U.S. patent application number 16/215579 was filed with the patent office on 2019-04-11 for sustained release dexamethasone formulation.
The applicant listed for this patent is ICON BIOSCIENCE, INC.. Invention is credited to Mae W. HU, Glenn T. HUANG, Faina KARASINA, William S. WHITE, Vernon G. WONG.
Application Number | 20190105330 16/215579 |
Document ID | / |
Family ID | 51934201 |
Filed Date | 2019-04-11 |
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United States Patent
Application |
20190105330 |
Kind Code |
A1 |
WONG; Vernon G. ; et
al. |
April 11, 2019 |
SUSTAINED RELEASE DEXAMETHASONE FORMULATION
Abstract
The present embodiments provide for a treatment regimen and use
of a short-term sustained release liquid formulation of
dexamethasone in citrate, wherein a single administration of a
minute dosage form into the anterior chamber of the eye provides
for anti-inflammatory therapy following cataract surgery
Inventors: |
WONG; Vernon G.; (Menlo
Park, CA) ; WHITE; William S.; (Birmingham, AL)
; HU; Mae W.; (Los Altos Hills, CA) ; HUANG; Glenn
T.; (Fremont, CA) ; KARASINA; Faina; (Mountain
View, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
ICON BIOSCIENCE, INC. |
Watertown |
MA |
US |
|
|
Family ID: |
51934201 |
Appl. No.: |
16/215579 |
Filed: |
December 10, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16018931 |
Jun 26, 2018 |
10159683 |
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16215579 |
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14893381 |
Nov 23, 2015 |
10028965 |
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PCT/US2014/039319 |
May 23, 2014 |
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16018931 |
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61827091 |
May 24, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 47/14 20130101;
A61P 27/12 20180101; A61K 9/0048 20130101; A61P 27/02 20180101;
A61K 31/573 20130101; A61P 29/00 20180101 |
International
Class: |
A61K 31/573 20060101
A61K031/573; A61K 9/00 20060101 A61K009/00; A61K 47/14 20060101
A61K047/14 |
Claims
1-30. (canceled)
31. A unit dosage form consisting of about 1 .mu.L to about 12
.mu.L of a composition consisting essentially of dexamethasone and
triethyl acetyl citrate, wherein the concentration of the
dexamethasone in the composition is about 9% to about 20% (w/w) and
the concentration of the triethyl acetyl citrate in the composition
is about 80% to about 91%.
32. The unit dosage form of claim 31, wherein said unit dosage form
releases the dexamethasone for at least 3 days, as measured in
saline solution under infinite sink conditions.
33. The unit dosage form of claim 32, wherein said unit dosage form
releases said dexamethasone for no more than 35 days as measured in
saline solution under infinite sink conditions.
34. The unit dosage form of claim 31, wherein said unit dosage form
releases said dexamethasone for at least 7 days, but no more than
35 days, as measured in saline solution under infinite sink
conditions.
35. The unit dosage form of claim 31, wherein the concentration of
the dexamethasone in the composition is about 9% (w/w) and the
concentration of the triethyl acetyl citrate in the composition is
about 91%.
36. The unit dosage form of claim 31, wherein the concentration of
the dexamethasone in the composition is about 12% (w/w) and the
concentration of the triethyl acetyl citrate in the composition is
about 88%.
37. The unit dosage form of claim 31, wherein the unit dosage form
consists of about 4 .mu.L to about 6 .mu.L of the composition.
38. The unit dosage form of claim 35, wherein the unit dosage form
consists of about 4 .mu.L to about 6 .mu.L of the composition.
39. The unit dosage form of claim 36, wherein the unit dosage form
consists of about 4 .mu.L to about 6 .mu.L of the composition.
40. A kit comprising: a pre-filled syringe or pre-filled vial
containing a formulation consisting of dexamethasone and triethyl
acetyl citrate, wherein the concentration of the dexamethasone in
the formulation is about 9% to about 20% (w/w) and the
concentration of the triethyl acetyl citrate in the formulation is
about 80% to about 91%; an injection syringe; a 25 gauge cannula,
28 gauge needle or 30 gauge needle, optionally connected to the
syringe; a dose loading guide; and a dose delivery guide.
41. The kit of claim 40, wherein the kit further comprises
instructions for administration of the formulation, wherein the
instructions describe injecting a single unit dose of the
formulation into the anterior segment of the eye to treat
inflammation following surgery.
42. The kit of claim 40, wherein the kit further comprises
instructions for administration of the formulation, wherein the
instructions describe injecting a single unit dose of about 4 .mu.L
to about 6 .mu.L of the formulation into the anterior segment of
the eye to treat inflammation following surgery.
43. The kit of claim 40, wherein the kit further comprises
instructions for administration of the formulation, wherein the
instructions describe injecting a single unit dose of about 5 82 L
of the formulation into the anterior segment of the eye to treat
inflammation following surgery.
44. The kit of claim 40, wherein the dose loading guide is designed
to load a dose of about 4 .mu.L to about 6 82 L.
45. The kit of claim 40, wherein the dose loading guide is designed
to load a dose of about 5 .mu.L.
Description
RELATED APPLICATION
[0001] This application is related to and claims priority benefit
of U.S. Application No. 61/927,091, filed May 24, 2013,
incorporated fully herein by reference.
BACKGROUND
[0002] A cataract is clouding of the lens of the eye, which impedes
the passage of light. Most cataracts are related to ageing, but
occasionally children are born with the condition; or the cataract
may develop after an injury, inflammation, or disease. Risk factors
for age-related cataracts include diabetes, prolonged exposure to
sunlight, tobacco use, and excessive alcohol consumption.
[0003] Vision can be restored by surgically removing the affected
lens, and in most cases replacing it by an artificial one. Indeed,
in Western countries the rate of cataract surgery has increased
significantly during the past two decades. In many countries,
cataract surgery now accounts for over half of all ophthalmic
surgery and has become the most common elective surgical procedure.
Although today the removal of the opaque lens and its replacement
with an artificial one represents a routine operation that involves
only minor risks, it consumes a considerable share of the resources
for ophthalmic care. Minimizing the side effects of cataracts
procedures and impact of the health care system remains an
important goal.
