NZ751841A - Stable povidone-iodine compositions with steroids or non-steroidal anti-inflammatories - Google Patents
Stable povidone-iodine compositions with steroids or non-steroidal anti-inflammatoriesInfo
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Abstract
Disclosed are stable ophthalmic composition, comprising: 0.3 to 1% (w/w) polyvinylpyrrolidinone-iodine complex; 0.05 to 2% (w/w) non-steroidal anti-inflammatory drug (NSAID) bromfenac, or 0.05 to 2% (w/w) steroid selected from the group consisting of prednisolone acetate, loteprednol etabonate, difluprednate, hydrocortisone acetate, and combinations thereof; 0.005% to 0.02% (w/w) EDTA; 0.01 to 0.5% (w/w) sodium chloride; 0.02 to 0.1% (w/w) tyloxapol as a co-solvent/surfactant; 0.5% to 2% (w/w) sodium sulfate; and 0.1 to 0.5% (w/w) hydroxyethylcellulose as a viscosity increasing agent. These ophthalmic compositions are suitable for the treatment and/or prophylaxis of an eye disorder selected from the group consisting of a microorganism infection of at least one tissue of the eye, conjunctivitis, corneal abrasion, ulcerative infectious keratitis, epithelial keratitis, stromal keratitis and herpesvirus-related keratitis.
Description
TITLE
Stable Povidone-Iodine Compositions with Steroids or Non-Steroidal Anti-Inflammatories
This application is a divisional of New Zealand patent application 734781, which is itself
a divisional of New Zealand patent application 717573, which is itself a divisional of New
Zealand patent application 617433, which is the national phase entry in New Zealand of PCT
international application , published as WO2012/155062, incorporated
herein by reference in its entirety.
BACKGROUND
Topical corticosteroids are routinely used to control ocular inflammation. Their
mechanism of action involves the inhibition of the immune response and the subsequent tissue
destruction that exuberant inflammation may cause. Corticosteroid has the undesirable side effect
of limiting the body's intrinsic ability to fight infection. In fact, inopportune steroids usage can
worsen the course of an infection secondary to mycobacteria, virus, or fungus. Thus, the use of a
combined antimicrobial-steroid medication in ocular infections is recommended only under
careful observation of a trained ophthalmologist because of these significant risks. In fact,
TOBRADEX (Alcon), the most commonly prescribed combination ophthalmic antimicrobial-
steroid drug, specifically lists `viral disease of the cornea and conjunctiva, mycobacteria
infection, and fungal infection` as absolute contraindications to its use. Clearly, these
combination drugs were not intended to be used in the face of infectious conjunctivitis in which
bacterial infection cannot be confirmed.
In U.S. Patent 7,767,217, it is shown that under certain specific conditions,
dexamethasone can be combined with povidone-iodine (PVP-I) to form an effective
antimicrobial-steroid pharmaceutical composition. However, it is also shown that most
preparations which combine PVP-I (or iodine) with a steroid suffer from instability due, in part,
to reactivity of the iodine with the steroid. In fact, U.S. Patent 3,886,268 demonstrates the well-
known instability of steroid-iodine combinations.
BRIEF SUMMARY
In a first aspect, the present invention provides an ophthalmic composition suitable for
topical administration to an eye, comprising
a) povidone-iodine in a concentration between 0.01% and 10%, and
b) a steroid,
wherein the steroid is prednisolone acetate, loteprednol etabonate or difluprednate, and
wherein after a period of one month after mixing the povidone-iodine and the steroid, the steroid
concentration is at least 95% by weight of the steroid starting concentration.
In a further aspect, the present invention provides use of an ophthalmic composition
according to the first aspect for the manufacture of a medicament for the treatment and/or
prophylaxis of a microorganism infection or a disorder of at least one tissue of the eye.
In another aspect, the present invention provides use of povidone-iodine and a steroid,
wherein the steroid is prednisolone acetate, loteprednol etabonate or difluprednate, in the
manufacture of a topical medicament for treatment and/or prophylaxis of a microorganism
infection or a disorder of at least one tissue of the eye, wherein the concentration of povidone-
iodine in the medicament is between 0.01% and 10%, and wherein after a period of one month
after mixing the povidone-iodine and the steroid, the steroid concentration in the medicament is
at least 95% by weight of the steroid starting concentration.
In an embodiment, disclosed herein is an ophthalmic composition suitable for topical
administration to an eye, effective for treatment and/or prophylaxis of a microorganism infection
or a disorder of at least one tissue of the eye, comprising povidone-iodine in a concentration
between 0.01% and 10%, and a steroid selected from the group consisting of prednisolone
acetate, loteprednol etabonate, difluprednate, hydrocortisone acetate, and combinations thereof.
In an embodiment, the povidone-iodine is between 0.1% and 2.5% by weight. In an
embodiment, the povidone-iodine is between 0.5% and 2% by weight. In an embodiment, the
total weight of the povidone-iodine and the steroid is between 0.1% and 4.5% in the solution. In
an embodiment, the steroid is at a concentration of between 0.01 and 2%. In an embodiment, the
steroid is at a concentration of between 0.05 and 1%.
In an embodiment, disclosed herein is a pharmaceutical composition comprising
povidone-iodine in a concentration between 0.01% and 10%, and a steroid selected from the
group consisting of prednisolone acetate, loteprednol etabonate, difluprednate, and combinations
thereof, wherein the steroid is at a concentration of between 0.05 and 1%. In an embodiment, the
PVP-I is at a concentration of about 0.4%. In an embodiment, the steroid is at a concentration
selected from the group consisting of about 0.1%, about 0.05% and about 0.005%.
In an embodiment, an ophthalmic composition further comprises a topical anesthetic
which relieves pain. In an embodiment, a topical anesthetic is selected from the group consisting
of proparacaine, lidocaine, tetracaine and a combination thereof.
In an embodiment, an ophthalmic composition further comprises a penetration enhancer
which enhances the penetration of povidone-iodine into the tissues of the eye. In an embodiment,
a penetration enhancer is a topical anesthetic.
In an embodiment, an ophthalmic composition further comprises an antimicrobial
preservative. In an embodiment, the antimicrobial preservative is selected from the group
consisting of benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl paraben,
phenylethyl alcohol, EDTA, sorbic acid, Onamer M and a combination thereof. In an
embodiment, the antimicrobial preservative is at a concentration of about 0.001% to 1.0% by
weight in said solution.
In an embodiment, an ophthalmic composition further comprises a co-solvent/surfactant.
In an embodiment, the co-solvent/surfactant is selected from the group consisting of polysorbate
, polysorbate 60, polysorbate 80, Pluronic F-68, Pluronic F-84, Pluronic P-103, cyclodextrin,
tyloxapol and a combination thereof. In an embodiment, the co-solvent/surfactant is at a
concentration of about 0.01% to 2% by weight in said composition.
In an embodiment, an ophthalmic composition further comprises viscosity increasing
agent. In an embodiment, the viscosity increasing agent is selected from the group consisting of
polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxy propyl methylcellulose,
hydroxyethyl cellulose, carboxymethyl cellulose, hydroxy propyl cellulose, and a combination
thereof. In an embodiment, the viscosity increasing agent is at a concentration of about 0.01% to
2% by weight in said solution.
In an embodiment, an ophthalmic composition suitable for topical administration to an
eye, effective for treatment and/or prophylaxis of a microorganism infection or a disorder of at
least one tissue of the eye, comprises povidone-iodine in a concentration between 0.01% and
%, and bromfenac. In an embodiment, an ophthalmic composition comprises:
0.3 to 1% (w/w) polyvinylpyrrolidinone-iodine complex;
0.05 to 2% (w/w) bromfenac;
0.005% to 0.02% (w/w) EDTA;
0.01 to 0.5% (w/w) sodium chloride;
0.02 to 0.1% (w/w) tyloxapol;
0.5% to 2% (w/w) sodium sulfate; and
0.1 to 0.5% (w/w) hydroxyethylcellulose.
In an embodiment, an ophthalmic composition is in the form of a solution, suspension,
emulsion, ointment, cream, gel, or a controlled-release/sustain-release vehicle.
In an embodiment, a microorganism treated or prevented by prophylaxis using a
composition encompassed herein is selected from the group consisting of bacteria, viruses, fungi,
and amoebae. In an aspect, bacteria is mycobacteria.
In an embodiment, a disorder treated using an ophthalmic composition encompassed
herein is selected from the group consisting of a microorganism infection of at least one tissue of
the eye, conjunctivitis, corneal abrasion, ulcerative infectious keratitis, epithelial keratitis,
stromal keratitis and herpesvirus-related keratitis.
In an embodiment, an ophthalmic composition is used for prophylaxis of infection
following corneal abrasion or ocular surgery.
In an embodiment, an ophthalmic composition comprises:
0.3 to 1% (w/w) polyvinylpyrrolidinone-iodine complex;
0.05 to 2% (w/w) steroid;
0.005% to 0.02% (w/w) EDTA;
0.01 to 0.5% (w/w) sodium chloride;
0.02 to 0.1% (w/w) tyloxapol;
0.5% to 2% (w/w) sodium sulfate; and
0.1 to 0.5% (w/w) hydroxyethylcellulose;
wherein the steroid is selected from the group consisting of prednisolone acetate, loteprednol
etabonate, difluprednate, hydrocortisone acetate, and combinations thereof.
In an embodiment, an ophthalmic composition comprises:
0.4% (w/w) polyvinylpyrrolidinone-iodine complex;
0.1% (w/w) steroid;
0.01% (w/w) EDTA;
0.3% (w/w) sodium chloride salt;
0.05% (w/w) tyloxapol;
0.2% (w/w) sodium sulfate; and
0.25% (w/w) hydroxyethylcellulose;
wherein the steroid is selected from the group consisting of prednisolone acetate, loteprednol
etabonate, difluprednate, hydrocortisone acetate, and combinations thereof.
In an embodiment, an ophthalmic composition retains 95% of its polyvinylpyrrolidinone-
iodine and 95% of its steroid after a period of 1 month. In an embodiment, an ophthalmic
composition retains 90% of its polyvinylpyrrolidinone-iodine and 90% of its steroid after a
period of 3 months. In an embodiment, an ophthalmic composition retains 90% of its
polyvinylpyrrolidinone-iodine and 90% of its steroid after a period of 1 month.
In an embodiment, an ophthalmic composition retains 95% of its polyvinylpyrrolidinone-
iodine and 95% of its NSAID after a period of 1 month. In an embodiment, an ophthalmic
composition retains 90% of its polyvinylpyrrolidinone-iodine and 90% of its NSAID after a
period of 3 months. In an embodiment, an ophthalmic composition retains 90% of its
polyvinylpyrrolidinone-iodine and 90% of its NSAID after a period of 1 month.
In an embodiment, an ophthalmic composition comprising polyvinylpyrrolidinone-iodine
(PVP-I) and at least one steroid retains about 89% of its PVP-I after a period of 1 month, about
90% of its PVP-I after a period of 1 month, about 91% of its PVP-I after a period of 1 month,
about 92% of its PVP-I after a period of 1 month, about 93% of its PVP-I after a period of 1
month, about 94% of its PVP-I after a period of 1 month, about 94% of its PVP-I after a period
of 1 month, about 95% of its PVP-I after a period of 1 month, about 96% of its PVP-I after a
period of 1 month, about 97% of its PVP-I after a period of 1 month, about 98% of its PVP-I
after a period of 1 month, or about 99% of its PVP-I after a period of 1 month.
In an embodiment, an ophthalmic composition comprising polyvinylpyrrolidinone-iodine
(PVP-I) and at least one NSAID retains about 89% of its PVP-I after a period of 1 month, about
90% of its PVP-I after a period of 1 month, about 91% of its PVP-I after a period of 1 month,
about 92% of its PVP-I after a period of 1 month, about 93% of its PVP-I after a period of 1
month, about 94% of its PVP-I after a period of 1 month, about 94% of its PVP-I after a period
of 1 month, about 95% of its PVP-I after a period of 1 month, about 96% of its PVP-I after a
period of 1 month, about 97% of its PVP-I after a period of 1 month, about 98% of its PVP-I
after a period of 1 month, or about 99% of its PVP-I after a period of 1 month.
