Note: Descriptions are shown in the official language in which they were submitted.
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DISPERSIBLE FORMULATION OF AN ANTI-INFLAMMATORY AGENT
FIELD OF THE INVENTION
[0001] The present invention relates to a method of treatment andlor
prevention of an
inflammatory condition in a fluid-containing organ having a natural exterior
orifice, such
as the udder of a milk-producing animal or an ear of a subject. The invention
also relates
to a dispersible pharmaceutical composition suitable for infusion into the
organ according
to the method of the invention, and a process for preparing such a
composition.
BACKGROUND OF THE INVENTION
(0002] Mastitis is an inflammation of the mammary gland of milk-producing
animals,
for example dairy cows, most often caused by bacterial infection. Bacteria
enter through
the teat canal of the animal and can cause acute, clinical or sub-clinical
mastitis. Over
135 organisms have been documented as causative pathogens for bovine mastitis.
Three
of the major groups of pathogens are gram-positive cocci, gram-negative
bacilli and gram-
positive bacilli. Hygiene, environmental factors and metabolic disturbances
deriving from
high milk yield combine to create conditions favorable to the onset of
mastitis. An
increased somatic cell count, associated with mastitis, is positively
correlated with
infection and negatively correlated with milk production. Frequently, an
infected cow
must be removed from the herd and dried up. Mastitis often affects a cow
during its
entire life unless the disease is properly treated. Infection rates average
from 10% to 30%
of the cows in a typical herd, with losses per cow ranging from $185 to $250
per cow per
year. Bovine mastitis is the most economically costly disease to the dairy
industry, with
losses estimated at two billion dollars annually in the United States alone.
The majority
of these losses are due to reduced milk production.
[0003] Because inflammation and leukocytosis resulting from coliform mastitis
often
persist after the bacteria can no longer be isolated from the gland, the use
of long term
anti-inflammatory drug therapy can be useful in the treatment of mastitis.
[0004] Intramammary administration of dispersible compositions comprising an
antibacterial agent for treatment of mastitis in milk-producing animals is
well known.
Several compositions suitable for such administration are formulated as oil-
based
formulations.
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[0005] , U.S. Patent No. 3,636,194 to Parizeau discloses a composition for
treating ,
mastitis by intramammary infusion, comprising an antibiotic, a vegetable oil,
an alcohol-
soluble fraction of natural lecithin phospholipid material for promoting
dispersion of the
oil in milk, the phospholipid being selected from the group consisting of
phosphatidyl
choline and phosphatidyl ethanolamine and mixtures thereof and present in an
amqunt of
at least 0.25% in said oil. Such compositions are said to provide rapid
dispersion into
milk and short milkout times.
[0006] British Patent Application No. 1,181,527 discloses a composition for
treating
mastitis comprising an active substance and a pharmaceutically acceptable oil
base, said
composition containing phospholipid material consisting substantially entirely
of alcohol=
soluble material for promoting dispersion of the composition in milk.
[0007] European Patent Application No. 0 222 712 discloses a composition which
contains one or more antimicrobial agents dispersed in an oil consisting'of a
mixture of
triglycerides of palmitic and stearic acid together with polyoxyethylenated
cetyl alcohol
and stearyl alcohol, and held in an oily medium of mineral, vegetable,
synthetic or mixed
extraction. Such compositions are said to speed up release of the
antimicrobial agent in
the udder, enhancing its biological potential, and reducing milkout time. '
[0008] The use of anti-inflammatory agents to treat mastitis has also been
proposed.
[0009] U.S. Patent No. 5,756,529 to Isakson ~ Talley discloses a method of
using
pyrazolyl benzenesulfonamide compounds to treat inflammation in a companion
anirrial.
Such compounds are said to be useful for treatment of pain, fever, joint
disease, traumatic
injury, arthritis, myositis, tendinitis, equine colic, mastitis, peritonitis,
skin conditions,
burns, gingivitis, hypersensitivity, conjunctivitis, eye inflammation,
swelling and.
myocardial ischemia.
[0010] International Patent Publication No. WO 02/22107 discloses compositions
comprising one or more bioactive agents in a liquid carrier, which has been
modified to
have an increased level of oxidation products, wherein the bioactive agents
include anti-
infectives, antineoplastics, immunomodulators, antipyretics, analgesics and
anti-
inflammatory agents (e.g., COX-2 inhibitors). Such compositions can be
administered by
a parenteral (e.g., subcutaneous, intramammary, intravenous, intraperitoneal
or
intramuscular), topical, intravaginal, oral or rectal route.
[0011] International Patent Publication No. WO 02/006865 discloses one or more
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bioactive 'substances in a non-aqueous carrier, wherein the composition has
been adjusted
to have a water activity of between about 0.2 and about 0.5. Parenteral,
topical, oral,
intravaginal, rectal and intramammary routes of administration are proposed.
Among the
bioactive agents listed are anti-infectives, antineoplastics,
immunomodulators,
antipyretics, analgesics and anti-inflammatory agents (e.g., COX-2
inhibitors).
[0012] International Patent Publication No. WO 99120259 discloses a
combination of
', ,
thiamphenicol and diclofenac for use in veterinary medicine to treat
infections with
associated inflammatory conditions.
~I
[0013] International Patent Publication No. WO O1J60409 discloses a paste
composition comprising a therapeutic agent, fumed silica, a viscosity modifier
and a
hydrophilic carrier; wherein the therapeutic agent is selected from
insecticides, acaricides,
parasiticides, antibiotics, growth enhancers, oil-soluble NSAIDs, avermectins,
milbemycins, nordulisporic acid, estrogens, progestins, phenylpyrazoles,
substituted
pyridyl methyl derivatives and COX-2 inhibitors. Oral, topical, dermal and
subdermal
routes of administration are contemplated for the paste composition. Such
compositions
are said to have application in veterinary practice in treatment of diseases
such as
pneumonia, mastitis, metritis, rhinitis and bronchitis.
[0014] U.S. Patent Application Publication No. 2002/0032228 discloses use of a
heterocycle containing compound, for example a Biphenyl heterocycle
derivative, to treat
diarrheal diseases, whooping cough, anthrax, smooth muscle contraction
conditions and
mastitis. Celecoxib and rofecoxib are listed as preferred Biphenyl heterocycle
derivatives.
[0015] A Labrafil product brochure (Notice OL 0050/5th edition) from
Gattefosse
Corporation contains an extract from a thesis by Valette (1957), discussing
characteristics
of LabrafilTM M-1944CS in the ear canal. The same thesis describes an
experiment
involving injecting LabrafilTM M-1944CS mixed with gentian violet into a cow
teat. It
was shown that LabrafilTM wetted the entire surface of the mammary parenchyma
section
and reached the retromammary ganglion.
[0016] Two articles by Gao et al. (1995) in Pharmaceutical Research 12(6), 857-
868,
"Controlled release of a contraceptive steroid from biodegradable and
injectable gel
formulations: ifa vitro evaluation" and "Controlled release of a contraceptive
steroid from
biodegradable and injectable gel formulations: in vivo evaluation", describe
preparation of
gels containing levonorgestrel, LabrafilTM M-1944CS and glyceryl
palmitostearate.
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[0017] , Otic disorders rank second only to the common cold as the most
frequent
illness among children in the United States. Most otic disorders are the
result of a painful
inflammatory response to infections, allergic reactions or trauma to the ear.
An otic
infection may be of bacterial, fungal or viral origin and determination of the
precise
etiology is not practical since the causative organism is often difficult to
isolate anti
culture. Otitis externs (external ear infections), otitis media (middle ear
infections) and
otorrhea (otitis media with ruptured ear drum causing effusion) are among the
most
prevalent otic disorders.
[0018] Otitis externs, involving the ear canal portion of the external ear, is
a common
otological problem occurring mainly during hot, humid weather, and five times
more
frequently in swimmers than in non-swimmers. In the incipient stage, symptoms
include
itching and pain in the ear canal, and tenderness when pressure is applied
around the
external auditory canal, the ear lobe is pulled or the jaw is moved. In the
definitive stage,
suppuration occurs in the ear canal and hearing may be decreased. Over 90% of
cases of
otitis externs are due to bacterial and fungal infections.
[0019] Pathological conditions can arise from, and can cause, changes in the
surface
tension of air/liquid interfaces of tissue surfaces, especially epithelial
surface 'tissues. The
external auditory canal is lined with epithelium. The cerumen exudate,
normally secreted
upon the epithelial tissue lining the external auditory canal, imparts a
particularlyhigh
surface tension thereto. Inflammatory by-products can further increase such
surface
tension. Increased surface tension is an important factor in both the symptoms
and
treatment of otitis. In addition, and even in the absence of canal closure,
the increased
surface tensions resident upon the epithelial lining of the outer ear canal,
tends to inhibit
uniform and/or effective application of therapeutic agents.
[0020] In the past, otitis externs has been treated with topical application
of
therapeutic agents demonstrating antimicrobial activity as well as anti-
inflammatory
action. Broad spectrum topically effective antibiotic otic suspensions
containing
antibacterial agents, for example neomycin sulfate, colistin sulfate,
polymyxin B, or
combinations thereof, all broad spectrum in effect, have been utilized to
destroy causative
bacteria. Antimycotic topically acting agents, for example nystatin and
clotrimazole, have
been employed to destroy underlying fungal disease. In addition, the antiviral
agent
acyclovir_has been utilized to treat viral otitis externs includingherpes
zoster.
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[0021] ' Anti-inflammatory agents including, for example, hydrocortisone,
hydrocortisone acetate and dexamethasone sodium phosphate, often included in
the
topically acting suspensions identified above, have been employed to control
the
inflammatory process of otitis externa. Most often, aritimicrobial and anti-
inflammatory
agents are utilized in combination to treat the causative, triggering
disorder, e.g., bacterial
infection, as well as the inflammatory process itself. They are also most
often
administered as suspensions ~in drop form fox topical administration to the
affected ear. In
order to enhance and provide a more uniform delivery of such medications,to
the
epithelial lining of the outer ear canal, wicks, made of absorbent material
such as cotton,
are utilized to draw the suspension into the ear canal. However, due to the
exudate
present in purulent forms of otitis externa, and the cerumen present in
virtually all
inflammatory conditions, high surface tension resists uniform distribution of
such
medications throughout the external auditory canal.
[0022] The most common otic disorder, otitis media, is a leading cause of
hearing loss
r
in the United States and represents a significant disability interfering with
childhood
learning processes. See Estrada (1997), Infect. Med. 14(3), 239-244. Otitis
media
accounts for over 35 percent of all childhood visits to pediatricians each
year and
represents more than $3.5 billion in U.S. health care costs annually.
[0023] During episodes of otitis media, the relatively high surface tensions
present at
the air/liquid interface located upon the epithelial lining of the tube lumen
increase the
opening pressure required to open this channel.
[0024] Typically otic infective disorders such as otitis media are treated
with a course
of antibiotic therapy. See The Merck Manual, 17th edition (1999), Section 7,
Chapter i~4.
Systemic administration of antibiotics generally requires high initial doses
and an
appreciable lag time to achieve therapeutic levels in the ear. Systemic
application of
drugs via parenteral or oral routes, while eventually reaching the eustachian
tube and
middle ear, may have adverse systemic effects and, more importantly, are not
especially
effective at delivering a concentrated dose of the applicable drugs where they
are truly
needed, directly to the target tissues. At the same time, direct drug
application has been
complicated by the sealed chamber anatomy of the middle ear.