[0004] In addition to antibiotic eye drops to prevent infection,
anti-inflammatory eye drops are also prescribed to help reduce any
internal inflammation. These eye drops are in some cases started
before surgery, and in some cases must be continued for 2 or 3
months. Compliance with dosing and application regimens in order to
minimize the side effects of inflammation can be challenging for
many patients. The quicker any inflammation is resolved the quicker
the patient realizes the full desired therapeutic outcome of the
surgery and can resume normal daily activities. Additionally, the
use of eye drops to delivery medication into the eye is at best
marginally effective. In most cases only a small percentage of the
dose actually enters the eye. This factor along with compliance
issues limit the effective drug levels that can be achieved using
eye drop technology. Therefore, there is a need for sustained
release anti-inflammation therapy that can benefit the cataract
patient by replacing the need for anti-inflammatory eye drops. In
particular, there is a need for a formulation and method that
delivers highly effective drug levels without the issues associated
with eye drops, which formulation results in superior clinical
results.
SUMMARY
[0005] The present embodiments provide for the post-cataract
surgery use of an easily injectable, short-term sustained release
formulation for sustained release of the anti-inflammatory drug
dexamethasone for about one to three weeks. In one embodiment, the
formulation consists essentially of dexamethasone in a citrate
vehicle, in which one dose volume ranging from about 1 .mu.L to
about 12 .mu.L of a formulation consisting essentially of
dexamethasone at a concentration ranging from about 1% to about 20%
(w/w) in about 80% to about 99% citric acid ester or a citric acid
ether, is injected into the anterior chamber of the eye for
treating inflammation after cataract surgery. In particular example
embodiments, a patient having undergone cataract surgery is
administered about 5 .mu.L of a formulation consisting of about 6%,
about 9% or about 12% (w/w) dexamethasone in triethyl acetyl
citrate, which is injected into the anterior chamber of the eye. In
use, inflammation is controlled post-cataract surgery by this
single, minute volume injection. The present medication regimen
replaces steroidal eye drops and provides improved benefit in ease
of treatment, patient compliance, and clinical outcome for cataract
surgery patients.
[0006] An aspect of the present embodiments provides for use of a
formulation consisting of about 1 .mu.L to about 12 .mu.L of a
composition consisting essentially of about 1% to about 20% (w/w)
dexamethasone and about 80% to about 99% (w/w) triethyl acetyl
citrate, that is administered as a single dose by injection into
the anterior chamber of eye for the treatment of inflammation
following cataract surgery, wherein said dosage form releases
dexamethasone for at least 3 days as measured in saline solution
under infinite sink conditions. In particular embodiments, the
formulation of said use includes about 6% (w/w) dexamethasone;
about about 9% (w/w) dexamethasone; or about 12% (w/w)
dexamethasone. In another embodiment, the use of the formulation
results in an anterior chamber cell count below 2 within 30 days of
administration when assessed by slit lamp microscopy. In yet
another embodiment, the use of the formulation comprises an
injection delivered using a needle; or an injection delivered using
a cannula.
[0007] Another aspect of the embodiments provides for a unit dosage
consisting essentially of about 1% to about 20% (w/w) dexamethasone
and about 80% to 99% triethyl acetyl citrate, wherein said dosage
form releases dexamethasone for at least 3 days, as measured in
saline solution under infinite sink conditions. In some
embodiments, the unit dosage form comprises about 200 .mu.g to
about 800 .mu.g of dexamethasone; about 342 .mu.g of dexamethasone;
about 517 .mu.g of dexamethasone; or about 697 .mu.g of
dexamethasone. In other embodiments, the total volume of said unit
dosage form is about 1 .mu.L to about 12 .mu.L; about 4 .mu.L to
about 6 .mu.L; or about 5 .mu.L. In other embodiments, the unit
dosage form releases dexamethasone for at least 7 days, as measured
in saline solution under infinite sink conditions. In particular
embodiments, the unit dosage form releases said dexamethasone for
at least 7 days, but no more than 35 days, as measured in saline
solution under infinite sink conditions. In other embodiments, the
unit dosage form retains at least 30% of its dexamethasone after 3
days, as measured in saline solution under infinite sink
conditions.
[0008] Another embodiment provides for a unit dosage for the
treatment of inflammation following cataract surgery consisting of
a unit dose of about 5 .mu.L of a formulation consisting
essentially of either 342 .mu.g, 517 .mu.g or 697 .mu.g
dexamethasone in triethyl acetyl citrate, wherein the unit dose is
injected into the anterior chamber of the eye following cataract
surgery, and wherein administration results in an anterior chamber
cell count below 2 within 30 days of administration when assessed
by slit lamp microscopy.
[0009] Another aspect of the present embodiments provides for a kit
comprising a pre-filled syringe or pre-filled vial containing a
formulation consisting essentially of dexamethasone and triethyl
acetyl citrate in a w/w dexamethasone:triethyl acetyl citrate ratio
of about 6:94, about 9:91, or about 12:88; and injection syringe, a
25 gauge cannula or 28 gauge needle or 30 gauge needle that is,
optionally, connected to the syringe; a dose loading guide;
optionally, a dose delivery guide; and instructions for
administration; wherein a single unit dose of about 5 .mu.L of the
formulation of the kit is injected into the anterior chamber of the
eye for treating inflammation following cataract surgery.
[0010] Still another aspect of the embodiments provides for a
method of treating inflammation following cataract surgery in a
patient in need thereof, comprising injecting into the anterior
chamber of the eye of the patient about 1 .mu.L to about 12 .mu.L
of a composition consisting essentially of about 1% to about 20%
(w/w) dexamethasone and about 80% to about 99% (w/w) triethyl
acetyl citrate. In some embodiments of this aspect, the
administration results in an anterior chamber cell count below 2
within 30 days of administration, when assessed by slit lamp
microscopy; or the administration results in an anterior chamber
cell count below 3 within 8 days of administration, when assessed
by slit lamp microscopy. In other embodiments, the composition
releases dexamethasone for at least 3 days, as measured in saline
solution under infinite sink conditions. In other embodiments, the
composition of the method includes about 200 .mu.g to about 1100
.mu.g of dexamethasone; about 342 .mu.g of dexamethasone; about 517
.mu.g dexamethasone; or about 697 .mu.g dexamethasone. In still
other embodiments of the method, the total dose volume of the
composition is about 4 .mu.L to about 7.5 .mu.L.