In an embodiment, an ophthalmic composition comprising polyvinylpyrrolidinone-iodine
(PVP-I) and at least one steroid retains about 89% of its PVP-I after a period of 3 months, about
90% of its PVP-I after a period of 3 months, about 91% of its PVP-I after a period of 3 months,
about 92% of its PVP-I after a period of 3 months, about 93% of its PVP-I after a period of 3
months, about 94% of its PVP-I after a period of 3 months, about 94% of its PVP-I after a period
of 3 months, about 95% of its PVP-I after a period of 3 months, about 96% of its PVP-I after a
period of 3 months, about 97% of its PVP-I after a period of 3 months, about 98% of its PVP-I
after a period of 3 months, or about 99% of its PVP-I after a period of 3 months.
In an embodiment, an ophthalmic composition comprising polyvinylpyrrolidinone-iodine
(PVP-I) and at least one NSAID retains about 89% of its PVP-I after a period of 3 months, about
90% of its PVP-I after a period of 3 months, about 91% of its PVP-I after a period of 3 months,
about 92% of its PVP-I after a period of 3 months, about 93% of its PVP-I after a period of 3
months, about 94% of its PVP-I after a period of 3 months, about 94% of its PVP-I after a period
of 3 months, about 95% of its PVP-I after a period of 3 months, about 96% of its PVP-I after a
period of 3 months, about 97% of its PVP-I after a period of 3 months, about 98% of its PVP-I
after a period of 3 months, or about 99% of its PVP-I after a period of 3 months.
In an embodiment, an ophthalmic composition comprising PVP-I and at least one steroid
retains about 89% of its at least one steroid after a period of 1 month, about 90% of its at least
one steroid after a period of 1 month, about 91% of its at least one steroid after a period of 1
month, about 92% of its at least one steroid after a period of 1 month, about 93% of its at least
one steroid after a period of 1 month, about 94% of its at least one steroid after a period of 1
month, about 94% of its at least one steroid after a period of 1 month, about 95% of its at least
one steroid after a period of 1 month, about 96% of its at least one steroid after a period of 1
month, about 97% of its at least one steroid after a period of 1 month, about 98% of its at least
one steroid after a period of 1 month, or about 99% of its at least one steroid after a period of 1
month.
In an embodiment, an ophthalmic composition comprising PVP-I and at least one NSAID
retains about 89% of its at least one NSAID after a period of 1 month, about 90% of its at least
one NSAID after a period of 1 month, about 91% of its at least one NSAID after a period of 1
month, about 92% of its at least one NSAID after a period of 1 month, about 93% of its at least
one NSAID after a period of 1 month, about 94% of its at least one NSAID after a period of 1
month, about 94% of its at least one NSAID after a period of 1 month, about 95% of its at least
one NSAID after a period of 1 month, about 96% of its at least one NSAID after a period of 1
month, about 97% of its at least one NSAID after a period of 1 month, about 98% of its at least
one NSAID after a period of 1 month, or about 99% of its at least one NSAID after a period of 1
month.
In an embodiment, an ophthalmic composition comprising PVP-I and at least one steroid
retains about 89% of its at least one steroid after a period of 3 months, about 90% of its at least
one steroid after a period of 3 months, about 91% of its at least one steroid after a period of 3
months, about 92% of its at least one steroid after a period of 3 months, about 93% of its at least
one steroid after a period of 3 months, about 94% of its at least one steroid after a period of 3
months, about 94% of its at least one steroid after a period of 3 months, about 95% of its at least
one steroid after a period of 3 months, about 96% of its at least one steroid after a period of 3
months, about 97% of its at least one steroid after a period of 3 months, about 98% of its at least
one steroid after a period of 3 months, or about 99% of its at least one steroid after a period of 3
months.
In an embodiment, an ophthalmic composition comprising PVP-I and at least one NSAID
retains about 89% of its at least one NSAID after a period of 3 months, about 90% of its at least
one NSAID after a period of 3 months, about 91% of its at least one NSAID after a period of 3
months, about 92% of its at least one NSAID after a period of 3 months, about 93% of its at least
one NSAID after a period of 3 months, about 94% of its at least one NSAID after a period of 3
months, about 94% of its at least one NSAID after a period of 3 months, about 95% of its at least
one NSAID after a period of 3 months, about 96% of its at least one NSAID after a period of 3
months, about 97% of its at least one NSAID after a period of 3 months, about 98% of its at least
one NSAID after a period of 3 months, or about 99% of its at least one NSAID after a period of 3
months.
In an embodiment, an ophthalmic composition is an aqueous solution.
In an embodiment, a method is provided for treating and/or prophylaxis of an eye
disorder or a microorganism infection of at least one tissue of the eye comprising the step of
administering one of more doses of an ophthalmic composition encompassed herein to the eye.
In an embodiment, the prophylaxis is prophylaxis of infection following corneal abrasion or
ocular surgery. In an embodiment, the eye disorder is selected from the group consisting of a
microorganism infection of at least one tissue of the eye, conjunctivitis, corneal abrasion,
ulcerative infectious keratitis, epithelial keratitis, stromal keratitis and herpesvirus-related
keratitis. In an embodiment, the microorganism is a bacteria, virus, fungi, or amoebae. In an
embodiment, the bacteria is mycobacteria.
In an embodiment, in a method of treatment, the sum of the povidone-iodine and the
steroid is between 0.001 mg to 5 mg per dose. In an embodiment, in a method of treatment, each
dose is between 10 microliters to 200 microliters. In an embodiment, in a method of treatment,
each dose is between 50 microliters to 80 microliters. In an embodiment, in a method of
treatment, the administering step comprises administering a composition encompassed herein to
an eye one to four times a day. In an embodiment, in a method of treatment, the administering
step comprises administering a composition encompassed herein to an eye one to twenty-four
times a day. In an embodiment, in a method of treatment, the method includes storing the
composition for at least one month, at least three months, at least six months, or at least 1 year
before the administration step.
In the description in this specification reference may be made to subject matter which is
not within the scope of the appended claims. That subject matter should be readily identifiable
by a person skilled in the art and may assist in putting into practice the invention as defined in
the appended claims.
The term “comprising” as used in this specification and claims means “consisting at least
in part of”. When interpreting statements in this specification and claims which include the term
“comprising”, other features besides the features prefaced by this term in each statement can also
be present. Related terms such as “comprise” and “comprises” are to be interpreted in similar
manner.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is an image depicting the HPLC-UV/(+)ESI-MS and MS/MS spectral data of
dexamethasone phosphate.
Figure 2 is an image depicting the HPLC-UV/(+)ESI-MS and MS/MS spectral data of
prednisolone acetate.
Figure 3 is an image depicting the HPLC-UV/(+)ESI-MS and MS/MS spectral data of
loteprednol etabonate.
Figure 4 is an image depicting the HPLC-UV/(+)ESI-MS and MS/MS spectral data of
difluprednate.
Figure 5 is an image depicting the HPLC/UV chromatograms of PVP-I at the
concentration of 200 µg/mL for dexamethasone sodium phosphate.
Figure 6 is an image depicting the HPLC/UV chromatograms of dexamethasone sodium
phosphate in PVP-I for Day 0.
Figure 7 is an image depicting the HPLC/UV chromatograms of dexamethasone sodium
phosphate.
Figure 8 is an image depicting the HPLC/UV chromatograms of dexamethasone sodium
phosphate in PVP-I for two weeks.
Figure 9 is an image depicting the HPLC/UV chromatograms of dexamethasone sodium
phosphate in PVP-I for two weeks.
Figure 10 is an image depicting the HPLC/UV chromatograms of dexamethasone sodium
phosphate in PVP-I for one month.
Figure 11 is an image depicting the HPLC/UV chromatograms of dexamethasone sodium
phosphate in PVP-I for one month.
Figure 12 is an image depicting the HPLC/UV chromatograms (expanded) of
dexamethasone sodium phosphate in PVP-I for one month.
Figure 13 is an image depicting the HPLC/UV chromatograms (expanded) of
dexamethasone sodium phosphate in PVP-I for one month.
Figure 14 is an image depicting the mass ion chromatograms (MRM Mode) of
dexamethasone sodium phosphate in reference standard samples.
Figure 15 is an image depicting the mass ion chromatograms (MRM Mode) of
dexamethasone sodium phosphate in one month room temperature stability sample in the
presence of PVP-I.
Figure 16 is an image depicting the mass ion chromatograms (MRM Mode) of
dexamethasone sodium phosphate in one month 40°C stability sample in the presence of PVP-I.
Figure 17 is an image depicting the HPLC/UV chromatograms of PVP-I at the
concentration of 20 µg/mL for prednisolone acetate.
Figure 18 is an image depicting the HPLC/UV chromatograms of prednisolone acetate in
PVP-I for Day 0.
Figure 19 is an image depicting the HPLC/UV chromatograms of prednisolone acetate in
PVP-I for Day 0.
Figure 20 is an image depicting the HPLC/UV chromatograms of prednisolone acetate in
PVP-I for two weeks.
Figure 21 is an image depicting the HPLC/UV chromatograms of prednisolone acetate in
PVP-I for two weeks.
Figure 22 is an image depicting the HPLC/UV chromatograms of prednisolone acetate in
PVP-I for one month.
Figure 23 is an image depicting the HPLC/UV chromatograms of prednisolone acetate in
PVP-I for one month.
Figure 24 is an image depicting the mass ion chromatograms (MRM Mode) of
prednisolone acetate in reference standard samples.
Figure 25 is an image depicting the mass ion chromatograms (MRM Mode) of
prednisolone acetate in one month room temperature stability sample in the presence of PVP-I.
Figure 26 is an image depicting the mass ion chromatograms (MRM Mode) of
prednisolone acetate in one month 40°C stability sample in the presence of PVP-I.
Figure 27 is an image depicting the HPLC/UV chromatograms of PVP-I at the
concentration of 40 µg/mL for loteprednol etabonate.
Figure 28 is an image depicting the HPLC/UV chromatograms of loteprednol etabonate
in PVP-I for Day 0.
Figure 29 is an image depicting the HPLC/UV chromatograms of loteprednol etabonate
in PVP-I for Day 0.
Figure 30 is an image depicting the HPLC/UV chromatograms of loteprednol etabonate
in PVP-I for two weeks.
Figure 31 is an image depicting the HPLC/UV chromatograms of loteprednol etabonate
in PVP-I for two weeks.
Figure 32 is an image depicting the HPLC/UV chromatograms of loteprednol etabonate
in PVP-I for one month.
Figure 33 is an image depicting the HPLC/UV chromatograms of loteprednol etabonate
in PVP-I for one month.
Figure 34 is an image depicting the mass ion chromatograms (MRM Mode) of
loteprednol etabonate in reference standard samples.
Figure 35 is an image depicting the mass ion chromatograms (MRM Mode) of
loteprednol etabonate in one month room temperature stability sample in the presence of PVP-I.
Figure 36 is an image depicting the mass ion chromatograms (MRM Mode) of
loteprednol etabonate in one month 40°C stability sample in the presence of PVP-I.
Figure 37 is an image depicting the HPLC/UV chromatograms of PVP-I at the
concentration of 400 µg/mL for difluprednate.
Figure 38 is an image depicting the HPLC/UV chromatograms of difluprednate in PVP-I
for Day 0.
Figure 39 is an image depicting the HPLC/UV chromatograms of difluprednate in PVP-I
for Day 0.
Figure 40 is an image depicting the HPLC/UV chromatograms of difluprednate in PVP-I
for two weeks.
Figure 41 is an image depicting the HPLC/UV chromatograms of difluprednate in PVP-I
for two weeks.
Figure 42 is an image depicting the HPLC/UV chromatograms of difluprednate in PVP-I
for one month.
Figure 43 is an image depicting the HPLC/UV chromatograms of difluprednate in PVP-I
for one month.
Figure 44 is an image depicting the mass ion chromatograms (MRM Mode) of
difluprednate in reference standard samples.
Figure 45 is an image depicting the mass ion chromatograms (MRM Mode) of
difluprednate in one month room temperature stability sample in the presence of PVP-I.
Figure 46 is an image depicting the mass ion chromatograms (MRM Mode) of
difluprednate in one month 40°C stability sample in the presence of PVP-I.
