Note: Descriptions are shown in the official language in which they were submitted.
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DISPERSIBLE PHARMACEUTICAL COMPOSITION FOR TREATMENT OF
MASTITIS AND OTIC DISORDERS
FIELD OF THE INVENTION
[0001] The present invention relates to a method of treatment and/or
prevention of an
infective 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 to 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] Intramammary administration of compositions comprising an antibiotic
for
treatment of mastitis in milk-producing animals is well known. Several
compositions
suitable for such administration are formulated as oil-based formulations.
[0004] 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
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oil in milk, the phospholipid being selected from the group consisting of
phosphatidyl
choline and phosphatidyl ethanolamine and mixtures thereof and present in an
amount of
at least 0.25% in said oil. Such compositions are said to provide rapid
dispersion into
milk and short milkout times.
[0005] 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.
[0006] 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 steaxic 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.
[0007] U.S. Patent No. 5,756,529 to Isakson & Talley discloses a method of
using
pyrazolyl benzenesulfonamide compounds to treat inflammation in a companion
animal.
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.
[0008] International Patent Publication No. WO 02/22107 discloses compositions
comprising one or more bioactive agents in a liquid Garner, 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., cyclooxygenase-2 (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.
[0009] International Patent Publication No. WO 02/06865 discloses a
composition
comprising one or more bioactive substances in a non-aqueous Garner wherein
the
composition has been adjusted to have a water activity of about 0.2 to about
0.5.
Parenteral, topical, oral, intravaginal, rectal and intramammary routes of
administration
are proposed. Among the bioactive agents listed are anti-infectives,
antineoplastics,
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immunomodulators, antipyretics, analgesics and anti-inflammatory agents (e.g.,
COX-2
inhibitors).
[0010] International Patent Publication No. WO 99/20259 discloses a
combination of
thiamphenicol and diclofenac for use in veterinary medicine to treat
infections with
associated inflammatory conditions.
[0011] International Patent Publication No. WO 01/60409 discloses a paste
composition comprising a therapeutic agent, fumed silica, a viscosity modifier
and a
hydrophilic Garner; wherein the therapeutic agent is selected from
insecticides, acaricides,
parasiticides, antibiotics, growth enhancers, oil-soluble NSAlDs, 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.
[0012] U.S. Patent Application Publication No. 2002/0032228 discloses use of a
heterocycle containing compound, for example a diphenyl heterocycle
derivative, to treat
diarrhea! diseases, whooping cough, anthrax, smooth muscle contraction
conditions and
mastitis. Celecoxib and rofecoxib are listed as preferred diphenyl heterocycle
derivatives.
[0013] A Labrafil product brochure (Notice OL 005015th 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.
[0014] 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: in 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.
[0015] 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
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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 and
culture. Otitis externa (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.
[0016] Otitis externa, 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 externa are due to bacterial and fungal infections.
[0017] 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
particularly high
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.
[0018] In the past, otitis externa 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 externa including herpes
zoster.
[0019] 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
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inflammatory process of otitis externa. Most often, antimicrobial 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 for 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.
[0020] The most common otic disorder, otitis media, is a leading cause of
hearing loss
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. '
[0021] 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.
[0022] 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 84.
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.
[0023] Combinations of antibacterial and anti-inflammatory agents, formulated
together in a pharmaceutically acceptable vehicle, have been proposed for
topical
application to the ear, in various patents and publications including those
individually
cited below.
[0024] U.S. Patent No. 6,395,746 to Cagle et al.
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[0025] U.S. Patent No. 6,440,964 to Cagle et al.
[0026] U.S. Patent No. 6,509,327 to Cagle et al.
[0027] U.S. Patent No. 5,679,665 to Bergamini et al.
[0028] U.S. Patent No. 5,965,549 to Purwar & Goldman.
[0029] U.S. Patent Application Publication No. 2001/0049366.
[0030] U.S. Patent Application Publication No. 2002/0142999.