[0011] Another aspect of the present embodiments provides for a
unit dosage form comprising a prefilled syringe comprising about 1
.mu.L to about 12 .mu.L of a composition consisting of 1% to 20%
(w/w) dexamethasone and 80% to 99% (w/w) triethyl acetyl citrate,
wherein said dosage form releases said dexamethasone for at least 3
days but no more than 35 days as measured in saline solution under
infinite sink conditions.
DESCRIPTION OF THE DRAWINGS
[0012] FIG. 1 shows the average in vitro dexamethasone (Dex)
release from 5 .mu.L aliquots of three formulations of Dex in
triethyl acetyl citrate (ATEC), as a percent of Dex release per day
in a 10 mL saline infinite sink, n=6: .circle-solid.342 .mu.g/5
.mu.L; .box-solid.517 .mu.g/5 .mu.L; .tangle-solidup.697 .mu.g/5
.mu.L.
[0013] FIG. 2 shows the average in vitro Dex release from two
formulations of Dex in ATEC, as percent release per day in a 20 mL
saline infinite sink, n=6: .tangle-solidup.342 .mu.g/5 .mu.L;
.box-solid.517 .mu.g/5 .mu.L.
[0014] FIG. 3 shows the average in vitro Dex release from two
formulations of Dex in ATEC, as percent release per day in 20 mL
saline/.beta.-cyclodextrin, n=6: .tangle-solidup.342 .mu.g/5 .mu.L;
.box-solid.517 .mu.g/5 .mu.L.
[0015] FIG. 4 shows the average in vitro Dex release from two
formulations of Dex in ATEC as percent release per day in 20 mL
saline/Tween-80, n=6: .tangle-solidup.342 .mu.g/5 .mu.L;
.box-solid.517 .mu.g/5 .mu.L.
[0016] FIG. 5 presents data on the viscosities of three
formulations of Dex in ATEC. .tangle-solidup.342 .mu.g/5 .mu.L;
.tangle-solidup.517 .mu.g/5 .mu.L; .tangle-solidup.697 .mu.g/5
.mu.L.
[0017] FIG. 6 shows in vivo pharmacokinetic release of
dexamethasone into the aqueous humor of rabbit eyes following
injection of 5 .mu.L into the anterior chamber of one of three
different formulations of dexamethasone in ATEC: .circle-solid.342
.mu.g/5 .mu.L; .tangle-solidup.517 .mu.g/5 .mu.L; .box-solid.697
.mu.g/5 .mu.L. The data demonstrate that dexamethasone was released
for 11 to 21 days.
[0018] FIG. 7 shows the proportion of patients with ACC grade=0 at
day 8 following cataract surgery and administration of a single 5
.mu.L unit dose of one of three concentrations of Dex in ATEC, as
indicated.
[0019] FIG. 8 shows the secondary endpoint in a Phase II clinical
trial (of cataract surgery patients treated with a single
administration of the formulations as in FIG. 7), as the proportion
of patients with ACC Grade=0 over time. .tangle-solidup.342 .mu.g/5
.mu.L; .box-solid.517 .mu.g/5 .mu.L; .tangle-solidup.697 .mu.g/5
.mu.L. Vertical bats are.+-.1 standard error of the unadjusted
mean. The last-observation-carried-forward (LOCF) method was used
to impute missing data.
[0020] FIG. 9 is a graph showing the percent of patients exhibiting
anterior chamber cell clearing in twenty-six human cataract surgery
patients injected with dexamethasone in citrate, as described
herein, compared with published data on anterior chamber cell
clearing using two commercially available products: dexamethasone
from Surodex.RTM. implants and difluprednate from Durezol.RTM. eye
drops. Dots: dexamethasone in citrate; hatching: Surodex.RTM.
implants; cross-hatching: Durezol.RTM. difluprednate eye drops.
DETAILED DESCRIPTION
[0021] It should be understood that this invention is not limited
to the particular methodology, protocols, and reagents, etc.,
described herein and as such may vary. The terminology used herein
is for the purpose of describing particular embodiments only, and
is not intended to limit the scope of the present invention, which
is defined solely by the claims Unless defined otherwise, all
technical and scientific terms used herein have the same meaning as
those commonly understood to one of ordinary skill in the art to
which this invention pertains.
[0022] As used herein and in the claims, the singular forms "a,"
"an," and "the" include the plural reference unless the context
clearly indicates otherwise. The term "or" is inclusive unless
modified, for example, by "either." Other than in the operating
examples, or where otherwise indicated, all numbers expressing
quantities of ingredients or reaction conditions used herein should
be understood as modified in all instances by the term "about." The
term "about" in relation to percentages, generally means.+-.1%.
"Consisting essentially of" means that the formulations described
herein can contain additional ingredients that do not interfere
with effectiveness of the drug product or drug release; or, in
general, the formulations may contain additional ingredients that
total less than 1%, 0.5% or 0.1% of the formulation, or are present
in trace amounts.
[0023] All patents and other publications identified are
incorporated herein by reference for the purpose of describing and
disclosing, for example, the methodologies described in such
publications that might be used in connection with the present
invention, but are not to provide definitions of terms inconsistent
with those presented herein. These publications are provided solely
for their disclosure prior to the filing date of the present
application. Nothing in this regard should be construed as an
admission that the inventors are not entitled to antedate such
disclosure by virtue of prior invention or for any other reason.
All statements as to the date or representation as to the contents
of these documents is based on information available to the
applicants and do not constitute any admission as to the
correctness of the dates or contents of these documents.