DETAILED DESCRIPTION
It is known that iodine, including preparations of PVP-I, reacts chemically with various
steroids when combined with a steroid, resulting in an unstable composition, due in part to
reactivity of the iodine with the steroid. U.S. Patent 3,886,268 demonstrates the well-known
instability of steroid-iodine combinations. It is also known that certain non-steroidal anti-
inflammatory compounds (“NSAIDS”) also react with iodine. However, U.S. Patent 7,767,217,
incorporated herein by reference in its entirety, illustrates that under certain specific conditions,
dexamethasone, for example, can be combined with PVP-I to form an effective antimicrobial-
steroid pharmaceutical composition. U.S. Provisional Patent Application No. 61/485,475, to
which the present application claims priority, is also incorporated herein by reference in its
entirety.
Compositions
In an embodiment, compositions disclosed herein comprise PVP-I and a steroid. In an
embodiment, compositions disclosed herein comprise PVP-I and an NSAID. In another
embodiment, a composition disclosed herein is a pharmaceutical composition. In another
embodiment, a composition disclosed herein is an ophthalmic composition.
Disclosed herein are compositions comprising PVP-I in the range of about 0.01% to
about 10% (weight/weight or weight/volume) and a steroid at a concentration of about 0.001% to
about 10%. Also disclosed herein are ophthalmic compositions comprising povidone-iodine in
the range of about 0.01% to about 10% (weight/weight or weight/volume) and a therapeutically
effective amount of a steroid at a concentration of about 0.001% to about 10%. Disclosed herein
are compositions comprising PVP-I in the range of about 0.01% to about 10% (weight/weight or
weight/volume) and an NSAID at a concentration of about 0.001% to about 10%. Also disclosed
herein are ophthalmic compositions comprising povidone-iodine in the range of about 0.01% to
about 10% (weight/weight or weight/volume) and a therapeutically effective amount of an
NSAID at a concentration of about 0.001% to about 10%.
The affinity of free iodine for reaction with --OH, --SH and --NH functional groups is
well described in the literature and forms the basis for the anti-microbial activity of iodine-
containing solutions (Rackur H. J. Hosp. Infect., 1985; 6: 13-23, and references therein).
Dexamethasone, (9-Fluoro-11.beta., 17, 21-trihydroxy-16.alpha.-methylpregna-1, 4-diene-3, 20-
dione) for example, contains three such moieties (--OH) at the 11, 17 and 21 positions. The
skilled artisan would conclude that these hydroxyl groups would be prone to covalent
substitution reactions by the free iodine generated in the solution equilibrium reaction described
above for PVP-I.
In preparing the present compositions, experiments of combinations of various steroids
and PVP-I, as well as combinations of various NSAIDS and PVP-I, were performed. It was
observed that many formulations were unsuccessful because of the rapid reaction between PVP-I
and the added steroid. It was surprising to discover that separate solutions of PVP-I and
prednisolone acetate, PVP-I and loteprednol etabonate, PVP-I and hydrocortisone acetate, and
PVP-I and difluprednate demonstrate unexpected stability, based on what was previously known
in the art. It was also surprising to discover that solutions of PVP-I and bromfenac demonstrate
unexpected stability, based on what was previously known in the art. In an embodiment, a
combination of PVP-I and one of the steroids or NSAIDS identified above each remains stable
for a month or longer.
In an embodiment, a composition comprises PVP-I and prednisolone acetate. In another
embodiment, a composition is a pharmaceutical composition comprising PVP-I and prednisolone
acetate. In another embodiment, a composition is an ophthalmic preparation comprising PVP-I
and prednisolone acetate.
In an embodiment, a composition comprises PVP-I and loteprednol etabonate. In another
embodiment, a composition is a pharmaceutical composition comprising PVP-I and loteprednol
etabonate. In another embodiment, a composition is an ophthalmic preparation comprising PVP-
I and loteprednol etabonate.
In an embodiment, a composition comprises PVP-I and hydrocortisone acetate. In
another embodiment, a composition is a pharmaceutical composition comprising PVP-I and
hydrocortisone acetate. In another embodiment, a composition is an ophthalmic preparation
comprising PVP-I and hydrocortisone acetate.
In an embodiment, a composition comprises PVP-I and difluprednate. In another
embodiment, a composition is a pharmaceutical composition comprising PVP-I and
difluprednate. In another embodiment, a composition is an ophthalmic preparation comprising
PVP-I and difluprednate.
In an embodiment, a composition comprises PVP-I and bromfenac. In another
embodiment, a composition is a pharmaceutical composition comprising PVP-I and bromfenac.
In another embodiment, a composition is an ophthalmic preparation comprising PVP-I and
bromfenac.
Percentages for components of compositions are provided herein as weight/weight (w/w),
unless otherwise indicated. For example, 0.6% PVP-I indicates 0.6% PVP-I by weight, with
respect to the total weight of 100% for a composition.
In an embodiment, a composition comprises povidone-iodine (PVP-I) at a concentration
in the range of about 0.1% to about 2.5%. In another embodiment, a composition comprises
povidone-iodine (PVP-I) at a concentration in the range between 0.2 and 1.5%, and in yet
another embodiment, between 0.3% and 1.0%. In an embodiment, a composition comprises
PVP-I at a concentration in the range of about 0.2 to about 2.0%, about 0.3% to about 1.5%,
about 0.36% to about 1.0%, and about 0.4% to about 0.75%. In an embodiment, a composition
comprises PVP-I at a concentration of about 0.05%, about 0.1%, about 0.2%, about 0.3%, about
0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9% or about 1.0%. In an
embodiment, a composition comprises povidone-iodine PVP-I at a concentration of 0.05%,
0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%,
0.75%, 0.8%, 0.85%, 0.9%, 0.95%, or 1.0%. In another embodiment, a composition comprises
PVP-I at a concentration of about 2%, about 3%, about 4%, about 5%, about 6%, about 7%,
about 8%, about 9% or about 10%. In another embodiment, a composition comprises PVP-I at a
concentration of about 2% or less, about 3% or less, about 4% or less, about 5% or less, about
6% or less, about 7% or less, about 8% or less, about 9% or less or about 10% or less. In another
embodiment, a composition comprises PVP-I at a concentration of about 1% or more, about 2%
or more, about 3% or more, about 4% or more, about 5% or more, about 6% or more, about 7%
or more, about 8% or more, about 9% or more or about 10% or more. In another embodiment, a
composition comprises PVP-I at a concentration of 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10%.
Compositions disclosed herein may comprise one or more steroids. Steroids include, but
are not limited to, dexamethasone, dexamethasone alcohol, dexamethasone sodium phosphate,
fluorometholone acetate, fluorometholone acetate, fluorometholone alcohol, loteprednol
etabonate, medrysone, prednisolone acetate, prednisolone sodium phosphate, difluprednate,
rimexolone, hydrocortisone, hydrocortisone acetate, lodoxamide tromethamine, and any
combinations thereof. In an embodiment, a steroid is present in the composition at a level of
about 0.001% to about 10%. In an embodiment, a steroid is present in the composition or
preparation at a level of 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%,
0.008%, 0.009%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%,
0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%,
1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, or 2.0%. In an embodiment, a steroid is present in the
composition or preparation at a level of about 0.001%, about 0.002%, about 0.003%, about
0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009%, about
0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about
0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%,
about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about
1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2.0%. In an
embodiment, a steroid is present in the composition or preparation at a level of about 0.001% or
less, about 0.002% or less, about 0.003% or less, about 0.004% or less, about 0.005% or less,
about 0.006% or less, about 0.007% or less, about 0.008% or less, about 0.009% or less, about
0.01% or less, about 0.02% or less, about 0.03% or less, about 0.04% or less, about 0.05% or
less, about 0.06% or less, about 0.07% or less, about 0.08% or less, about 0.09% or less, about
0.1% or less, about 0.2% or less, about 0.3% or less, about 0.4% or less, about 0.5% or less,
about 0.6% or less, about 0.7% or less, about 0.8% or less, about 0.9% or less, about 1.0% or
less, about 1.1% or less, about 1.2% or less, about 1.3% or less, about 1.4% or less, about 1.5%
or less, about 1.6% or less, about 1.7% or less, about 1.8% or less, about 1.9% or less, or about
2.0% or less. In an embodiment, a steroid is present in the composition or preparation at a level
of about 0.001% or more, about 0.002% or more, about 0.003% or more, about 0.004% or more,
about 0.005% or more, about 0.006% or more, about 0.007% or more, about 0.008% or more,
about 0.009% or more, about 0.01% or more, about 0.02% or more, about 0.03% or more, about
0.04% or more, about 0.05% or more, about 0.06% or more, about 0.07% or more, about 0.08%
or more, about 0.09% or more, about 0.1% or more, about 0.2% or more, about 0.3% or more,
about 0.4% or more, about 0.5% or more, about 0.6% or more, about 0.7% or more, about 0.8%
or more, about 0.9% or more, about 1.0% or more, about 1.1% or more, about 1.2% or more,
about 1.3% or more, about 1.4% or more, about 1.5% or more, about 1.6% or more, about 1.7%
or more, about 1.8% or more, about 1.9% or more, or about 2.0% or more.
Compositions disclosed herein may comprise one or more NSAIDS. NSAIDS include,
but are not limited to, bromfenac, ketorolac, nepafenac, ketotifen fumarate, diclofenac sodium,
flurbiprofen sodium, ketorlac tromethamine, suprofen, celecoxib, naproxen, rofecoxib, and any
combinations thereof. In an embodiment, an NSAID is present in the composition at a level of
about 0.001% to about 10%. In an embodiment, an NSAID is present in the composition or
preparation at a level of 0.001%, 0.002%, 0.003%, 0.004%, 0.005%, 0.006%, 0.007%,
0.008%, 0.009%, 0.01%, 0.02%, 0.03%, 0.04%, 0.05%, 0.06%, 0.07%, 0.08%, 0.09%,
0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 1.1%, 1.2%, 1.3%,
1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, or 2.0%. In an embodiment, an NSAID is present in
the composition or preparation at a level of about 0.001%, about 0.002%, about 0.003%, about
0.004%, about 0.005%, about 0.006%, about 0.007%, about 0.008%, about 0.009%, about
0.01%, about 0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about
0.08%, about 0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%,
about 0.7%, about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about
1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2.0%. In an
embodiment, an NSAID is present in the composition or preparation at a level of about 0.001%
or less, about 0.002% or less, about 0.003% or less, about 0.004% or less, about 0.005% or less,
about 0.006% or less, about 0.007% or less, about 0.008% or less, about 0.009% or less, about
0.01% or less, about 0.02% or less, about 0.03% or less, about 0.04% or less, about 0.05% or
less, about 0.06% or less, about 0.07% or less, about 0.08% or less, about 0.09% or less, about
0.1% or less, about 0.2% or less, about 0.3% or less, about 0.4% or less, about 0.5% or less,
about 0.6% or less, about 0.7% or less, about 0.8% or less, about 0.9% or less, about 1.0% or
less, about 1.1% or less, about 1.2% or less, about 1.3% or less, about 1.4% or less, about 1.5%
or less, about 1.6% or less, about 1.7% or less, about 1.8% or less, about 1.9% or less, or about
2.0% or less. In an embodiment, an NSAID is present in the composition or preparation at a
level of about 0.001% or more, about 0.002% or more, about 0.003% or more, about 0.004% or
more, about 0.005% or more, about 0.006% or more, about 0.007% or more, about 0.008% or
more, about 0.009% or more, about 0.01% or more, about 0.02% or more, about 0.03% or more,
about 0.04% or more, about 0.05% or more, about 0.06% or more, about 0.07% or more, about
0.08% or more, about 0.09% or more, about 0.1% or more, about 0.2% or more, about 0.3% or
more, about 0.4% or more, about 0.5% or more, about 0.6% or more, about 0.7% or more, about
0.8% or more, about 0.9% or more, about 1.0% or more, about 1.1% or more, about 1.2% or
more, about 1.3% or more, about 1.4% or more, about 1.5% or more, about 1.6% or more, about
1.7% or more, about 1.8% or more, about 1.9% or more, or about 2.0% or more.
