Note: Descriptions are shown in the official language in which they were submitted.
PHARMACEUTICAL OPHTHALMIC COMPOSITIONS AND METHODS FOR
FABRICATING THEREOF
10001]
FIELD OF THE INVENTION
[0002] The present invention relates generally to the field of ophthalmology
and more
specifically to injectable ophthalmological compositions having anti-bacterial
and anti-
inflammatory properties, and to methods of preparing such compositions.
BACKGROUND
[0003] In ophthalmological treatments and procedures, e.g., cataract surgery,
pre- and
post-operative eye drops are frequently used by the patients to eliminate or
alleviate negative
post-surgery complications such as infections, inflammation, and tissue edema.
It has been
reported that as many as 8% of all ocular surgery patients may suffer from
infections,.
including the potentially catastrophic endoplithalmitis, and various negative
sight threatening
side effects after surgery, such as inflammatory uveitis, corneal edema, and
cystoid macular
edema. Typically, the topical postoperative medications are prescribed for at-
home use
starting before and then after cataract surgery, and are typically self-
administered, unless
requiring a caregiver or family assistance.
[0004] These ophthalmic medication drops include anti-inflarnmatory and
antibiotic agents
and are highly effective, but require strict adherence to the treatment
regimens, which is often
difficult for many patients (with physical limitations or aversions to eyelid
touching and
manipulation) and is frequently expensive (well over $200 per procedure),
causing
patients dissatisfaction. It is desirable to have an alternative procedure
that would permit
avoiding the necessity of the use of such post-surgery medications to save the
associated post-operative trouble and expenses.
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[0005] One such alternative procedure includes the intraoperative
intravitreal injection by
an atraumatic transzonular route that can achieve patient outcomes that are as
good as, or
better than, the current at-home eye drop regimen, removing the issues of
compliance and
medication administration accuracy. This patent specification discloses
pharmaceutical
compositions suitable for intraoperative ocular injections that can achieve
such positive
patient outcomes, and methods of fabricating and administering the same.
SUMMARY
[0006] According to one embodiment of the invention, an ophthalmic
pharmaceutical
composition is provided, the composition comprising a therapeutic component
consisting
essentially of a therapeutically effective quantity of an anti-bacterial agent
and a
therapeutically effective quantity of an anti-inflammatory agent, a
combination of at least two
pharmaceutically acceptable excipients, and a pharmaceutically acceptable
carrier, wherein
the composition is suitable for delivery via intraocular injection or via eye
drops.
[0007] According to another embodiment of the invention, an anti-bacterial
agent described
herein can be a compound selected from the group of quinolone (including a
fluorinated
quinolone), e.g., moxifloxacin, and pharmaceutically acceptable salts,
hydrates, solvates or
N-oxides thereof
[0008] According to yet another embodiment of the invention, an anti-
inflammatory agent
described herein can be a corticosteroid, e.g., triamcinolone, and
pharmaceutically acceptable
salts, hydrates, solvates, ethers, esters, acetals and ketals thereof
[0009] According to another embodiment of the invention, the pharmaceutical
compositions described herein further include at least two solubilizing and
suspending agents
of which one is any of non-ionic polyoxyethlene-polyoxypropylene block
copolymers, e.g.,
Poloxamer 4Q7 , and the other is any of water-soluble derivatives of cellulose
(e.g.,
carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, or
hydroxypropyl
cellulose), non-cross-linked or partially cross-linked polyacrylates,
polyoxyethylene sorbitan
monolaurates, polyoxyethylene sorbitan monopalmitates, polyoxyethylene
sorbitan
monostearates, polyoxyethylene sorbitan monooleates or combinations thereof
[0010] According to other embodiments of the invention, the pharmaceutical
compositions
described herein may be intravitreally transzonularly injected into a
mammalian subject as a
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part of the process of treatment of a variety of ophthalmological diseases,
conditions or
pathologies associated with intraocular surgery, such as cataracts, retinal
and glaucoma
disease.
DETAILED DESCRIPTION
A. Terms and Definitions
[0011] Unless specific definitions are provided, the nomenclatures utilized in
connection
with, and the laboratory procedures and techniques of analytical chemistry,
synthetic organic
and inorganic chemistry described herein, are those known in the art. Standard
chemical
symbols are used interchangeably with the full names represented by such
symbols. Thus, for
example, the terms "hydrogen" and "H" are understood to have identical
meaning. Standard
techniques may be used for chemical syntheses, chemical analyses, formulating
compositions
and testing them. The foregoing techniques and procedures can be generally
performed
according to conventional methods well known in the art.
[0012] It is to be understood that both the foregoing general description and
the following
detailed description are exemplary and explanatory only and are not
restrictive of the
invention claimed. As used herein, the use of the singular includes the plural
unless
specifically stated otherwise. The section headings used herein are for
organizational
purposes only and are not to be construed as limiting the subject matter
described.
[0013] As used herein, "or" means "and/or" unless stated otherwise.
Furthermore, use of
the term -including" as well as other forms, such as -includes," and
"included," is not
limiting.