[0024] Currently cataract surgery is accompanied by a lengthy and
messy regimen of eye drops that are required to reduce inflammation
in the eye. For example, following cataract surgery, prednisolone
eye drops are typically applied four times daily for the first
week, three times daily for the second week, two time daily for the
third week, and once daily for the fourth week and beyond until the
bottle runs dry. Additionally and concurrently, ketorolac eye drops
are applied four times daily for the first through the fourth weeks
following cataract surgery. These anti-inflammatory eye drops are
used along with other eye drops such as antibiotic eye drops. The
anti-inflammatory eye drops are sometimes opaque and render vision
blurry. They are also messy, as the eye floods with drops and
insoluble components collect in the corner of the eyes or on the
eye lids. Moreover, many individuals have trouble applying these
drops formulations correctly, with the right amount of dosing at
the right time, for the correct length of weeks. In other words,
beyond the inconvenience of such eye drops, compliance in the eye
drops dosing regimen can be an issue.
[0025] The present embodiments provide for the use of an
anti-inflammatory formulation in treating an acute inflammatory
response to a surgical event. In particular, the present
embodiments relate to the treatment of inflammation following
cataract surgery comprising, in a particular embodiment, injecting
into the anterior chamber of the eye a small volume, for example a
dose form having a volume of about 4 .mu.L to about 12 .mu.L, of a
liquid formulation consisting essentially of dexamethasone in
citrate, for example triethyl acetyl citrate. Although the release
is sustained release, the dosage form herein provides for
relatively short-term sustained release of the active drug, lasting
from about one to three weeks. By design, the formulation delivers
a relatively high dose of dexamethasone very quickly to give a
quick response; it then tapers off quickly to minimize the
potential of any adverse events associated with the use of
steroids. This liquid formulation maintains a single, generally
spherical bolus shape (a monolithic shape or cohesive structure),
at the site of placement; is biocompatible, biodegradable; provides
for the sustained release of dexamethasone; then disappears
entirely after delivering dexamethasone to the desired site. The
formulations provide for novel post-cataract surgery therapy that
is manipulated easily and injected by qualified medical
practitioners, and can be used instead of the current
anti-inflammatory eye drops regimen or solid implants. This use
avoids the inconvenience and compliance issues associated with the
current anti-inflammatory eye drops regimen, by replacing it with a
physician-administered, one-time application that assures correct
dosing, compliance, and provides beneficial anti-inflammatory
therapy following cataract surgery.
[0026] Dexamethasone is an anti-inflammatory glucocorticoid. Its
chemical names include
(11.beta.,16.alpha.)-9-Fluoro-11,17,21-trihydroxy-16-methylpregna-1,4-die-
ne-3,20-dione; 9.alpha.-Fluoro-16.alpha.-methylprednisolone; and
16.alpha.-mehtyl-9.alpha.-fluoro-1,4-pregnadiene-11.beta.,17.alpha.,
21-triol-3,20-dione. Pharmaceutical formulations of dexamethasone
include dexamethasone, dexamethasone acetate and dexamethasone
sodium phosphate. Thus, the term dexamethasone refers to
dexamethasone salts, acids, variants, polymorphs, derivatives,
prodrugs and metabolites, etc., that have (or will have) regulatory
approval for use as anti-inflammatories for use in the eye.
[0027] Citrates, as used herein, include citric acid esters or
citric acid ethers such as triethyl citrate (TEC), acetyl triethyl
citrate (ATEC) and tributyl citrates such as acetyl tributyl
citrate (ATBC) and tributyl citrate (TBC). Citrates vary in
hydrophilicity or hydrophobicity, and citrates may be used in
combination. Active agents can be dissolved, dispersed, emulsified
or suspended in citrates and form liquids, gels or solids depending
on the citrate(s) and active agents used in a particular
formulation. In vitro and animal in vivo studies have reported the
use of various citrates as sustained release vehicles. See U.S.
Pat. Nos. 7,906,136, 7,560,120, 6,960,346; U.S. Patent Appl. Pub.
No. 2011/0111006. A particularly useful citrate for the short-term
sustained release of dexamethasone in the anterior chamber of the
eye is acetyl triethyl citrate (also called ATEC, triethyl acetyl
citrate, TEAC, triethyl O-acetyl citrate, or
1,2,3-Propanetricarboxylic acid,2-(acetyloxy)-triethyl ester).
[0028] Embodiments of the present invention use a citrate vehicle,
in particular ATEC, as the delivery vehicle for dexamethasone in
the treatment of inflammation following surgery for cataract(s).
The dose volume of the formulation administered into the eye is
relatively minute, in a range of from about 1 .mu.L to about 12
.mu.L, inclusive, for example, about 3 .mu.L to about 10 .mu.L,
about 2.5 .mu.L, to about 7.5 .mu.L, or about 4 .mu.L to about 6
.mu.L, inclusive, such as about 5 .mu.L, about 7.5 .mu.L or about
10 .mu.L as a single dose delivered into the eye by injection.
[0029] The amount of dexamethasone in the formulation can be
expressed in strength, such as from about 100 micrograms (.mu.g) to
about 1100 pg per dose, inclusive, for example about200 .mu.g to
about 800 .mu.g, about 300 .mu.g to about 750 .mu.g, about 300
.mu.g to about 400 .mu.g, about 500 .mu.g to about 600 .mu.g, and
about 650 pg to about 750 pg, inclusive, such as about 114 .mu.g,
about 342 pg, about 513 .mu.g, about 517 .mu.g, about 684 .mu.g,
about 697 .mu.g about 776 .mu.g, or about 1046 .mu.g. The amount of
dexamethasone in the formulation can also be expressed as a range
in concentration of from about 1% to about 45% dexamethasone (w/w),
inclusive, for example, about 2% to about 35%, about 3% to about
25%, about 3% to about 20% about 5% to about 15%, about 4% to about
14% (w/w) dexamethasone, inclusive, such as about 1%, 4.5%, 6%, 9%
or 12% (w/w) dexamethasone. The amount of in a citrate vehicle,
such as ATEC, in the formulation can range from about 55% to about
99% (w/w) citrate, inclusive, for example, about 65% to about 85%,
about 75% to about 97%, about 80% to about 97%, about 85% to about
95%, about 86% to about 96%, inclusive, such as about 91%, about
94%, or about 88%.