The compositions disclosed herein can be administered as solutions, suspensions,
emulsions (dispersions), gels, creams, or ointments in a suitable ophthalmic vehicle. In any of the
compositions of this disclosure for topical administration, such as topical administration to the
eye, the mixtures are preferably formulated as aqueous solutions at a pH of 3.5 to 6.5.
Preferentially the pH is adjusted to between 4 and 5. This pH range may be achieved by the
addition of acids/bases to the solution.
In an embodiment, an ophthalmic composition may comprise an optional co-solvent. In
another embodiment, the solubility of the components of the present compositions may be
enhanced by a surfactant or other appropriate co-solvent in the composition. Such co-solvents or
surfactants include polysorbate -20, -60, and -80, a polyoxyethylene/polyoxypropylene surfactant
(e.g. Pluronic F-68, F-84 and P-103), cyclodextrin, tyloxapol, PEG 35 Castor oil (Cremophor
EL), polyoxyl 40 Stearate (Myrj 52), other agents known to those skilled in the art, or a
combination thereof. Typically, such co-solvents are present at a level of from about 0.01% to
about 2% by weight. In an embodiment, a co-solvent is present at a level of about 0.01%, about
0.02%, about 0.03%, about 0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about
0.09%, about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%,
about 0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about
1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2.0%.
In an embodiment, a composition may comprise an optional agent that can increase
viscosity. As will be understood by the skilled artisan when armed with the present disclosure, it
may be desirable to increase viscosity above that of a simple aqueous solution in order to
increase ocular absorption of the active compound, to decrease variability in dispensing the
formulation, to decrease physical separation of components of a suspension or emulsion of the
formulation and/or to otherwise improve the ophthalmic formulation. Such viscosity-enhancing
agents include, but are not limited to, polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose,
hydroxypropylmethyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, hydroxypropyl
cellulose, other agents known to those skilled in the art, or any combination thereof. Such agents
are typically employed at a level of from about 0.01% to about 2% by weight. In an
embodiment, such optional agents are present at about 0.01%, about 0.02%, about 0.03%, about
0.04%, about 0.05%, about 0.06%, about 0.07%, about 0.08%, about 0.09%, about 0.1%, about
0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%,
about 1.0%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about
1.7%, about 1.8%, about 1.9%, or about 2.0%.
In another aspect, bioadhesive agents may comprise the compositions, in order to
increase the retention time of the drug gradient over a biological substrate. The bioadhesive
agents include, but are not limited to, polyvinylpyrrolidone (PVP), xanthan gum, locust bean
gum, acacia gum, hydroxypropyl methylcellulose (HPMC), sodium alginate, pectin, gelatin,
carbomer, polyvinylalcohol, gellan gum, tragacanth, acacia, and sodium carboxymethyl
cellulose, as well as other agents known to those skilled in the art, or any combination thereof.
In yet another embodiment, compositions of the invention may comprise viscoelastic agents such
as methyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose, polyvinyl alcohol, dextran,
chondroitin sulfate and salts thereof, and hyaluronic acid and salts thereof.
In an embodiment, an ophthalmic composition may further comprise one or more of (1) a
penetration enhancer which enhances the penetration of povidone-iodine into the tissues of the
eye (this may be a topical anesthetic) (2) a co-solvent or a nonionic surface agent - surfactant,
which, for example, may be about 0.01% to 2% by weight; (3) a viscosity increasing agent,
which, for example, may be about 0.01% to 2% by weight; and (4) a suitable ophthalmic vehicle.
The ophthalmic composition may be in the form of a solution, a suspension, an emulsion,
a preparation, an ointment, a cream, a gel, or a controlled-release/sustain-release vehicle. By way
of a non-limiting example, the composition may be in the form of a contact lens solution,
eyewash, eyedrop, and the like.
Methods
In an embodiment, compositions disclosed herein are useful for preparation of and use as
pharmaceutical compositions. In another embodiment, compositions disclosed herein are useful
for preparation of and use as compositions other than pharmaceutical compositions.
In an embodiment, compositions disclosed herein are useful for preparation of and use as
ophthalmic compositions. In an aspect, a composition of the invention is useful in the treatment
of infections of the conjunctiva and cornea. In another aspect, the broad spectrum antimicrobial
activity of povidone-iodine enables a composition of the invention to be used to treat ocular
conjunctival or corneal infection caused by mycobacteria, viruses, fungi, and amoeba.
Additionally the composition is useful in the infectious prophylaxis of patients recovering from
ophthalmic surgery.
In an embodiment, an ophthalmic composition is provided that is suitable for topical
administration to an eye, effective for treatment and/or prophylaxis of a microorganism infection
or a disorder of at least one tissue of the eye. Prophylaxis may be, for example, prophylaxis from
infection following surgery, prophylaxis from infection after birth for the newborn, or
prophylaxis from accidental contact with contaminating material. Accidental contact with
contaminating material may occur, for example, during surgery or during food processing.
In an aspect, the ophthalmic composition may be used for treatment and/or prophylaxis of
a microorganism infection. The microorganism may be a bacterium, a virus, a fungus, or an
amoeba, a parasite, or a combination thereof. In an embodiment, the bacteria may be a
mycobacterium.
In an aspect, an ophthalmic composition may be used to treat a disorder such as, but not
limited to, conjunctivitis, corneal abrasion, ulcerative infectious keratitis, epithelial keratitis,
stromal keratitis, herpesvirus-related keratitis, ocular surface irregularity, tear deficiency, dry
syndrome, meibomian gland dysfunction, blepharitis and uveitis. In another aspect, an
ophthalmic composition may be used for prophylaxis of disorders such as conjunctivitis, corneal
abrasion, ulcerative infectious keratitis, epithelial keratitis, stromal keratitis, herpesvirus-related
keratitis, ocular surface irregularity, tear deficiency, dry syndrome, meibomian gland
dysfunction, blepharitis and uveitis.
Disclosed herein is a method for treating and/or prophylaxis of an eye disorder or a
microorganism infection of at least one tissue of the eye comprising the step of administering
one of more doses of an ophthalmic composition, discussed above, to the eye. The eye disorder
may be, for example, a microorganism infection of at least one tissue of the eye, conjunctivitis,
corneal abrasion, ulcerative infectious keratitis, epithelial keratitis, stromal keratitis, herpes
virus-related keratitis, ocular surface irregularity, tear deficiency, dry syndrome, meibomian
gland dysfunction, and blepharitis. The microorganism may be bacteria (e.g., mycobacteria),
virus, fungi, or amoebae.
In an embodiment, the dose volume administered to a subject may be between about 10
microliters and about 200 microliters, in another embodiment, between about 20 microliters and
100 microliters, and in another embodiment, between about 50 microliters and about 80
microliters, or about one drop per eye. Two or more drops may be added to an eye. Treatment
of an eye may be effected by adding a single drop of composition disclosed herein, or by adding
two or more drops, as required to achieve the desired result.
In an embodiment, administration frequency may be between 1 and 24 times a day. In an
embodiment, administration frequency may be between 1 and 48 times a day. In another
embodiment, administration frequency may be between 2 and 24 times a day. In another
embodiment, administration frequency may be between 2 and 4 times a day. In another
embodiment, administration frequency may be twice a day. In another embodiment,
administration frequency may be once a day. In another embodiment, administration frequency
may be less frequent than once a day. In another embodiment, administration frequency may be
on demand, as therapeutic treatment is required or desired. In another embodiment,
administration frequency may be 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,
21, 22, 23, 24, 48, or 96 times a day.
In an embodiment, a composition disclosed herein is used for prophylaxis and/or
treatment of a non-ophthalmic tissue by contacting the tissue with the composition.
The invention is further described by the following examples. It should be recognized
that variations based on the inventive features are within the skill of the ordinary artisan, and that
the scope of the invention should not be limited by the examples. To properly determine the
scope of the present disclosure, an interested party should consider the claims herein, and any
equivalent thereof. All patents, patent applications, and references cited herein are hereby
incorporated by reference in their entirety.
In this specification where reference has been made to patent specifications, other
external documents, or other sources of information, this is generally for the purpose of
providing a context for discussing the features of the invention. Unless specifically stated
otherwise, reference to such external documents is not to be construed as an admission that such
documents, or such sources of information, in any jurisdiction, are prior art, or form part of the
common general knowledge in the art.
EXAMPLES
The invention is now described with reference to the following Examples. These
Examples are provided for the purpose of illustration only and the invention should in no way be
construed as being limited to these Examples, but rather should be construed to encompass any
and all variations which become evident as a result of the teaching provided herein.
Example 1: Stability Testing For Steroids Combined With Povidone Iodine
The objective of this study was to determine whether povidone iodine (PVP-I) at the
concentration of 4 mg/mL (0.4%) reacts with any of four different steroids (dexamethasone
sodium phosphate, prednisolone acetate, loteprednol etabonate, and difluprednate), the active
ingredients, in pharmaceutical formulations under both room temperature and 40 ºC for a time
period of one month.
Dexamethasone sodium phosphate ophthalmic solution (USP, 0.1%) from Alcon
Laboratories, prednisolone acetate ophthalmic suspension (USP, 1%) from Alcon Laboratories,
loteprednol etabonate ophthalmic suspension (0.5%) from Bausch & Lomb, and difluprednate
ophthalmic emulsion (0.05%) from Sirion Therapeutics were used for this study. PVP-I was
prepared in water at the concentration of 100 mg/mL (10%). One milliliter of the solution,
suspension, or emulsion was mixed with 40 µL of 10% PVP-I in 1.5 mL amber glass vials,
followed by storage under both room temperature and 40 ºC for 2 weeks and one month. The
resultant samples in the presence of PVP-I were analyzed using HPLC. The four steroid levels
were measured against the reference standard samples stored under room temperature in the
absence of PVP-I (0.4%). The One Month stability test samples were analyzed with the
reference standard sample using LC-MS/MS Method in MRM mode with three characteristic ion
transitions to confirm the identity of four steroids in stability testing samples. The presence of
each of the four steroids in the respective pharmaceutical formulations tested was confirmed by
LC/UV-MS and MS/MS. Thus, the four pharmaceutical formulations can be used in the study.
After storage under room temperature and 40 C at the presence of PVP-I (0.4%), the
levels of dexamethasone phosphate in two week samples were only 83.04% and 84.57% of those
in room temperature and 40 C Day 0 samples, respectively. The respective data are 84.24% and
84.09% for one month testing, indicating that dexamethasone phosphate was not stable in the
presence of PVP-I (0.4%) under the current testing conditions. Three degradation products (D1,
D2, and D3) were observed.
After storage under room temperature and 40 C in the presence of PVP-I (0.4%), the
levels of prednisolone acetate in two week testing samples were 99.24% and 96.60% of those in
room temperature and 40 C Day 0 samples, respectively. The respective data are 95.66% and
96.79% for one month testing. Identical mass ion chromatograms and same intensities of mass
ion response were observed in the reference standard and one month stability testing samples.
The results from both HPLC/UV and LC-MS/MS analysis indicate that prednisolone acetate was
stable in the presence of PVP-I (0.4%) under the current testing conditions.
After storage under room temperature and 40 C in the presence of PVP-I (0.4%), the
levels of loteprednol etabonate in two week testing samples were 101.43% and 100.07% of those
in room temperature and 40 C Day 0 samples, respectively. The respective data are 100.72%
and 96.02% for one month testing. Identical mass ion chromatograms and same intensities of
mass ion response were observed in the reference standard and one month stability testing
samples. The results from both HPLC/UV and LC-MS/MS analysis indicate that loteprednol
etabonate was stable in the presence of PVP-I (0.4%) under the current testing conditions.
After storage under room temperature and 40 C in the presence of PVP-I (0.4%), the
levels of difluprednate in two week testing samples were 103.23% and 99.30% of those in room
temperature and 40 C Day 0 samples, respectively. The respective data are 104.47% and
100.24% for one month testing. Identical mass ion chromatograms and same intensities of mass
ion response were observed in the reference standard and one month stability testing samples.
The results from both HPLC/UV and LC-MS/MS analysis indicate that difluprednate was stable
in the presence of PVP-I (0.4%) under the current testing conditions.
1. MATERIALS
1.1 Test Pharmaceutical Formulations
The four steroids and their related pharmaceutical formulations are listed in Table I and
Table II.
