound and hence to the half life
of the drug. A known corticosteroid, the dexamethasone has a half
life of 3.5 hours when injected intraocularly (Kwak, Arch
Ophthalmol, 1992). Thus, the injections must be repeated to
maintain a therapeutic effect.
[0011] However, repeated injections are difficult to cope with for
the patients suffering of long or chronic diseases. Moreover,
repeated injections are likely to increase harmful side effects
such as retina detachment, endophtalmy, and cataracts.
[0012] In view of the additional side effects caused by repeated
injections, intraocular implants of steroids have been
developed:
[0013] RETISERT.TM. (fluocinolone acetonide intravitreal implant,
Bausch & Lomb) 0.59 mg is a sterile implant designed to release
fluocinolone acetonide locally to the posterior segment of the eye.
RETISERT.TM. was recently approved by the FDA and is indicated for
the treatment of chronic non-infectious uveitis affecting the
posterior segment of the eye. However, clinical trials of this
implant systematically results in a raise of the intraocular
pressure (IOP) and cataracts as main adverse effects. Holekamp et
al. found that after long-term follow-up, high-dose intraocular
fluocinolone acetonide results in significant complications rate,
with 100% of the eyes developing elevated IOP and 30% showing
nonischemic central retinal vein occlusion. These complications
required the implant removal in almost 60% of the eyes (Am J
Ophthalmol 2005). Implantation of 0.59 mg or 2.1 mg fluocinolone
acetonide in noninfectious posterior uveitis patients results in a
5-fold augmentation of the need of IOP lowering agents (Jaffe,
Ophthalmology, 2005). In a randomized clinical trial of 0.59 mg
fluocinolone acetonide intravitreal implant in patients with
diabetic macular edema, the most common adverse included serious
cataract progression (43.1%) and a serious intraocular pressure
rise (8.6%) (Pearson, ISOPT communication, Berlin, 2006). Based on
clinical trials with RETISERT, within 34 weeks post-implantation,
approximately 60% of patients will require IOP lowering medications
to control intraocular pressure. Within an average postimplantation
period of approximately 2 years, approximately 32% of patients are
expected to require filtering procedures to control intraocular
pressure. Moreover, within an average post-implantation period of
approximately 2 years, nearly all phakic eyes are expected to
develop cataracts and require cataract surgery (source Bausch &
Lomb).
[0014] Posurdex is another intraocular device being developed by
Allergan containing 700 micrograms of dexamethasone which are
released during the first month post implantation. Its efficacy has
been evaluated among others in cases of persistant macular edema
(Williams, ISOPT communication, 2006) and for anti-inflammatory
effects after cataract surgery (Tan, Ophthalmology, 2004). However,
a safety and efficacy clinical study of 700 micrograms
dexamethasone implant for the treatment of macular edema showed
significant increases in IOP (to .gtoreq.25 mm Hg) in 15% of
patients (Williams, ISOPT communication, Berlin, 2006).
[0015] The off-label use of triamcinolone acetonide (Kenalog
40.TM., Bristol Myers Squib) intraocularly results indirectly in
the slow-release of the drug, as the insoluble steroid precipitates
following injection in the vitreous cavity and is only gradually
solubilized. Therefore, it can be considered as well as a sustained
release steroidal formulation. However, this formulation which was
not originally developed for intraocular use can cause serious
complications such as infectious endophthalmitis and sterile
endophthalmitis, retinal toxicity and crystalline retinal deposits.
Nevertheless, it has been used intravitreally to treat ocular
inflammation as well as macular edema due to numerous causes. In
addition, retrospective analysis of subtenon triamcinolone
acetonide cases also reveals intraocular pressure rise in 21% of
the patients (Bui Quoc, J Fr Ophtalmol, 2002).
[0016] Other steroid-containing devices being developed in research
are triamcinolone acetonide/polycaprolactone implants (Beeley, J
Biomed Mater Res A, 2005), triamcinolone/polyvinyl alcohol implants
(Ciulla, Br J Ophthalmol, 2003), betamethasone polymeric implants
(Kato, IOVS, 2004 and Okabe, IOVS, 2003) and others.