[0030] In other words, it is possible to design a dosage form in
which a volume of about 4 .mu.L to about 12 .mu.L consists
essentially of from 1% to 45% dexamethasone in corresponding 55% to
99% citrate. Thus, in a formulation consisting essentially of
dexamethasone and ATEC, the weight ratio of dexamethasone:ATEC can
be about 1:99, about 3:97, about 4:96, about 4.5:95.5, about 6:94,
about 9:91, about 12:88, or about 20:80, inclusive. More
specifically, for a low dose formulation consisting of 6%
dexamethasone, a 5 .mu.L dose weighs 5.7 mg, and contains 0.342 mg
dexamethasone and 5.358 mg ATEC; for a medium dose of 9%
dexamethasone, a 5 .mu.L dose weighs 5.75 mg, and contains 0.5175
mg dexamethasone and 5.2325 mg ATEC. Alternative dosage foinis
include, for example, the following amounts of dexamethasone in the
given dose volume: about 342 .mu.g/about 5 .mu.L, about 517
.mu.g/about 5 .mu.L, about 697 .mu.g/about 5 .mu.L, about 1046
.mu.g/about 7.5 .mu.L, about 776 .mu.g/about 7.5 .mu.L, about 513
.mu.g/about 7.5 .mu.L, about 513 .mu.g/about 10 .mu.L, about 684
.mu.g/about 10 .mu.L, or about 114 .mu.g/about 10 .mu.L.
[0031] A single administration of the dosage form, for example
about 5 .mu.L, about 7.5 .mu.L or about 10 .mu.L, into the anterior
chamber of the eye can alleviate inflammation and replace the
current eye drops regimen or the need for solid implants in
patients in need thereof, i.e., following cataract surgery.
[0032] After the cataract surgery--any type of cataract surgery,
such as phacoemulsification or extracapsular cataract surgery--is
completed, the formulation is administered into the anterior
chamber through a small gauge cannula or needle. The dosage form
can be placed in the anterior chamber of the eye, either in front
of or behind the iris, and the dosage form does not interfere with
the patient's vision. The formulation can be administered using a
cannula and vial, a prefilled vial, or prefilled syringe. A small
gauge cannula and syringe can be used for administration behind the
iris, but a small gauge needle can also be used, especially for
injection in front of the iris. For example, at 25 gauge cannula
(e.g., single use, anterior chamber cannula, 25 gauge, 8 mm, bend
to tip from MSI Precision Specialty Instruments, Phoenixville, Pa.)
or 28 or 30 gauge needle are suitable to administer the dosage
foam, for example from about 4 .mu.L to about 12 .mu.L, inclusive,
such as about 5 .mu.L, about 7.5 .mu.L or about 10 .mu.L into the
anterior chamber. Because the foimulation retains its monolithic
shape after injection, the physician can view proper placement of
the formulation dosage form. After administration, as the
dexamethasone is delivered by sustained release from the dosage
form, the formulation disappears leaving behind nothing. The use of
one administration of about 4 .mu.L to about 12 .mu.L of this
dexamethasone formulation is sufficient to provide relief from
inflammation following cataract surgery, and is may be used without
the use of additional anti-inflammatory therapy such as steroidal
or non-steroidal anti-inflammatory eye drops or solid implants.
[0033] A dosing guide for a syringe can be used to accurately load
and deliver the minute volume of the present regimen. See WO
2012/149040. Briefly, an injection syringe is filled in excess of
the volume required for the correct dose, and a spacer that is
configured to regulate the dose loaded into the syringe is inserted
abutting the plunger rod of the syringe at the top of the barrel of
the syringe (the proximal end of the syringe) in between the
grip-end of the plunger, and the excess formulation expelled until
the spacer impedes further axial distal motion of the plunger. This
physical mechanism relieves the user from having to visually
determine or "eye-ball" the correct dose volume loaded in the
syringe. The dose loading spacer guide can then be removed from the
syringe device. Because many syringes comprise elastomeric gaskets
as seals at the proximal end of the syringe barrel such that
individual user strength in depressing the plunger can lead to
variation in the a dose delivered, a dose dispensing guide can be
placed on the plunger (or has already been placed on the syringe
plunger "as sold"), which guide is configured generally as a "ring"
that physically impedes further depression of the plunger after the
correct dose volume has been delivered into the eye. Syringe
loading and dosing guides have been made commercially (Berlin Food
& Lab Equip., South San Francisco, Calif.; Encore Machining,
San Jose, Calif.), and specifications are designed for the
particular syringe and dose volume. For example, using such dosing
and delivery guides, minute amounts of medicament, such as about
5.0 .mu.L or about 7.5 .mu.L, can be placed into the eye, depending
on the size guide(s) used. Syringes suitable for use in delivering
the formulations include disposable insulin syringes with
permanently attached needles, particularly a 0.3 mL sterile insulin
syringe (Becton Dickenson), or a sterile single-use glass syringe
without attached needle, such as a 0.5 ml glass syringe (Hypak by
Becton Dickenson). In one embodiment, the formulation, syringe,
cannula or needle, dose loading guide and, optionally, dose
delivery guide are included in a kit for accurate administration of
the formulation dose unit.
[0034] The administration of a single dose of the formulation
consisting essentially of dexamethasone in citrate has been
observed to adequately control (prevent or ameliorate) inflammation
following cataract surgery in humans. Thus, a particular embodiment
of the present invention provides for the use of a dosage form of
about 5 .mu.L of a formulation consisting essentially of
dexamethasone and ATEC in a single administration into the anterior
chamber for the treatment of inflammation in the human eye
following cataract surgery. The dexamethasone can be present in the
particular embodiment is in the concentration of example, about 6%,
about 9% or about 12% (w/w). As examples, the dexamethasone can be
in an amount of about 342 .mu.g, about 517 .mu.g, or about 697
.mu.g in the dosage form volume of about 5 .mu.L delivered into the
anterior chamber of the eye. More specifically, for a low dose
formulation consisting of 6% dexamethasone, a 5 .mu.L dose weighs
5.7 mg, and contains 0.342 mg dexamethasone and 5.358 mg ATEC; for
a medium dose of 9% dexamethasone, a 5 .mu.L dose weighs 5.75 mg,
and contains 0.5175 mg dexamethasone and 5.2325 mg ATEC. These
dosage forms are injected only once: at the time of cataract
surgery, after the surgery is complete and while the patient is
still under anesthesia (local or systemic anesthesia). The
administration is done after the new lens has been inserted,
essentially after the cataract replacement portion of the surgery
has been completed.
