U.S. patent application number 14/629173 was filed with the patent office on 2015-06-18 for pharmaceutical compositions for intraocular administration and methods for fabricating thereof.
This patent application is currently assigned to IMPRIMIS PHARMACEUTICALS, INC.. The applicant listed for this patent is IMPRIMIS PHARMACEUTICALS, INC.. Invention is credited to Mark L. Baum, Joseph S. Bitterman, Richard Dilzer, Forest J. Flodin.
Application Number | 20150164882 14/629173 |
Document ID | / |
Family ID | 53367105 |
Filed Date | 2015-06-18 |
United States Patent
Application |
20150164882 |
Kind Code |
A1 |
Dilzer; Richard ; et
al. |
June 18, 2015 |
PHARMACEUTICAL COMPOSITIONS FOR INTRAOCULAR ADMINISTRATION AND
METHODS FOR FABRICATING THEREOF
Abstract
Pharmaceutical compositions for intraocular injection are
described, the compositions consisting essentially of a
therapeutically effective quantity of an anti-bacterial agent (such
as moxifloxacin), a therapeutically effective quantity of an
anti-inflammatory agent (such as triamcinolone), at least one
pharmaceutically acceptable excipient and a pharmaceutically
acceptable carrier. Methods for fabricating the compositions and
using them for intraocular injections are also described.
Inventors: |
Dilzer; Richard; (Long
Valley, NJ) ; Flodin; Forest J.; (San Diego, CA)
; Bitterman; Joseph S.; (San Diego, CA) ; Baum;
Mark L.; (San Diego, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
IMPRIMIS PHARMACEUTICALS, INC. |
San Diego |
CA |
US |
|
|
Assignee: |
IMPRIMIS PHARMACEUTICALS,
INC.
San Diego
CA
|
Family ID: |
53367105 |
Appl. No.: |
14/629173 |
Filed: |
February 23, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14227819 |
Mar 27, 2014 |
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14629173 |
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61958170 |
Jul 22, 2013 |
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Current U.S.
Class: |
514/3.1 ;
514/171 |
Current CPC
Class: |
A61K 31/496 20130101;
A61K 31/58 20130101; A61K 38/14 20130101; A61K 31/4709 20130101;
A61K 31/496 20130101; A61K 45/06 20130101; A61K 31/58 20130101;
A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 2300/00
20130101; A61K 2300/00 20130101; A61K 2300/00 20130101; A61K 31/573
20130101; A61K 31/4709 20130101; A61K 31/407 20130101; A61K 38/14
20130101; A61K 31/573 20130101; A61K 9/0048 20130101 |
International
Class: |
A61K 31/4709 20060101
A61K031/4709; A61K 31/573 20060101 A61K031/573; A61K 38/14 20060101
A61K038/14; A61K 31/407 20060101 A61K031/407; A61K 9/00 20060101
A61K009/00; A61K 31/58 20060101 A61K031/58 |
Claims
1. An ophthalmological pharmaceutical composition, comprising: (a)
a therapeutic component consisting essentially of: (a1) a
therapeutically effective quantity of an anti-inflammatory agent
independently selected from the group consisting of corticosteroids
and pharmaceutically acceptable salts, hydrates, solvates, ethers,
esters, acetals and ketals thereof; and (a2) a therapeutically
effective quantity of non-steroid anti-inflammatory drug that is
free of bromfenac; (b) optionally, at least one pharmaceutically
acceptable excipient; and (c) optionally, a pharmaceutically
acceptable carrier therefor.
2. The pharmaceutical composition of claim 1, wherein the
therapeutic component further comprises a therapeutically effective
quantity of a primary anti-bacterial agent independently selected
from the group consisting of quinolone, a fluorinated quinolone and
pharmaceutically acceptable salts, hydrates, solvates or N-oxides
thereof.
3. The pharmaceutical composition of claim 2, wherein the primary
anti-bacterial agent is a fluorinated quinolone.
4. The pharmaceutical composition of claim 3, wherein the
fluorinated quinolone is selected from the group consisting of
moxifloxacin and gatifloxacin.