[0014] "About" as used herein means that a number referred to as "about"
comprises the
recited number plus or minus 1-10% of that recited number. For example,
"about" 100
degrees can mean 95-105 degrees or as few as 99-101 degrees depending on the
context.
Whenever it appears herein, a numerical range such as "1 to 20" refers to each
integer in the
given range; i.e., meaning only 1, only 2, only 3, etc., up to and including
only 20.
[0015] The term -pharmaceutical composition" is defined as a chemical or a
biological
compound or substance, or a mixture or combination of two or more such
compounds or
substances, intended for use in the medical diagnosis, cure, treatment,
or prevention of disease or pathology.
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[0016] The term "intraocular injection" refers to an injection that is
administered by
entering the eyeball of the patient. The term "pen-ocular injection" refers to
an injection that
is administered behind the eye but outside the eye wall. The term -
transzonular" refers to an
injection administered through the ciliary zonule which is a series of fibers
connecting the
ciliary body and lens of the eye.
[0017] The term "intrayitreal" refers to an injection administered through an
eye of the
patient, directly into the inner cavity of the eye.
[0018] The term "intraoperative" is defined as an action occurring or carried
during, or in
the course of, surgery.
[0019] The term "suspension- is defined for the purposes of the present
application as a
two-phase dispersion system haying a first phase and a second phase. It is
further specifically
provided that dispersion systems having three, four or more phases are not
within the
meaning of -suspension" for the purposes of the instant application.
[0020] Furthermore, the above mentioned first phase of the suspension consists
of a
multitude of solid particles and is designated and defined as the "dispersed
phase", and the
above mentioned second phase of the suspension is a liquid and is designated
and defined as
the "dispersion medium-, or, interchangeably and synonymously, the "continuous
phase".
[0021] Furthermore, the above mentioned dispersed phase is dispersed in the
above
mentioned dispersion medium, and the term "dispersed" is defined as meaning
that the
dispersed phase is statistically evenly distributed throughout the entire
volume of the
suspension, with no statistically meaningful deviations in the concentrations
of the dispersed
phase in different portions of the suspension.
[0022] The term `teratomileusis" refers to a surgical procedure whereby
the refractive state of the cornea is improved. This procedure can be
performed as a laser-
assisted in situ surgery also known as "LASIK." Other comeal refractive
surgical procedures
that are encompassed by the term "keratomileusis" include, without
limitations,
photorefractive keratectomy (PRK), laser-assisted sub-epithelial keratectomy
(LASEK),
corneal ring segments, corneal cross linking, refractive corneal inlays (e.g.,
"raindrop",
"Kamra-) and corneal lenticular surgery ("SMILE").
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[0023] The terms "anti-bacterial" and "antibiotic" are broadly covered by the
term "anti-
microbial" and are used herein interchangeably, refer to substances or
compounds that
destroy bacteria and/or viruses and/or inhibit the growth thereof via any
mechanism or route.
[0024] The term "anti-inflammatory- refers to substances or compounds that
counteract or
suppress inflammation via any mechanism or route.
[0025] The term "quinolone" for the purposes of this application refers to a
genus of anti-
bacterial compounds that are derivatives of benzopyridine and in some
embodiments include
fluorine atom, such as in the following structure ("fluoroquinolone"):
RR
R.
HOyJO
0 0
[0026] The terms "corticosteroid" and closely related "glucocorticoid" are
defined as
compounds belonging to a sub-genus of steroids that are derivatives of
corticosterone, the
latter having the chemical structure:
0 OH
HO
11111111.1'
0)00
[0027] The term "salt" refers to an ionic compound which is a product of the
neutralization
reaction of an acid and a base.
[0028] The terms "solvate" and "hydrate" are used herein to indicate that a
compound or a
substance is physically or chemically associated with a solvent for "solvates-
such as water
(for "hydrates").
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[0029] The term "ether" refers to a chemical compound containing the structure
R-O-Rt,
where two organic fragments R and RI are connected via oxygen.
100301 The term "ester" refers to a chemical compound containing the ester
group
R-O-C(0)-Ri, connecting two organic fragments R and RI.
[0031] The terms "acetal" and "ketal" refer to a chemical compound containing
the
functional group R-C(R1)(0R2)2, where R and R2 are organic fragments and Ri is
hydrogen
atom (for acetals), and is inclusive of "hemiacetals- where one R2 (but not
the other) is
hydrogen atom; or where none of R, RI and R2 is a hydrogen atom and each is an
organic
fragment (for ketals).
[0032] The terms "non-steroid anti-inflammatory drug" or "MAID" refer to
substances or
compounds that are free of steroid moieties and provide analgesic, antipyretic
and/or anti-
inflammatory effects.
[0033] The term "carrier" refers to a substance that serves as a vehicle for
improving the
efficiency of delivery and the effectiveness of a pharmaceutical composition.
[0034] The term -excipient" refers to a pharmacologically inactive substance
that is
formulated in combination with the pharmacologically active ingredient of the
pharmaceutical composition and is inclusive of bulking agents, fillers,
diluents and products
used for facilitating drug absorption or solubility or for other
pharmacokinetic considerations.