[0035] The present use can be combined with other therapies.
Antibiotic therapy will likely be used after cataract surgery, such
as antibiotic drops or sustained release antibiotic therapy (see
U.S. Pat. No. 7,906,136), as the healthcare provider prescribes.
Additionally, should the patient require additional
anti-inflammatory medications for some reason, these are not
contraindicated by the use of the present formulations. Also, some
patients may need anti-glaucom a therapy after cataract surgery.
These therapies are known in the art.
[0036] Another aspect of the present invention provides for use of
a formulation consisting of dexamethasone in ATEC for the
preparation of a medicament for the treatment of intraocular
inflammation following cataract surgery wherein the single, fixed
dosage amount is, for example, about 5 .mu.L of about 342 .mu.g,
517 .mu.g, or 697 .mu.g of dexamethasone.
[0037] Importantly, the present invention provides use of a
formulation that treats an acute inflammatory response to a
surgical event. By design it is formulated to deliver an immediate,
high dose very quickly to give a quick response. The amount of
dexamethasone released from the formulation then tapers off quickly
to minimize the potential of any adverse events associated with the
use of steroids. In clinical trials, this use resulted in positive
outcome for humans following cataract surgery.
EXAMPLES
Example 1
In Vitro Release of Dexamethasone from Citrate Formulations
[0038] A series of in vitro experiments were conducted to measure
the dexamethasone release kinetics from formulations of
dexamethasone and citrate. Liquid formulations of dexamethasone
(Dex) and triethyl O-acetyl citrate (ATEC) were made by weighing
each component and mixing them together with ample stirring to form
a homogenous mixture (drug product). A volume of 5 .mu.L of the
following three separate formulations of Dex/ATEC drug product was
used in the in vitro study:
[0039] 342 .mu.g/5 .mu.L, Equivalent dose: 342 .mu.g
[0040] 517 .mu.g/5 .mu.L, Equivalent dose: 517 .mu.g
[0041] 697 .mu.g/5 .mu.L, Equivalent dose: 697 .mu.g
[0042] Five microliters (5 .mu.L) of the drug product was placed in
a 20 mL scintillation vial then a sufficient quantity (q.s.) of
saline solution (0.9% NaCl, pH 6-8) added to bring the total volume
to 10 mL. The vials containing the drug product in saline were
incubated at 37.degree. C. At each time point, the sample vials
were removed from the incubator and cooled to room temperature.
Aliquots of solution (5 mL) were removed from each vial and tested
for dexamethasone concentration using ultra performance liquid
chromatography. Five mL of fresh saline was added back to each test
vial to maintain infinite sink conditions, and the sample vials
placed back into the incubator at 37.degree. C. Aliquots were
removed, as just described, and tested on days 1, 3, 7 and weekly
thereafter for dexamethasone release. This drug release measurement
approach is referred to as the 5/10 saline drug release method,
because the total volume was 10 ml and the amount removed and
replaced for testing was 5 mL. The in vitro Dex average release
from the drug product is shown in Table 1 (see also FIG.1):
TABLE-US-00001 TABLE 1 Dexamethasone Average Percent Release in 10
mL Saline Time (Days) Ave. % Total Dex Released SD % RSD Drug
Product 342 .mu.g Dex 1 44.6 1.8 4.0 3 71.1 3.0 4.2 7 97.3 2.8 2.9
Drug Product 517 .mu.g Dex 1 30.5 0.9 2.8 3 48.3 1.6 3.3 7 70.6 4.1
5.9 14 87.0 2.6 3.0 21 98.7 2.2 2.2 Drug Product 697 .mu.g Dex 1
23.5 1.7 7.1 3 40.9 3.3 8.1 7 59.5 3.3 5.5 14 76.9 2.8 3.7 21 90.9
4.1 4.5 28 96.1 4.5 4.7 35 99.8 1.2 1.3 n = 6 for each time
point.
[0043] In another in vitro test series, 342 .mu.g/5 .mu.L or 517
.mu.g/5 .mu.L (Dex in ATEC) were placed in vials and q.s. to 20 mL
with 0.9% saline. Storage and testing were conducted as above,
except that at each time point 15 mL withdrawn for sampling and was
replaced with 15 mL of fresh saline. This method was named the
15/20 saline drug release method. The release of Dex from the drug
product is shown in Table 2 (see also FIG. 2):
TABLE-US-00002 TABLE 2 Dexamethasone Average Percent Release in 20
mL Saline Time (Days) Ave. % Total Dex Released SD % RSD Drug
Product 342 .mu.g Dex 1 43.49 0.42 0.97 3 66.20 0.37 0.56 7 87.73
0.72 0.82 14 97.36 0.74 0.76 Drug Product 517 .mu.g Dex 1 30.70
0.58 1.88 3 53.01 1.25 2.36 7 76.66 1.86 2.42 14 99.14 0.59 0.59 n
= 6 for each time point.
[0044] To test in vitro release in an alternative buffer system,
342 .mu.g/5 .mu.L or 517 .mu.g/5 .mu.L (Dex in ATEC) were placed in
vials and q.s. to 20 mL with a solution of 0.9% saline, 0.05%
.beta.-cyclodextrin. Storage and testing were conducted as above,
except that at each time point 10 mL withdrawn for sampling and was
replaced with 10 mL of fresh solution. This method was named the
10/20 saline/BCD drug release method. The release of Dex from the
drug product is shown in Table 3 (see also FIG. 3):
TABLE-US-00003 TABLE 3 Dexamethasone Average Percent Release in 20
mL Saline/.beta.-cyclodextrin Time (Days) Ave. % Total Dex Released
SD % RSD Drug Product 342 .mu.g Dex 1 54.40 2.35 4.33 3 87.04 7.67
8.81 7 99.23 0.95 0.96 Drug Product 517 .mu.g Dex 1 39.34 1.02 2.60
3 70.11 7.14 10.19 7 97.39 4.79 4.92 n = 6 for each time point.