[0025] Combinations of antibacterial and anti-inflammatory agents, formulated
together_in a pharmaceutically acceptable. vehicle, have been proposed for
topical
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application to the ear, in various patents and publications including those
individually
cited below.
[0026] U.S. Patent No. 6,395,746 to Cagle et al.
[0027] U.S. Patent No. 6,440,964 to Cagle et al.
[0028] U.S. Patent No. 6,509,327 to Cagle et al.
[0029] U.S. Patent No. 5,679,665 to Bergamini et al.
[0030] U.S. Patent No. 5,965,549 to~Purwar & Goldman.
[0031] U.S. Patent Application Publication No. 2001/0049366.
[0032] U.S. Patent Application Publication No. 2002/0142999.
[0033) 'U.S. Patent Application Publication No. 2002/0044920 discloses
treating
immune-mediated ear disorders by administering a TNF antagonist and a
pyriinidine
synthesis inhibitor with a steroid, an anti-inflammatory compound (for example
a non-
steroidal anti-inflammatory drug also known as a NSAID or a COX-2 inhibitor),
a
cytotoxic compound, an anti-neoplastic metabolite, or a secondary
antirheumatic agent.
[0034] U.S. Patent Application Publication No. 2002/0076383 discloses
administration of a composition as an aerosol through the external auditory
Banal, the
composition comprising a lipid surfactant in an amount effective in lowering
surface
tension of an air/liquid interface upon epithelial tissue lining, a spreading
agent and a
propellant, wherein the spreading agent is selected from the group consisting
of lipids,
sterols, fatty acid, cholesterol esters, phospholipids, carbohydrates and
proteins, all in
powder form. The composition is said to increase external auditory canal
patency while
providing protection against occurrence of otitis externa.
[0035] U.S. Patent Application Publication No. 2002/0064503 discloses
administration of a composition as an aerosol through an external airway,
wherein the
composition comprises a lipid surfactant in an amount effective in lowering
surface
tension of an air/liquid interface upon epithelial tissue lining, and a
spreading agent
selected from a group consisting of sterols, lipids, fatty acids, cholesterol
esters,
phospholipids, carbohydrates and, proteins, all in powder form. The
composition is said to
increase the patency and pressure equalization performance of the eustachian
tube lumen.
[0036] Ear drops have been contemplated as a formulation type for selective
COX-2
inhibitors, for example in the patents and publications individually cited
below.
-[0037] -__ U.S. Patent Application No. 20011004726.
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[0038] ~ U.S. Patent Application No. 2001/p053764.
[0039] U.S. Patent Application No. 2002/0010146.
[0040] U.S. Patent Application No. 2002/00133'18.
[0041] U.S. Patent No. 6,307,047 to Black et. al. ~,
[0042] U.S. Patent No. 6,329,526 to Adams et al.
[0043] All patents and publications cited' above are incorporated herein by
reference.
[0044] Despite recent advances that have been made in understanding the causes
of
otic disorders, they remain largely unpreventable and are difficult to
effectively treat. It
would be useful, therefore, to provide efficacious methods and compositions
for~the
prevention and treatment of otic'disorders and complications related thereto..
[0045] The most commonly used packaging containers and delivery devices for
compositions intended for intramammary administration to treat or prevent
mastitis in
milk-producing animals as well as for compositions for otic administration to
treat otic
disorders are constructed of oxygen-permeable plastic materials, for example
polyethylene, polypropylene, etc. and mixtures thereof. The use of oxygen-
permeable
packaging containers and delivery devices for anti-mastitis compositions and
for
compositions for,treatment or prevention of otic disorders poses serious
problems for long
term chemical and/or physical stability of a composition contained therein, if
the
composition comprises an ingredient, for example an active medicament or an
excipient,
that is prone to oxidative degradation.
[0046] Although the references cited above disclose a number of compositions
for
treatment of mastitis or for treatment of otic disorders, none addresses the
problem of
providing extended chemical and/or physical stability of a composition
packaged in an
oxygen-permeable container, where the composition comprises a pharmaceutically
active
agent and/or excipient that is prone to oxidative degradation. Despite the
above
teachings, there still exists a need in the art for pharmaceutical
compositions having one
or more of the following advantages over prior art compositions used in
treatment of
mastitis or over prior art compositions used in treatment or prevention of
otic disorders:
(a) extended chemical and/or physical stability even when packaged in oxygen-
permeable
containers and delivery devices, particularly where the composition comprises
a
pharmaceutically active agent or excipient that is prone to oxidative
degradation, (b) safe,
effective.treatment_of the inflammatory component of mastitis or of an otic
disorder, (c)
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safe, effective treatment of the pain,' inflammation, edema, fever and
swelling associated
with mastitis or an otic disorder, (d) minimal to no irritation after
administration of the
composition, (e) rapid dispersibility of an anti-mastitis composition in milk
and in udder
fluids to quickly achieve efficacious medicament levels at sites of
inflammation, (f) rapid
dispersibility of an otic composition in the waxy moist environment of an ear
to quickly
achieve efficacious medicament levels at sites of inflamrriation, (g) a
lowering of the
surface tension of the air/liquid interface of epithelial tissue, increasing
patency of the
auditory canal, and (h) a protective coating for inflamed mucous membranes of
the ear.
SUMMARY OF THE INVENTION
[0047] Novel methods of treatment and pharmaceutical compositions having some
or
all of the advantageous attributes described above have now been developed.
,In
particular, there is provided a novel method of treatment and/or prevention of
an
inflammatory condition in a fluid-containing organ having a natural exterior
orifice, for
example an udder of a milk-producing animal or an ear of a human or animal
subject.
The method comprises administering an anti-inflammatory agent to the organ via
the
exterior orifice and administering in combination therapy therewith a second
agent as
defined herein. The anti-inflammatory agent is administered as a
pharmaceutical
composition comprising, in addition to said agent, a vehicle that comprises
(a) an
amphipathic oil that is water dispersible and ethanol insoluble, (b)
microcrystalline wax,
and (c) a pharmaceutically acceptable non-aqueous carrier.
[0048] Such a composition has low interfacial tension when placed in contact
with an
aqueous medium. It is believed, without being bound by theory, that this low
interfacial .
tension results in the composition dispersing readily in udder fluids such as
milk'as well
as in the more waxy moist environment of an ear. In a preferred method of the
invention,
therefore, upon administration to the fluid-containing organ, the composition
disperses in
the fluid.
[0049] A preferred anti-inflammatory agent for use in the method of the
invention is a
selective COX-2 inhibitor.
[0050] The method can, for example, comprise intramammary infusion of such a
composition for treatment of mastitis or other diseases of the udder in a milk-
producing
animal, or otic infusion of such a composition for treatment and/or prevention
of otic
disorders and-is--efficacious-un a-wide variety of inflammatory disorders
which can be
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associated with a wide variety of infectious organisms. The term "infusion"
herein
embraces any operation wherein a liquid composition is caused to flow into the
fluid-
containing organ via the exterior orifice, for example the teat canal in the
case of
intramammary infusion or the external auditory canal 'in the case of otic
infusion,
regardless of the timescale involved. In the present context, "infusion" and
"injection"
are substantially synonymous. For example; the composition can be
intramammarily
administered by inserting the cannula nozzle of a mastitis syringe into the
external orifice
of a teat canal and injecting the composition through the nozzle into the
udder.
[0051] In another embodiment the anti-inflammatory agent, for example a
selective
COX-2 inhibitor, is administered in combination therapy with a second agent.
The
second agent can be any therapeutically active agent useful in treatment of
mastitis or otic
disorders. Such second agents include, without limitation, antibacterial
agents,
antineoplastic agents, anesthetics, sodium channel blockers, antipyretics,
analgesics,
antiedemic agents, and the like, and combinations thereof.
[0052] The second agent can be administered~by a route that is other than the
route of
administration of the anti-inflammatory agent. Alternatively, both agents can
be
administered by the same route, i.e., via the~exterior orifice of the organ,
for example the
teat canal in the case of an udder or the external auditory canal in the case
of an ear.
Where administration is by the same route, it is preferred that both agents be
administered
by intramammary or otic infusion in the form of a liquid composition
comprising a
vehicle as described above. It is especially preferred that the anti-
inflammatory agent and
the second agent be administered in a single composition containing both
agents.
[0053] Accordingly, there is further provided a pharmaceutical composition
comprising a vehicle that comprises (a) an amphipathic oil that is water
dispersible and
ethanol insoluble, (b) microcrystalline wax, and (c) a pharmaceutically
acceptable non-
aqueous carrier. The vehicle has stably dispersed therein an anti-inflammatory
agent, for
example a selective COX-2 inhibitor, in an anti-inflammatorily effective
amount.
[0054] In one embodiment the anti-inflammatory agent andlor an excipient in
the
composition is prone to oxidative degradation, and the composition exhibits
extended
chemical and/or physical stability when packaged in a container or delivery
device having
an oxygen permeable wall.
60055] The novel composition has a low interfacial_tension in aqueous fluids,
thereby
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increasing dispersibility of the composition in milk and udder.fluids, as
compared to a
conventional oil based formulation. This results in rapid distribution of the
composition
throughout the udder and thereby allows the anti-inflammatory agent andlor the
second
agent to reach inflamed tissue quickly, providing an efficacious level of
medicament at a
site of inflammation. The interfacial tension of a composition in an aqueous
fluid ,
determines the energy needed for dispersion and spreading of the composition
in the~fluid,
as well as the energy necessary for a suspended particle in the composition to
cross the
oillmilk or oilludder fluid interfacial boundary.
[0056] The low interfacial tension of the composition also increases
dispersibility of
the composition in the waxy moist environment of an ear, as compared to a
conventional
composition. The resulting rapid distribution of the composition throughout
mucous
membranes and lipid containing wax of the ear canal allows the anti-
inflammatory agent
and/or the second agent to reach inflamed tissue quickly, providing an
efficacious level of
the medicament at the site of inflammation. Such a composition can also
produce a
protective coating for inflamed mucous membranes of the ear.
[0057] Preferably the method or composition provides effective treatment of
the
inflammatory component of a mammary or otic disorder. Preferably the method or
composition provides effective treatment and/or prevention of pain,
inflammation,
swelling, edema, andlor fever associated with such a disorder.
[0058] When administered by intramammary infusion, for example in treatment of
mastitis, preferred methods and compositions can have additional advantages.
For
example, a preferred method enables suitably short milkout times. Milkout time
for a
lactating cow is the period of time from administration of a mastitis
treatment to,
resumption of production of saleable milk. Following such administration, the
concentration of active agents) in milk must fall to a level acceptable to the
appropriate
regulatory body before the milk is deemed suitable for human consumption. A
suitably
short milkout time reduces monetary losses to a dairy farmer caused by a
mastitis
outbreak.
(0059] Alternatively or in addition, a preferred method enables a low milk
withholding time post calving after dry cow mastitis treatment, with no active
agent
residues in the offspring.
_0060] _ __ Alternatiyel~y or in addition, a preferred method enables a zero
day slaughter
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meat withdrawal period following mastitis treatment. This attribute is
especially
important since it allows a farmer to dispose of a treated cow at any time it
is financially
advantageous to do, so, rather than being required to keep and feed a cow for
a specified
amount of time after its treatment.