1.2 Povidone Iodine
Povidone iodine (USP) was obtained from Spectrum Chemicals. Lot No. and expiration
date are YQ0429 and January 31, 2011, respectively.
1.3 Solvents, Reagents, and Supplies
OmniSolv Water was obtained from EM Science. Acetonitrile, methanol, and
ammonium acetate were purchased from Sigma-Aldrich.
1.4 Suppliers and Equipment
1.4.1 Supplies
• Serological Pipettes, Kimble Glass Inc
• Wiretrol Micropipettes, Drummond Scientific Company
• Autosampler Vials, Sun International
• Automatic Pipettes, Gilson
1.4.2 Equipment
• Sartorius Balances, BP301S, Sartorius Corporation
2. METHODS
2.1 Preparation of Stability Test Samples
2.1.1 Preparation of PVP-I Solution (10%, 100mg/mL)
Weigh 1 g of PVP-I and dissolve in 10 mL of water.
2.1.2 Preparation of Stability Test Samples
2.1.2.1 Preparation of Dexamethasone Sodium Phosphate Stability Test Samples
Aliquot 1 mL of ophthalmic solution (USP, 0.1%) into eight amber HPLC vials to give
the following samples:
Dexamethasone Sodium Phosphate-1, 2, 3, 4, 5, 6, 7, 8, and 9.
Added 40 µL of PVP-I stock solution (10%) into Dexamethasone Sodium Phosphate-3,
4, 5, and 6, and mixed well to give the following samples:
Dexamethasone Sodium Phosphate+ PVP-I-3, 4, 5, and 6
Store Dexamethasone Sodium Phosphate+PVP-I-3 and 4 on the lab bench at room
temperature and store Dexamethasone Sodium Phosphate+PVP-I -5 and 6 in a stability test
chamber at 40 ºC.
Added 40 µL of water into Dexamethasone Sodium Phosphate-7, 8, and 9, and mixed
well to give the following samples:
Dexamethasone Sodium Phosphate+H O-7, 8, and 9
Stored Dexamethasone Sodium Phosphate+H O-9 on the lab bench at room temperature
and store Dexamethasone Sodium Phosphate+H O-7 and 8 in a stability test chamber at 40 ºC.
Used Dexamethasone Sodium Phosphate+ PVP-I-3 and -5 and Dexamethasone Sodium
Phosphate+H O-7 for two week stability test. Used Dexamethasone Sodium Phosphate+ PVP-I-
4 and -6 and Dexamethasone Sodium Phosphate+H O-8 for one month stability test. Used
Dexamethasone Sodium Phosphate+H O-9 to prepare reference standard.
Stored Dexamethasone Sodium Phosphate-1 and 2 on the lab bench at room temperature.
On Week 4, added 40 µL of PVP-I (10%, freshly prepared) and mix well to give Dexamethasone
Sodium Phosphate+PVP-I-1 and 2. Used the resultant samples as time zero samples for HPLC
analysis.
2.1.2.2 Preparation of Prednisolone Acetate Stability Test Samples
Aliquot ted1 mL of ophthalmic suspension (USP, 1%) into eight amber HPLC vials to
give the following samples:
Prednisolone Acetate-1, 2, 3, 4, 5, 6, 7, 8, and 9
Added 40 µL of PVP-I stock solution (10%) into Prednisolone Acetate -3, 4, 5, and 6,
and mixed well to give the following samples:
Prednisolone Acetate + PVP-I-3, 4, 5, and 6
Stored Prednisolone Acetate +PVP-I-3 and 4 on the lab bench at room temperature and
stored Prednisolone Acetate +PVP-I -5 and 6 in a stability test chamber at 40 ºC.
Added 40 µL of water into Prednisolone Acetate -7, 8, and 9, and mixed well to give the
following samples:
Prednisolone Acetate +H O-7, 8, and 9
Stored Prednisolone Acetate +H O-9 on the lab bench at room temperature and stored
Prednisolone Acetate +H O-7 and 8 in a stability test chamber at 40 ºC.
Used Prednisolone Acetate + PVP-I-3 and -5 and Prednisolone Acetate +H O-7 for two
week stability test. Used Prednisolone Acetate + PVP-I-4 and -6 and Prednisolone Acetate
+H O-8 for one month stability test. Used Prednisolone Acetate +H O-9 to prepare reference
standard.
Stored Prednisolone Acetate -1 and 2 on the lab bench at room temperature. On Week 4,
added 40 µL of PVP-I (10%, freshly prepared) and mixed well to give Prednisolone Acetate
+PVP-I-1 and 2. Used the resultant samples as time zero samples for HPLC analysis.
2.1.2.3 Preparation of Difluprednate Stability Test Samples
Aliquotted 1 mL of Ophthalmic emulsion (0.05%) into eight amber HPLC vials to give
the following samples:
Difluprednate-1, 2, 3, 4, 5, 6, 7, 8, and 9
Added 40 µL of PVP-I stock solution (10%) into Difluprednate-3, 4, 5, and 6, and mixed
well to give the following samples:
Difluprednate+ PVP-I-3, 4, 5, and 6
Stored Difluprednate+PVP-I-3 and 4 on the lab bench at room temperature and stored
Difluprednate+PVP-I -5 and 6 in a stability test chamber at 40 ºC.
Added 40 µL of water into Difluprednate-7, 8, and 9, and mixed well to give the
following samples:
Difluprednate+H O-7, 8, and 9
Stored Difluprednate+H O-9 on the lab bench at room temperature and stored
Difluprednate+H O-7 and 8 in a stability test chamber at 40 ºC.
Used Difluprednate+ PVP-I-3 and -5 and Difluprednate+H2O-7 for two week stability
test. Used Difluprednate+ PVP-I-4 and -6 and Difluprednate+H O-8 for one month stability test.
Used Difluprednate+H O-9 to prepare reference standard.
Stored Difluprednate-1 and 2 on the lab bench at room temperature. On Week 4, added
40 µL of PVP-I (10%, freshly prepared) and mix well to give Difluprednate+PVP-I-1 and 2.
Used the resultant samples as time zero samples for HPLC analysis.
2.1.2.4 Preparation of Loteprednol Etabonate Stability Test Samples
Aliquotted 1 mL of ophthalmic solution (USP, 0.1%) into eight amber HPLC vials to
give the following samples:
Loteprednol Etabonate-1, 2, 3, 4, 5, 6, 7, 8, and 9
Added 40 µL of PVP-I stock solution (10%) into Loteprednol Etabonate-3, 4, 5, and 6,
and mix well to give the following samples:
Loteprednol Etabonate+ PVP-I-3, 4, 5, and 6
Stored Loteprednol Etabonate+PVP-I-3 and 4 on the lab bench at room temperature and
stored Loteprednol Etabonate+PVP-I -5 and 6 in a stability test chamber at 40 ºC.
Added 40 µL of water into Loteprednol Etabonate-7, 8, and 9, and mixed well to give the
following samples:
Loteprednol Etabonate+H O-7, 8, and 9
Stored Loteprednol Etabonate+H O-9 on the lab bench at room temperature and stored
Loteprednol Etabonate+H O-7 and 8 in a stability test chamber at 40 ºC.
Used Loteprednol Etabonate+ PVP-I-3 and -5 and Loteprednol Etabonate+H O-7 for two
week stability test. Used Loteprednol Etabonate+ PVP-I-4 and -6 and Loteprednol
Etabonate+H2O-8 for one month stability test. Used Loteprednol Etabonate+H2O-9 to prepare
reference standard.
Stored Loteprednol Etabonate-1 and 2 on the lab bench at room temperature. On Week
4, added 40 µL of PVP-I (10%, freshly prepared) and mix well to give Loteprednol
Etabonate+PVP-I-1 and 2. Used the resultant samples as time zero samples for HPLC analysis.
2.2 Preparation of Stability Test Samples for HPLC/UV Analysis
2.2.1 Preparation of PVP-I Solution for HPLC/UV Analysis
2.2.1.1 Preparation of PVP-I-4 mg/mL
Mixed 40 µL of PVP-I (10%) with 1 mL of water to give PVP-I-4 mg/mL.
2.2.1.2 Preparation of PVP-I Solution for Dexamethasone Sodium Phosphate Testing
Mixed 100 µL of PVP-I-4 mg/mL with 1.9 mL of water to give PVP-I-200 µg/L for
HPLC analysis.
2.2.1.3 Preparation of PVP-I Solution for Prednisolone Acetate Testing
Mixed 100 µL of PVP-I-4 mg/mL with 9.9 mL of acetonitrile:water (1:1) to give PVP-I-
40 µg/L.
Mixed 750 µL of PVP-I-40 µg/L with 750 µL of acetonitrile:water (1:1) to give PVP-I-20
µg/L for HPLC analysis.
2.2.1.4 Preparation of PVP-I Solution for Difluprednate Testing
Mixed 100 µL of PVP-I-4 mg/mL with 0.9 mL of methanol to give PVP-I-400 µg/L for
HPLC analysis.
2.2.1.5 Preparation of PVP-I Solution for Loteprednol Etabonate Testing
Mixed 100 µL of PVP-I-4 mg/mL with 9.9 mL of acetonitrile:water (1:1) to give PVP-I-
40 µg/L for HPLC analysis.
2.2.2 Preparation of Dexamethasone Sodium Phosphate for HPLC/UV Analysis
2.2.2.1 Preparation of Dexamethasone Sodium Phosphate Standard
Mixed 100 µL of Dexamethasone Sodium Phosphate +H O-9 with 1.9 mL of H O in an
HPLC vial to give Dexamethasone Sodium Phosphate+ H O50 µg/mL.
2.2.2.2 Preparation of Dexamethasone Sodium Phosphate Stability Test Samples
Mixed 100 µL of Dexamethasone Sodium Phosphate+PVP-1, 2, 3, 4, 5, or 6 with 1.9 mL
of H O in an HPLC vial to give Dexamethasone Sodium Phosphate+PVP-1, 2, 3, 4, 5, or 6-
50µg/mL for HPLC analysis.
2.2.2.3 Preparation of Control Dexamethasone Sodium Phosphate Stability Test Samples
Mixed 100 µL of Dexamethasone Sodium Phosphate+H O-7, or 8 with 1.9 mL of H O in
an HPLC vial to give Dexamethasone Sodium Phosphate+H O-7, or 8-50 µg/mL for HPLC
analysis.
2.2.3 Preparation of Prednisolone Acetate for HPLC/UV Analysis
2.2.3.1 Preparation of Prednisolone Acetate Standard
Mixed 100 µL of Prednisolone Acetate+H2O-9 with 9.9 mL of acetonitrile:water (1:1) to
give Prednisolone Acetate+H O100 µg/mL.
Mixed 750 µL of Prednisolone Acetate+H O100 µg/mL with 750 µL of
acetonitrile:H2O (1:1) in HPLC vial to give Prednisolone Acetate+H O50 µg/mL for HPLC
analysis.
2.2.3.2 Preparation of Prednisolone Acetate Stability Test Samples
Mixed 100 µL of Prednisolone Acetate+PVP-I-1, 2, 3, 4, 5, or 6 with 9.9 mL of
acetonitrile:water (1:1) to give Prednisolone Acetate+PVP-I-1, 2, 3, 4, 5, or 6-100 µg/mL.
Mixed 750 µL of give Prednisolone Acetate+PVP-I-1, 2, 3, 4, 5, or 6-100 µg/mL with
750 µL of acetonitrile:H2O (1:1) in HPLC vial to give Prednisolone Acetate+PVP-I-1, 2, 3, 4, 5,
or 6-50 µg/mL for HPLC analysis.
2.2.3.3 Preparation of Control Prednisolone Acetate Stability Test Samples
Mixed 100 µL of Prednisolone Acetate+H O-7, or 8 with 9.9 mL of acetonitrile:water
(1:1) to give Prednisolone Acetate+H O-7, or 8-100 µg/mL.
Mixed 750 µL of give Prednisolone Acetate+H O-7, or 8-100 µg/mL with 750 µL of
acetonitrile:H2O (1:1) in HPLC vial to give Prednisolone Acetate+H O-7, or 8-50 µg/mL for
HPLC analysis.