[0035] The term "solubilizing agent" for the purposes of the instant
application refers
broadly to chemical compounds that improve the process of incorporating the
solubilizate
(i.e., active components described herein) into micelles; in other words, the
presence of a
solubilizing agent makes the process of solubilization faster, easier, and/or
more complete
compared with compositions without it.
[0036] The term "suspending agent" for the purposes of the instant application
refers
broadly to chemical compounds that help active pharmaceutical ingredients stay
suspended in
the formulation and prevents and/or reduces the phase separation of two-phase
dispersion
systems described herein.
[0037] The term "therapeutically effective amount" is defined as the amount of
the
compound or pharmaceutical composition that will elicit the biological or
medical response
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of a tissue, system, animal or human that is being sought by the researcher,
medical doctor or
other clinician.
100381 The term "pharmaceutically acceptable" is defined as a carrier, whether
diluent or
excipient, that is compatible with the other ingredients of the formulation
and not deleterious
to the recipient thereof
[0039] The terms "administration of a composition" or "administering a
composition" is
defined to include an act of providing a compound of the invention or
pharmaceutical
composition to the subject in need of treatment.
B. Embodiments of the Invention
[0040] According to embodiments of the present invention, pharmaceutical
compositions
intended to prevent and/or treat inflammation and/or infections are provided.
The
compositions include an active component comprising, consisting essentially
of, or consisting
of a therapeutically effective quantity of an anti-bacterial agent (i.e., an
antibiotic) and a
therapeutically effective quantity of an anti-inflammatory agent (e.g., a
corticosteroid). In
some embodiments, the pharmaceutical compositions can be used for intraocular
injections.
In other embodiments the pharmaceutical compositions can be used for intra-
articular or
intra-lesional use. In yet other embodiments the pharmaceutical compositions
can be used for
delivery via eye drops. The compositions further include one or several
pharmaceutically
acceptable excipient(s) and one or several pharmaceutically acceptable
carrier(s).
[0041] The concentration of the anti-bacterial agent in the pharmaceutical
composition
may be between about 0.01mg/mL and about 50.0 mg/mL, such as between about 0.5
mg/mL
and about 10 mg/mL, for example, about 1.0 mg/mL. The concentration of the
anti-
inflammatory agent in the pharmaceutical composition may be between about
0.1mg/mL and
about 100.0 mg/mL, such as between about 5.0 mg/mL and about 50.0 mg/mL, for
example,
about 15.0 mg/mL.
[0042] According to further embodiments, the anti-bacterial agent to be
employed in the
active component of the composition may be selected from the group of
quinolones,
including fluoroquinolones, and suitable derivatives of the same, such as
pharmaceutically
acceptable salts, hydrates or solvates thereof In one embodiment, the
fluoroquinolone that
may be so employed is moxifloxacin (chemically, 1-cyclopropy1-740 S,6S)-2,8-
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diazabicyclo-[4.3.01non-8-y1]-6-fluoro-8-methoxy-4-oxo-quinoline-3-carboxylic
acid), which
is available, e.g., under trade name Avelox from Bayer Healthcare Corp. of
Wayne, New
Jersey, and under other trade names from other suppliers such as Alcon Corp.
and Bristol-
Myers Squibb Co., and has the following chemical structure:
11(1ZOCHY
-1
N N
OH
F
0 .
[0043] A non-limiting example of a possible alternative fluoroquinolone
antibiotic that
may be used instead of, or in combination with. moxifloxacin is gatifloxacin.
[0044] In some further embodiments one or several glycopeptide antibiotic(s),
or a
combination of some or all of them, may be optionally used as a part of the
anti-bacterial
agent, in combination with (i.e., in addition to) moxifloxacin. One example of
such an
acceptable additional glycopeptide antibiotic is vancomycin, which can be
introduced into the
pharmaceutical composition at a concentration between about 1.0 mg/mL and
about 100.0
mg/mL, such as between about 5.0 mg/mL and about 50.0 mg/mL, for example,
about 10.0
mg/mL. Vancomycin is available under the trade name Vancocin from Eli Lilly &
Co. of
Indianapolis, Indiana. Other acceptable additional glycopeptide antibiotics
that may be so
optionally used include teicoplanin, telavancin, decaplanin, ramoplanin,
gentamicin,
tobramyein, amikacin, cefuroxime, polymyxin B sulfate, and trimethoprim.
[0045] According to further embodiments, the anti-inflammatory agent to be
employed in
the active component of the composition may be selected from the group of
corticosteroids,
such as derivatives of coriicosterone, and pharmaceutically acceptable salts,
hydrates,
solvates, ethers, esters, acetals and ketals thereof. For example, a product
obtained as a result
of a chemically reasonable substitution of any hydrogen and/or hydroxyl group
in the
molecule of corticosterone may be used. In one embodiment, a corticosteroid
that can be so
utilized is triamcinolone (chemically, (1113,16a)-9-fluoro-11,16,17,21-
tetrahydroxypregna-
1,4-diene-3,20-dione), having the following chemical formula:
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OH
HO
10,
110 II fa
0
100461 In another embodiment, a corticosteroid that can be so utilized is
triamcinolone
acetonide (chemically, (4aS,4bR,5S,6aS,6bS,9aR,10aS,1 ObS)-4b-fluoro-6b-
glycoloy1-5-
hydroxy-4a,6a,8,8-tetrarnethy1-4a,4b,5,6,6a,6b,9a,1 0, 10a, l ob,11,1 2-
dodecahydro-2H-
naphtho[2',1':4,51indeno[1,2-d][1,3]dioxol-2-one), which is a ketal derivative
of
triamcinolone available, e.g., under the trade name Kenalog from Bristol-
Myers Squibb Co.