[0061] When administered by otic infusion, for example in treatment of
infective
disorders of the ear having an inflammatorycomponent, preferred methods and
' '
compositions can have additional advantages. For example,, a preferred method
increases
patency of the auditory canal and thereby reduces resistance to conduction of
sound,
improving the clarity and sensitivity of hearing.
[0062] Alternatively or in addition, a preferred method provides a coating on
the
epithelial .lining of the ear that protects against deleterious effects of
water and water-
borne toxins, irritants and antigenic materials, and helps prevent otic
disorders.
[0063] A further benefit of methods and compositions of the invention, whether
for
intramammary or otic use, is that they permit targeted delivery of at least
the anti-
inflammatory agent to the site of inflammation. Where a composition of the
invention is
used comprising both an anti-inflammatory agent and' a second agent as defined
herein,
targeted delivery of both agents is provided~to the site of infection and/or
inflammation.
[0064] A still further benefit of preferred compositions, whether for
intramammary or
otic administration, is that they cause minimal to no irritation after
administration.
[0065] A still further benefit of a composition of the invention is improved
physical
stability when compared to conventional oil and aqueous compositions, for
example by
virtue of improved composition resuspendability. A composition of the
invention has
been shown to cause flocculation of certain drugs, thereby improving
resuspendability and
eliminating the problem of suspension caking and possible delivery of a
subpotent or non-
efficacious dose.
[0066] A process is provided for preparing a pharmaceutical composition of the
invention. The process comprises mixing, in any suitable order, an amphipathic
oil that is
water dispersible and ethanol insoluble, microcrystalline wax, a
pharmaceutically
acceptable non-aqueous carrier and an anti-inflammatory agent, for example a
selective
COX-2 inhibitor, to provide the composition, such a composition preferably
having
extended chemical and/or physical stability as described herein.
[0067] _ _ The.present invention thus pr_oyides_solutions to several long
standing
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problems in the art and possesses one or more advantages over methods and
compositions
of prior art. Other features, advantages and benefits of the invention will be
apparent
from the description that follows.
DETAILED DESCRIPTION OF THE INVENTION
[0068] The invention provides a method of treatment and/or prevention of an
inflammatory condition in a fluid-containing organ having a natural exterior
orifice, the
method comprising administering an anti-inflammatory agent to the organ via
the exterior
orifice, in the form of a pharmaceutical composition comprising the anti-
inflammatory
agent in an anti-inflammatorily effective amount and a vehicle that comprises
(a) an
amphipathic oil that is water dispersible and ethanol insoluble, (b)
microcrystalline wax,
and (c) a pharmaceutically acceptable non-aqueous carrier. The invention also
provides
for the use of a composition of the present invention in the manufacture of a
medicament
to treat or prevent an inflammatory condition in a fluid-containing organ
having a natural
exterior orifice. The invention further provides for a composition for use in
a method of
treatment or prevention of an inflammatory condition in a fluid-containing
organ having a
natural exterior orifice.
[0069] ~'he method is particularly useful in treatment and/or prevention of
inflammation accompanying an infective condition. An "infective condition"
herein
includes any disease, disorder or condition mediated by a pathogenic bacterium
or that is
otherwise responsive to treatment with an antibacterial agent such as an
antibiotic drug.
[0070] It will be understood that reference herein to methods involving and
compositions comprising "an anti-inflammatory agent" embraces such methods and
compositions wherein more than one anti-inflammatory agent is used. Further,
more than
one therapeutically active agent other than an anti-inflammatory agent can
optionally form
the "second agent" herein.
[0071] The term "anti-inflammatorily effective amount" as used herein refers
to an
amount of an anti-inflammatory agent that is sufficient, when administered by
the method
of the invention, to reduce, relieve, prevent or delay onset of one or more
symptoms of an
inflammatory condition being treated. ~ The term "therapeutically effective
amount" as
used herein refers to an amount of an active agent that is sufficient, when
administered by
the method of the invention, to reduce, relieve, prevent or delay onset of one
or more
symptoms-of a condition beiwg-treated, or to-reduce numbers and/or activity of
a causal
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organism: The phrase "in therapeutically effective amounts of each" means that
when
administered in combination therapy according to the method of the invention,
the amount
of the anti-inflammatory agent and the amount of the second agent are
sufficient to '
provide both an anti-inflammatory effect and an,effect selected from anti-
bacterial,
anesthetic, sodium channel blocker, anti-edemic, analgesic, antineoplastic,
and/or
antipyretic effects. Such amounts can be the same as, greater or less than the
amount of
anti-inflammatory agent orlthe amount of the second agent that are
therapeutically
effective when used in,monotherapy. ,
[0072] A fluid-containing organ as contemplated herein includes a mammary
organ,
for example an udder of a milk-producing animal such as a cow, a goat or
a,sheep. A ~
"milk-producing animal" can be a female of any mammalian species but is
preferably an
animal raised for the purpose of providing milk, e.g., a cow, a goat or a
sheep, and
encompasses such animals whether or not they are lactating at the time of the
inflammatory and/or infective condition or at the time of treatment. The
natural exterior
orifice of the mammary organ is the orifice of the~teat canal. A fluid-
containing organ
also includes an ear of a human or animal subject. The natural exterior
orifice of the ear
is the orifice of the external auditory canal.
[0073] The invention further provides a method of treatment of an inflammatory
condition in a fluid-containing organ having a natural exterior orifice, the
method
comprising administering an anti-inflammatory agent to the organ via the
exterior orifice
and administering in combination therapy therewith a second agent as defined
herein in
therapeutically effective amounts of each; wherein the anti-inflammatory agent
is
administered as a pharmaceutical composition comprising said agent and a
vehicle that
comprises (a) an amphipathic oil that is water dispersible and ethanol
insoluble, (b)
microcrystalline wax, and (c) a pharmaceutically acceptable non-aqueous
carrier.
[0074] The term "combination therapy" herein means a treatment regimen wherein
the anti-inflammatory agent and the second agent are administered individually
or
together in such a way as to provide a beneficial effect from co-action of
these therapeutic
agents. Such beneficial effect can include, but is not limited to,
pharmacokinetic or
pharmacodynamic co-action of the therapeutic agents. Combination therapy can,
for
example, enable administration of a lower dose of one or both agents than
would normally
be administered during monotherapy, thus decreasing risk or incidence of
adverse effects
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associated with higher doses. Alternatively, combination therapy can result in
increased
therapeutic effect at the normal dose of each agent in monotherapy.
"Combination
therapy" herein is not intended to encompass administration of two or more
therapeutic
agents as part of separate monotherapy regimens that incidentally and
arbitrarily result in
sequential or simultaneous treatment.
[0075] Administration of the~anti-inflammatory agent'and the second agent
typically
is carried out over a defined time period (usually minutes, hours, days or
weeks depending
upon the combination selected). These therapeutic agents can be administered
in a .
sequential manner, that is, at different times, typically separated by no more
than about 24
hours, or in a substantially simultaneous manner. .
[0076] When administered simultaneously, the anti-inflammatory agent and the
second agent can be administered in separate dosage forms or in coformulation,
i.e., in a
single dosage form. When the two agents are administered sequentially'or in
separate
dosage forms, the second agent can be administered by any suitable route and
in any
pharmaceutically acceptable dosage form, for example by a route and/or in a
dosage form
other than that used for the anti-inflammatory agent. Alternatively, the
second agent, like
the anti-inflammatory agent, can be dispersed in a vehicle that comprises (a)
an
amphipathic oil that is water dispersible and ethanol insoluble, (b)
microcrystalline wax,
and (c) a pharmaceutically acceptable non-aqueous carrier and administered via
the
natural exterior orifice of the fluid-containing organ. In a preferred
embodiment, both
agents are co-dispersed in the same vehicle and administered in a single
operation.
[0077] Preferably the second agent is formulated in a pharmaceutically
acceptable
vehicle, and both the anti-inflammatory agent and the second agent are
administered into
the same fluid containing organ, for example by intramammary or otic infusion.
A
pharmaceutically acceptable carrier or vehicle is one that has. no
unacceptably injurious or
toxic effect on the subject when administered as a component of a composition
in an
amount required herein. No excipient ingredient of such a carrier or vehicle
reacts in a
deleterious manner with another excipient or with the therapeutic agents) in a
composition.
[0078] The pharmaceutical composition comprising the anti-inflammatory agent
is a
liquid injectable or infusible composition having said agent dispersed in a
vehicle as
.described_herein. The_term"dispersed''herein.means dissolved (i.e.,
molecularly
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dispersed) or colloidally dispersed, for example as an emulsion or suspension.
Typically
the anti-inflammatory agent is suspended in solid particulate form in the
vehicle.
[0079] The vehicle comprises three essential ingredients, optionally together
with
additional ingredients.
[0080] The first of these essential ingredients is an amphipathic oil that is
water
dispersible and ethanol insoluble. An "amphipathic oil" is defined as a
substance having
a molecular structure with a distinctly polar region and a distinctly non-
polar region.
Structurally these two regions of,the amphipathic oil are sufficiently far
apart that the
unique properties of the two regions are distinctly separate. The term
"ethanol insoluble"
means that the amphipathic oil i's essentially insoluble in ethanol at
20°C.
[0081] The second essential ingredient of the vehicle is microcrystalline wax.
[0082] The third essential ingredient of the vehicle is a pharmaceutically
acceptable
non-aqueous carrier. Such a carrier is typically an oil, as described more
fully
hereinbelow. '
[0083] The selection of vehicle components is important in providing a
composition
that, upon administration to the fluid-containing organ, disperses in the
fluid. It is
believed, without being bound by theory, that such dispersion in the fluid
within the organ
results in targeted delivery of the anti-inflammatory agent and, optionally,
the second
agent, to the site of inflammation in the organ.
[0084] Where the method of the invention comprises injection or infusion of
the
composition into an udder via the teat canal, it can provide effective
treatment of mastitis,
other diseases of the udder, and/or a condition associated with a mammary
disease.
"Intramammary infusion" is an operation wherein a liquid composition is caused
to flow
into an udder via a teat canal, regardless of the timescale involved. In the
present context,
"infusion" and "injection" are substantially synonymous.
[0085] Where the method of the invention comprises injection or infusion of
the
composition into an ear via the external auditory canal, a process described
herein as "otic
infusion" regardless of the timeseale involved, it can provide effective
treatment and/or
prevention of an otic disorder and/or a complication associated therewith. The
subject
suffering such otic disorder or complication associated therewith can be a
human,
companion animal, horse, farm livestock or the like.