5. The pharmaceutical composition of claim 4, wherein the
fluorinated quinolone is moxifloxacin.
6. The pharmaceutical composition of claim 2, wherein the primary
anti-bacterial agent is a fluorinated quinolone having the chemical
structure (A): ##STR00007##
7. The pharmaceutical composition of claim 1, wherein the
corticosteroid is selected from the group consisting of
triamcinolone, triamcinolone acetonide, triamcinolone diacetate,
triamcinolone benetonide, triamcinolone furetonide, triamcinolone
hexacetonide, betamethasone acetate, dexamethasone,
fluorometholone, fluocinolone acetonide, prednisone, prednisolone,
methylprednisone, corticol, cortisone, fluorocortisone,
deoxycorticosterone acetate, aldosterone, budesonide and
derivatives, analogs or combinations thereof.
8. The pharmaceutical composition of claim 2, wherein: (a) the
anti-bacterial agent is moxifloxacin; and (b) the corticosteroid is
triamcinolone or a derivative thereof.
9. The pharmaceutical composition of claim 1, wherein the
corticosteroid is triamcinolone.
10. The pharmaceutical composition of claim 1, wherein the
corticosteroid has the chemical structure (B): ##STR00008##
11. The pharmaceutical composition of claim 1, wherein the
non-steroid anti-inflammatory drug is selected from the group
consisting 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, ternoxicam,
droxicam, lornoxicam, isoxicam, celecoxib, rofecoxib, valdecoxib,
parecoxib, lumiracoxib, etoricoxib, firocoxib, nimesulide,
clonixin, licofelone, pharmaceutically acceptable salts, hydrates,
solvates, ethers, esters, acetals and ketals thereof and a
combination thereof.
12. The pharmaceutical composition of claim 1, wherein the
excipient is a solubilizing and suspending agent selected from the
group consisting of non-ionic polyoxyethylene-polyoxypropylene
block copolymers.
13. The pharmaceutical composition of claim 12, wherein the
excipient is Poloxamer 407.RTM..
14. The pharmaceutical composition of claim 1, wherein the
therapeutic component further comprises a therapeutically effective
quantity of a secondary anti-bacterial agent selected from the
group consisting of vancomycin, teicoplanin, telavancin,
decaplanin, ramoplanin, gentamicin, tobramycin, amikacin,
cefuroxime and a combination thereof.
15. The pharmaceutical composition of claim 14, wherein the
anti-bacterial agent is vancomycin.
16. The pharmaceutical composition of claim 2, wherein the
therapeutic component further comprises a therapeutically effective
quantity of a secondary anti-bacterial agent selected from the
group consisting of vancomycin, teicoplanin, telavancin,
decaplanin, ramoplanin, gentamicin, tobramycin, amikacin,
cefuroxime and a combination thereof.
17. The pharmaceutical composition of claim 16, wherein the
anti-bacterial agent is vancomycin.
18. An ophthalmological pharmaceutical composition, comprising: (a)
a therapeutic component consisting essentially of: (a1) a
therapeutically effective quantity of a primary anti-bacterial
agent independently selected from the group consisting of
quinolone, a fluorinated quinolone and pharmaceutically acceptable
salts, hydrates, solvates or N-oxides thereof; and (a2) a
therapeutically effective quantity of non-steroid anti-inflammatory
drug that is free of bromfenac; (b) optionally, at least one
pharmaceutically acceptable excipient; and (c) optionally, a
pharmaceutically acceptable carrier therefor.
19. The pharmaceutical composition of claim 18, wherein the primary
anti-bacterial agent is a fluorinated quinolone.
20. The pharmaceutical composition of claim 19, wherein the
fluorinated quinolone is selected from the group consisting of
moxifloxacin and gatifloxacin.
21. The pharmaceutical composition of claim 20, wherein the
fluorinated quinolone is moxifloxacin.