2.2.4 Preparation of Loteprednol Etabonate for HPLC/UV Analysis
2.2.4.1 Preparation of Loteprednol Etabonate Standard
Mixed 100 µL of Loteprednol Etabonate+H O-9 with 9.9 mL of acetonitrile:water (1:1)
to give Loteprednol Etabonate+H O50 µg/mL.
2.2.4.2 Preparation of Loteprednol Etabonate Stability Test Samples
Mixed 100 µL of Loteprednol Etabonate+PVP-I-1, 2, 3, 4, 5, or 6 with 9.9 mL of
acetonitrile:water (1:1) to give Loteprednol Etabonate+PVP-I-1, 2, 3, 4, 5, or 6-50 µg/mL.
2.2.4.3 Preparation of Control Loteprednol Etabonate Stability Test Samples
Mixed 100 µL of Loteprednol Etabonate+H O-7, or 8 with 9.9 mL of acetonitrile:water
(1:1) to give Loteprednol Etabonate+H O-7, or 8-50 µg/mL.
2.2.5 Preparation of Difluprednate for HPLC/UV Analysis
2.2.5.1 Preparation of Difluprednate Standard
Mixed 100 µL of Difluprednate +H O-9 with 0.9 mL of methanol in an HPLC vial to
give Difluprednate+ H O50 µg/mL.
2.2.5.2 Preparation of Difluprednate Stability Test Samples
Mixed 100 µL of Difluprednate+PVP-1, 2, 3, 4, 5, or 6 with 0.9 mL of methanol in an
HPLC vial to give Difluprednate+PVP-1, 2, 3, 4, 5, or 6-50µg/mL for HPLC analysis.
2.2.5.3 Preparation of Control Difluprednate Stability Test Samples
Mixed 100 µL of Difluprednate+H O-7, or 8 with 0.9 mL of methanol in an HPLC vial to
give Difluprednate+H O-7, or 8-50 µg/mL for HPLC analysis.
2.3 Preparation of Stability Test Samples for LC-MS/MS Analysis
2.3.1 Preparation of Dexamethasone Sodium Phosphate for LC-MS/MS Analysis
2.3.1.1 Preparation of Dexamethasone Sodium Phosphate Standard
Mixed 100 µL of Dexamethasone Sodium Phosphate+ H O50 µg/mL with 0.9 mL of
water in an HPLC vial.
2.3.1.2 Preparation of Dexamethasone Sodium Phosphate Stability Test Samples
Mixed 100 µL of Dexamethasone Sodium Phosphate+PVP-4, or 6-50µg/mL with 0.9 mL
of water in an HPLC vial.
2.3.2 Preparation of Prednisolone Acetate for HPLC Analysis
2.3.2.1 Preparation of Prednisolone Acetate Standard
Mixed 100 µL of Prednisolone Acetate+H O50 µg/mL with 0.9 mL of
acetonitrile:water (1:1) in an HPLC vial.
2.3.2.2 Preparation of Prednisolone Acetate Stability Test Samples
Mixed 100 µL of Prednisolone Acetate+PVP-I-4, or 6-50 µg/ with 0.9 mL of
acetonitrile:water (1:1) in an HPLC vial.
2.3.3 Preparation of Loteprednol Etabonate for HPLC Analysis
2.3.3.1 Preparation of Loteprednol Etabonate Standard
Mixed 100 µL of Loteprednol Etabonate+H O50 µg/mL with 0.9 mL of
acetonitrile:water (1:1) in an HPLC vial.
2.3.3.2 Preparation of Loteprednol Etabonate Stability Test Samples
Mixed 100 µL of Loteprednol Etabonate+PVP-I-4, or 6-50 µg/mL with 0.9 mL of
acetonitrile:water (1:1) in an HPLC vial.
2.3.4 Preparation of Difluprednate for HPLC Analysis
2.3.4.1 Preparation of Difluprednate Standard
Mixed 100 µL of Difluprednate+ H O50 µg/mL with 0.9 mL of methanol in an HPLC
vial.
2.3.4.2 Preparation of Difluprednate Stability Test Samples
Mixed 100 µL of Difluprednate+PVP-4, or 6-50µg/mL for HPLC analysis with 0.9 mL
of methanol in an HPLC vial.
2.4 HPLC/UV Chromatography
2.4.1 HPLC Method 1 (for Dexamethasone Sodium Phosphate)
HPLC System: SHIMADZU HPLC system (Pump: LC-10ADVP;
Autosampler: SIL-HTC)
UV: SPD-10AVvp @239 and 210nm
Column: Waters XTerra MS C18 3.5µm, 2.1x150mm, S/N
019435216117
Column Temperature: Room Temperature
Autosampler Temperature: Room Temperature
Injection Vol.: 10 µL
Mobile Phase A: 0.01M NH4OAc in H2O
Mobile Phase B: ACN
Gradient:
Time (min) Flow (mL/min) A B
Initial 0.2 100 0
40 0.2 40 60
45 0.2 2 98
50 0.2 2 98
51 0.2 100 100
70 0.2 Stop
2.4.2 HPLC Method 2 (for Prednisolone Acetate)
The same as Method 1 except the gradient was changed as follows:
Time (min) Flow (mL/min) A B
Initial 0.2 100 0
40 0.2 30 70
45 0.2 2 98
50 0.2 2 98
51 0.2 100 100
70 0.2 Stop
2.4.3 HPLC Method 3 (for Loteprednol Etabonate and Difluprednate)
The same as Method 1 except the gradient was changed as follows:
Time (min) Flow (mL/min) A B
Initial 0.2 100 0
40 0.2 20 80
45 0.2 2 98
50 0.2 2 98
51 0.2 100 100
70 0.2 Stop
2.4.4 Date Integration and Calculation
The software provided with the HPLC system (LCSolution software, version 1.23,
installed by SHIMADZU) was used to integrate the peak area.
The measured peak area was converted into concentrations (µg/mL) using the following
equation:
C =A Cs A
x x x
where,
C = Concentration (µg/mL) of analyte in stability samples
A = Peak area from analyte in stability samples
Cs = Concentration (µg/mL) of analyte in standard samples
A = Peak area from analyte in standard samples
2.5 Liquid Chromatography/Tandem Mass Spectrometry (LC-MS/MS)
HPLC Methods: The same as HPLC Method 1,2, and 3 under Section 2.4.
MS Conditions:
Mass Spectrometer: API 3000 LC/MS/MS System
Ionization Mode: ESI in Positive mode
ESI: 5,000 V
Temperature: 350 C
Nebulizer Gas Flow (NEB): 12 psi
Curtain Gas Flow (CUR): 12 units
Turbo-Ion Spray Gas Flow: 7,000-8,000 mL/min
Collision Gas (CAD): 6 units
DP: 30
FP: 80
EP: 8
CXP: 10
Precursor Ion, Product Ion, Collision Energy, and HPLC Retention Time
Compound Precursor ion Product ion Collision Retention
(m/z) (m/z) Energy (eV) Time (min)
473.3 355.2 20 ~21.82
Dexamethasone
473.3 337.2 20 ~21.82
Phosphate
473.3 237.2 35 ~21.82
403.1 325.2 20 ~27.62
307.2 20 ~27.62
Prednisolone Acetate 403.1
403.1 147.1 30 ~27.62
467.3 359.2 20 ~33.15
Loteprednol
467.3 265.2 30 ~33.15
Etabonate
467.3 147.1 35 ~33.15
509.3 303.2 20 ~31.85
Difluprednate 509.3 279.2 20 ~31.85
509.3 101.1 30 ~31.85
3. RESULTS
3.1 LC/MS and MS/MS Analyses of Four Formulations
The four formulations used in this study were analyzed by HPLC –UV and MS and
MS/MS. The HPLC-UV chromatograms and ESI-MS and MS/MS spectral data were presented
in Figure 1 to Figure 4.
The presence of four steroids in the pharmaceutical formulations was confirmed by
LC/UV-MS and MS/MS. Thus, the four pharmaceutical formulations can be used for this study.
3.2 HPLC System Suitability Testing
The four standard samples at the concentration of 50 µg/mL were analyzed using
HPLC/UV methods developed at PharmaOn. The data are summarized in Table III.
As shown in Table III, the system used in this study was suitable to determine the levels
of four steroids in the stability test samples.
3.3 HPLC/UV and LC-MS/MS Analysis of Stability Testing Samples
3.3.1 Dexamethasone Sodium Phosphate
3.3.1.1 PVP-I Sample
PVP-I in solvent at the same concentration as in stability test samples of dexamethasone
sodium phosphate was analyzed using HPLC Method 1. The HPLC/UV chromatograms are
depicted in Figure 5.
No dexamethasone phosphate was observed in PVP-I sample.
3.3.1.2 Dexamethasone Sodium Phosphate Stability Samples
The Day 0, Two Week, and One Month stability test samples were analyzed with
reference standard samples (stored at room temperature in the absence of PVP I) using HPLC
Method 1. The sample in the absence of PVP-I with the same concentration of dexamethasone
phosphate as those stability samples at the presence of PVP-I was stored in the same stability
chamber at 40°C for one month as control sample. The control sample was analyzed under the
same conditions. The concentrations of dexamethasone phosphate in the stability samples were
calculated. The data were summarized in Table IV. The HPLC/UV chromatograms of all
reference standards and stability testing samples are depicted in Figure 6 to Figure 13.
The One Month stability test samples were analyzed with the reference standard sample
using LC-MS/MS Method in MRM mode with three characteristic ion transitions to confirm the
identity of dexamethasone phosphate in stability testing samples. The mass ion chromatograms
are presented in Figure 14 to Figure 16.
Identity of dexamethasone phosphate in reference standard sample and two One month
stability test samples was confirmed by LC-MS/MS.
After storage at room temperature and 40°C in the presence of PVP-I (0.4%), the levels
of dexamethasone phosphate in two weeks samples were only 83.04% and 84.57% of those in
room temperature and 40°C Day 0 samples, respectively (Table IV). The respective data are
84.24% and 84.09% for one month testing (Table IV), indicating that dexamethasone phosphate
was not stable in the presence of PVP-I (0.4%) under the current testing conditions.
As shown in Figure 6 to Figure 13, three additional peaks, Degradation Product 1, 2, and
3 (D1, D2, and D2), were observed in both Two Week and/or One Month stability testing
samples at the presence of PVP I.
3.3.2 Prednisolone Acetate
3.3.2.1 PVP-I Sample
PVP-I in solvent at the same concentration as in stability test samples of prednisolone
acetate was analyzed using HPLC Method 2. The HPLC/UV chromatograms are depicted in
Figure 17.
No prednisolone acetate was observed in PVP-I sample.
3.3.2.2 Prednisolone Acetate Stability Samples
The Day 0, Two Week, and One Month stability test samples were analyzed with
reference standard samples (stored at room temperature in the absence of PVP I) using HPLC
Method 2. The sample in the absence of PVP-I with the same concentration of prednisolone
acetate as those stability samples at the presence of PVP-I was stored in the same stability
chamber at 40 oC for two week and one month as control samples. The control samples were
analyzed under the same conditions. The concentrations of prednisolone acetate in the stability
samples were calculated. The data were summarized in Table V. The HPLC/UV
chromatograms of all reference standards and stability testing samples are depicted in Figure 18
to Figure 23.
The One Month stability test samples were analyzed with the reference standard sample
using LC-MS/MS Method in MRM mode with three characteristic ion transitions to confirm the
identity of prednisolone acetate in stability testing samples. The mass ion chromatograms are
presented in Figure 24 to Figure 26.
After storage at room temperature and 40°C in the presence of PVP-I (0.4%), the levels
of prednisolone acetate in two week testing samples were 99.24% and 96.60% of those in room
temperature and 40°C Day 0 samples, respectively (Table V). The respective data are 95.66%
and 96.79% for one month testing (Table V). Identical mass ion chromatograms and same
intensities of mass ion response were observed in the reference standard and one month stability
testing samples. The results from both HPLC/UV and LC-MS/MS analysis indicate that
prednisolone acetate was stable in the presence of PVP-I (0.4%) under the current testing
conditions.
3.3.3 Loteprednol Etabonate
3.3.3.1 PVP-I Sample
PVP-I in solvent at the same concentration as in stability test samples of loteprednol
etabonate was analyzed using HPLC Method 3. The HPLC/UV chromatograms are depicted in
Figure 27.