__. [0086] Examples of such otic disorders.include, but are not limited to,
otitis externa
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(external ear infections), otitis media (middle ear infections), including
acute, secretory,
serous and chronic forms of otitis media; otorrhea (otitis media with ruptured
ear drum
causing effusion), acute mastoiditis, infections related to otic surgical
procedures (such as
tympanostomy and the like), otosclerosis, otalgia, otic pain, otic
inflammation, otic
bleeding, Lermoyez's syndrome, Meniere's disease, vestibular neuronitis,
benign' ,
paroxysmal positional vertigo, herpes zoster oticus, Ramsay Hunt's syndrome,
viral
neuronitis, ganglionitis, geniculate herpes, labyrinthitis, including purulent
labyrinthitis
and viral endolymphatic labyrinthitis, perilymph fistulas, presbycusis, drug-
induced
ototoxicity, acoustic neuromas, aerotitis media, infectious myringitis,
bullous myringitis,
otic neoplasm, squamous cell carcinoma, basal cell carcinoma, other otic
cancers, pre-
cancerous otic conditions, nonchromaffin paragangliomas, chemodectomas, glomus
jugulare tumors, glomus tympanicum tumors, perichondritis, aural eczematoid
dermatitis,
malignant external otitis, subperichondrial hematoma, ceruminomas, impacted
cerumen,
sebaceous cysts, osteomas, keloids, tinnitus, vertigo, tympanic membrane
infection,
tympanitis, otic furuncles, petrositis, conductive and sensorineural hearing
loss, epidural
abscess, lateral sinus thrombosis, subdural empyema, otitic hydrocephalus,
Dandy's
syndrome, bullous myringitis, diffuse external otitis, foreign bodies,
keratosis' obturans,
otomycosis, trauma, acute barotitis media, acute eustachian tube obstruction,
a
complication associated with any of the above infections (such as hearing
loss, brain
abscess, fever, cholesteatomas, calcification of the middle and inner ear,
ruptured ear
drum, meningitis, facial paralysis and the like), postsurgical otalgia and the
like.
[0087] The method of the invention is particularly suitable for treatment of
otitis
externa, otitis media, otorrhea, and infections having an inflammatory
component that are
related to an otic surgical procedure.
[0088] In one embodiment the otic disorder is a neoplasia. Examples of such
neoplasia include, but are not limited to, otic neoplasia, squamous cell
carcinoma, basal
cell carcinoma, malignant external otitis, malignant nonchromaffin
paraganglioma,
malignant jugulare tumor, malignant glomus tympanicum tumor, a pre-cancerous
otic
condition and the like.
[0089] Combination therapy of the anti-inflammatory agent together with the
second
agent provides enhanced treatment options as compared to administration of
either agent
alone. As indicated above, the anti-inflammatory agent is dispersed in a
vehicle that
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comprises (a) an amphipathic oil that is water dispersible and ethanol
insoluble, (b)
microcrystalline wax, and (c) a pharmaceutically acceptable non-aqueous
carrier, and is
administered for example by intramammary or otic'infusion, while the second
agent' is
formulated into any acceptable immediate release or sustained release
pharmaceutical
dosage form. Suitable dosage forms for the second agent include, but are not
limited to, a
suspension, solution, emulsion, tablet, capsule, pill, powder, granules,
elixir, tincture,
syrup, lozenge, dragee, gel, ointment, spreadable paste, slurry, aerosol
spray, ear drops,
nasal drops, eye drops,, suppository, implant and the like, and can be
administered via any
,,,
route including, but not limited to, oral, including peroral and intraoral,
e.g., sublingual,
buccal, etc.; parenteral, e.g., intramuscular, subcutaneous, intravenous,
intraperitoneal~,
intra-articular, intradermal, intraspinal, intrasternal, intramedullary,
intrasynovial,
intrathecal, intracardiac, intraventricular, intracapsular, intracranial,
etc.; intramammary,
topical, transdermal, intranasal, otic, mucosal, rectal, intravaginal,
pulmonary and the like.
[0090] Optionally, administration of the therapeutic agents describedtabove
can take '
place in further combination with other biologically active agents and non-
drug therapies.
[0091] In all embodiments of the invention, at least the anti-inflammatory
agent is
administered locally. An advantage of such local administration is that the
anti-
inflammatory agent is preferentially directed toward its site of action,
resulting in more
rapid onset of therapeutic action and more complete delivery to the site of
inflammation,
compared with other routes of administration such as intramuscular,
subcutaneous and
oral routes. Local administration can allow the total therapeutic dose for a
given effect to
be decreased and avoids the hepatic first pass effect. In addition, local
administration
decreases or eliminates secondary effects, especially those linked to the
active agent, at
sites other than the site of infection. Local'administration of an active
agent can also
improve its therapeutic index by decreasing its general toxicity and
minimizing risk of
undesirable systemic effects. Therapeutic index is a measure of the margin
between a
therapeutically effective dose and a toxic dose of a drug and is typically
expressed as the
ratio of LDSO (a dose lethal to 50% of a population) to EDSO (a dose
therapeutically
effective in 50% of the population).
[0092] The invention provides, in a further embodiment, a pharmaceutical
composition adapted for intramammary andlor otic infusions comprising a
vehicle that
comprises (a) an amphipathic oil that is water dispersible and ethanol
insoluble, (b)
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microcrystalline wax, and (c) a pharmaceutically acceptable non-aqueous
carrier; the
vehicle having stably dispersed therein an anti-inflammatory agent, for
example a
selective COX-2 inhibitor, in an anti-inflammatorily effective amount.
[0093] Preferably such a composition lowers, the high surface tension of the
air/liquid
interface of epithelial tissues associated with an otic disorder, so as to
increase patency of
the auditory canal. A decrease in the surface tension of the air/liquid
interface of the
epithelium lining can minimize fluid~accumulation, and in some instances
enable
evacuation of fluids held in the c~rlal due to elevated surface tensions
therein, and/or
allow separation of the proximal and opposing epithelial walls of the auditory
canals (often
brought closer together due to elevated surface tension of the tissues)
thereby improving
conduction of sound. The term "increase patency" as used herein refers to
opening, and
reduction or elimination of blockage, of the auditory canal so as to form a
patent conduit.
Resistance to conduction of sound results from reduction of the volume,
partial
obstruction, or complete occlusion of the auditory canal due to swelling of
the epithelial
walls as a result of inflammation, the accumulation of increased amounts of
cerumen
secreted thereupon, and/or collection of fluids therewithin, including fluids
containing
waste products of the immune response or exogenous water.
[0094] In a particular embodiment of the invention an ingredient of the
composition
(the anti-inflammatory agent and/or a second agent and/or an excipient
ingredient) is
prone to oxidative degradation. Such a composition exhibits extended chemical
and/or
physical stability even when packaged in an oxygen permeable container or
delivery
device. The term "extended chemical and/or physical stability" herein means
that a
composition of the present embodiment has greater chemical and/or physical
stability than
a reference composition comprising the same medicament at the same
concentration. A
"reference composition" in the present context means a composition lacking one
or both
of the amphipathic oil and the microcrystalline wax, but otherwise similar to
the
composition of the invention.
[0095] Oxygen permeable containers or delivery devices can be made of any
suitable
thermoplastic material. Examples of such materials include, but are not
limited to,
polymers and copolymers of polystyrene, polyacrylonitrile, polyvinyl chloride,
and
particularly polyolefins. Polyolefins include, for example, polyethylene,
polypropylene,
polybutenes, polyisopre_nes, polypentenes, copolymers thereof and mixtures
thereof.
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[0096] , Compositions for intramammary administration are commonly packaged in
syringes that are provided with a cannula nozzle for insertion into the teat
to allow
extrusion of the composition directly into the mammary gland via the teat
canal.
Intramammary suspension formulations are generally prepared in thickened
vehicles to
prevent settling of drug particles in the cannula nozzle, which can cause
nozzle plugging
resulting in incomplete expulsion of the composition. '
[0097] The anti-inflammatory agent herein can have one or both of analgesic
and
antipyretic properties in addition to its anti-inflammatory activity. The term
"anti-
inflammatory agent" herein embraces compounds that are primarily analgesics or
' antipyretics but that have a secondary anti-inflammatory effect. Examples of
anti-
inflammatory agents useful herein include, but are not limited to,
aceclofenac~
acemetacin, e-acetamidocaproic acid, acetaminophen, acetaminosalol,
acetanilide,
acetylsalicylic acid (aspirin), S-adenosylmethionine, alclofenac,
alclometasone, alfentanil,
algestone, allylprodine, alminoprofen, aloxiprin, alphaprodine, aluminum
bis(acetylsalicylate), amcinonide, amfenac, aminochlorthenoxazin, 3-amino-4-
hydroxybutyric acid, 2-amino-4-picoline, aminopropylon, aminopyrine,
amixetrine,
ammonium salicylate, ampiroxicam, amtolmetin guacil, anileridine, antipyrine,
antrafenine, apazone, beclomethasone, bendazac, benorylate, benoxaprofen,
benzitramide,
benzpiperylon, benzydamine, benzylmorphine, bermoprofen, betamethasone,
bezitramide,
a-bisabolol, bromfenac, p-bromoacetanilide, 5-bromosalicylic acid acetate,
bromosaligenin, bucetin, bucloxic acid, bucolome, budesonide, bufexamac,
bumadizon,
buprenorphine, butacetin, butibufen, butophanol, carbamazepine, carbiphene,
carprofen,
carsalam, celecoxib, chlorobutanol, chloroprednisone, chlorthenoxazin, choline
,
magnesium trisalicylate, choline salicylate, cinchophen, cinmetacin,
cinnoxicam,
ciramadol, clidanac, clobetasol, clocortolone, clometacin, clonitazene,
clonixin, clopirac,
cloprednol, clove, codeine, codeine methyl bromide, codeine phosphate, codeine
sulfate,
cortisone, cortivazol, cropropamide, crotethamide, cyclazocine, deflazacort,
dehydrotestosterone, deracoxib, desomorphine, desonide, desoximetasone,
dexamethasone, dexoxadrol, dextromoramide, dextropropoxyphene, dezocine,
diamorphone, diampromide, diclofenac, difenamizole, difenpiramide,
diflorasone,
diflucortolone, diflunisal, difluprednate, dihydrocodeine, dihydrocodeinone
enol acetate,
dihydrocodeine phosphate, dihydromorphine, dihydroxyaluminum acetylsalicylate,
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dimenoxadol, dimepheptanol, dimethylthiaml?utene, dioxaphetyl butyrate,
diphenhydramine hydrochloride, dipipanone, diprocetyl, dipyrone, ditazol, dl-
chlorpheniramine maleate, droxicam, emorfazone, enfenamic acid, enoxolone,
epirizole,
eptazocine, etersalate, ethenzamide, ethoheptazine, etodolac, ethoxazene,
ethoheptazine,
ethylmethylthiambutene, ethylmorphine, etodolac, etofenamate, etonitazene,
etoricoxib,
eugenol, felbinac, fenbufen, fenchlofenac, fenclozic acid, fendosal,
fenoprofen, fentanyl,
fentiazac, fepradinol, feprazone, floctafenine, fluazacort, flucloronide,
flufenamic acid,
flumethasone, flunisolide, flunixir<, flunoxaprofen, fluocinolone acetonide,
fluocinonide,
~.~
fluocinolone acetonide, fluocortin butyl, fluocortolone, fluoresone,
fluorometholone,
fluperolone, flupirtine, fluprednidene, fluprednisolone, fluprofen,
fluproqua~one,
flurandrenolide, flurbiprofen, fluticasone, formocortal, fosfosal, furofenac,
gentisic acid,
glafenine, glucametacin, glycol salicylate, guaiazulene, halcinonide,
halobetasol,
halometasone, haloprednone, heroin, hydrocodone, hydrocortamate,
hydrocortisone,
hydromorphone, hydroxypethidine, ibufenac, ibuprofen, ibuproxam, imidazole
salicylate,
indomethacin, indoprofen, isofezolac, isoflupredone acetate, isoladol,
isomethadone,
isonixin, isoxepac, isoxicam, ketobemidone, ketoprofen, ketorolac, p-
lactophenetide,
lefetamine, levallorphan, levorphanol, levophenacyl-morphan, lofentanil,
lonazolac,
lornoxicam, loxoprofen, lysine acetylsalicylate, lysozyme chloride,
mazipredone,
meclofenamic acid, medrysone, mefenamic acid, meloxicam, meperidine,
meprednisone,
meptazinol, mesalamine, metazocine, methadone, methotrimeprazine,
methylephedrine
hydrochloride, methylprednisolone, methylsalicylate, metiazinic acid,
metofoline,
metopon, miroprofen, mofebutazone, mofezolac, mometasone, morazone, morphine,
morphine hydrochloride, morphine sulfate, morpholine salicylate, myrophine,
nabumetone, nalbuphine, nalorphine, 1-naphthyl salicylate, naproxen, narceine,
nefopam,
nicomorphine, nifenazone, niflumic acid, nimesulide, 5'-nitro-2'-
propoxyacetanilide,
norlevorphanol, normethadone, normorphine, norpipanone, noscapine, olsalazine;
opium,
oxaceprol, oxametacine, oxaprozin, oxipinac, oxycodone, oxymorphone,
oxyphenbutazone, papaveretum, paramethasone, paranyline, parecoxib,
parsalmide,
pentazocine, perisoxal, phenacetin, phenadoxone, phenomorphan, phenazocine,
phenazopyridine hydrochloride, phenocoll, phenoperidine, phenopyrazone, phenyl
acetylsalicylate, phenylbutazone, phenylpropanolamine hydrochloride, phenyl
salicylate,
phenyramidol,~piketoprofen, piminodine, pipebuzone, piperylone, pirazolac,
piritramide,
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piroxicarY~, pirprofen, pranoprofen, prednicarbate, prednisolone, prednisone,
prednival,
prednylidene, proglumetacin, proheptazine, promedol, propacetamol,
properidine,
propiram, propoxyphene, propyphenazone, proquazone, protizinic acid,
proxazole,
ramifenazone, remifentanil, rimazolium metilsulfate, 'rofecoxib, salacetamide,
salicin,
salicylamide, salicylamide o-acetic acid, salicylic acid, salicylsulfuric
acid, salsalate,
salverine, serratiopeptidase, simetride, sudoxicam, sufentanil, sulfasalazine,
sulindac,
superoxide dismutase, suprofen, suxibuzone, talniflumate, tenidap, tenoxicam,
terofenamate, tetrandrine, thiazolinobutazone, tiaprofenic acid,
tiaprofenic,acid,~tiaramide,
tilidine, tinoridine, tiopinac, tioxaprofen, tixocortol, tolfenamic acid,
tolmetin, trarriadol,
triamcinolone, tropesin, valdecoxib, viminol, xenbucin, ximoprofen,
zaltop~ofen,,
zidometacin, zomepirac and the like, and combinations thereof.