22. The pharmaceutical composition of claim 18, wherein the primary
anti-bacterial agent is a fluorinated quinolone having the chemical
structure (A): ##STR00009##
23. The pharmaceutical composition of claim 18, wherein the
non-steroid anti-inflammatory drug is selected from the group
consisting 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, ternoxicam,
droxicam, lornoxicam, isoxicam, celecoxib, rofecoxib, valdecoxib,
parecoxib, lumiracoxib, etoricoxib, firocoxib, nimesulide,
clonixin, licofelone, pharmaceutically acceptable salts, hydrates,
solvates, ethers, esters, acetals and ketals thereof and a
combination thereof.
24. The pharmaceutical composition of claim 18, wherein the
excipient is a solubilizing and suspending agent selected from the
group consisting of non-ionic polyoxyethylene-polyoxypropylene
block copolymers.
25. The pharmaceutical composition of claim 24, wherein the
excipient is Poloxamer 407.RTM..
26. The pharmaceutical composition of claim 18, wherein the
therapeutic component further comprises a therapeutically effective
quantity of a secondary anti-bacterial agent selected from the
group consisting of vancomycin, teicoplanin, telavancin,
decaplanin, ramoplanin, gentamicin, tobramycin, amikacin,
cefuroxime and a combination thereof.
27. The pharmaceutical composition of claim 26, wherein the
secondary anti-bacterial agent is vancomycin.
28. An ophthalmological pharmaceutical composition, comprising: (a)
a therapeutic component consisting essentially of: (a1) a
therapeutically effective quantity of an anti-inflammatory agent
independently selected from the group consisting of corticosteroids
and pharmaceutically acceptable salts, hydrates, solvates, ethers,
esters, acetals and ketals thereof; and (a2) a secondary
anti-bacterial agent selected from the group consisting of
vancomycin, teicoplanin, telavancin, decaplanin, ramoplanin,
gentamicin, tobramycin, amikacin, cefuroxime and a combination
thereof; (b) optionally, at least one pharmaceutically acceptable
excipient; and (c) optionally, a pharmaceutically acceptable
carrier therefor.
29. The pharmaceutical composition of claim 28, wherein the
secondary anti-bacterial agent is vancomycin.
30. The pharmaceutical composition of claim 28, wherein the
corticosteroid is selected from the group consisting of
triamcinolone, triamcinolone acetonide, triamcinolone diacetate,
triamcinolone benetonide, triamcinolone furetonide, triamcinolone
hexacetonide, betamethasone acetate, dexamethasone,
fluorometholone, fluocinolone acetonide and a combination
thereof.
31. The pharmaceutical composition of claim 30, wherein the
corticosteroid is triamcinolone.
32. The pharmaceutical composition of claim 28, wherein the
corticosteroid has the chemical structure (B): ##STR00010##
33. A method for treating an ophthalmological disease, condition or
pathology in a mammalian subject in need of such treatment
comprising delivery to the subject the composition of claim 1,
wherein the method of delivery is selected from the group
consisting of intravitreal injection, intraocular intracameral
injection, intra-lesional injection, intra-articular injection,
subconjunctival injection, sub-tenon injection, delivery via eye
drops, delivery via spray and intra-canalicular delivery, to treat
the ophthalmological disease, condition or pathology thereby.
34. A method for treating an ophthalmological disease, condition or
pathology in a mammalian subject in need of such treatment
comprising delivery to the subject the composition of claim 2,
wherein the method of delivery is selected from the group
consisting of intravitreal injection, intraocular intracameral
injection, intra-lesional injection, intra-articular injection,
subconjunctival injection, sub-tenon injection, delivery via eye
drops, delivery via spray and intra-canalicular delivery, to treat
the ophthalmological disease, condition or pathology thereby.
35. A method for treating an ophthalmological disease, condition or
pathology in a mammalian subject in need of such treatment
comprising delivery to the subject the composition of claim 18,
wherein the method of delivery is selected from the group
consisting of intravitreal injection, intraocular intracameral
injection, intra-lesional injection, intra-articular injection,
subconjunctival injection, sub-tenon injection, delivery via eye
drops, delivery via spray and intra-canalicular delivery, to treat
the ophthalmological disease, condition or pathology thereby.