[0031] U.S. Patent Application Publication No. 2002/0044920 discloses treating
immune-mediated ear disorders by administering a TNF antagonist and a
pyrimidine
synthesis inhibitor with a steroid, an anti-inflammatory compound (for example
a non-
steroidal anti-inflammatory drug also known as a NSA>D or a COX-2 inhibitor),
a
cytotoxic compound, an anti-neoplastic metabolite, or a secondary
antirheumatic agent.
[0032] U.S. Patent Application Publication No. 2002/0076383 discloses
administration of a composition as an aerosol through the external auditory
canal, 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 externs.
[0033] 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.
[0034] Ear drops have been contemplated as a formulation type for selective
COX-2
inhibitors, for example in the patents and publications individually cited
below.
[0035] U.S. Patent No. 6,307,047 to Black et al.
[0036] U.S. Patent No. 6,329,526 to Adams et al.
[0037] U.S. Patent Application No. 2001/0041726.
[0038] U.S. Patent Application No. 2001/0053764.
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[0039] U.S. Patent Application No. 2002/0010146.
[0040] U.S. Patent Application No. 2002/0013318.
[0041] All patents and publications cited above are incorporated herein by
reference.
[0042] 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.
[0043] Very few antibacterial agents possess anti-inflammatory, anesthetic,
antipyretic or analgesic properties in addition to their antibacterial
activity. Therefore,
treating an infective condition with an antibacterial agent alone typically
does not
alleviate the inflammation, pain, swelling, fever and other complications that
often
accompany such an infective condition. These problems are usually not totally
resolved
until the causal organism of the infective condition has been eliminated or
reduced to a
subpathogenic population by the antibacterial agent.
[0044] Treatment of an infective condition having an inflammatory component
with
an anti-inflammatory agent alone can reduce inflammation, swelling, pain,
fever and other
complications, but does not treat the underlying infective condition.
[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 andlor excipient that is prone to oxidative degradation. Despite the
above
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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 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) efficacy against a wide variety of infectious
organisms, (c)
effective treatment for the inflammatory component as well as the infectious
component
of mastitis or of an otic disorder, (d) effective treatment of the pain,
inflammation, fever,
edema and infectious components of mastitis or otic disorders, (e) minimal to
no irntation
after administration of the composition, (f) targeted delivery of the active
agents) to sites
of infection, (g) rapid dispersibility of an anti-mastitis composition in milk
and in udder
fluids to quickly achieve efficacious medicament levels at sites of infection,
(h) short
milkout times following mastitis treatment for lactating cows, (i) zero day
slaughter meat
withdrawal period following mastitis treatment, (j) short milk withholding
times post
calving after dry cow mastitis treatment, (k) rapid dispersibility of an otic
composition in
the waxy moist environment of an ear to quickly achieve efficacious medicament
levels at
sites of infection, (1) a lowering of the surface tension of the air/liquid
interface of
epithelial tissue, increasing patency of the auditory canal, (m) a protective
coating for
inflamed mucous membranes of the ear, (n) improvement of the therapeutic index
of an
active agent while decreasing its general toxicity and minimizing the risk of
systemic
effects, (o) decreased time required to alleviate an infective condition
having an
inflammatory component, (p) reduction in side effects, (q) potential to
administer a lower
dose of an active agent while still providing efficacy, and (r) potential to
administer a
higher dose of an antibacterial agent without increased side effects.
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 infective
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 antibacterial agent to the organ via the exterior
orifice and
administering in combination therapy with the antibacterial agent a second
agent that is an
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anti-inflammatory agent, an anesthetic, a sodium channel blocker, an analgesic
andlor an
antipyretic. The antibacterial agent is administered as a pharmaceutical
composition
comprising, in addition to the antibacterial 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] 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 in a wide variety of infective disorders
involving 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.