[0017] This analysis of the intraocular corticosteroid-containing
implants shows that the long lasting presence of corticosteroid in
the posterior segment of the eye causes undesirable side effects,
even though the therapeutic effect is undoubtful.
[0018] There is need therefore for an ophthalmic device or
composition which will succeed in delivering the active compound
not only for a sustained period in the eye, but more specifically
in the disease site.
[0019] From this assumption, the inventors searched alternative
therapeutic pathways for an efficient administration of
corticosteroids inside the eye this invention relates to the use of
prodrugs of steroids, especially corticosteroids, for the
preparation of a medicament or an ophthalmic composition intended
for the treatment of an ocular condition or disease of a human
being or an animal, said medicament or ophthalmic composition being
administered by invasive means, preferably by intraocular
injection, more preferably by intravitreal injection, for in-situ
sustained release of therapeutic effective agents.
[0020] The inventors observed that intraocular, more especially
intravitreal, injections of a corticosteroid prodrug, the
dexamethasone palmitate, resulted in the in-situ release of
dexamethasone.
[0021] Without wanting to being linked by this theory, the
Inventors suppose that there might be a selective uptake of the
steroid prodrug, preferably a lipophilic ester of a steroid, by the
ocular inflammatory cells (macrophages). The increased macrophage
activity at the inflamed sites may result in a targeted cleavage of
the active moiety only in the disease location, with no unspecific
release. Therefore, fewer side effects occasioned by the
therapeutic agent are expected to be observed. The drug would be
release at the very location of the disease, resulting in a
decrease of unwanted adverse effects in other ocular structures
where the prodrug is not hydrolyzed. The invention also allows to
maintain the desired effect in the ocular condition for an extended
period of time during which an amount of the prodrug is present at
the ocular site such that it allows the release of an effective
amount of the active drug for an extended period of time, which is
preferably at least one month
[0022] By prodrug in the invention is meant a lipophilic long-chain
prodrug ester of steroid, preferably of corticosteroid, said ester
group comprising an alkyl group of more than 10 carbons
preferentially of more than 14 carbons, even more preferentially of
16 carbons. According to a preferred embodiment of the invention,
the prodrug does not have any direct therapeutic and/or physiologic
effect, and is therefore called "inactive", whereas the drug
released by hydrolysis of the prodrug does have a physiological
therapeutic effect.
[0023] The invention is directed to the use of a composition
comprising at least one prodrug of a steroid, preferably of a
corticosteroid, for the preparation of an ophthalmic composition
intended for the treatment of an ocular condition or disease of a
human being or an animal.
[0024] The composition according to the invention comprises at
least one prodrug of corticosteroid, which is preferably selected
from: alclometasone dipropionate, amcinonide, amcinafel,
amcinafide, beclamethasone, betamethasone, betamethasone
dipropionate, betamethasone valerate, clobetasone propionate,
chloroprednisone, clocortelone, Cortisol, cortisone, cortodoxone,
difluorosone diacetate, descinolone, desonide, defluprednate,
dihydroxycortisone, desoximetasone, dexamethasone, deflazacort,
diflorasone, diflorasone diacetate, dichlorisone, esters of
betamethasone, fluazacort, flucetonide, flucloronide, fludrotisone,
fluorocortisone, flumethasone, flunisolide, fluocinonide,
fluocinolone, fluocinolone acetonide, flucortolone, fluperolone,
fluprednisolone, fluroandrenolone acetonide, fluocinolone
acetonide, flurandrenolide, fluorametholone, fluticasone
propionate, hydrocortisone, hydrocortisone butyrate, hydrocortisone
valerate, hydrocortamate, loteprendol, medrysone, meprednisone,
methylprednisone, methylprednisolone, mometasone furoate,
paramethasone, paramethasone acetate, prednisone, prednisolone,
prednidone, triamcinolone acetonide, triamcinolone hexacatonide,
and triamcinolone, salts, derivatives, and a mixture thereof.
[0025] More preferably, the corticosteroid is selected from:
cortisone, dexamethasone, fluocinolone, hydrocortisone,
methylprednisolone, prednisolone, prednisone, and
triamcinolone.