36. A method for treating an ophthalmological disease, condition or
pathology in a mammalian subject in need of such treatment
comprising delivery to the subject the composition of claim 28,
wherein the method of delivery is selected from the group
consisting of intravitreal injection, intraocular intracameral
injection, intra-lesional injection, intra-articular injection,
subconjunctival injection, sub-tenon injection, delivery via eye
drops, delivery via spray and intra-canalicular delivery, to treat
the ophthalmological disease, condition or pathology thereby.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This is a continuation-in-part patent application of U.S.
patent application Ser. No. 14/227,819 filed on Mar. 27, 2014
entitled "Pharmaceutical Compositions for Intraocular
Administration and Methods for Fabricating Thereof," and claims
priority under 35 U.S.C. .sctn.120 to the same, which in turn
claims priority under 35 U.S.C. .sctn.119(e) to U.S. Provisional
Application No. 61/958,170 filed on Jul. 22, 2013 entitled
"Pharmaceutical Compositions for Intraocular Administration and
Methods for Fabricating Thereof," the entire contents of each of
which is hereby incorporated by reference.
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 endophthalmitis, 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-inflammatory
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.
[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 embodiments of the invention, ophthalmological
pharmaceutical compositions are provided, the compositions
comprising a therapeutic component, at least one pharmaceutically
acceptable excipient and/or a pharmaceutically acceptable carrier
that are suitable for intraocular administration such as an
injection. Embodiments of the invention further provide that the
therapeutic component comprises, consists or consists essentially
of various combinations of a therapeutically effective quantity of
an anti-bacterial agent (i.e., an antibiotic), and/or a
therapeutically effective quantity of an anti-inflammatory agent
(e.g., a corticosteroid) and/or a therapeutically effective
quantity of a non-steroid anti-inflammatory drug (NSAID).
[0007] According to further embodiments of the invention, such
ophthalmological pharmaceutical compositions comprise a therapeutic
component consisting essentially of a therapeutically effective
quantity of an anti-inflammatory agent independently selected from
the group consisting of corticosteroids and pharmaceutically
acceptable salts, hydrates, solvates, ethers, esters, acetals and
ketals thereof and a therapeutically effective quantity of
non-steroid anti-inflammatory drug that is free of bromfenac;
optionally, at least one pharmaceutically acceptable excipient; and
optionally, a pharmaceutically acceptable carrier.
[0008] According to other embodiments of the invention,
ophthalmological compositions are provided that comprise what is
described in the immediately preceding paragraph and in addition
further comprise a therapeutically effective quantity of a primary
anti-bacterial agent such as quinolone, a fluorinated quinolone and
pharmaceutically acceptable salts, hydrates, solvates or N-oxides
thereof, or alternatively such antibacterial agent as vancomycin or
related products described below with particularity.
[0009] According to yet further embodiments, such ophthalmological
pharmaceutical compositions comprise a therapeutic component
consisting essentially of a therapeutically effective quantity of a
primary anti-bacterial agent independently selected from the group
consisting of quinolone, a fluorinated quinolone and
pharmaceutically acceptable salts, hydrates, solvates or N-oxides
thereof and a therapeutically effective quantity of non-steroid
anti-inflammatory drug that is free of bromfenac; and optionally,
at least one pharmaceutically acceptable excipient; and optionally,
a pharmaceutically acceptable carrier.
[0010] According to further embodiments of the invention, such
ophthalmological pharmaceutical compositions comprise
[0011] 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.
[0012] 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.
[0013] According to another embodiment of the invention, the
pharmaceutical compositions described herein may further include a
solubilizing and suspending agent such as non-ionic
polyoxyethylene-polyoxypropylene block copolymer, e.g., Poloxamer
407.RTM..
[0014] According to other embodiments of the invention, the
pharmaceutical compositions described herein may be intravitreally
transzonularly injected into a mammalian subject as a 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
[0015] 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.
[0016] 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.
[0017] 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.
[0018] "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.
[0019] 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.
[0020] The term "intraocular injection" refers to an injection that
is administered by entering the eyeball of the patient.
[0021] 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.
[0022] The term "intravitreal" refers to an injection administered
through an eye of the patient, directly into the inner cavity of
the eye.