of Princeton, New Jersey, and under other trade names from other suppliers,
and having the
following chemical formula:
OH
0
HO
01110v ..A0
0
0
100471 Other corticosteroids, or a combination of some or all of them, may
be used
instead of all or a portion of triamcinolone and/or of all or a portion of
triamcinolone
acetonide. Some non-limiting examples of such acceptable other corticosteroids
or
glucocorticoids include triamcinolone diacetate, triamcinolone benetonide,
triamcinolone
furetonide, triamcinolone hexacetonide, betamethasone acetate, dexamethasone,
fluorometholone and fluocinolone acetonide, prednisone, prednisolone,
methylprednis one,
corticol, cortisone, fluorocortisone, deoxycorticosterone acetate,
aldosterone, budesonide and
derivatives, analogs or combinations thereof
100481 Some of these corticosteroids, e.g., without limitation, prednisone,
prednisolone,
dexamethasone, or methylprednisone are considered particularly suitable in
methods for
performing a keratomileusis or corneal refractive surgery (e.g., LASIK
surgery) described
below in more detail. Those having ordinary skill in the art of ophthalmology
or pharmacy
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will determine which corticosteroids are to be used in a specific surgical
procedure to be
performed.
100491 According to other embodiments, pharmaceutical compositions
described herein
may further optionally include pharmaceutically effective quantities of one or
several non-
steroid anti-inflammatory drug(s) or NSAID(s). The concentration of NSAID(s)
in the
pharmaceutical composition, if used, may be between about 0.1mg/mL and about
100.0
mg/mL, such as between about 5.0 mg/mL and about 50.0 mg/mL. for example,
about 15.0
mg/mL.
[0050] If the pharmaceutical compositions disclosed herein do include
NSAID(s), it is
envisioned that some compositions should be free of the specific NSAID,
bromfenac. In
other embodiments, however, bromfenac may be used as well as such NSAID(s) as
any of
ketorolac, etodolac, sulindac, diclofenac, aceclofenac, nepafenac, tolmetin,
indomethacin,
nabumetone, ketoprofen, dexketoprofen, ibuprofen, flurbiprofen, dexibuprofen,
fenoprofen,
loxoprofen, oxaprozin, naproxen, aspirin, salicylic acid, diflunisal,
salsalate, mefenamic acid,
meclofenamic acid, flufenamic acid, tolfenamic acid, meloxicam, piroxicam,
temoxicam,
droxicam, lomoxicam, isoxicam, celecoxib, rofecoxib, valdecoxib, parecoxib,
lurniracoxib,
etoricoxib, firocoxib, nimesulide, clonixin, licofelone, and pharmaceutically
acceptable salts,
hydrates, solvates, ethers, esters, acetals and ketals thereof
[0051] As mentioned above, the pharmaceutical composition that is the
subject matter of
the instant application may further optionally include one or several
pharmaceutically
acceptable excipient(s). Those having ordinary skill in the art will be able
to select the
suitable excipient(s). It is worth mentioning that when moxifloxacin is used
in
pharmaceutical formulations, it is often difficult to obtain a stable
suspension of another
product (e.g., a corticosteroid such as triamcinolone acetonide) that is
present in the same
formulation and that needs to be in a form of a stable suspension. Without
being bound by
any particular scientific theory, such difficulties in obtaining the stable
suspension are
believed to be caused by moxifloxacin's tendency to deactivate many suspending
agents
resulting in unacceptable coagulation, clumping and flocculation. As a result,
normal
delivery through a typical 27-29 gage cannula is often difficult or even
impossible.
[0052] Therefore, it is desirable to select an excipient that is stable in
the presence of
moxifloxacin and can, therefore, be used as a solubilizing and suspending
agent to ensure that
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the corticosteroid such as triamcinolone acetonide safely forms a stable
suspension even
when moxifloxacin is also present in the same formulation. Numerous attempts
by others to
produce a stable moxifloxacin/triamcinolone acetonide pharmaceutical
composition suitable
for intraocular injection have not been successful.
[0053] Presently disclosed embodiments teach that combinations of at least
two
solubilizing and suspending agents, i.e., a first solubilizing and suspending
agent and a
second solubilizing and suspending agent, can be used to formulate the
excipients to be used
in the compositions of the present invention. According to embodiments of the
invention, at
least one first solubilizing and suspending agent and at least one second
solubilizing and
suspending agent are present in the compositions.
[0054] In some embodiments, an excipient that can be used as the first
solubilizing and
stabilizing agent to overcome the above-described difficulties, and thus to
obtain a stable
suspension of the corticosteroid such as triamcinolone acetonide or
prednisolone, may be a
non-ionic polyoxyethlene-polyoxypropylene block copolymer having the following
general
structure:
HO¨(CI-12¨CH2-0)x¨(C3I-16-0))¨(CH2¨CE2-0),,¨H,
wherein x is an integer having the value of at least 8 and y is an integer
having the value of at
least 38.