(0050] The second agent can be administered by a route that is other than the
route of
administration of the antibacterial 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 the second agent as
well as the
antibacterial agent 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 antibacterial agent and the second agent be administered in a single
composition
containing both agents.
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[0051] 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 antibacterial
agent in an
antibacterially effective amount and a second agent that is an anti-
inflammatory agent, an
anesthetic, a sodium channel blocker, an analgesic, antiedemic agents, and/or
an
antipyretic in a therapeutically effective amount.
[0052] In one embodiment the antibacterial agent, the second agent and/or an
excipient in the composition is prone to oxidative degradation, and the
composition
exhibits extended chemical andlor physical stability when packaged in a
container or
delivery device having an oxygen permeable wall.
[0053] The novel composition has a low interfacial tension in aqueous fluids,
thereby
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 antibacterial agent and/or the
second agent to
reach infected tissue quickly, providing an efficacious level of medicament at
a site of
infection. 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
oil/milk or
oil/udder fluid interfacial boundary.
[0054] 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 antibacterial
agent and/or
the second agent to reach infected tissue quickly, providing an efficacious
level of the
medicament at the site of infection. Such a composition can also produce a
protective
coating for inflamed mucous membranes of the ear.
[0055] Combination therapy according to the invention provides effective
treatment
for both the infectious as well as the inflammatory components of an infective
condition,
and can reduce the time required to resolve the infective condition and
associated
inflammation. Preferably the method or composition provides effective
treatment andlor
prevention of the pain, inflammation, fever, swelling, edema, redness, heat,
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mucous or mucous/catarrhal secretions, anorexia, sensory dulling, loss of
organ or system
function, as well as the infectious components associated with mastitis or
otic infections.
[0056] Inflammation associated with an infective condition can inhibit an
antibacterial agent from effectively reaching the site of infection. Use of a
selective
COX-2 inhibitor in combination therapy with an antibacterial agent reduces the
inflammation associated with an infective condition and can result in
improvement in the
ability of the antibacterial agent to effectively reach the site of infection.
[0057] Certain antibacterial agents, while being very effective against
infective
bacteria, are associated with a risk of undesirable side effects, such as
transient redness,
swelling and inflammation. Acceptable dosages of some antibacterial agents can
be
practically limited by the need to minimize risk of such side effects. The
combination
therapy method of the present invention minimizes these risks, thereby
providing
improved treatment of mastitis and otic conditions.
[0058] It is believed, without being bound by theory, that certain
antibacterial agents,
when administered to certain subjects, can promote release of endotoxins that
in turn sets
off a TNFa (tumor necrosis factor alpha) mediated response, and it is further
believed that
such response can be blocked or mitigated by the selective COX-2 inhibitor.
[0059] Combination therapy according to the invention can enable
administration of a
lower dose of a therapeutic agent while still providing efficacy. Further,
local
administration of the antibacterial agent, and optionally the second agent,
according to the
invention provides targeted delivery to the site of infection and/or
inflammation.
[0060] Combination therapy as provided herein can improve the therapeutic
index of
an active agent by decreasing its general toxicity and minimizing the risk of
systemic side
events. 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).
[0061] 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
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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.
[0062] 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.
[0063] Alternatively or in addition, a preferred method enables a zero day
slaughter
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.
[0064] The term "treatment" herein includes administration of a therapeutic
agent to a
nan-lactating animal, for example a dry cow, which does not yet show clinical
signs of
mastitis, but which is at risk for developing clinical mastitis. The invention
therefore
provides a method for reducing risk of developing clinical mastitis in a
future lactating
animal at such risk, the method comprising intramammary administration to the
animal of
an antibacterial ,agent in combination therapy with a second agent as defined
herein, in
therapeutically effective amounts of each.
[0065] In a preferred embodiment, however, combination therapy according to
the
invention is administered to a milk-producing animal that has clinical signs
of mastitis.
The invention therefore provides a method for treating clinical mastitis in a
milk-
producing animal, the method comprising intramammary administration to the
animal, of
an antibacterial agent in combination therapy with a second agent as defined
herein, in
therapeutically effective amounts of each.