[0023] The term "intraoperative" is defined as an action occurring
or carried during, or in the course of, surgery.
[0024] 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"):
##STR00001##
[0025] The term "corticosteroid" is defined as a compound belonging
to a sub-genus of steroids that are derivatives of corticosterone,
the latter having the chemical structure:
##STR00002##
[0026] The term "non-steroid anti-inflammatory drug" or "NSAID"
refer to substances or compounds that are free of steroid moieties
and provide analgesic, antipyretic and/or anti-inflammatory
effects.
[0027] The terms "anti-bacterial" and "antibiotic" used herein
interchangeably, refer to substances or compounds that destroy
bacteria and/or inhibit the growth thereof via any mechanism or
route.
[0028] The term "anti-inflammatory" refers to substances or
compounds that counteract or suppress inflammation via any
mechanism or route.
[0029] The term "salt" refers to an ionic compound which is a
product of the neutralization reaction of an acid and a base.
[0030] 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").
[0031] The term "ether" refers to a chemical compound containing
the structure R--O--R.sub.1, where two organic fragments R and
R.sub.1 are connected via oxygen.
[0032] The term "ester" refers to a chemical compound containing
the ester group R--O--C(O)--R.sub.1, connecting two organic
fragments R and R.sub.1.
[0033] The terms "acetal" and "ketal" refer to a chemical compound
containing the functional group R--C(R.sub.1)(OR.sub.2).sub.2,
where R and R.sub.2 are organic fragments and R.sub.1 is hydrogen
atom (for acetals), and is inclusive of "hemiacetals" where one
R.sub.2 (but not the other) is hydrogen atom; or where none of R,
R.sub.1 and R.sub.2 is a hydrogen atom and each is an organic
fragment (for ketals).
[0034] 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.
[0035] The term "excipient" refers to a pharmacologically inactive
substance that is formulated in combination with the
pharmacologically active ingredient of pharmaceutical composition
and is inclusive of bulking agents, fillers, diluents and products
used for facilitating drug absorption or solubility or for other
pharmacokinetic considerations.
[0036] The term "therapeutically effective amount" is defined as
the amount of the compound or pharmaceutical composition that will
elicit the biological or medical response of a tissue, system,
animal or human that is being sought by the researcher, medical
doctor or other clinician.
[0037] 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.
[0038] 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
[0039] 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, any combination of two or three of the following
components:
[0040] (1) a therapeutically effective quantity of any
anti-bacterial agent (i.e., an antibiotic); and/or
[0041] (2) a therapeutically effective quantity of any
anti-inflammatory agent (e.g., a corticosteroid); and/or
[0042] (3) a therapeutically effective quantity of any non-steroid
anti-inflammatory drug (NSAID) except for bromfenac which is
explicitly excluded as described below.
[0043] In some embodiments, the active component of the
pharmaceutical compositions comprises, consists essentially of, or
consists of, all three of the above-mentioned agents, i.e., both an
antibiotic, a corticosteroid and an NSAID. In other embodiments,
only a corticosteroid and an NSAID are both present in the active
component but an antibiotic is absent. In yet other embodiments
only an antibiotic and an NSAID are both present in the active
component but a corticosteroid is absent.
[0044] In some embodiments, the pharmaceutical compositions can be
used for intraocular injections or can be administered as eye drops
or eye sprays as mentioned below. In other embodiments the
pharmaceutical compositions can be used for intra-articular or
intra-lesional use as also discussed below. The compositions
further include one or several pharmaceutically acceptable
excipient(s) and one or several pharmaceutically acceptable
carrier(s).
[0045] According to further embodiments, two kinds of
anti-bacterial agents may be used in the active component of
pharmaceutical compositions disclosed herein, primary
anti-bacterial agents and secondary anti-bacterial agents. When the
active component of pharmaceutical compositions disclosed herein
does include anti-bacterial agent(s), either a primary
anti-bacterial agent alone may be used (i.e., with no secondary
anti-bacterial agent being used) or a secondary anti-bacterial
agent alone may be used (i.e., with no primary anti-bacterial agent
being used); in some embodiments both primary and secondary
anti-bacterial agents may be used in the same compositions, if
desired.