[0055] When a non-ionic polyoxyethlene-polyoxypropylene block copolymer is
used as
the first solubilizing and stabilizing agent in the pharmaceutical
compositions of the instant
invention, its contents in the overall composition may be between about 0.01
mass % and
about 10.0 mass (?4), such as between about 1.0 mass % and about 8 mass (?4),
for example,
about 5.0 mass %.
100561 One non-limiting example of a specific non-ionic polvoxyethlene-
polyoxypropylene block copolymer that can be used as the first solubilizing
and stabilizing
agent in the pharmaceutical compositions of the instant invention is the
product known under
the trade name Poloxamer 407 (poly(ethylene glycol)-block-poly(propylene
glycol)-block-
poly(ethylene glycol)) available from Sigma-Aldrich Corp. of St. Louis,
Missouri, with the
molecular weight of the polyoxypropylene portion of about 4,000 Daltons, about
a 70%
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polyoxyethylene content, the overall molecular weight of between about 9,840
Daltons and
about 14,600 Daltons and having the following chemical structure:
CH3
0
H 0 OH
X Y. =
[0057] An excipient that can be used as the second solubilizing and
stabilizing agent can
be a water-soluble derivative of cellulose, water-soluble, optionally
partially cross-linked
polyacrylates, and products of Polysorbate family, or combinations thereof
[0058] Suitable water-soluble derivatives of cellulose that may be used
include, without
limitations, carboxymethyl cellulose, methyl cellulose, hydroxyethyl
cellulose, and
hydroxypropyl cellulose available, among other sources, from The Dow Chemical
Company
of Midland, Michigan. Examples of acceptable water-soluble, partially cross-
linked,
polyacrylates that may be used include, without limitations, such polymers of
the Carbopol
family available from The Lubrizol Corporation of Wickliffe, Ohio. Typically,
the cross-
linking agents that may be used to cross-link such polyacrylates are ally'
sucrose or allyl
pentaerythritol.
[0059] Suitable products of the Polysorbate family (i.e., ethoxylated
sorbitan esterified
with fatty acids) that may be used include, without limitations,
polyoxyethylene sorbitan
monolaurates, polyoxyethylene sorbitan monopalmitates, polyoxyethylene
sorbitan
monostearates, or polyoxyethylene sorbitan monooleates, some of which are also
known as
Tween0 products, such as Polysorbate 80t, can be used as the second
solubilizing and
stabilizing agent. Such products are available from Croda Americas, L.L.C. of
Wilmington,
Delaware or from Sigma-Aldrich Corp., among other suppliers making these
products
available.
[0060] One typical product of the latter family that can be used is
Polysorbate 80
(chemically, polyoxyethylene (20) sorbitan monooleate, also known as sorbitan
mono-9-
octadecenoate poly(oxy-1,2-ethanediy1), i.e., a product of polycondensation of
polyethoxylated
sorbitan and oleic acid having 20 units derived from ethylene glycol), a
nonionic surfactant and
emulsifier having the structure:
12
0
Ovt, 0
0 OH
HO
w*x*y*z =20
[0061] Non-limiting examples of some other excipients and carriers that
may be used in
preparing in the pharmaceutical compositions of the instant invention include
edetate calcium
disodium (EDTA, a chelating agent), hydrochloric acid (the pH adjuster) and
sterile water.
[0062] According to embodiments of the present application, the
pharmaceutical
compositions described herein are formulated as stable two-phase suspensions,
as defined
above. More specifically, according to these embodiments, the suspensions at
issue consist
of two phases, i.e., a dispersed phase that is dispersed within the dispersion
medium. The
dispersed phase consists of solid particles consisting of a therapeutically
effective quantity of
a corticosteroid. No compounds other than the corticosteroids described
hereinabove are
present within the solid particles that form the dispersed phase.
[0063] According to such embodiments, the dispersion medium is a liquid
that includes all
other compounds that are present in the pharmaceutical compositions described
in the
application. The application envisions no embodiment where a corticosteroid
can be used
outside the dispersed phase such as in the dispersion medium. Specifically,
the dispersion
medium includes the following components (a)-(e):
(a) at least one anti-bacterial agent of the quinolone group (i.e., quinolone,
a
fluorinated quinolone and derivatives as described);
(b) at least two solubilizing and suspending agents (i.e., a non-ionic
polyoxyethlene-polyoxypropylene block copolymer plus a polysorbate);
(c) at least one glycopeptide antibiotic (i.e., vancomycin, or other
antibiotic(s)
described hereinabove), the use of this component in the dispersion medium is
optional;
(d) also optionally, at least one non-steroid anti-inflammatory drug such as
bromfenac or other NSAIDs described hereinabove; and
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(e) a carrier.
[0064] According to further embodiments, methods for fabricating the above-
described
pharmaceutical compositions are provided. A one-batch formulation method may
be used,
where the components of the pharmaceutical formulation can be combined in
single
container; the components may be added to the container simultaneously or
consecutively.