[0066] When administered by otic infusion, for example in treatment of
infective
disorders of the ear, 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.
[0067] 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-
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borne toxins, irntants and antigenic materials, and helps prevent otic
disorders.
[0068] 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 antibacterial
agent to the site of infection and/or inflammation. Where a composition of the
invention
is used comprising both an antibacterial agent and a second agent as defined
herein,
targeted delivery of both agents is provided to the site of infection andlor
inflammation.
[0069] A still further benefit of preferred compositions, whether for
intramammary or
otic administration, is that they cause minimal to no irritation after
administration.
[0070] 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.
[0071] 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, an antibacterial agent and a second agent as
defined
herein to provide the composition, such a composition preferably having
extended
chemical and/or physical stability as described herein.
[0072] The present invention thus provides solutions to several long standing
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
[0073] The invention provides a method of treatment of an infective condition
in a
fluid-containing organ having a natural exterior orifice, the method
comprising
administering an antibacterial agent to the organ via the exterior orifice and
administering
in combination therapy therewith a second agent as defined herein; wherein the
antibacterial agent is administered as a pharmaceutical composition comprising
the
antibacterial agent and a vehicle that comprises (a) an amphipathic oil that
is water
dispersible and ethanol insoluble, (b) microcrystalline wax, and (c) a
pharmaceutically
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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
infective 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 infective condition in a fluid-containing organ having a
natural exterior
orifice.
[0074] It will be understood that reference herein to methods involving and
compositions comprising "an antibacterial agent" embraces such methods and
compositions wherein more than one antibacterial agent is used. Further, more
than one
anti-inflammatory, anesthetic, antipyretic, sodium channel blocker, antiedemic
agents,
and/or analgesic agent can optionally form the "second agent" herein.
[0075] 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, whether or not accompanied by
pain, fever,
swelling or inflammation. The invention is, however, especially drawn to such
conditions
having a component of pain, fever, swelling or inflammation.
[0076] 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
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.
[0077] The term "antibacterially effective amount" as used herein refers to an
amount
of an antibacterial 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
infective condition being treated, or to reduce numbers and/or activity of a
causal
organism.
[0078] The term "combination therapy" herein means a treatment regimen wherein
the antibacterial agent and the second agent are administered individually or
together in
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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
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.
[0079] Administration of the antibacterial 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.
[0080] When administered simultaneously, the antibacterial 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 antibacterial agent. Alternatively, the second
agent, like the
antibacterial 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.
[0081] 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
being
treated, or to reduce numbers and/or activity of a causal 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
antibacterial agent
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and the amount of the second agent are sufficient to provide both an
antibacterial effect
and an effect selected from anti-inflammatory, anesthetic, sodium channel
blocker, anti-
edemic, analgesic, and/or antipyretic effects. Such amounts can be the same
as, greater or
less than the amount of antibacterial agent or the amount of the second agent
that are
therapeutically effective when used in monotherapy.
[0082] The "second agent" herein is an active pharmaceutical agent having anti-
inflammatory, anesthetic, anti-edemic, analgesic, sodium channel blocker,
and/or
antipyretic properties. Preferably such an agent exhibits at least an anti-
inflammatory
effect when administered according to the invention.
[0083] The pharmaceutical composition comprising the antibacterial agent and,
in
certain embodiments, the second agent is a liquid injectable or infusible
composition, for
example a composition adapted for intrarnammary or otic infusion, having the
agents)
dispersed in a vehicle as described herein. The term "dispersed" in the
present context
means dissolved (i.e., molecularly dispersed) or colloidally dispersed, for
example as an
emulsion or suspension. Typically at least one of the therapeutic agents is
suspended in
solid particulate form in the vehicle.
[0084] The vehicle comprises three essential ingredients, optionally together
with
additional ingredients.