[0046] The concentration of the primary anti-bacterial agent in the
pharmaceutical composition may be between about 0.01 mg/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.
[0047] If the primary anti-bacterial agent is to be employed in the
active component of the composition, such primary agent 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,
fluoroquinolone that may be so employed is moxifloxacin
(chemically,
1-cyclopropyl-7-[(1S,6S)-2,8-diazabicyclo-[4.3.0]non-8-yl]-6-fluoro-8-met-
hoxy-4-oxo-quinoline-3-carboxylic acid), which is available, e.g.,
under trade name Avelox.RTM. from Bayer Healthcare Corp. of Wayne,
N.J., and under other trade names from other suppliers such as
Alcon Corp. and Bristol-Myers Squibb Co. and has the following
chemical structure:
##STR00003##
[0048] A non-limiting example of a possible alternative
fluoroquinolone antibiotic that may be used instead of, or in
combination with, moxifloxacin is gatifloxacin.
[0049] If the secondary anti-bacterial agent is to be employed in
the active component of the composition, such secondary agent may
be selected from the group of glycopeptide antibiotic(s), or a
combination of some or all of them. One example of such an
acceptable additional glycopeptide antibiotic is vancomycin which
can be introduced into the pharmaceutical composition at a
concentration between about lmg/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.RTM. from Eli Lilly & Co. of Indianapolis, Ind. Other
acceptable additional glycopeptide antibiotics that may be used
include teicoplanin, telavancin, decaplanin, ramoplanin,
gentamicin, tobramycin, amikacin and cefuroxime.
[0050] According to further embodiments, the concentration of the
corticosteroid-type anti-inflammatory agent in the pharmaceutical
composition, if used, may be between about 0.1 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 15.0 mg/mL. Acceptable corticosteroid(s) may be
selected from the group of derivatives of corticosterone, 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,
(11.beta.,16.alpha.)-9-fluoro-11,16,17,21-tetrahydroxypregna-1,4-diene-3,-
20-dione) having the following chemical formula:
##STR00004##
[0051] In another embodiment, a corticosteroid that can be so
utilized is triamcinolone acetonide (chemically,
(4aS,4bR,5S,6aS,6bS,9aR,10aS,10bS)-4b-fluoro-6b-glycoloyl-5-hydroxy-4a,6a-
,8,8-tetramethyl-4a,4b,5,6,6a,6b,9a,10,10a,10b,11,12-dodecahydro-2H-naphth-
o[2',1':4,5]indeno[1,2-d][1,3]dioxol-2-one) which is a ketal
derivative of triamcinolone available, e.g., under the trade name
Kenalog.RTM. from Bristol-Myers Squibb Co. of Princeton, N.J., and
under other trade names from other suppliers, and having the
following chemical formula:
##STR00005##
[0052] 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
include triamcinolone diacetate, triamcinolone benetonide,
triamcinolone furetonide, triamcinolone hexacetonide, betamethasone
acetate, dexamethasone, fluorometholone and fluocinolone acetonide,
prednisone, prednisolone, methylprednisone, corticol, cortisone,
fluorocortisone, deoxycorticosterone acetate, aldosterone,
budesonide and derivatives, analogs or combinations thereof.
[0053] According to further embodiments, the concentration of
NSAID(s) in the pharmaceutical composition, if used, may be between
about 0.1 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 15.0 mg/mL. If the
active component of compositions disclosed herein does includes
NSAID(s) as anti-inflammatory agent(s), it is envisioned that the
active component should be free of the specific NSAID, bromfenac,
but instead be selected from 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,
ternoxicam, droxicam, lornoxicam, isoxicam, celecoxib, rofecoxib,
valdecoxib, parecoxib, lumiracoxib, etoricoxib, firocoxib,
nimesulide, clonixin, licofelone, pharmaceutically acceptable
salts, hydrates, solvates, ethers, esters, acetals and ketals
thereof or any combination thereof.
[0054] 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.
[0055] 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 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.