[0065] In one exemplary, non-limiting procedure, the process of preparing
the
pharmaceutical compositions described hereinabove may commence by forming the
aqueous
dispersion medium. To form the aqueous dispersion medium, a quantity of an
anti-bacterial
agent such as moxifloxacin may be put into a mixing container followed by
adding a quantity
of sterile water and hydrochloric acid to obtain a slightly acidic mixture
(e.g., having a pH of
about 6.5), which can be stirred until a clear solution is obtained. In case
of moxifloxacin/HC1
system, the solution is stable, allowing the formulation to remain closed
system thus
preventing contamination and the loss of sterility.
[0066] After such clear stable solution has been formed, more components
may be added
to the solution that is to become the dispersion medium of the final
suspension, i.e., a quantity
of Poloxamer 407 and/or a quantity of polysorbate 80, a quantity of edetate
calcium
disodium, optionally a quantity of an antibiotic (e.g., vancomycin), and
optionally a quantity
of an NSAID (e.g., bromfenac) may all be added to the same container with the
already
prepared moxifloxacinIHC1 solution.
[0067] At the same time, a quantity of corticosteroid such as micronized
triamcinolone
acetonide can be added to the above described solution, followed by stirring
everything
together (e.g., by spinning) for a period of time, e.g., about 6 hours, until
a homogenous
suspension has been obtained. In the resulting suspension two phases are
therefore formed:
the dispersed phase of the corticosteroid and the dispersion medium into which
the aqueous
solution described above has now been transformed.
[0068] The resulting suspension may then be transferred into single dose
vials, capped,
sealed, autoclaved and shaken until cool. Finally, a complete testing for
sterility and the
presence of endotoxin may be performed on the product according to commonly
used
methods known to those having ordinary skill in the art.
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[0069] Pharmaceutical compositions prepared as described above can be used
to prevent
complications that may arise after ophthalmic surgical operations and
procedure. For
example, the formulations can be used during any intraocular surgery, such as
cataract
surgery, planned vitrectomy or glaucoma procedures, to prevent or at least
substantially
reduce the risk of post-surgery complications, such as the development of
endophthalmitis or
cystoid macular edema (CME), without having the patient use pre- or post-
operative topical
ophthalmic drops. Individuals with evidence of endophthalmitis from prior
surgical
procedures or traumatic ocular penetration will benefit from concurrent
injection of these
formulations to sterilize infection and reduce damaging inflammation.
[0070] Pharmaceutical formulations described herein can be delivered via
intraocular
intravitreal injection which can be transzonular, or, if desired not
transzonular. Intraocular
intravitreal injection of this formulation, whether done via transzonular or
via direct pars
plana (trans-scleral) injection, delivers potent broad spectrum antibiotics
directly into
the suppurative tissue without requiring the urgent compounding of multiple
individual
medications or multiple individual injections into the eye.
[0071] Typically, a pharmaceutical composition described above will be
intraocularly
administered to a mammalian subject (e.g., humans, cats, dogs, other pets,
domestic, wild or
farm animals) in need of emergent, urgent or planned ophthalmic surgery
treatment. The
effect achieved by such use of pharmaceutical composition described above may
last up to
four weeks. The composition is to be injected intravitreally and trans-
zonularly using
methods and techniques known to those having ordinary skilled in the art of
ophthalmology.
In some embodiments, the injection can be intraoperative.
[0072] Typically, the delivery through a typical 27 gauge cannula can be
employed
utilizing a 1 mL TB syringe, with attention to re-suspending the formulation
using
momentary flicks and shake just prior to injection. The medicinal volume
(i.e., dosage)
required of this formulation varies based on the type of intraocular
procedure, the degree of
postoperative inflammation induced or anticipated, the risk assessment for
postoperative
infection, and anatomic considerations regarding the available volume for the
injection being
added to a closed intraocular space.
[0073] It is worth mentioning that while intracameral (that is, anterior
chamber) injections
are within the scope of the instant invention, such injections instead of
posterior chamber
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(intravitreal) injection may not be satisfactory in some cases, as the
suspension clogs the
trabecular meshwork and aggravates intraocular drainage, resulting in a
postoperative rise in
intraocular pressure. This may be avoided with intravitreal injection, in
addition to retaining
the formulation components into the protein matrix of the vitreous of a
greater
duration. Anterior chamber wash out occurs over hours (antibiotic in solution)
and days
(steroid in suspension), while intravitreal injection is retained for weeks.
[0074] In alternative embodiments, if desired or necessary, the
formulations may also be
delivered in the form of eye drops or eye sprays; as well as via
subconjunctival injection,
intraocular intracameral injection, sub-tenon injection, intra-articular
injection or intra-
lesional injection, particularly, in, but not limited to, some cases when
necessary to deliver
additional medication when local ocular inflammation and extra-ocular
infection need
suppression. Intravitreal delivery of steroid has historically been used to
treat clinically
significant cystoid macular edema (CME); the application of this formulation
into the
vitreous during routine intraocular procedures brings more aggressive
prophylaxis against
CME occurrence. Additionally, the suspension of this formulation is useful for
staining
vitreous during planned and unplanned vitrectomies, improving visualization of
this
otherwise transparent intraocular tissue, improving vitrectomy outcomes and
reducing
complications resulting from inadequate or tractional vitreous removal. In
still further
embodiments, there is also envisioned intra-canalicular delivery, i.e.,
delivery via a lacrimal
canaliculus implant. In yet other embodiments, the formulation may be also
delivered via
anterior chamber injection or capsular bag placement of medication. A solution
could be also
added to the irrigating solution that is used during cataract surgery which
could allow for the
bottles, tubing, etc. to become "sterilized" during surgery. Intracomeal
delivery through laser
created corneal channels that could hold medication can be also used, if
desired.