[0085] 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 is essentially insoluble in ethanol at
20°C.
[0086] The second essential ingredient of the vehicle is microcrystalline wax.
[0087] The third essential ingredient of the vehicle is a pharmaceutically
acceptable
non-aqueous carrier. Such a Garner is typically an oil, as described more
fully
hereinbelow.
[0088] 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 antibacterial agent and, optionally, the
second agent, to
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the site of infection in the organ.
[0089] Where the method of the invention comprises injection or infusion of
the
composition into an udder via the teat canal, a process described herein as
"intramammary
infusion" regardless of the timescale involved, it can provide effective
treatment of
mastitis, other diseases of the udder, and/or a condition associated with a
mammary
disease.
[0090] 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 timescale 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, livestock or the like.
[0091] Examples of such otic disorders include, but are not limited to, otitis
externs
(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 csrcinorna, 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
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abscess, fever, cholesteatomas, calcification of the middle and inner ear,
ruptured ear
drum, meningitis, facial paralysis and the like), postsurgical otalgia and the
like.
[0092] The method of the invention is particularly suitable for treatment of
otitis
externs, otitis media, otorrhea, and infections having an inflammatory
component that are
related to an otic surgical procedure.
[0093] 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.
[0094] Combination therapy of the antibacterial agent together with the second
agent
provides enhanced treatment options as compared to administration of either
the
antibacterial agent or the second agent alone. As indicated above, the
antibacterial agent
is 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 earner, 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.
[0095] Preferably the second agent is formulated in a pharmaceutically
acceptable
vehicle, and both the antibacterial agent and the second agent are
administered into the
same fluid-containing organ, for example by intramammary or otic infusion. A
pharmaceutically acceptable earner or vehicle is one that has no unacceptably
injurious or
toxic effect on the animal when administered as a component of a composition
in an
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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.
[0096] Optionally, administration of the therapeutic agents described above
can take
place in further combination with other biologically active agents and non-
drug therapies.
For example, for treatment of a cancerous or pre-cancerous otic condition
(such as 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) an
antineoplastic agent
can be added to a combination therapy of the invention. Such antineoplastic
agents
include, but are not limited to, anastrozole, calcium carbonate, capecitabine,
carboplatin,
cisplatin, docetaxel, eflornithine, etoposide, exemestane, fluoxymestrine,
gemcitabine,
goserelin, irinotecan, ketoconazole, letrozol, leucovorin, levamisole,
megsetrol,
paclitaxel, raloxifene, retinoic acid, selenium (selenomethionine), sulindac
sulfone,
tamoxifen, thiotepa, topotecan, toremifen, vinbastine, vincristin, vinorelbine
and the like,
and combinations thereof.
[0097] In all embodiments of the invention, at least the antibacterial agent
is
administered locally. An essential requirement for successful therapy of a
local infective
condition such as mastitis is that an antibacterial agent must reach the site
of infection at a
concentration near or higher than the minimal inhibitory concentration and
that such
concentration must be maintained for a certain minimal time. There are
significant
differences among antibacterial agents in their ability to reach a site of
infection in, for
example, an udder, and these are greater than the differences in their
intrinsic antibacterial
activities. One advantage of local administration according to the invention
is that the
antibacterial agent and, preferably, the second agent, are preferentially
directed toward
their site of action, resulting in more rapid onset of therapeutic action and
more complete
delivery to the site of infection, 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 one or both of the active agents, at sites other than the site
of infection.
Local administration of an active agent can also improve its therapeutic index
by
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decreasing its general toxicity and minimizing risk of undesirable systemic
effects.
[0098] The invention provides, in a further embodiment, a pharmaceutical
composition adapted for intramammary infusion, 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
having stably
dispersed therein an antibacterial agent in an antibacterially effective
amount and a second
agent as defined herein in a therapeutically effective amount. Such a
composition is
suitable for single administration providing combination therapy in accordance
with the
method of the invention.