[0098] In one embodiment the anti-inflammatory agent is a steroid. Suitable
steroids
include, but are not limited to, alclometasone, amcinonide, betamethasone,
betamethasone
17-valerate, clobetasol, clobetasol propionate, clocortolone, cortisone,
dehydrotestosterone, deoxycorticosterone, desonide, desoximetasone,
dexamethasone,
dexamethasone 21-isonicotinate, diflorasone, fluocinbnide, fluocinolone,
fluorometholone, flurandrenolide, fluticasore, halcinonide, halobetasol,
hydrocortisone,
hydrocortisone acetate, hydrocortisone cypionate, hydrocortisone
hemisuccinate,
hydrocortisone 21-lysinate, hydrocortisone sodium succinate, isoflupredone,
isoflupredone acetate, methylprednisolone, methylprednisolone acetate,
methylprednisolone sodium succinate, methylpredriisolone suleptnate,
mornetasone,
prednicarbate, prednisolone,~ prednisolone acetate, prednisolone
hemisuccinate,
prednisolone sodium phosphate, prednisolone sodium succinate, prednisolone
valerate-
acetate, prednisone, triamcinolone, triamci$olone acetonide and the like, and
combinations thereof.
[0099] In another embodiment the anti-inflammatory agent is an analgesic,
selected
for example from alfentanil, allylprodine, alphaprodine, anileridine,
benzylmorphine,
bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine,
desomorphine, dextromoramide, dextropropoxyphene, dezocine, diampromide,
diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,
dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,
ethoheptazine,
ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin,
hydrocodone,
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hydromorphone, hydroxypethidine, isomethadone, ketobemidone; levallorphan,
levo hanol, levo henac 1-mo han lofentanil me eridine me tazinol metazocine
iP p Y iP > > P ~ P > >
methadone, meto on mo hine m ro hine nalbu hine, nalo 1 hine narceine
P ~ ~ ~ Y P ~ P iP > >
nicomorphine, norlevorphanol, normethadone, normorphine, norpipanone, opium,
oxycodone, oxymoiphone, papaveretum, pentazocine, phenadoxone, phenazocine,
phenomorphan, phenoperidine, piminodine, piritramide, proheptazine, promedol,
properidine, propiram, propoxyphene, sufentanil, tilidine, tramadol and the
like, and
combinations thereof. ~ .
[0100] In yet another embodiment the anti-inflammatory agent is an NSA>D,
selected
for example, from salicylic acid derivatives (such as salicylic acid,
acetylsalicylic acid;
methyl salicylate, diflunisal, olsalazine, salsalate, sulfasalazine and the
like), indole end
indene acetic acids (such as indomethacin, etodolac, sulindac and the like),
fenamates
(such as etofenamic, meclofenamic, mefenamic, flufenamic, niflumic and
tolfenamic
acids and the like), heteroaryl acetic acids (such as acemetacin, alclofenac,
clidanac,
diclofenac, fenchlofenac, fentiazac, furofenac, ibufenac, isoxepac, ketorolac,
oxipinac,
tiopinac, tolmetin, zidometacin, zomepirac and the like), aryl acetic acid and
propionic
acid derivatives (such as alminoprofen, benoxaprofen, bucloxic acid,
carprofen, fenbufen,
fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen,
miroprofen,
naproxen, naproxen sodium, oxaprozin, pirprofen, pranoprofen, suprofen,
tiaprofenic
acid, tioxaprofen and the like), enolic acids (such as the oxicam derivatives
ampiroxicam,
cinnoxicam, droxicam, lornoxicam, meloxicam, piroxicam, sudoxicam and
tenoxicam,
and the pyrazolone derivatives aminopyrine, antipyrine, apazone, dipyrone,
oxyphenbutazone, phenylbutazone and the like), para-aminophenol derivatives
(such as
acetaminophen and the like), alkanones (such as nabumetone and the like)
nimesulide,
proquazone and the like, and combinations thereof.
[0101] In a preferred embodiment the anti-inflammatory agent is a selective
COX-2
inhibitor. A selective COX-2 inhibitor is a compound that selectively inhibits
cyclooxygenase-2 (COX-2,) activity. The terms "selective COX-2 inhibitor" and
"selective cyclooxygenase-2 inhibitor" interchangeably refer to a therapeutic
compound
that selectively inhibits the COX-2 isoform of the enzyme cyclooxygenase, with
less
significant inhibition of cyclooxygenase-1 (COX-1). As used herein the term
"selective
COX-2 inhibitor" also refers to a prodrug or salt that is converted in vivo to
a compound
22
CA 02533101 2006-O1-19
WO 2005/009436 PCT/IB2004/002461
that exhibits selective inhibition of COX-2 relative to COX-1. Preferred
selective COX-2
inhibitors exhibit a selectivity factor of at least about 10, more preferably
at least about 50
and still more preferably at least about 100, wherein "selectivity factor" is
defined as
ICSO(COX-1)/ICSO(COX-2), ICSO being the concentration of a compound producing
50%
inhibition of enzyme activity in an in vitro or in vivo test.
[0102] Selective COX-2 inhibitors applicable to the invention include, but are
not
limited to, the compounds described below' and include tautomers,
stereoisomers,
enantiomers, salts, hydrates, prodi-ugs and combinations thereof. Any such
selective
COX-2 inhibitory drug or prodrug known in the art can be used.
[0103] A preferred selective' COX-2 inhibitory drug useful herein is a
compound of
formula (~:
1
~X)n R.
A~R3
R2.
(
or a prodrug or pharmaceutically acceptable salt thereof, wherein:
A is a substituent selected from partially unsaturated or unsaturated
heterocyclyl and partially unsaturated or unsaturated carbocyclic rings,
preferably a heterocyclyl group selected from pyrazolyl, furanonyl,
isoxazolyl, pyridinyl, cyclopentenonyl and pyridazinonyl groups;
X is O, S or CH2;
nis0orl;
Rl is at least one substituent selected from heterocyclyl, cycloalkyl,
cycloalkenyl and aryl, and is optionally substituted at a substitutable
position with one or more radicals selected from alkyl, haloalkyl, cyano,
carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino,
alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy and
alkylthio;
RZ is methyl, amino or aminocarbonylalkyl; .
R3 is one or more radicals selected from hydrido, halo, alkyl, alkenyl,
alkynyl,
23
CA 02533101 2006-O1-19
WO 2005/009436 PCT/IB2004/002461
oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy,'alkyloxy, alkylthio,
alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl, cycloalkenyl,
aralkyl, heterocyclylalkyl, acyl, alkylthioalkyl, hydroxyalkyl,
alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl,
aiylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl,
alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl,
aminocarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-
N-arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl,
alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N-
alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-
aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkyl-N- ,
arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl,
alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl,
arylsulfonyl and N-alkyl-N-arylaminosulfonyl, R3 being optionally
substituted at a substitutable position with one or more radicals selected
from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl,
hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro,
alkoxyalkyl, alkylsulfinyl, halo, alkoxy and alkylthio; and
R4 is selected from hydrido and halo.
[0104] A particularly preferred group of selective COX-2 inhibitory drugs are
compounds having the formula (In:
Y~
Z
\S
Rs/ ~O
where RS is a methyl or amino group, R6 is hydrogen or a Cl_4 alkyl or alkoxy
group, X' is
N or CRS where R~ is hydrogen or halogen, and Y and Z are independently carbon
or
nitrogen atoms defining adjacent atoms of a five- to six-membered ring that is
optionally
substituted at one or more positions with oxo, halo, methyl or halomethyl
groups, or an
isomer, tautomer, pharmaceutically-acceptable salt or prodrug thereof.
Preferred such
24
CA 02533101 2006-O1-19
WO 2005/009436 PCT/IB2004/002461
five- to six-membered rings are cyclopentenqne, furanone, methylpyrazole,
isoxazole and
pyridine rings substituted at no moxe than one position.
[0105] Another particularly preferred group of selective COX-2 inhibitory
drug's are
compounds having the formula (111):
Ri~ COOH
Ri~ Ra
(
I
where X" is O, S or N-lower alkyl; R8 is lower haloalkyl; R9 is hydrogen
or'halogen; Rlo
is hydrogen, halogen, lower alkyl, lower alkoxy or haloalkoxy, lower
aralkylcarbonyl,
lower dialkylaminosulfonyl, lower alkylaminosulfonyl, lower
aralkylaminosulfonyl, lower
heteroaralkylaminosulfonyl, or 5- or 6- membered nitrogen-containing
heterocyclosulfonyl; and RI1 and Rl~' are independently hydrogen, halogen,
lower alkyl,
lower alkoxy or aryl; and pharmaceutically acceptable salts thereof.