[0056] In some embodiments, an excipient that can be used as a
solubilizing and stabilizing agent to overcome the above-described
difficulties and thus to obtain a stable suspension of the
corticosteroid such as triamcinolone acetonide may be a non-ionic
polyoxyethylene-polyoxypropylene block copolymer having the
following general structure:
HO--(CH.sub.2--CH.sub.2--O).sub.x--(C.sub.3H.sub.6--O).sub.y--(CH.sub.2--
-CH.sub.2--O).sub.xH,
wherein x is an integer having the value of at least 8 and x is an
integer having the value of at least 38.
[0057] If a non-ionic polyoxyethylene-polyoxypropylene block
copolymer is used as a 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 % such as between about 1.0 mass % and about 8 mass
%, for example, about 5.0 mass %.
[0058] One non-limiting example of a specific non-ionic
polyoxyethylene-polyoxypropylene block copolymer that can be used
as a solubilizing and stabilizing agent in the pharmaceutical
compositions of the instant invention is the product known under
the trade name Poloxamer 407.RTM. (poly(ethylene
glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol))
available from Sigma-Aldrich Corp. of St. Louis, Mo., with the
molecular weight of the polyoxypropylene portion of about 4,000
Daltons, about a 70% polyoxyethylene content, the overall molecular
weight of between about 9,840 Daltons and about 14,600 Daltons and
having the following chemical structure
##STR00006##
wherein each x and z is an integer having the value between about
78 and about 116, and y is an integer having the value of about
69.
[0059] Non-limiting examples of some other excipients and carriers
that may be used in preparing in the pharmaceutical compositions of
the instant invention include polysorbate (an emulsifier), edetate
calcium disodium (EDTA, a chelating agent), hydrochloric acid (the
pH adjuster) and sterile water.
[0060] 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.
[0061] In one exemplary, non-limiting procedure, a quantity of an
anti-bacterial agent such as moxifloxacin may be placed into a
mixing container followed by adding a quantity of sterile water and
hydrochloric acid to obtain a slightly acidic mixture (e.g., having
pH of about 6.5) which is stirred until a clear solution is
obtained. In case of moxifloxacin/HCl system, the solution is
stable, allowing the formulation to remain closed system thus
preventing contamination and the loss of sterility.
[0062] Next, a quantity of corticosteroid such as micronized
triamcinolone acetonide, a quantity of Poloxamer 407.RTM., a
quantity of edetate calcium disodium and a quantity of polysorbate
80 may be all added to be combined in the same container with the
already prepared moxifloxacin/HCl solution and stirred together
(e.g., by spinning) for a period of time, e.g., about 6 hours,
until a homogenous suspension has been obtained. 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.
[0063] 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.
[0064] 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.
[0065] 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.
[0066] 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.
[0067] 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
(intravitreal) injection may not be satisfactory in some cases, as
the suspension clogs the trabecular meshwork and aggravates
intraocular drainage, resulting in an intraocular pressure rise
postoperative. This is 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.
[0068] 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.
[0069] 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 may be
injected first, immediately followed by the injection of
moxifloxacin or vice versa.
[0070] 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.
[0071] 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.
[0072] 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 Containing Triamcinolone and
Moxifloxacin
[0073] A pharmaceutical composition was prepared as described
below. The following products were used in the amounts and
concentrations specified:
[0074] (a) about 1.5 g of aqueous solution of triamcinolone
acetonide, at a concentration of about 15.0 mg/mL;
[0075] (b) about 0.1 g of aqueous solution of moxifloxacin
hydrochloride, at a concentration of about 1.0 mg/mL;
[0076] (c) about 1 mL of aqueous solution of Polysorbate 80.RTM.,
at a concentration of about 1.0 mass %; [0077] (d) about 0.2 g of
aqueous solution of edetate calcium disodium, at a concentration of
about 0.2 mass %; [0078] (e) about 1 g of aqueous solution of
Poloxamer 407.RTM., at a concentration of about 1.0 mass %; [0079]
(f) 20% aqueous solution of hydrochloric acid, to adjust pH to
about 6.5; and [0080] (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.RTM., edetate calcium disodium 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 (2 mL 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
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.