[0026] In the most preferred embodiment of the invention, the
composition comprises a prodrug of dexamethasone, more preferably
dexamethasone palmitate.
[0027] Preferably, the prodrug is comprised in the emulsion in an
amount of about 0.01% to about 10% w/w of the composition.
According to an embodiment, the prodrug is comprised in the amount
of about 0.5% to about 3% w/w of the composition. In a preferred
embodiment, the prodrug is comprised in a amount of about 2% w/w of
the composition. In another preferred embodiment of the present
invention, the prodrug is comprised in an amount of about 1% w/w of
the composition.
[0028] According to the invention, the composition of the invention
includes at least one steroid prodrug dissolved in a
ophthalmologically acceptable oil.
[0029] According to another embodiment of the invention, the
composition of the invention includes at least one steroid prodrug
dissolved in a physiologically acceptable oil which is emulsified
into a oil-in-water emulsion by different techniques such as high
shear and high pressure homogenization with suitable emulsifiers;
final preparation can be sterilized by filtration or by
autoclave.
[0030] According to an embodiment of the invention, the composition
comprises at least one prodrug as above-defined, in combination
with any ophtalmologically acceptable excipient or carrier. The
carrier may be selected from an ophtalmologically acceptable oil,
phospholipid vesicles or oil-in-water emulsion or water-in-oil
emulsion or any other suitable carrier about 20, at least about 30
or at least about 40 weight percent of the composition/emulsion,
preferably 10% of the emulsion.
[0031] Excipient characteristics that are considered include, but
are not limited to, the biocompatibility and biodegradability at
the site of implantation, compatibility with the prodrug of
interest, and processing temperatures.
[0032] When the excipient or the carrier is an emulsion, according
to an embodiment of the invention, the oil phase comprises at least
about 1, at least about 5, at least about 10, at least about 20, at
least about 30 or at least about 40 weight percent of the
composition. In a preferred embodiment, the oil represents 10
weight percent of the composition.
[0033] In the meaning of this invention the term "about" means
approximately or nearly and in the context of a numerical value or
range set forth herein means .+/-. 10% of the numerical value or
range recited or claimed.
[0034] According to an embodiment of the invention, the composition
of the invention is administered through one intraocular injection,
more preferably through one intravitreal injection.
[0035] According to another embodiment of the invention, the
composition of the invention is administered through the placement
of an intraocular implant containing or combined with the
composition of the invention.
[0036] According to another embodiment of the invention, the
composition further comprises an active agent selected from
cyclosporine, anti-VEGF, and/or an antibiotic.
[0037] According to another embodiment of the invention, wherein
the composition comprises dexamethasone palmitate and at least one
active agent selected from the group consisting of cyclosporine,
anti-VEGF, and an antibiotic.
[0038] The invention also relates to a method of treatment of a
human or animal ophthalmic condition or disease comprising the
intraocular administration of the composition of the invention.
[0039] According to an embodiment, the method of the invention
includes the administration of a steroid prodrug into an ocular
site of a patient suffering from an ocular condition or disease.
The prodrug can be administered alone or in an ophtalmologically
carrier suitable for intraocular administration. The carrier may be
an oil, phospholipid vesicles or oil-in-water emulsion, or any
other suitable carrier.
[0040] The administrated prodrug will gradually release through its
hydrolysis by endogenous enzymes in situ, to generate therapeutic
levels of the active drug. This results in the improvement of
ocular conditions by the action of the active drug in the very site
of inflammation due to the ocular condition or disease.
[0041] According to an embodiment of the invention, the frequency
of administration of the composition of the invention trough
injection is once a month, preferably once every two months, more
preferably once every six months. It is an advantage of this
invention to provide a less frequent need for repeated
administration.
[0042] According to an embodiment of the invention, the amount of
the composition of the invention administered is such that, after
one month, the molar ratio drug/prodrug in the target tissue,
preferably in choroid or in retina, is equal or less than 1,
preferentially of 0.5, more preferentially of 0.1.