[0045] Another in vitro release in an alternative buffer system was
undertaken, in which 342 .mu.g/5 .mu.L or 517 .mu.g/5 .mu.L (Dex in
ATEC) were placed in vials and q.s. to 20 mL with a solution of
0.9% saline, 0.05% Tween-80. Storage and testing were conducted as
above, except that at each time point 10 mL withdrawn for sampling
and was replaced with 10 mL of fresh solution. This method was
named the 10/20 saline/T80 drug release method. The release of Dex
from the drug product is shown in Table 4 (see also FIG. 4):
TABLE-US-00004 TABLE 4 Dexamethasone Average Percent Release in 20
mL Saline/Tween-80 Time (Days) Ave. % Total Dex Released SD % RSD
Drug Product 342 .mu.g Dex 1 39.69 3.29 8.28 3 75.71 10.23 13.52 7
92.44 5.70 6.16 Drug Product 517 .mu.g Dex 1 29.06 4.08 14.05 3
59.77 11.86 19.84 7 90.14 10.00 11.10 n = 6 for each time
point.
Example 2
In Vivo Release of Dexamethasone from Citrate
[0046] Liquid formulations of dexamethasone and ATEC were made by
weighing each component and mixing them together with ample
stirring to form a homogenous mixture, a uniformed blend.
Dexamethasone, USP micronized, GMP manufacturing, is commercially
available (e.g., IIawkins Pharmaceutical Group, Minneapolis, Minn.;
Pharmacia Upjohn, Kalamazoo, Mich.), with a certificate of
analysis. Additional tests for identity and purity of dexamethasone
were undertaken using infrared absorption and HPLC. ATEC, NF, is
available commercially (e.g., from Vertellus Performance Materials
Inc., Greensboro, N.C.) with a certificate of analysis. Additional
testing for identity and purity were undertaken. The formulations
were either 6%, 9% or 12% dexamethasone, such that each 5 .mu.L
dose contained 342 .mu.g, 517 .mu.g or 697 .mu.g dexamethasone.
Using a 30 gauge needle, a single dose of 5 .mu.L was injected
under humane conditions into the anterior chamber of the eyes of
rabbits. Subsequently, samples of the aqueous humor of treated eyes
were collected (generally about 100 .mu.L to 150 .mu.L, in volume),
pooled, concentrated 10-fold, and analyzed by liquid
chromatography-mass spectrometry (LCMS) to afford the level of
dexamethasone released into the aqueous humour. This drug release
study was named the in vivo aqueous humor Dex release study. The
sampling days and results are shown in FIG. 6. Dexamethasone was
released for about 11 to about 21 days. One skilled in the art can
readily extrapolate the sustained release profile from FIG. 6.
Example 3
Use of Sustained Release Dexamethasone Post Cataract Surgery
[0047] A Phase II post-cataract surgery inflammation study was
undertaken to compare three dosage forms of short-term sustained
release dexamethasone. This was a multicenter, randomized,
double-masked, dose ranging study for efficacy and safety. The
human patients were over 40 years of age, having visual acuity
potential greater than 20/30 in the study eye and having a corneal
endothelial cell count of.gtoreq.2000 cells/mm.sup.2 underwent
unilateral cataract surgery by phacoemulsification. Patients eye
were excluded from the study who had (a) used any ocular, topical
or oral corticosteroids within 7 days prior to day 0; (b) received
a periocular corticosteroid injection in the study eye in the 3
months prior to screening; (c) used topical NSAIDs in the study eye
within 15 days prior to screening; or (d) received any intravitreal
corticosteroid delivery vehicle (e.g., Restisert or Ozurdex), in
the study eye.
[0048] Dexamethasone in ATEC, prepared as a mixture as in Example
2, was supplied with a fill volume of 0.5 mL and packaged in a 2 L
glass vial, sealed with a ruber stopper and an aluminum seal. Each
vial was intended to be used only once. The formulations were
sterile, preservative-free suspensions; sterilization was
accomplished using E-beam at 28.+-.3 kGy after vial fill. Particle
size % volume-size was 10%<10.0 .mu.m, 50%<30.0 .mu.m,
90%<90 .mu.m. SOP for product content, uniformity, endotoxin,
pH, sterility, etc. were followed. Dexamethasone release in saline
from the 697 .mu.g/5 .mu.L, Dex, average value n=6: 24 hours:
10%-50% (ave. 20.4%), 3 days: 30%-70% (ave. 41.0%), 7 days: 45%-90%
(ave. 57.4%). Dexamethasone release in saline from the 517 .mu.g/5
.mu.L, Dex, average value n=6: 24 hours: 15%-55% (ave. 27.6%), 3
days: 35%-75% (ave. 47.1%), 7 days: 50%-95% (ave. 66.8%).
Dexamethasone release in saline from the 342 .mu.g/5 .mu.L, Dex,
average value n=6: 24 hours: 15%-55% (ave. 39.2%), 3 days: 40%-80%
(ave. 62.4%), 7 days: >50% (ave. 89.1%).
[0049] Osmolality was tested by incubating a 5 .mu.L aliquot in 4.5
mL or 0.45% saline at 37.degree. C. overnight, then samples were
allowed to cool to room temperature and osmolality compared with
0.45% saline. The data observed was: 0.45% saline, pH 6.55, mOsm
(milli Osmols per liter) 147; 342 .mu.g/5 .mu.L Dex, pH 6.56, mOsm
148; 517 .mu.g/5 .mu.L Dex, pH 6.50 mOsm 150; 697 .mu.g/5 .mu.L
Dex, pII6.40, mOsm 174.