[0099] 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 canal due to elevated surface tensions
therein, and/or
allow separation of the proximal and opposing epithelial walls of the auditory
canal (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.
[0100] In a particular embodiment of the invention an ingredient of the
composition
(the antibacterial agent and/or the second agent andlor 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 andlor 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
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the invention.
[0101] 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, polyisoprenes, polypentenes, copolymers thereof and mixtures
thereof.
[0102] 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.
[0103] Cephalosporins are a class of antibacterial substances, many of which
have a
broad spectrum of activity against both gram positive and gram negative
bacteria.
[0104] 1n an early effort by the present applicant to develop an intramammary
suspension of the cephalosporin ceftiofur, 12.5 mg/ml ceftiofur hydrochloride
was
suspended in a thickened vehicle comprising 20 mg/ml glyceryl monostearate in
peanut
oil. Although clinically efficacious the potency of this composition fell to
below 90% of
label after storage for less than 18 months at room temperature when packaged
in
polyethylene syringes. Oxidative degradation of ceftiofur hydrochloride was
determined
to be the primary cause of this potency decline. A room temperature shelf life
wherein at
least 90% of label potency is retained for a minimum of 24 months is desired
for an
intramammary suspension.
[0105] A number of ceftiofur hydrochloride suspension compositions were then
prepared in a variety of thickened vehicles and packaged in oxygen permeable
polyethylene syringes. Ceftiofur hydrochloride formulations at a concentration
of 12.5
mg/ml were manufactured. All vehicles were based on cottonseed oil, with the
following
additional components:
1) 50 mg/ml microcrystalline wax.
2) 70 mg/ml microcrystalline wax + 1.0 mg/ml propyl gallate.
3) 100 mg/ml microcrystalline wax + 50 mg/ml LabrafilTM M-1944CS.
4) 40 mg/ml GelucireTM 62!05 + 10 mg/ml GelucireTM 33/01.
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5) 70 mg/ml LexemulTM AR.
6) 2.5 mg/ml CoagulanTM GP-1.
7) 10 mg/ml microcrystalline wax + 5 mg/ml Hydrofol GlyceridesTM T 57L.
8) 30 mg/ml DrewpolTM 10-10-S.
9) 15 mg/ml beeswax blend.
10) 60 mg/ml DrewpolTM 10-10-S.
11) 10 mg/ml beeswax blend + 50 mg/ml LabrafilTM M-1944CS.
12) 100 mg/ml microcrystalline wax + 1.0 mg/ml propyl gallate.
13) 70 mg/ml microcrystalline wax + 100 mg/ml LabrafilTM M-1944CS.
14) 70 mg/ml microcrystalline wax + 100 mg/ml LabrafilTM M-1944CS +
0.2 mg/ml butylated hydroxytoluene.
15) 70 mg/ml microcrystalline wax + 50 mg/ml LabrafilTM M-1944CS +
1.0 mg/ml propyl gallate.
16) 70 mg/ml microcrystalline wax + 50 mg/ml LabrafilTM M-1944CS +
0.2 mg/ml butylated hydroxytoluene.
17) 50 mg/ml microcrystalline wax + 1.0 mg/ml propyl gallate.
18) 100 mg/ml microcrystalline wax + 100 mg/ml LabrafilTM M-1944CS +
1.0 mg/ml propyl gallate.
19) 100 mg/ml microcrystalline wax + 100 mg/ml LabrafilTM M-1944CS +
0.2 mg/ml butylated hydroxytoluene.
20) 100 mg/ml microcrystalline wax + 50 mg/ml LabrafilTM M-1944CS +
1.0 mg/ml propyl gallate.
21) 100 mg/ml microcrystalline wax + 50 mg/ml LabrafilTM M-1944CS +
0.2 mg/ml butylated hydroxytoluene.
22) 50 mg/ml microcrystalline wax + 100 mg/ml LabrafilTM M-1944CS +
0.2 mg/ml butylated hydroxytoluene.