No loteprednol etabonate was observed in PVP-I sample.
3.3.3.2 Loteprednol Etabonate Stability Samples
The Day 0, Two Week, and One Month stability test samples were analyzed with
reference standard samples (stored at room temperature in the absence of PVP I) using HPLC
Method 3. The sample in the absence of PVP-I with the same concentration of loteprednol
etabonate as those stability samples at the presence of PVP-I was stored in the same stability
chamber at 40°C for two week and one month as control samples. The control samples were
analyzed under the same conditions. The concentrations of loteprednol etabonate in the stability
samples were calculated. The data were summarized in Table VI. The HPLC/UV
chromatograms of all reference standards and stability testing samples are depicted in Figure 28
to Figure 33.
The One Month stability test samples were analyzed with the reference standard sample
using LC-MS/MS Method in MRM mode with three characteristic ion transitions to confirm the
identity of loteprednol etabonate in stability testing samples. The mass ion chromatograms are
presented in Figure 34 to Figure 36.
After storage at room temperature and 40°C in the presence of PVP-I (0.4%), the levels
of loteprednol etabonate in two week testing samples were 101.43% and 100.07% of those in
room temperature and 40°C Day 0 samples, respectively (Table VI). The respective data are
100.72% and 96.02% for one month testing (Table VI). Identical mass ion chromatograms and
same intensities of mass ion response were observed in the reference standard and one month
stability testing samples. The results from both HPLC/UV and LC-MS/MS analysis indicate that
loteprednol etabonate was stable in the presence of PVP-I (0.4%) under the current testing
conditions.
3.3.4 Difluprednate
3.3.4.1 PVP-I Sample
PVP-I in solvent at the same concentration as in stability test samples of difluprednate
was analyzed using HPLC Method 3. The HPLC-UV chromatograms are depicted in Figure 37.
No difluprednate was observed in PVP-I sample.
3.3.4.2 Difluprednate Stability Samples
The Day 0, Two Week, and One Month stability test samples were analyzed with
reference standard samples (stored at room temperature in the absence of PVP I) using HPLC
Method 3. The sample in the absence of PVP-I with the same concentration of difluprednate as
those stability samples at the presence of PVP-I was stored in the same stability chamber at 40°C
for two week and one month as control samples. The control samples were analyzed under the
same conditions. The concentrations of difluprednate in the stability samples were calculated.
The data were summarized in Table VII. The HPLC/UV chromatograms of all reference
standards and stability testing samples are depicted in Figure 38 to Figure 43.
The One Month stability test samples were analyzed with the reference standard sample
using LC-MS/MS Method in MRM mode with three characteristic ion transitions to confirm the
identity of difluprednate in stability testing samples. The mass ion chromatograms are presented
in Figure 44 to Figure 46.
After storage at room temperature and 40°C in the presence of PVP-I (0.4%), the levels
of difluprednate in two week testing samples were 103.23% and 99.30% of those in room
temperature and 40°C Day 0 samples, respectively (Table VII). The respective data are 104.47%
and 100.24% for one month testing (Table VII). Identical mass ion chromatograms and same
intensities of mass ion response were observed in the reference standard and one month stability
testing samples. The results from both HPLC/UV and LC-MS/MS analysis indicate that
difluprednate was stable in the presence of PVP-I (0.4%) under the current testing conditions.
TABLES
Table I
Four Pharmaceutical Formulations
Steroids Name Formulation/Product Manufacture/Vendor Lot No.
Dexamethasone Ophthalmic solution
Alcon Laboratories 153643F
Sodium Phosphate USP, 0.1%
Ophthalmic
Prednisolone
Suspension USP, Alcon Laboratories 148757F
Acetate
Loteprednol Ophthalmic
Bausch & Lomb 437291
Etabonate Suspension, 0.5%
Ophthalmic
Difluprednate Sirion Therapeutics SIR9F001
emulsion, 0.05%
Table II
Four Steroids
Name Structure MW Rt (min)
O P ONa
Dexamethasone
516.41 ~21.13
Sodium Phosphate
Prednisolone Acetate 402.49 ~26.51
Loteprednol O
466.96 ~32.15
Etabonate
Difluprednate 508.56 ~31.04
Table III
Summary of System Suitability Testing
Dexamethasone Sodium Phosphate
Replicate HPLC Run No. Rt (min) Peak Area
1 09701005_002 21.16 4860116
2 09701005_003 21.12 4887168
3 09701005_004 21.16 4845056
4 09701005_005 21.12 4841633
09701005_006 21.11 4815314
Mean 21.13 4849857
SD 0.024 26369
CV (%) 0.11 0.54
Prednisolone Acetate
Replicate HPLC Run No. Rt (min) Peak Area
1 09701005_012 26.53 5275846
2 09701005_013 26.52 5280425
3 09701005_014 26.54 5197617
4 09701005_015 26.39 5262924
09701005_016 26.55 5237854
Mean 26.51 5250933
SD 0.066 34088
CV (%) 0.25 0.65
Loteprednol Etabonate
Replicate HPLC Run No. Rt (min) Peak Area
1 09701005_017 32.19 4352552
2 09701005_018 32.27 4272956
3 09701005_019 32.11 4368753
4 09701005_020 32.11 4281766
09701005_021 32.08 4292832
Mean 32.15 4313772
SD 0.078 43748
CV (%) 0.24 1.01
Difluprednate
Replicate HPLC Run No. Rt (min) Peak Area
1 09701005_007 31.02 4746034
2 09701005_008 31.02 4715228
3 09701005_009 31.04 4761819
4 09701005_010 31.06 4715455
09701005_011 31.07 4728211
Mean 31.04 4733349
SD 0.023 20288
CV (%) 0.07 0.43
Table IV
Analytical Data Summary of Dexamethasone Sodium Phosphate Stability Testing in PVP-I (0.4 %)
Nominal
Conc. Calc Conc. Calc Conc.
a b c d
Samples HPLC Run No. Rt (min) Peak Area (µg/mL) (µg/mL) DF (mg/mL) % of Std % of Day 0
Day 0
Std1 09701006_002 20.96 4964292
Std2 09701006_003 21.23 4873676
Mean 4918984 50 — 20 1.0000 — —
Room Temp 1 09701006_004 21.17 5084959 51.69 20 1.0337 103.37 —
Room Temp 2 09701006_005 21.20 5093624 51.78 20 1.0355 103.55 —
Mean 5089292 51.73 20 1.0346 103.46 —
2 Weeks
Std1 09701004_001 23.91 5019426
Std2 09701004_002 23.07 5004047
Mean 5011737 50 — 20 1.0000 — —
Room Temp 09701004_003 23.08 4305845 42.96 20 0.8592 85.92 83.04
40 C 09701004_004 23.08 4385137 43.75 20 0.8750 87.50 84.57
One Month
Std1 09701007_023 20.99 4845855
Std2 09701007_024 21.03 4810095
Mean 4827975 50 — 20 1.0000 — —
Room Temp 09701007_025 21.06 4207982 43.58 20 0.8716 87.16 84.24
40 C 09701007_026 21.08 4216932 43.67 20 0.8734 87.34 84.42
40 C 09701007_027 21.07 4184100 43.33 20 0.8666 86.66 83.76
Mean 4200516 43.50 20 0.8700 87.00 84.09
40 C Control 09701007_028 21.11 4471624 46.31 20 0.9262 92.62 92.62
a b c d e
: Nominal concentration in HPLC samples; : Calculated concentration in HPLC samples; : Dilution factor; : Calculated concentration in stability samples; : Stored at 40 C without PVP-I.
Table V
Analytical Data Summary of Prednisolone Acetate Stability Testing in PVP-I (0.4 %)
Nominal
Conc. Calc Conc. Calc Conc.
a b c d
Samples HPLC Run No. Rt (min) Peak Area (µg/mL) (µg/mL) DF (mg/mL) % of Std % of Day 0
Day 0
Std1 09701006_010 26.74 5112497
Std2 09701006_011 26.75 5081143
Mean 5096820 50 — 200 10.000 — —
Room Temp 1 09701006_012 26.76 5342803 52.41 200 10.483 104.83
Room Temp 1 09701006_013 26.77 5323574 52.22 200 10.445 104.45
Mean 5333189 52.32 20 10.464 104.64
2 Weeks
Std1 09701004_012 27.70 5305927
Std2 09701004_013 27.73 5317386
Mean 5311657 50 — 200 10.000 — —
Room Temp 09701004_014 27.74 5515685 51.92 200 10.384 103.84 99.24
40 C
09701004_015 27.71 5369264 50.54 200 10.108 101.08 96.60
40 C Control 09701004_016 27.61 5351149 50.37 200 10.074 100.74 100.74
One Month
Std1 09701007_012 26.78 5181293
Std2 09701007_013 26.79 5127543
Mean 5154418 50 — 200 10.000 — —
Room Temp 09701007_014 26.81 5159554 50.05 200 10.010 100.10 95.66
40 C 09701007_015 26.78 5220242 50.64 200 10.128 101.28 96.79
40 C Control 09701007_016 26.80 5169543 50.15 200 10.029 100.29 100.29
a b c d e
: Nominal concentration in HPLC samples; : Calculated concentration in HPLC samples; : Dilution factor; : Calculated concentration in stability samples; : Stored at 40 C without PVP-I.
Table VI
Analytical Data Summary of Loteprednol Etabonate Testing in PVP-I (0.4 %)
Nominal
Conc. Calc Conc. Calc Conc.
a b c d
Samples HPLC Run No. Rt (min) Peak Area (µg/mL) (µg/mL) DF (mg/mL) % of Std % of Day 0
Day 0
Std1 09701006_014 32.41 4172610
Std2 09701006_015 32.41 4193226
Mean 4182918 50 — 100 5.0000 — —
Room Temp 1 09701006_016 32.45 4224688 50.50 100 5.0499 101.00
Room Temp 2 09701006_017 32.27 4180845 49.98 100 4.9975 99.95
Mean 09701006_017 32.27 4202767 50.24 20 5.0237 100.48
2 Weeks
Std1 09701004_017 32.87 4460467
Std2 09701004_018 33.02 4431159
Mean 4445813 50 — 100 5.0000 — —
Room Temp 09701004_019 33.03 4530572 50.95 100 5.0953 101.91 101.43
40 C
09701004_020 32.99 4470012 50.27 100 5.0272 100.54 100.07
40 C Control 09701004_021 32.98 4521010 50.85 100 5.0846 101.69 101.69
One Month
Std1 09701007_017 32.45 4074874
Std2 09701007_018 32.30 4068504
Mean 4071689 50 — 100 5.0000 — —
Room Temp 09701007_019 32.34 4120353 50.60 100 5.0598 101.20 100.72
40 C 09701007_020 32.48 3928248 48.24 100 4.8239 96.48 96.02
40 C Control 09701007_021 32.46 3975565 48.82 100 4.8820 97.64 97.64
a b c d e
: Nominal concentration in HPLC samples; : Calculated concentration in HPLC samples; : Dilution factor; : Calculated concentration in stability samples; : Stored at 40 C without PVP-I.
Table VII
Analytical Data Summary of Difluprednate Stability Testing in PVP-I (0.4 %)
Nominal
Conc. Calc Conc. Calc Conc.
a b c d
Samples HPLC Run No. Rt (min) Peak Area (µg/mL) (µg/mL) DF (mg/mL) % of Std % of Day 0
Day 0
Std1 09701006_006 31.17 4647615
Std2 09701006_007 31.10 4757011
Mean 4702313 50 — 10 0.5000 — —
Room Temp 1 09701006_008 31.17 4503933 47.89 10 0.4789 95.78 —
Room Temp 2 09701006_009 31.16 4548076 48.36 10 0.4836 96.72 —
Mean 09701006_009 31.16 4526005 48.13 20 0.4813 96.25 —
2 Weeks
Std1 09701004_007 31.76 4849758
Std2 09701004_008 31.76 4871971
Mean 4860865 50 — 10 0.5000 — —
Room Temp 09701004_009 31.75 4829559 49.68 10 0.4968 99.36 103.23
40 C
09701004_010 31.74 4645691 47.79 10 0.4779 95.57 99.30
40 C Control 09701004_011 31.85 4350242 44.75 10 0.4475 89.50 89.50
One Month
Std1 09701007_007 31.26 4519656
Std2 09701007_008 31.21 4538123
Mean 4528890 50 — 10 0.5000 — —
Room Temp 09701007_009 31.20 4554140 50.28 10 0.5028 100.56 104.47
40 C 09701007_010 31.21 4369678 48.24 10 0.4824 96.48 100.24
40 C Control 09701007_011 31.24 4432171 48.93 10 0.4893 97.86 97.86
a b c d e
: Nominal concentration in HPLC samples; : Calculated concentration in HPLC samples; : Dilution factor; : Calculated concentration in stability samples; : Stored at 40 C without PVP-I.