[0075] In some further alternative embodiments, instead of delivering the
above-described
compositions comprising both anti-bacterial and anti-inflammatory agents,
consecutive
injections may be used instead, if desired. For example, triamcinolone or
prednisolone may
be injected first, immediately followed by the injection of moxifloxacin or
vice versa.
[0076] In still further embodiments, the pharmaceutical applications described
hereinabove
may be used before or after performing corneal refractive surgery or a
keratomileusis surgery
such as LASIK surgery. To illustrate, a pharmaceutical composition to be used
for these
purposes may include any corticosteroid and any anti-bacterial agent described
above, to be
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selected by the skilled practitioner. To further exemplify, but 1101 10 unduly
limit, prednisone,
prednisolone or methylprednisone may be chosen as the former and moxifloxacin
as the
latter. As a further non-limiting illustration, the formulations used in
conjunction with a
keratomileusis surgery may have the concentration of the anti-bacterial agent
such as
moxifloxacin between about 0.01mg/mL and about 50.0 mg/mL, such as between
about 0.5
mg/nil, and about 10 mg/mL, for example, about 1.0 mg/mL; and the
concentration of the
corticosteroid such as prednisone between about 0.1mg/mL and about 100.0
mg/mL, such as
between about 5.0 mg/mL and about 50.0 mg/mL, for example, about 15.0 mg/mL.
[0077] It will be understood by those having ordinary skill in the art that
the specific dose
level and frequency of dosage for any particular patient may be varied and
will depend upon
a variety of factors including the activity of the specific compound employed,
the metabolic
stability and length of action of that compound, the age, body weight, general
health, gender,
diet, and the severity of the particular ophthalmological condition being
treated.
[0078] In additional embodiments, pharmaceutical kits are provided. The kit
includes a
sealed container approved for the storage of pharmaceutical compositions, the
container
containing one of the above-described pharmaceutical compositions. An
instruction for the
use of the composition and the information about the composition are to be
included in the
kit.
[0079] The following examples are provided to further elucidate the
advantages and
features of the present invention, but are not intended to limit the scope of
the invention. The
examples are for the illustrative purposes only. USP pharmaceutical grade
products were
used in preparing the formulations described below.
C. Examples
Example 1. Preparing a Pharmaceutical Composition
[0080] A pharmaceutical composition was prepared as described below. The
following
components were used in the amounts and concentrations specified:
(a) about 1.5 g of triamcinolone acetonide, at a concentration of about 15.0
mg/mL;
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(b) about 0.1 g of moxifloxacin hydrochloride, at a concentration of about 1.0
mg/mL:
(c) about 1 mL of polysorbate 80, at a concentration of about 1.0 mass %;
(d) about 0.2 g of edetate calcium disodium, at a concentration of about 0.2
mass %;
(e) about 1 g of Poloxamer 407 , at a concentration of about 1.0 mass %;
(f) hydrochloric acid, to adjust pH to about 6.5; and
(g) about 100.0 mL of sterile water for injection.
[0081] Moxifloxacin hydrochloride was placed into a de-pyrogenated beaker
with a spin
bar. Sterile water for injection was added to about 1/3 of the volume of the
beaker. While
spinning, moxifloxacin was dissolved by adding hydrochloric acid until a clear
solution
having the final pH of about 6.5 was obtained.
[0082] The solution was combined with micronized triamcinolone acetonide,
Poloxamer
407, edetate calcium disoudium and polysorbate 80 and allowed to spin for
about 6 hours
until a hydrated and homogenous suspension was obtained.
[0083] The suspension was transferred into de-pyrogenated, single dose
vials (2mL size),
capped and sealed, followed by autoclaving and shaking the vials until cool.
Complete
sterility and endotoxin testing was performed by an outside laboratory to
ensure safety.
[0084] The formulation prepared as described above was tested for the
particle sizes and
their distribution. The results showed that very fine particles were obtained
and the size
distribution was quite uniform. Specifically, about 99% of all the particles
had the diameter
of 5 04 or less, where the sizes within the range between about 1 ttIVI and 4
tiM dominated
and constituted about 82% of all particles. Just 0.1 to 0.2 % of all the
particles were large
than about 10 uM in diameter.
100851 The formulation prepared as described above was also tested for
stability after 6
months of storage. After this period of storage no loss of potency was
observed (as measured
by HPLC); the formulation was visually stable at room temperature and readily
re-suspended
with gentle shaking with no increase of particle size or flocculation.
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Example 2. Preparing a Pharmaceutical Composition Containing Vancomycin
[0086] A pharmaceutical composition was prepared as described in Example 1,
supra.