[0106] A particularly useful compound of formula ()~ is (S)-6,8-dichloro-2-
(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid.
[0107] Another particularly preferred gxoup of selective COX-2 inhibitory
drugs are
5-alkyl-2-arylaminophenylacetic acids and derivatives thereof. Particularly
useful
compounds of this class are lumiracoxib and pharmaceutically acceptable salts
thereof.
[0108] Illustratively, cel~coxib, deracoxib, valdecoxib, parecoxib, rofecoxib,
etoricoxib, lumiracoxib, 2-(3,5-difluorophenyl)-3-[4-(methylsulfonyl)phenyl]-2-
cyclopenten-1-one, (S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-
carboxylic
acid, 2-(3,4-difiuorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-
(methylsulfonyl)phenyl]-3-(2H)-pyridazinone, 4-[5-(4-fluorophenyl)-3-
(trifluoromethyl)-
1H-pyrazol-1-yl]benzenesulfonamide (also known as abelacoxib), tent-butyl 1
benzyl-4-
[(4-oxopiperidin-1-yl}sulfonyl]piperidine-4-carboxylate, 4-[5-(phenyl)-3-
(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide and their salts, more
particularly
celecoxib, deracoxib, valdecoxib, parecoxib and its salts, rofecoxib,
etoricoxib,
lumiracoxib, 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
yl]benzenesulfonamide, tent-butyl 1 benzyl-4-[(4-oxopiperidin-1-yl }
sulfonyl]piperidine-4-
carboxylate, and 4-[5-(phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
yl]benzenesulfonamide
CA 02533101 2006-O1-19
WO 2005/009436 PCT/IB2004/002461
are useful in the method and composition of the invention.
[0109] Valdecoxib used in compositions of the invention can be prepared by and
known process, for example in the manner set forth in U.S. Patent No.
5,633,272 to
Talley et al. Parecoxib and salts thereof used in compositions of the
invention can be
prepared by any known. process, for example in the manner set forth in U.S.
Patent No.
5,932,598 to Talley et al. Rofecoxib used in compositions of the invention can
be
prepared by any known process, for example in the manner set forth in U.S.
Patent No.
5,474,995 to Ducharme et al. Etoricoxib used in compositions of the invention
can be
prepared by any known process, for example in the manner set forth in
International
Patent Publication No. WO 98/03484. 2-(3,5-Difluorophenyl)-3-[4-
(methylsulfonyl)
phenyl]-2-cyclopenten-1-one used in.compositions of the invention~can be
prepared by
any known process, for example in the manner set forth in European Patent No.
0 863 134. Deracoxib used in compositions of the invention can be prepared by
any
known process, for example in the manner set forth in U.S. Patent No.
5,466,823 to
Talley et al. 2-(3,4-Difluorophenyl)-4-(3-hydroxy-3-methyl-1-butoxy)-5-[4-
(methylsulfonyl)phenyl]-3-(2H)-pyridazinone used in compositions of the
invention can
be prepared by any known process, for example in the manner set forth in
International
Patent Publication No. WO 00/24719. Other selective COX-2 inhibitory drugs can
be
prepared by any known process, including processes set forth in patent
publications
disclosing such drugs; for example imthe case of celecoxib in above-cited U.S.
Patent No.
5,466,823 or in U.S. Patent No. 5,892,053 to Zhi et al. All patents and
publications cited
above are incorporated herein by reference.
[0110] Where the anti-inflammatory agent is a selective COX-2 inhibitor a
preferred
concentration range in a composition of the invention is about 0.01 to about
1000 mglml,
more preferably about 0.1 to about 750 mg/ml, and still more preferably about
5 to about
250 mg/ml. For second agents other than a selective COX-2 inhibitor, suitable
concentration ranges can be determined by one of skill in the art based upon
published
data.
[0111] It should be understood that any reference herein to a particular drug
compound includes tautomers, stereoisomers, enantiomers, salts, hydrates and
prodrugs of
that compound and is not specific to any one solid state form of the drug
unless the
context so requires.
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[0112] ' In one embodiment the second agent administered in combination
therapy with
the selective COX-2 inhibitor is an antibacterial agent. Antibacterial agents
applicable for
use according to the invention include any such agents that are effective for
treatment
and/or prevention of mammary disorders and/or otic disorders and/or
complications
associated therewith. Suitable antibacterial agents include, but are not
limited to, beta-
lactam antibacterials such as natural and synthetic penicillin type agents
including penam
penicillins (such as benzyl penicillin, phenoxymethyl penicillin, coxacillin,
nafcillin,
methicillin, oxacillin, amoxycilliri, temocillin, ticarcillin and the like),
penicillinase-stable
penicillins, acylamino and carboxypenicillins (such as piperacillin,
azlocillin, mezlocillin,
carbenicillin, temocillin, ticarcillin and the like), and broader spectrum
penicillins (such
as streptomycin, neomycin, framycetin, gentamicin, apramycin, amikacin,
spectinomycin,
amoxycillin, ampicillin and the like), cephalosporins, macrolides (such as
tylosin,
tilmicosin, aivlosin, erythromycin, azithromycin, spiramycin, josamycin,
kitasamycin and ,
the like), lincosamides (such as lincomycin, clindamycin, pirlimycin and the
like),
pleuromutilins (such as tiamulin, valnemulin and the like), polypeptides,
glycopeptides
(such as vancomycin and the like), polymixins (such as polymixin B, polymixin
E and the
like), sulfonamides (such as sulfamethazine, sulfadiazine, silver
sulfadiazine,
sulfatroxazole, sulfamethoxypyridazine, sulfanilamide, sulfamethoxazole,
sulfisoxazole,
sulfamethizole, mafenide and the like, alone or in combination with
trimethoprim),
chloramphenicol, thiamphenicol, florfenicol, tetracycline type agents (such as
tetracycline,
chlortetracycline, oxytetracycline, domeclocycline, doxycycline, minocycline
and the
like), quinolones and fluoroquinolones (such as ciprofloxacin, enoxacin,
grepafloxacin,
levofloxacin, lomefloxacin, norfloxaciri, ofloxacin, sparfloxacin,
trovafloxacin, cinocacin,
nalidixic acid and the like), tiamulin, colistin, meropenem, sulbactam,
tazobactam,
methacycline, pyrimethamine, sulfacetamide, oxazolidinones, e.g., eperezolid,
linezolid,
N-((5S)-3-(3-fluoro-4-(4-(2-fluoroethyl)-3-oxy-1-piperazinyl)phenyl-2-oxy-5-
oxazolidinyl)methyl)acetamide, (S)-N-((3-(5-(3- pyridyl)thiophen-2-yl)-2-oxy-5-
oxazolidinyl)methyl)acetamide, 2,2-difluoro-N-({(5S)-3-[3-fluoro-4-(4-
glycoloylpiperazin-1-yl)phenyl]-2-oxo-1,3-oxazolidin-5-
yl}methyl)ethanethioamide, (S)-
N-((3-(5-(4-pyridyl)pyrid-2-yl)-2-oxy-5-oxazolidinyl)methyl)acetamide
hydrochloride and
the like, aminoglycosides (kanamycin, tobramycin, netilmicin and the like),
aminocyclitols, amphenicol, ansamycin, carbaphenem,_cephamycin, rifampicin,
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WO 2005/009436 PCT/IB2004/002461
monobactam, oxacephem, streptogramins (such as quinupristin, dalfopristin and
the like),
cycloserines, mupirocin, urea hydroxamates, folic acid analogs (such as
trimethoprim and
the like), antibiotic-type antineoplastic agents (such as aclarubicin,
actinomycin D, I
actinoplanone, aeroplysinin derivative, Nippon Soda anisomycins,
anthracycline, azino-
micyin-A, busucaberin, bleomycin sulfate, bryostatin-l, calichemycin,
chromoximycin,
dactinomycin, daunorubicin, ditrisarubicin B, doxorubicin, doxorubicin-
fibrinogen,
elsamicin-A, epirubicin, erbstatin, esoru~bicin, esperamicin-Alb, fostriecin,
glidobactin,
gregatin-A, grincamycin, herbimycin, idarubicin, illudins, kazusamycin,
kesarirhodins,~
menogaril, mitomycin, mitoxantorone, mutamycin, mycophenolate mofetil,
neoenactin,
oxalysine, oxaunomycin, peplomycin, pilatin, pirarubicin, porothramycin,
pyrindamycin
A, rapamycin, rhizoxin, rodorubicin, sibanomicin, siwenmycin, sorangicin-A~ ,
sparsomycin, steffimycin B, talisomycin, terpentecin, thrazine, tricrozarin A,
zorubicin,
systemic antibacterials (such as 2,4-diaminopyrimidine), nitrofuran sulfones,
marbofloxacin and the like, and combinations thereof.
[0113] Preferred antibacterial agents are cephalosporins including, but not
limited to,
ceftiofur hydrochloride, ceftiofur free acid, e.g., ceftiofur crystalline free
acid; ceftiofur
sodium, other ceftiofur salts, cephalexin, cephradine, cefquinome,
cephacetril'e,
cephalonium, cefuroxime, cefazidime, cefoperazone, sodium
cephemethcarboxylate,
cephem heptahydrate, cephalosporin di- or tri-hydrate, cephadroxil
monohydrate,
cephazolin sodium monohydrate, cefiximine, ceftaxime, ceftizoxime,
ceftriaxone, o-
formylcefamandole, salts of 3-acetoxymethyl-7-(iminocetamido)-cephalosporanic
acid
derivatives, monohydrate of 7-(D-alpha-amino-alpha-(p-hydroxyphenyl)acetamino)-
3-
methyl-3-cephem-1-carboxylic acid, hydrochloride salt of syn-7-((2-amino-1- ,
thiazolyl)(methoxyimino)acetyl)amino)-3-methyl-3-cephem-4-carboxylic acid,
cephem
acid addition salts, (pivaloyloxy)methyl 7-beta-(2-(2-amino-4-
thiazolyl)acetamido)-3-
((( 1-(2-(dimethylamino)ethyl)-1 H-tetraazol-5-yl)thio)methyl)-3-cephem-4-
carboxylate,
cephalexin, cephalexin monohydrate, 7-(D-2-naphthyglycylamino)-3-methyl-3-
cephem-4-
carboxylic acid tetrahydrate and the like. The most preferred cephalosporins
for use
according to the present invention are ceftiofur and pharmaceutically
acceptable salts
thereof. Especially preferred are ceftiofur free acid, most especially in
crystalline form,
and ceftiofur hydrochloride.
[0114] Where the antibacterial substance is ceftiofur or a salt other form
thereof, a
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WO 2005/009436 PCT/IB2004/002461
preferred concentration range in a composition of the invention is about 1 to
about 1000
mg/ml, more preferably about 5 to 'about 750 mg/ml, and still more preferably
about 10 to
about 100 mg/ml. For antibacterial substances other than ceftiofur, suitable
concentration
ranges that are antibacterially equivalent can be determined by one of skill
in the art based
upon published data.
[0115] In another embodiment the second agent is an antineoplastic agent.