Example 2: Stability Testing For Steroids and NSAIDS Combined With 0.6% Povidone
Iodine
Steroids and NSAIDS were mixed with PVP-I at the concentration of 0.6% w/w on
Day 1. The resultant mixtures will be split to glass vials and stored at room temperature.
fluorometholone alcohol, medrysone, prednisone sodium phosphate, rimexolone,
hydrocortisone, hydrocortisone acetate, lodoxamide tromethamine, nepafenac, bromfenac,
and ketorolac. Testing timepoints included day 0 (Time Zero), and week 4. Tests were
conducted at room temperature. The testing samples were analyzed using liquid
chromatography and tandem mass spectrometry (LC/MS/MS) methods at Day 0, and
Week 4. The steroids and NSAIDS standards were also analyzed and steroids and
NSAIDS levels in testing samples were determined.
Rimexolone, hydrocortisone acetate, lodoxamide, and bromfenac samples
appeared to be stable. Nepafenac was generally stable, but to a lesser degree. Prednisone
sodium phosphate was stable to a lesser degree than nepafenac. In an embodiment, a
result wherein about 10% or greater reduction in concentration of a compound of interest
is observed is an indication that the compound is not stable. In an embodiment, a result
wherein a reduction in the concentration of a compound of interest is observed, but about
less than 10% reduction in concentration of a compound of interest is observed, is an
indication that the compound is semi-stable. In an embodiment, a result wherein there is
substantially no reduction in concentration of a compound of interest observed is an
indication that the compound is stable.
Table VIII illustrates the analytical data summary of bromfenac stability testing in
0.6% PVP-I at room temperature. Table IX illustrates the analytical data summary of
hydrocortisone acetate stability testing in 0.6% PVP-I at room temperature. Table X
illustrates the analytical data summary of rimexolone stability testing in 0.6% PVP-I at
room temperature. Table XI illustrates the analytical data summary of prednisone sodium
phosphate stability testing in 0.6% PVP-I at room temperature. Table XII illustrates the
analytical data summary of nepafenac stability testing in 0.6% PVP-I at room temperature.
Table XIII illustrates the analytical data summary of fluorometholone stability testing in
0.6% PVP-I at room temperature. For Tables VIII-XIII, a: Nominal concentration in HPLC
samples; b: Calculated concentration in HPLC samples; c: Dilution factor; d: Calculated
concentration in stability samples; e: Spiked 50µL of H O and stored at room temperature without
PVP-I.
Table VIII: Bromfenac testing.
Samples Rt (min) Peak Area Nominal Calc DF Calc Conc. % of Std % of Day 0
Conc. Conc.
a b d
(µg/mL) (µg/mL) (µg/mL)
Standard 1 24.925 11390037 90 — 10 900 — —
Standard 2 25.034 11288449 90 — 10 900 — —
Mean 24.980 11339243 90 — 10 900 — —
Day 0
Replicate 1 24.900 11310534 90 89.77 10 897.7 99.74 —
Replicate 2 24.889 11107933 90 88.16 10 881.6 97.96 —
Mean 24.895 11209234 90 88.97 10 889.7 98.86 —
Four Weeks
Replicate 1 24.960 11211003 90 88.98 10 889.8 98.87 100.01
Replicate 2 24.963 11066657 90 87.84 10 878.4 97.6 98.73
Mean 24.962 11138830 90 88.41 10 884.1 98.23 99.37
Control 24.978 11342445 90 90.03 10 900.3 100.03 101.19
Table IX: Hydrocortisone acetate testing.
Samples Rt (min) Peak Area Nominal Calc DF Calc Conc. % of Std % of Day 0
Conc. Conc.
a b d
(µg/mL) (µg/mL) (µg/mL)
Standard 1 29.087 9578995 100 — 50 5000 — —
Standard 2 29.215 9456921 100 — 50 5000 — —
Mean 29.151 9517958 100 — 50 5000 — —
Day 0
Replicate 1 29.067 9672596 100 101.62 50 5081 101.62 —
Replicate 2 29.107 9472035 100 99.52 50 4976 99.52 —
Mean 29.087 9572316 100 100.57 50 5029 100.57 —
Four Weeks
Replicate 1 29.125 9627042 100 101.15 50 5058 101.15 100.58
Replicate 2 29.127 9699896 100 101.91 50 5096 101.91 101.33
Mean 29.126 9663469 100 101.53 50 5077 101.53 100.95
Control 29.178 9676282 100 101.66 50 5083 101.66 101.08
Table X: Rimexolone testing.
Samples Rt (min) Peak Area Nominal Calc DF Calc Conc. % of Std % of Day
Conc. Conc. 0
a b d
(µg/mL) (µg/mL) (µg/mL)
Standard 1 39.98 3399891 100 — 100 10,000 — —
Standard 2 39.961 3404392 100 — 100 10,000 — —
Mean 39.971 3402142 100 — 100 10,000 — —
Day 0
Replicate 40.004 3362494 100 98.83 100 9883 98.83 —
Replicate 40.018 3418997 100 100.5 100 10050 100.5 —
Mean 40.011 3390746 100 99.67 100 9967 99.67 —
Four Weeks
Replicate 40.035 3398853 100 99.9 100 9990 99.9 100.23
Replicate 39.948 3375059 100 99.2 100 9920 99.2 99.53
Mean 39.992 3386956 100 99.55 100 9955 99.55 99.88
Control 20.117 3303121 100 97.09 100 9709 97.09 97.41
Table XI: Prednisone sodium phosphate testing.
Samples Rt Peak Area Nominal Calc DF Calc % of Std % of
(min) Conc. Conc. Conc. Day 0
a b d
(µg/mL) (µg/mL) (µg/mL)
Standard 1 26.61 8422981 100 — 50 5000 — —
Standard 2 26.748 8470831 100 — 50 5000 — —
Mean 26.679 8446906 100 — 50 5000 — —
Day 0
Replicate 1 26.843 8272276 100 97.93 50 4897 97.93 —
Replicate 2 26.717 8243394 100 97.59 50 4880 97.59 —
Mean 26.780 8257835 100 97.76 50 4888 97.76 —
Four Weeks
Replicate 1 26.608 7853275 100 92.97 50 4649 92.97 95.1
Replicate 2 26.738 7946048 100 94.07 50 4704 94.07 96.23
Mean 26.673 7899661.5 100 93.52 50 4676 93.52 95.66
Control 26.477 8495335 100 100.57 50 5029 100.57 102.87
Table XII: Nepafenac testing (270nm).
Samples Rt Peak Nominal Calc DF Calc Conc. % of Std % of Day 0
(min) Area Conc. Conc.
a b d
(µg/mL) (µg/mL) (µg/mL)
Standard 1 34.589 727 50 — 100 5,000 — —
Standard 2 34.580 729 50 — 100 5,000 — —
Mean 34.585 728 50 — 100 5,000 — —
Day 0
Replicate 1 34.568 715 50 49.11 100 4911 98.22 —
Replicate 2 34.548 722 50 49.59 100 4959 99.18 —
Mean 34.558 719 50 49.35 100 4935 98.7 —
Four Weeks
Replicate 1 34.538 703 50 48.28 100 4828 96.56 97.83
Replicate 2 34.577 694 50 47.66 100 4766 95.32 96.58
Mean 34.558 698.5 50 47.97 100 4797 95.94 97.2
Control 34.570 719 50 49.38 100 4938 98.76 100.06
Table XIII: Fluorometholone testing.
Samples Rt (min) Peak Nominal Calc DF Calc % of Std % of Day
Area Conc. Conc. Conc. 0
a b d
(µg/mL) (µg/mL) (µg/mL)
Standard 1 38.664 1872 50 — 20 — —
1,000
Standard 2 38.614 1877 50 — 20 — —
1,000
Mean 38.639 1875 50 — 20 — —
1,000
Day 0
Replicate 1 38.648 1901 50 50.71 20 1014 101.42 —
Replicate 2 38.646 1896 50 50.57 20 1011 101.14 —
Mean 38.647 1899 50 50.64 20 1013 101.28 —
Four Weeks
Replicate 1 38.611 1861 50 49.64 20 993 99.28 98.03
Replicate 2 38.613 1877 50 50.07 20 1001 100.14 98.87
Mean 38.612 1869 50 49.85 20 997 99.7 98.44
Control 38.602 1860 50 49.61 20 992 99.22 97.97
It is to be understood that at least some of the descriptions of the invention have been
simplified to focus on elements that are relevant for a clear understanding of the invention,
while eliminating, for purposes of clarity, other elements that those of ordinary skill in the art
will appreciate may also comprise a portion of the invention. However, because such
elements are well known in the art, and because they do not necessarily facilitate a better
understanding of the invention, a description of such elements is not provided herein.
Further, to the extent that the method does not rely on the particular order of steps set
forth herein, the particular order of the steps should not be construed as limitation on the
claims. The claims directed to the method of the present invention should not be limited to
the performance of their steps in the order written, and one skilled in the art can readily
appreciate that the steps may be varied and still remain within the spirit and scope of the
present invention.
Claims (7)
1. An ophthalmic composition suitable for topical administration to an eye, comprising a) povidone-iodine in a concentration between 0.01% and 10% (w/w), and b) a steroid, wherein the steroid is prednisolone acetate, loteprednol etabonate or difluprednate, and wherein after a period of one month after mixing the povidone-iodine and the steroid, the steroid concentration is at least 95% by weight of the steroid starting concentration.
2. The ophthalmic composition of claim 1, comprising: 0.3 to 1% (w/w) polyvinylpyrrolidinone-iodine complex; 0.05 to 2% (w/w) steroid; 0.005% to 0.02% (w/w) EDTA; 0.01 to 0.5% (w/w) sodium chloride; 0.02 to 0.1% (w/w) tyloxapol; 0.5% to 2% (w/w) sodium sulfate; and 0.1 to 0.5% (w/w) hydroxyethylcellulose.
3. Use of an ophthalmic composition according to claim 1 or 2 for the manufacture of a medicament for the treatment and/or prophylaxis of a microorganism infection or a disorder of at least one tissue of the eye.
4. Use of povidone-iodine and a steroid, wherein the steroid is prednisolone acetate, loteprednol etabonate or difluprednate, in the manufacture of a topical medicament for treatment and/or prophylaxis of a microorganism infection or a disorder of at least one tissue of the eye, wherein the concentration of povidone-iodine in the medicament is between 0.01% and 10% (w/w), and wherein after a period of one month after mixing the povidone- iodine and the steroid, the steroid concentration in the medicament is at least 95% by weight of the steroid starting concentration.
5. The use of claim 4, wherein the medicament comprises: 0.3 to 1% (w/w) polyvinylpyrrolidinone-iodine complex; 0.05 to 2% (w/w) steroid; 0.005% to 0.02% (w/w) EDTA; 0.01 to 0.5% (w/w) sodium chloride; 0.02 to 0.1% (w/w) tyloxapol; 0.5% to 2% (w/w) sodium sulfate; and 0.1 to 0.5% (w/w) hydroxyethylcellulose.
6. An ophthalmic composition of claim 1 or 2 substantially as herein described with reference to any example thereof and with or without reference to the accompanying figures.
7. Use of any one of claims 3 to 5 substantially as herein described with reference to any example thereof and with or without reference to the accompanying figures.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
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US201161485475P | 2011-05-12 | 2011-05-12 | |
US61/485,475 | 2011-05-12 | ||
NZ73478112 | 2012-05-11 |
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NZ751841B2 NZ751841B2 (en) | 2020-11-03 |
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