[0106] LabrafilTM M-1944CS is an amphipathic oil that is dispersible in water
and is
essentially insoluble in ethanol at 20°C. GelucireTM 62/05 and
GelucireTM 33/01 are
essentially inert excipients derived from natural hydrogenated food grade fats
and oils.
LexemulTM AR is an acid stable cationic, self emulsifying glyceryl
monostearate.
"Beeswax blend" refers to a blend containing white beeswax, carnauba wax and
candelilla
wax. CoagulanTM GP-1 is N-acyl glutamic acid diarnide, an amino acid
gelatinization
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agent for oil. DrewpolTM is a modified glyceride.
[0107] Most surprisingly, it was discovered that after 24 months storage at
room
temperature in oxygen permeable polyethylene syringes, only those ceftiofur
hydrochloride compositions comprising both LabrafilTM M-1944CS and
microcrystalline
wax provided formulations that maintained at least 90% of label potency.
Estimated
room temperature shelf lives for the ceftiofur hydrochloride formulations
comprising both
LabrafilTM M-1944CS and microcrystalline wax in cottonseed oil were 2.4 to 3.7
times
greater than estimated room temperature shelf lives of comparable formulations
which did
not contain LabrafilTM M-1944CS. Additionally, while a ceftiofur hydrochloride
composition comprising LabrafilTM M-1944CS and beeswax blend in cottonseed
oil,
stored at room temperature, had a potency of less than 90% after storage for
24 months in
oxygen permeable polyethylene syringes at room temperature, a ceftiofur
hydrochloride
formulation of comparable viscosity comprising LabrafilTM M-1944CS and
microcrystalline wax in cottonseed oil exhibited a potency of greater than 90%
of label
after 24 months in the same storage conditions.
[0108] Compositions comprising a cephalosporin, an amphipathic oil that is
water
dispersible and ethanol insoluble, microcrystalline wax and a non-aqueous
carrier, in
addition to providing extended chemical and/or physical stability, can also
provide
efficacy against a wide variety of infectious organisms, rapid dispersion of
the
composition in milk and in udder fluids to quickly achieve efficacious
medicament levels
at the site of infection, short milkout times for lactating cows, a zero day
slaughter meat
withdrawal period, short milk withholding times post calving after dry cow
treatment, and
minimal to no irritation after administration.
[0109] Antibacterial agents applicable for use according to the invention
include any
such agents that are effective for treatment and/or prevention of mammary
disorders
andlor 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,
amoxycillin,
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,
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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, norfloxacin, 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,
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,
actinoplanone, aeroplysinin derivative, Nippon Soda anisomycins,
anthracycline, azino-
micyin-A, busucaberin, bleomycin sulfate, bryostatin-1, calichemycin,
chromoximycin,
dactinomycin, daunorubicin, ditrisarubicin B, doxorubicin, doxorubicin-
fibrinogen,
elsamicin-A, epirubicin, erbstatin, esorubicin, 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
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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.
[0110] 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.
[0111] 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,
cephacetrile,
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)-1H-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.
[0112] Where the antibacterial substance is ceftiofur or a salt other form
thereof, a
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 mglml. 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.
[0113) The second agent can have one or more of anti-inflammatory, anesthetic,
as
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sodium channel blocker, anti-edemic, analgesic, and antipyretic properties.