Suitable
antineoplastic agents include, but are not limited to, anastrozole, calcium
carbonate,
capecitabine, carboplatin, cisplatii~, docetaxel, eflornithine, etoposide,
exemestane, .
fluoxymestrine, gemcitabine, goserelin, irinotecan, ketoconazole, letrozol,
leucovorin,
levamisole, megsetrol, paclitaxel, raloxifene, retinoic acid, selenium
(selenomethionirie),
sulindac sulfone, tamoxifen, thiotepa, topotecan, toremifen, vinbastine,
vincristin,
vinorelbine and the like, and combinations thereof.
[0116] In another embodiment the second agent is an anesthetic agent.
Anesthetic
agents include, but are not limited to, ambucaine, amolanone, amylocaine,
benoxinate,
benzocaine, betoxycaine, biphenamine, bupivacaine, butacaine, butamben,
butamben
picrate, butanilicaine, butethamine, butoxycaine, carticaine, chloroprocaine,
cocaethylene,
cocaine, cyclomethycaine, dibucaine, dimethisoquin, dimethocaine, diperodon,
diphenylhydramine, dyclonine, ecgonidine, ecgonine, ethyl chloride,
etidocaine, (3-
eucaine, fomocaine, hexylcaine, hydroprocaine, hydroxyprocaine,
hydroxytetracaine,
isobucaine, isobutyl p-aminobenzoate, ketocaine, leucinocaine, levoxadrol,
lidocaine,
mepivacaine, meprylcaine, metabutoxycaine, metabutethamine, myrtecaine,
octacaine,
orthocaine, oxethazaine, oxyprocaine, parethoxycaine, phenacaine, phenol,
piperocaine,
piridocaine, polidocanol, pramoxine, prilocaine, procaine, primacaine,
proparacaine,
propipocaine, propoxycaine, pseudococaine, pyrrocaine, replivicane,
ropivacaine, salicyl
alcohol, tetracaine, tolycaine, trimecaine, xylocaine, and the like, and
combinations
thereof.
[0117] Preferred anesthetic agents include lidocaine, bupivacaine, prilocaine,
ropivacaine, and tautomers, stereoisomers, enantiomers, salts, hydrates,
prodrugs and
combinations thereof.
[0118] In another embodiment the second agent is a sodium channel Mocker.
Sodium
channel blockers useful for the invention comprise those which complement the
effect of
__ the anti-inflammatory agent by any mechanism, including but not limited to,
reduction of
29
CA 02533101 2006-O1-19
WO 2005/009436 PCT/IB2004/002461
pain, reduction of edema, and the like.
[0119] Sodium channel blockers useful according to the invention can be
selected
from the following non-limiting list: NaVl.B (PN3) subtype sodium channel
blockers,
NaV 1.3 (Type III] subtype sodium channel blockers, carboxamides, fenamates,
oxicams,
propanamides, pyrazinoylguanidine semicarbazones, semicarbazides, and the
like.,
[0120] Alternatively, sodium channel blockers applicable for use according to
the
invention can be selected from the following non-limiting list: amiloride, 4-
amino-2-(4-
methylpiperazin-1-yl)-5-(2,3,5-trichlorophenyl)pyrimidine, amitryptiline,
anhydrotetrodotoxin, aprindine, azure A, benzamil, benzothiazole,
benzoxazinate,
carvedilol,~ deoxytetrodotoxin, disopyramide, encainide, ethoxytetrodotoxin,
euprocin,
fenalcomine, fluarizine, gabapentin, isoflurane, lifarizine, lorcainide, 1-
methanesulfonyl-
3-(4-phenoxy)phenyl-1H-pyrazole, methoxyflurane xylocaine,
methoxytetrodotixin,
methyl chloride, 2-methyl-1-[3-(4-phenoxyphenyl)-1H-pyi-azole]propanone,
mexiletine,
N-acenaphth-5-yl-N'-4-methoxynaphthyl guanidine, naepaine, N-(2-chloro-6-
methylphenyl)-N-4-pyridinyl urea, N-[3-(2,6-dimethyl-1-piperidinyl)]-a-
phenylbenzeneacetamide, N-methylstrychnine, 1-[3-[4-(4-nitrophenoxy)phenyl]-1H-
pyrazole]ethanone, oxcabazepine, oxesazeine, oxyburocaine, oxythazaine,
pat~curonium,
phenamil, phenyl benzothiazole, phenytoin, pregabalin, procainamide,
propafenone,
propanocaine ralitoline, riluzole, saxitoxin, tekacaine, tetrodiaminotoxin,
tetrodonic acid,
tetrodotoxin, topiramate, 5-(2,3,5-trichlorophenyl)-2,4-diamino-pyrimidine, 6-
(2,3,5-
trichlorophenyl)-1,2,4-triazin-5-ylamine, verapamil, zolamine, zonisamide, and
the like,
and combinations thereof.
[0121] Amphipathic oils applicable to the current invention include all
amphipathic
oils that are water dispersible and ethanol insoluble.
[0122] Preferred such amphipathic oils are polyglycolized glycerides prepared
by an
alcoholosis reaction of natural triglycerides with polyethylene glycols, and
examples
include, but are not limited to, the following Gattefosse oils or
substantially equivalent
oils from another manufacturer: LabrafilTM M-1944CS, LabrafilTM M-1966CS,
LabrafilTM
M-1969CS, LabrafilTM M-1980CS, LabrafilTM M-2125CS, LabrafilTM WL-2609BS,
LabrafilTM ISO and combinations thereof.
[0123] Still more preferred amphipathic oils are polyglycolized glycerides
prepared as
above, comprising a main fatty acid component of either oleic acid or linoleic
acid, and
CA 02533101 2006-O1-19
WO 2005/009436 PCT/IB2004/002461
examples 'include, but are not limited to, the following Gattefosse oils or
substantially
equivalent oils from another manufacturer: LabrafiITM M-1944CS, LabrafilTM M-
1966CS,
LabrafilTM M-1969CS, LabrafilTM M-1980CS, LabrafiITM M-2125CS, LabrafilTM WL-
2609BS and combinations thereof. '
[0124] Still more preferred amphipathic oils are polyglycolized glycerides
prepared as
above, comprising a main fatty acid component of oleic acid, and examples
include, but
are not limited to, the following Gattefosse Qils or substantially equivalent
oils from
another manufacturer: LabrafilTM~M-1944CS,.LabrafilTM M-1966CS, LabrafilTM
M-1980CS and combinations thereof.
[0125] The most preferred amphipathic oil is pegicol 5-oleate, for example
Labra~ilTM
M-1944CS of Gattfosse Corporation.
[0126] A preferred concentration range for the amphipathic oil in a
composition of the
invention is about 0.01 % to about 99% weight/volume, more preferably about 1
% to
about 80% weight/volume, and still more preferably about 3% to about 25%
weight/volume.
[0127] Microcrystalline wax is as defined for example in Handbook of
Pharnaaceutical Excipients, 3rd ed. or in National Formulary, 19th ed. (NF 19)
and can
be obtained from a number of manufacturers including Witco Corporation.
[0128] A preferred concentration range for microcrystalline wax in a
composition of
the invention is about 0.001 % to about 50% weight/volume, more preferably
about 0.1 %
to about 40% weightfvolume, and still more preferably about 1% to about 15%
weight/volume.
[0129] Pharmaceutically acceptable non-aqueous carriers of the invention can
be fully
saturated, or partially or fully unsaturated. $xamples of non-aqueous carriers
include, but
are not limited to, vegetable oils, mineral oils, synthetic oils and
combinations thereof.
Examples of fully saturated non-aqueous carriers include, but are not limited
to, esters of
medium to long chain fatty acids (such as fatty acid triglycerides with a
chain length of
about C6 to about C24). Mixtures of fatty acids are split from the natural oil
(for example
coconut oil, palm kernel oil, babassu oil or the like) and are refined. In
some
embodiments, medium chain (about C8 to about C12) triglycerides are useful. An
illustrative saturated non-aqueous carrier comprises capric acid (about 20% to
about 45%)
... _and caprylic acid (about 45% to about 80%). Other fully saturated non-
aqueous carriers
31
CA 02533101 2006-O1-19
WO 2005/009436 PCT/IB2004/002461
include, but are not limited to, saturated coconut oil (which typically
includes a mixture of
lauric, myristic, palmitic, capric and caproic acids), including those sold
under the
MiglyolTM trademark from Huls and bearing trade designations 810, 812, 829 and
840).
Also noted are the NeoBeeTM products sold by Drew Chemicals. Isopropyl
myristate is
another example of a non-aqueous carrier useful in compositions of the
invention. ~ '
Examples of synthetic oils include triglycerides and propylene glycol diesters
of saturated
or unsaturated fatty acids having 6 to 24. carbon atoms such as, for example
hexanoic acid,
octanoic (caprylic), nonanoic (pelargonic), decanoic (cupric), undecanoic,
lauric,
tridecanoic, tetradecanoic (myristic), pentadecanoic; hexadecanoic (palmitic),
heptadecanoic, octadecanoic (stearic), nonadecanoic, heptadecanoic,
eicosanoic,
heneicosanoic, docosanoic and lignoceric acids and the like. Examples of
unsaturated
carboxylic acids include oleic, linoleic and linolenic acids and the like. It
is understood
that the non-aqueous carrier can comprise the mono-, di- and
triglyceryl,esters of fatty
acids or mixed glycerides andlor propylene glycol diesters wherein at least
one molecule
of glycerol has been esterified with fatty acids of varying carbon atom
length. A non-
limiting example of a "non-oil" useful as a carrier in compositions of the
invention is
polyethylene glycol.
[0130] Preferred non-aqueous Barriers are vegetable oils such as cottonseed
oil, corn
oil, sesame oil, soybean oil, olive oil, fractionated coconut oil, peanut oil,
sunflower oil,
safflower oil, almond oil, avocado oil, palm oil, palm kernel oil, babassu
oil, beechnut oil,
linseed oil, rape oil and the like. The most preferred non-aqueous carrier is
cottonseed
oil. By way of example cottonseed oil is available in a preparation of 70%
unsaturated
fatty acids from Sigma Chemical Co.
[0131] A preferred concentration range for the non-aqueous carrier in a
composition
of the invention is about 0.5% to about 99% weight/volume, more preferably
about 10%
to about 95% weight/volume, and still more preferably about 40% to about 90%
weight/volume.
[0132] A composition of the invention can optionally further comprise any
conventional pharmaceutical excipient that does not deleteriously react with
the essential
ingredients of the composition. Such excipients include, but are not limited
to,
antioxidants, preservatives, suspending agents, stabilizers, solvbilization
agents, wetting
agents, lubricants, emulsifiers, salts for influencing osmotic pressure,
coloring agents,
32
CA 02533101 2006-O1-19
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alcohols, isotonic agents, buffering agents, permeation agents, anti-
irritants, and
combinations thereof.
[0133] A composition of the invention can be administered for treatment of
mastitis
by inserting the cannula nozzle of a mastitis syringe into the external
orifice of the teat
canal of an udder of a milk-producing animal and infusing the composition into
the udder.
[0134] A composition ~f the invention can be administered for treatment or
prevention of an otic disorder by inserting the nozzle of an ear syringe, otic
drop dispenser
or other appropriate otic delivery eievice into the external auditory canal
of,the ear of a~
subject and infusing the composition into the ear.