[0043] The improvement of the ocular condition obtained by a method
within the scope of the present invention can be determined by
observing: an improved visual acuity, an improved visual contrast
sensitivity, a decreased retinal or choroidal blood vessel leakage,
a decreased retinal or macular thickness, or a reduced number of
cells in the aqueous or vitreous humor or by determining a reduced
flare.
[0044] According to an embodiment of the invention, the
administration of the composition of the invention is invasive.
More preferably, the composition of the invention is administered
through an implant or through intraocular, preferably intravitreal
injection.
[0045] The compositions of the invention are useful for the
treatment of conditions or diseases affecting the interior of the
eye, preferably of the back of the eye. These compositions are
especially useful for the treatment of the following conditions or
diseases: uveitis, macular edema, macular degeneration, retinal
detachment, ocular tumors, bacterial, fungal but viral infections,
multifocal choroiditis, diabetic retinopathy, proliferative
vitreoretinopathy (PVR), sympathetic opthalmia, Vogt
Koyanagi-Harada (VKH) syndrome, histoplasmosis, uveal diffusion,
and vascular occlusion.
[0046] In a preferred embodiment, the composition of the invention
is within an implantable device and then used for the treatment of
uveitis, macular edema, vascular occlusive conditions,
proliferative vitreoretinopathy (PVR), and various other
retinopathies.
[0047] The invention is further illustrated by the following
example, which should not be considered in any way as a limitation
the scope of the protection.
EXAMPLE
1. Analytical Methods for Simultaneous Determination of
Dexamethasone and Dexamethasone Palmitate in Ocular Tissues
[0048] A liquid chromatographic-mass spectrometric method for the
simultaneous determination of dexamethasone and dexamethasone
palmitate in ocular tissues was developed. Analytes and internal
standard (roxithromycine) were extracted from the tissues using
acetonitrile and separated by reverse phase liquid chromatography
with a C8 column and a gradient mobile phase. The compounds were
detected by mass spectrometric detection (atmospheric pressure
ionization) with selected ion monitoring (SIM) (393.0 for
dexamethasone and 631.5 for dexamethasone palmitate). The method
was selective for both compounds and the limits of quantification
were 32.7 ng/g of retina and 71.6 ng/g choroid. The unweighed
linear model was applied.
2. Intraocular Pharmacokinetics of Dexamethasone Palmitate and
Dexamethasone Following Intravitreal Administration
Methods:
[0049] One single unilateral intravitreal injection of a 0.8% (8
mg/ml) dexamethasone palmitate emulsion to rabbits (100 .mu.L).
Sacrifice at days 1, 7, 14, 21, 28 or 60 days (n=4/timepoint).
Dexamethasone (D) and dexamethasone palmitate (DP) in tissues were
determined. All concentrations are expressed in nmol/g tissue
Results:
TABLE-US-00001 [0050] Day 1 Day 7 Day 14 Day 28 Day 60 Mean sd Mean
sd Mean sd Mean sd Mean sd Retina DP 106 74 93 38 136 19 146 109 55
37 (nmol/g) D 7 2 11 4 6 4 4 1 2 2 (nmol/g) D/DP 0.660 0.118 0.044
0.027 0.036 Choroid DP 191 69 103 77 22 11 143 61 52 22 (nmol/g) D
12 6 12 7 9 4 4 1 3 2 (nmol/g) D/DP 0.063 0.117 0.409 0.028 0.057
Aqueous DP ND ND ND ND ND ND ND ND 0 0 humor (nmol/g) D ND ND ND ND
ND ND ND ND 0 1 (nmol/g) ND: Not determined.
[0051] Following IVT injection of a dose of 800 .mu.g of prodrug,
dexamethasone of more than 800 ng/g (higher than therapeutic
levels) were maintained for at least 2 months in the target
tissues. Moreover, considerable amounts of the prodrug
dexapalmitate remained in both retina and choroid, indicating an
even more long-lasting release.
[0052] At the same time, the amounts of steroid in the aqueous
humor was undetectable, suggesting fewer (if any) side effects in
adjacent sites. This last fact was corroborated by IOP
measurements, which were normal 2 months following the
injection.
* * * * *