The composition was autoclaved and sonicated for about 60 minutes and about 96
mL of the
composition were combined with about 4 mL of vancomycin at a concentration of
about 250
mg/mL. The pH of the mixture was adjusted to about 6.0-6.5 using hydrochloric
acid. The
product was then transferred into vials (at about 1 mL plus 5 drops per vial)
and frozen. The
product has kept its stability and potency for at least six months.
Example 3. Using a Pharmaceutical Composition
[0087] A pharmaceutical composition fabricated as described in Example 1,
supra. was
administered to about 1,600 patients. To each, it was introduced using
intravitreal
transzonular injection. The injection was intraoperative. Only a very few
patients, at the rate
of about only 1 in 4,000, have developed any infection or suffered from other
side effects that
required further treatment, which is a substantial improvement over a typical
rate of about 8%
for the patients that did not receive the injection.
Example 4. Preparing a Pharmaceutical Composition Containing Prednisolone
[0088] A pharmaceutical composition was prepared as described below. The
following
components were used in the amounts specified:
(a) about 1.5 g of micronized prednisolone acetate;
(b) about 0.1 g of moxifloxacin hydrochloride;
(c) about 1 mL of an aqueous solution of polysorbate 80, at a concentration of
about
1.0 mass %;
(d) about 0.2 g of edetate calcium disodium;
(e) about 1.2 g of Poloxamer 4071';
(f) hydrochloric acid; to adjust pH to about 6.5; and
(g) about 100.0 mL of sterile water for injection.
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[0089] Moxifloxacin hydrochloride was placed into a de-pyrogenated beaker
with a spin
bar. Sterile water for injection was added to about 1/3 of the volume of the
beaker. While
spinning, moxifloxacin was dissolved by adding hydrochloric acid until a clear
solution
having the final pH of about 6.0 to 6.5 was obtained.
[0090] The solution was combined with micronized prednisolone acetate,
Poloxamer
407 , edetate calcium disoudium and polysorbate 80 and allowed to spin until a
hydrated and
homogenous product was obtained. It is expected that the particle sizes and
their distribution
are similar to those described in Example 1, above. The product was then
transferred into de-
pyrogenated, single dose vials (about 1 mL of the product in 3mL size vial),
capped and
sealed, followed by autoclaving, shaking and sonicating the vials for about 1
hour.
[0091] In a second experiment, another prednisolone-based composition was
prepared in
exactly the same way, except that the quantity of micronized prednisolone
acetate was about
1.0 g (instead of about 1.5 g) and the quantity of moxifloxacin hydrochloride
was about 0.5 g
(instead of 0.1 g).
[0092] Prednisolone based composition obtained as described in this Example
can then be
administered to a patient by ordinarily skilled ophthalmologists as eye drops
after performing
a keratomileusis surgery such as LASIK surgery, e.g., as follow-up care.
Example 5. Preparing a Pharmaceutical Composition Containing NSAID Bromfenac
[0093] A pharmaceutical composition was prepared as described below. The
following
components were used in the amounts specified:
(a) about 10.0 g of micronized prednisolone acetate;
(b) about 5.454 g of moxifloxacin hydrochloride monohydrate;
(c) about 1.035 g of bromfenac sodium powder;
(d) about 10.0 nit of an aqueous solution of polysorbate 80, at a
concentration of
about 1.0 mass %;
(e) about 4.0 g of boric acid powder;
(t) about 14.0 g of Poloxamer 407 ;
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(g) about 3.17 g of sodium chloride granules;
(h) 20% solution of sodium hydroxide, to adjust pH; and
(i) about 1.0 L of sterile water for injection.
[0094] Moxifloxacin hydrochloride was placed into a de-pyrogenated beaker
with a spin
bar. Sterile water for injection was added, about 60% of the total volume of
water. While
spinning, moxifloxacin was dissolved by adding sodium hydroxide to adjust the
pH to about
7.4 to 7.8, followed by additional stirring for about 5 minutes, until a clear
solution was
obtained. Bromfenac was then added, with continued stirring, until completely
dissolved
which is indicated by the solution being visibly clear. The pH then was
adjusted again to
maintain it in the range of 7.4 to 7.8.
[0095] The solution was combined with polysorbate 80, Poloxamer 407 and
boric acid,
with continued stirring, followed by slowly adding micronized prednisolone
acetate, the
remainder of water, with continued spinning for about 20 minutes, until a
hydrated and
homogenous product was obtained.
[0096] The product was then transferred into pre-sterilized de-pyrogenated,
100 mL vials,
capped and sealed, followed by autoclaving (about 121 C and about 15.0 psi of
pressure for
about 30 minutes) shaking and sonicating the vials for about 30 minutes.
[0097] The composition obtained as described in this Example can then be
administered to
a patient by ordinarily skilled ophthalmologists as eye drops after performing
a
keratomileusis surgery such as LASIK surgery, e.g.; as follow-up care.
[0098] Although the invention has been described with reference to the
above examples,
it will be understood that modifications and variations are encompassed within
the spirit and
scope of the invention. Accordingly, the invention is limited only by the
following claims.
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