Example 2
Preparing a Pharmaceutical Composition Containing Triamcinolone,
Moxifloxacin and Vancomycin
[0085] 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 of Example 1
[0086] 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,
Moxifloxacin and Ketorolac
[0087] A pharmaceutical composition was prepared as described
below. In this Example, the composition included an NSAID
(ketorolac). The following products were used in the amounts and
concentrations specified:
[0088] (a) about 10.0 g of aqueous solution of prednisolone
acetate, at a concentration of about 10.0 mg/mL;
[0089] (b) about 10.0 mL of aqueous solution of Polysorbate
80.RTM., at a concentration of about 10.0 mg/mL;
[0090] (c) about 4.0 g of aqueous solution of boric acid, at a
concentration of about 4.0 mg/mL;
[0091] (d) about 14.0 g of aqueous solution of Poloxamer 407.RTM.,
at a concentration of about 14.0 mg/mL;
[0092] (e) about 5.0 g of aqueous solution of moxifloxacin
hydrochloride, at a concentration of about 5.0 mg/mL;
[0093] (f) about 5.0 g of aqueous solution of ketarolac
tromethamine, at a concentration of about 5.0 mg/mL;
[0094] (g) 20% aqueous solution of hydrochloric acid, to adjust pH
to about 6.5; and [0095] (h) about 1,000.0 mL of sterile water for
injection.
[0096] 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 the solution of hydrochloric acid until a
clear solution having the final pH of about 6.0 was obtained. The
other components (b) through (f) listed above were then added
followed by homogenization for about 1 hour and by adjusting the pH
to about 6.5 by using hydrochloric acid and water. In this manner a
hydrated and homogenous suspension was obtained.
[0097] The suspension was transferred into de-pyrogenated vials
(100 mL size), capped, autoclaved, shaken and sonicated for about
60 minutes. The product was then transferred into 3 mL droppers
which were capped, sealed and labeled. Complete sterility and
endotoxin testing was performed by an outside laboratory to ensure
safety.
Example 5
Preparing a Pharmaceutical Composition Containing Prednisolone and
Ketorolac
[0098] A pharmaceutical composition was prepared as described
below. In this Example, the composition included an NSAID
(ketorolac) but was free of any anti-bacterial agent(s) that was
(were) present in compositions of Examples 1, 2 and 4, supra. The
following products were used in the amounts and concentrations
specified:
[0099] (a) about 4.0 g of aqueous solution of prednisolone acetate,
at a concentration of about 10.0 mg/mL;
[0100] (b) about 4.0 mL of aqueous solution of Polysorbate 80.RTM.,
at a concentration of about 10.0 mg/mL;
[0101] (c) about 1.6 g of aqueous solution of boric acid, at a
concentration of about 4.0 mg/mL;
[0102] (d) about 5.6 g of aqueous solution of Poloxamer 407.RTM.,
at a concentration of about 14.0 mg/mL;
[0103] (e) about 2.0 g of aqueous solution of ketarolac
tromethamine, at a concentration of about 5.0 mg/mL;
[0104] (f) 20% aqueous solution of hydrochloric acid, to adjust pH
to about 6.5; and [0105] (g) about 400.0 mL of sterile water for
injection.
[0106] Ketorolac was dissolved in about 3/4quantity of water (i.e.,
about 300 mL of water), while the solution of hydrochloric acid was
added until a clear solution having the final pH of about 6.0 was
obtained. The volume was then brought to just below the Q.S. line
by adding more water. The other components (b) through (f) listed
above were then added followed by homogenization for about 1 hour
and by adjusting the pH to about 6.5 by using hydrochloric acid and
water. In this manner a hydrated and homogenous suspension was
obtained.
[0107] The suspension was transferred into de-pyrogenated vials
(100 mL size), capped, autoclaved, shaken and sonicated for about
60 minutes. The product was then transferred into 3 mL droppers
which were capped, sealed and labeled. Complete sterility and
endotoxin testing was performed by an outside laboratory to ensure
safety.
[0108] 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.
* * * * *