[0050] Viscosity was also measured at 25.degree. C. At shear rates
ranging from 7.5 to 23.55 sec-1, the viscosity of 697 .mu.g/5 .mu.L
Dex ranged from 106.66 cp to 84.24 cp. At shear rates ranging from
7.50 to 34.28 sec-1, the viscosity of 517 .mu.g/5 .mu.L Dex ranged
from 73.87 cP to 62.64 cP. At shear rates ranging from 7.50 to
45.00 sec-1, the viscosity of 342 .mu.g/5 .mu.L Dex ranged from
53.02 cP to 43.47 cP. From the viscosity data, the formulations
showed characteristics of Non-Newtonian (pseudo-plastic) fluids.
See also FIG. 5.
[0051] After the completion of cataract surgery, a single dose
containing either 342 .mu.g, 517 .mu.g or 697 .mu.g Dex in ATEC was
delivered by injection using a disposable sterile insulin syringe
that was used to withdraw and inject about 5 .mu.L, using syringe
loading and dosing guides to position the plunger to deliver a unit
dose volume of 5 .mu.L into the anterior chamber of the study eye.
The amount of dexamethasone per patient was assigned at random.
Anterior chamber cells (ACC) were graded as a score of 0 to 4,
assessed by slit lamp biomicroscopy. Ocular and non-ocular safety
was monitored through day 90.
[0052] As a primary endpoint, the proportion of patients with ACC
Grade=0 at day 8 was 53.4%/342 .mu.g (n=58), 51.8%/517 .mu.g
(n=56), and 63.8%/697 .mu.g (n=58). See FIG. 7. As a secondary
endpoint, the proportion of patient with ACC Grade=0 over time is
shown in FIG. 8. There was no statistically significant difference
among the three treatment groups.
[0053] Regarding safety and efficacy, no patients suffered
suprachoroidal hemorrhage or retinal detachment, and only on
patient (in the 342 .mu.g group) suffered endophthalmitis. The
study eye serious adverse events were consistent with published
serious adverse events following cataract surgery.
Example 4
Comparative Efficacy
[0054] Use of three formulations of dexamethasone in citrate (as
described in Examples 2 and 3) was compared with standard
anti-inflammatory eye drops therapy in reduction of anterior
chamber inflammation.
[0055] For a comparison with steroidal Lotemax.RTM. (loteprednol
0.5%), data was collected in which the primary endpoint was
reduction of anterior chamber inflammation (ACI), the sum of
anterior chamber cells (ACC=0-5 cells* and flare=0) in the
post-operative eye:
TABLE-US-00005 loteprednol QID Vehicle Trial 1 - Visit Days 7-12**
43% 18% Trial 2 - Visit Days 7-12** 34% 17% * For ACC grading, this
endpoint is equivalent to ACC Grade 0 and 1 for IBI-10090. **The
Target Date was Day 8, but allowed patients to receive the dose up
to Day 12.
[0056] For comparison with steroidal Durazol.RTM. (difluprednate
0.05%), data was collected in which the primary endpoint was the
proportion of subjects with an anterior chamber cell grade of "0"
on Day 8:
TABLE-US-00006 difluprednate QID Vehicle Trial 1 - Day 3 7.3% .sup.
0% Day 8 23.6% 10.3% Day 15 45.0% 14% Trial 2 - Day 3 1.9% 1.7% Day
8 21.2% 5.3% Day 15 36.5% 8.8%
[0057] For comparison with an NSAID eye drop, Acuvail.RTM.
(ketorolac 0.4%) the primary endpoint was the proportion of
patients with clearing of anterior chamber inflammation (summed
ocular inflammation score=0):
TABLE-US-00007 ketorolac BID Vehicle Trial 1 - Day 8 29% 16% Day 14
46% 25% Trial 2 - Day 8 33% 17% Day 14 58% 25%
[0058] For comparison with another NSAID eye drop, Bromday.RTM.
(bromfenac 0.09%), the primary endpoint was the sum of anterior
chamber cell (ACC=0-5 cells)* and flare equal to zero at Day
15:
TABLE-US-00008 bromfenac 0.09% Vehicle Trial 1 - Day 8 33.8% 13.3%
Day 14 62.6% 39.8% Trial 2 - Day 8 38.6% 21.9% Day 14 65.8% 47.9% *
For ACC grading, this endpoint is equivalent to ACC Grade 0 and 1
for the injected dexamethasone in citrate. These numbers also
included patients who were on additional anti-inflammatory
drops.
[0059] For comparison with another brofenac NSAID eye drop,
Prolensa.RTM. (bromfenac 0.07%), the primary endpoint was the
proportion of patients with clearance of ocular inflammation (0
cell and no flare):
TABLE-US-00009 bromfenac 0.07% Vehicle Trial 1 - Day 8 24.1% 6.5%
Day 14 45.5% 13.0% Trial 2 - Day 8 30.0% 12.7% Day 14 45.5% 27.3%
Dosing schedule: Day before surgery, prior to surgery, once a day
thereafter.
[0060] For comparison with another NSAID eye drop, Ilevro.RTM.
(nepafenac 0.3%), the primary endpoint was the proportion of
patients with clearance of ocular inflammation (0 cell and no
flare) at Day 7:
TABLE-US-00010 nepafenac 0.3% Vehicle Trial 1 - Day 3 11.4% 10.7%
Day 7 34.1% 18.8% Day 14 68.4% 34.0% Trial 2 - Day 3 6.4% 3.2% Day
7 31.3% 10.3% Day 14 64.6% 25.0% Dosing schedule: Day before
surgery, prior to surgery, once a day thereafter.
[0061] An additional comparison was undertaken measuring anterior
chamber cell clearing in human patients. A comparison graph is
shown in FIG. 9, for anterior chamber cell clearing at Day 8 and
Day 15, created using preliminary data in twenty-six patients
treated with dexamethasone in citrate following cataract surgery as
described herein, compared with published data for anterior chamber
cell clearing using Durezol.RTM. difluprednate steroid eye drops
and Surodex.RTM. PLGA-based sustained release-dexamethasone
implant.
[0062] When data for commercially available drug products are
compared with data for the injected formulations as described
herein, it is clear that the efficacy provided by the instant
embodiments is superior to other dosage forms and regimens.
* * * * *