[0135] It will be appreciated that preferred amounts of compositions to be
administered in a specific case will'vary according to the specific
composition being
utilized, the mode of application; the particular situs and organism being
treated, and
other factors. Dosages for a given purpose can be determined using
conventional
considerations, for example, by customary comparison of the differential
'activities of the
subject compositions and of a known agent, e.g., by means of an appropriate
conventional
pharmaceutical protocol. '
[0136] Although the present invention is directed primarily to local delivery
of an
anti-inflammatory agent to a site of inflammation in the organ to which it is
administered,
it is contemplated that compositions of the invention are also useful for
systemic delivery
of the anti-inflammatory agent to a milk-producing animal via intramammary
infusion.
For example, it is often more efficient and convenient to administer a
therapeutic agent to
a milk-producing animal such as a cow by intramammary infusion than by other
routes,
such as orally or parenterally. Thus in treatment of inflammatory conditions
elsewhere
than the udder, including for example arthritic conditions, a composition as
herein
described can be administered by intramammary infusion.
[0137] An illustrative suspension composition of the invention containing an
anti-
inflammatory agent, e.g., the selective COX-2 inhibitor deracoxib, has the
following
composition:
selective COX-2 inhibitor 1-350 mg/ml
LabrafilTM M-1944CS 1-75%
microcrystalline wax 0.1-25%
cottonseed oil q.s. to 100%
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EXAMPLES
[0138] The following examples illustrate aspects of the present invention but
should
not be construed as limitations.
Example 1
[0139] A suspension to be administered by intramammary infusion is prepared
having
the following composition:
parecoxib free acid 100 mg/ml
LabrafilTM M-1944CS 50 mg/ml
microcrystalline wax NF 70 mg/ml
cottonseed oil NF q,s,
[0140] The microcrystalline wax and approximately 27% of the total amount of
the
cottonseed oil are heated to 85-98°C with mixing, in a kettle. The
balance of the
cottonseed oil is heated to 85-98°C with mixing, in a manufacturing
tank. After the
microcrystalline wax is completely melted the microcrystalline wax/cottonseed
oil
mixture in the kettle is transferred to the manufacturing tank containing
cottonseed oil and
mixed thoroughly. The resulting mixture is cooled to 38-4.5°C and the
LabrafilTM
M-1944CS, is added to the manufacturing tank with mixing to form a vehicle.
The
parecoxib is then added to the vehicle and the resulting composition is mixed
to form a
uniform suspension. The suspension is screened and filled into 12 ml high
density
polyethylene mastitis syringes. The packaged product is terminally sterilized
by gamma
irradiation at a dose of 25-40 kGy.
[0141] The above suspension is administered by intramammary infusion to each
infected quarter of an udder of a lactating cow at a dose of 1,200 mg '
parecoxib/quarter/day. The suspension is effective in treatment of lactating
cow mastitis.
[0142] A suspension to be administered by intramammary infusion is prepared
having
the following composition:
deracoxib 170 mg/ml
LabrafilTM M-1966CS 100 mg/ml
microcrystalline wax NF 50 mg/ml
corn oil NF q,s,
[0143] The microcrystalline wax and the corn oil are heated to 85-98°C
with mixing,
in a manufacturing tank. After the microcrystalline wax is completely melted,
the mixture
34
CA 02533101 2006-O1-19
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is cooled to 30-45°C and the LabrafilTM M-1~66CS is added to the
manufacturing tank
with mixing to form a vehicle. The deracoxib is added to the vehicle and mixed
to form a
uniform suspension: The suspension is screened and filled into 12 ml high
density
polyethylene mastitis syringes. The packaged product is terminally sterilized
by gamma
irradiation at a dose of 25-40 kGy.
[0144] The above suspension is administered to all four quarters of a dry cow
at a
dose of 3,400 mg deracoxib%quarter by intramammary infusion. The suspension is
effective in treatment of dry cow mastitis.
Example 3
[0145] A suspension to be administered by otic infusion is prepared having the
following composition:
rofecoxib 25 mg/ml
Labrafil ~ M-1980CS 500 mg/ml
microcrystalline wax NF ~ 0.10 mg/ml
propyl gallate 1.0 mg/ml
mineral oil q.s.
[0146] The microcrystalline wax and approximately 27% of the total amount of
mineral oil are heated to 85-98°C with mixing, in a kettle. The balance
of the mineral oil
is heated to 85-98°C with mixing, in a manufacturing tank. After the
microcrystalline
wax is completely melted, the microcrystalline wax/mineral oil mixture in the
kettle is
transferred to the manufacturing tank containing mineral oil and mixed
thoroughly. The
resulting mixture is cooled to 38-45°C and the LabrafilTM M-1980CS is
added to the
manufacturing tank with mixing. The propyl gallate is added to the
manufacturing tank
with mixing to form the vehicle. The rofecoxib is added to the resulting
vehicle and
mixed to form a uniform suspension. The suspension is screened and filled into
20 ml
polypropylene containers.
[0147] The above suspension is administered at a dose of 2.5 mg rofecoxib/kg
of
body weight, by infusion to the ear of a dog. The suspension is effective in
treatment of
canine otitis externa.
Example 4
[0148] A suspension to be administered by intramammary infusion is prepared
having
CA 02533101 2006-O1-19
WO 2005/009436 PCT/IB2004/002461
the following composition:
deracoxib , 300 mg/ml
LabrafilTM M-1944CS 50 mg/ml
microcrystalline wax NF 70 mg/ml
cottonseed oil NF q.s.
[0149] The microcrystalline wax and approximately 27% of the total amount of
the
cottonseed oil are heated to 85-98°C with mixing, in a kettle. The
balance of the
cottonseed oil is heated to 85-98°C with mixing, in a manufacturing
tank. After the.
microcrystalline wax is completely melted, the microcrystalline wax/cottonseed
oil
mixture in the kettle is transferred to the manufacturing tank containing
cottonseed oil and
mixed thoroughly. The resulting mixture is cooled to 38-45°C and the
LabrafilTM 1UI_
1944CS is added to the manufacturing tank with mixing to form the vehicle. The
deracoxib is added to the resulting vehicle and mixed to form a uniform
suspension. The
suspension is screened and filled into 12 ml high density polyethylene
mastitis syringes.
The packaged product is terminally sterilized by gamma irradiation at a dose
of 25-40
kGy.
[0150] The above suspension is administered to all four quarters of a dry cow
at a
dose of 12,000 mg deracoxiblquarter by intramammary infusion. The suspension
is
effective in treatment of dry cow mastitis.
Example 5
[0151] A suspension to be administered by intramammary infusion is prepared
having
the following composition:
valdecoxib 1.5 mg/ml
Labrafil ~ WL-2609BS 75 mg/ml
microcrystalline wax NF 100 mg/ml
Miglyol TM 812 q.s.
[0152] The microcrystalline wax and approximately 30°70 of the total
amount of the
MiglyolTM 812 are heated to 85-98°C with mixing, in a kettle. The
balance of the
MiglyolTM 812 is heated to 85-98°C with mixing, in a manufacturing
tank. After the
microcrystalline wax is completely melted, the microcrystalline wax/MiglyolTM
812
mixture in the kettle is transferred to the manufacturing tank containing the
MiglyolTM
-8lWand-mixed-thoroughly:-The-resulting-mixture-is-cooled to38--45°C
and the
36
CA 02533101 2006-O1-19
WO 2005/009436 PCT/IB2004/002461
LabrafilTM WL-2609BS is added to the manufacturing tank with mixing to form
the
vehicle. The valdecoxib is added to the resulting vehicle and mixed to form a
uniform
suspension. The suspension is screened and filled into 12 ml high density
polyethylene
mastitis syringes. The packaged product is term~nally~,sterilized by gamma
irradiation at a
dose of 25-40 kGy.
[0153] The above suspension is administered to all four quarters of a dry cow
at a
dose of 30 mg valdecoxib/quarter by intramammary infusion. The suspension is
effective
in treatment of dry cow mastitis.,
Example 6
[0154] A suspension to be administered by otic infusion is prepared having the
following composition:
ceftiofur hydrochloride (micronized) 100 mg/ml
deracoxib 100 mg/ml
Labrafil ~ M-1944CS , ~ 700 mg/ml
microcrystalline wax NF 0.05 mg/ml
mineral oil q,s,
[0155] The microcrystalline wax and approximately ~7°l0 of the total
amount of
mineral oil are heated to 85-98°C with mixing, in a kettle. The balance
of the mineral oil
is heated to 85-98°C with mixing, in a manufacturing tank. After the
microcrystalline
wax is completely melted, the microcrystalline wax/mineral oil mixture in the
kettle is
transferred to the manufacturing tank containing mineral oil and mixed
thoroughly. The
resulting mixture is cooled to 38-45°C and the LabrafilTM M-1944CS is
added to the
manufacturing tank with mixing to form the vehicle. The ceftiofur
hydrochloride and the
deracoxib are added to the resulting vehicle and mixed to form a uniform
suspension.
The suspension is screened and filled into 50 ml polypropylene containers.
[0156] The above suspension is administered at a dose of 4 mg ceftiofur
hydrochloride/kg body weight and 4 mg deracoxib/kg of body weight by infusion
to the
ear of a subject. The suspension is effective in treatment and/or prevention
of otitis
media.
Example 7
[0157] A suspension to be administered by otic infusion is prepared having the
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CA 02533101 2006-O1-19
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following, composition:
ceftiofur hydrochloride (micronized) 100 mg/ml
parecoxib free acid 100 mg/ml
LabrafilTM M-1944CS 700 mg/ml
microcrystalline wax NF 0.1 mglml
cottonseed oil NF q.s.
[0158] The microcrystalline wax and cottonseed oil are heated to 85-
98°C with
mixing, in a manufacturing tank. After the microcrystalline wax is completely
melted, the
mixture is cooled to 38-45°C and the LabrafilTM M=1944CS is added to
the manufacturing
tank with mixing to form the vehicle. The ceftiofur hydrochloride and
parecoxib are
added to the resulting vehicle and mixed to form a uniform suspension. The
suspension is
screened and filled into 60 ml polypropylene containers.
[0159] The above suspension is administered at a dose of 4 mg cefti~ofur
hydrochloride/kg body weight and 4 mg parecoxib/kg of body weight by infusion
into the
ear of a subject. The combination therapy is effective in treatment andlor
prevention of
otitis externa.
Example 8 ,
[0160] A suspension to be administered by otic infusion is prepared having the
following composition:
lidocaine 100 mg/ml
parecoxib free acid 100 mg/ml
LabrafilTM M-1944CS 700 mg/ml
microcrystalline wax NF 0.1 mg/ml
cottonseed oil NF q.s.
[0161] The microcrystalline wax and cottonseed oil are heated to 85-
98°C with
mixing, in a manufacturing tank. After the microcrystalline wax is completely
melted, the
mixture is cooled to 38-45°C and the LabrafilTM M-1944CS is added to
the manufacturing
tank with mixing to form the vehicle. The lidocaine and parecoxib are added to
the
resulting vehicle and mixed to form a uniform suspension. The suspension is
screened
and filled into 60 ml polypropylene containers.
[0162] The above suspension is administered at a dose of 4 mg lidocaine/kg
body
weight and 4 W g parecoxib/kg of~body weight-byinfusion into the ear of a
subject. The
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combination 'therapy is effective in treatment and/or prevention of otitis
externa.
[0163] The invention having been described in detail and by reference to the
preferred
embodiments thereof, it will be apparent that modifications and variations are
possible
without departing from the scope of the appended claims.
39