Examples of
agents having anti-inflammatory, analgesic andlor antipyretic properties
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, dimenoxadol, dimepheptanol,
dimethylthiambutene,
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, flunixin,
flunoxaprofen,
fluocinolone acetonide, fluocinonide, fluocinolone acetonide, fluocortin
butyl,
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fluocortolone, fluoresone, fluorometholone, fluperolone, flupirtine,
fluprednidene,
fluprednisolone, fluprofen, fluproquazone, flurandrenolide, flurandrenolone
acetonide,
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, S'-nitro-2'-propoxyacetanilide, norlevorphanol,
normethadone,
normorphine, norpipanone, noscapine, olsalazine, opium, oxaceprol,
oxametacine,
oxaprozin, oxepinac, 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, piprofen, pirazolac, piritramide,
piroxicam,
pranoprofen, prednicarbate, prednisolone, prednisone, prednival, prednylidene,
pirprofen,
piroxicam, proglumetacin, proheptazine, promedol, propacetamol, properidine,
propiram,
propoxyphene, propyphenazone, proquazone, protizinic acid, proxazole,
ramifenazone,
remifentanil, rimazolium metilsulfate, rofecoxib, salacetamide, salicin,
salicylamide,
salicylamide ~-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,
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tinoridine, tiopinac, tioxaprofen, tixocortol, tolfenamic acid, tolmetin,
tramadol,
triamcinolone, tropesin, valdecoxib, viminol, xenbucin, ximoprofen,
zaltoprofen,
zidometacin, zomepirac and the like, and combinations thereof.
[0114] In one embodiment the second agent is a steroidal anti-inflammatory
agent.
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,
fluocinonide, fluocinolone, fluorometholone, flurandrenolide, fluticasone,
halcinonide,
halobetasol, hydrocortisone, hydrocortisone acetate, hydrocortisone cypionate,
hydrocortisone hemisuccinate, hydrocortisone 21-lysinate, hydrocortisone
sodium
succinate, isoflupredone, isoflupredone acetate, methylprednisolone,
methylprednisolone
acetate, methylprednisolone sodium succinate, methylprednisolone suleptnate,
mometasone, prednicarbate, prednisolone, prednisolone acetate, prednisolone
hemisuccinate, prednisolone sodium phosphate, prednisolone sodium succinate,
prednisolone valerate-acetate, prednisone, triamcinolone, triamcinolone
acetonide and the
like, and combinations thereof.
[0115] In another embodiment the second 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, hydromorphone,
hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol,
levophenacyl-
morphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,
morphine, myrophine, nalbuphine, nalorphine, narceine, nicomorphine,
norlevorphanol,
normethadone, normorphine, norpipanone, opium, oxycodone, oxymorphone,
papaveretum, pentazocine, phenadoxone, phenazocine, phenomorphan,
phenoperidine,
piminodine, piritramide, proheptazine, promedol, properidine, propiram,
propoxyphene,
sufentanil, tilidine, tramadol and the like, and combinations thereof.
[0116] In yet another embodiment the second agent is an NSAID, selected for
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example from salicylic acid derivatives (such as salicylic acid,
acetylsalicylic acid, methyl
salicylate, diflunisal, olsalazine, salsalate, sulfasalazine and the like),
indole and 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 anvnopyrine, 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.
[0117] In a preferred embodiment the second agent is an anti-inflammatory
agent of
the class of selective COX-2 inhibitors. 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 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.
[0118] 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, prodrugs and combinations thereof. Any such
selective
COX-2 inhibitory drug or prodrug known in the art can be used.
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[0119] A preferred selective COX-2 inhibitory drug useful herein is a compound
of
formula ()]:
1
~x)n
APRs
R2
(n
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,
oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio,
alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl, cycloalkenyl,
aralkyl, heterocyclylalkyl, acyl, alkylthioalkyl, hydroxyalkyl,
alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl,
arylthioalkyl, 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-
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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, alkylsulfmyl, halo, alkoxy and alkylthio; and
R4 is selected from hydrido and halo.
[0120] A particularly preferred group of selective COX-2 inhibitory drugs are
compounds having the formula (IIy:
\ Y\z
Ii,
(~
where RS is a methyl or amino group, R6 is hydrogen or a C1_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
five- to six-membered rings are cyclopentenone, furanone, methylpyrazole,
isoxazole and
pyridine rings substituted at no more than one position.
[0121) Another particularly preferred group of selective COX-2 inhibitory
drugs are
compounds having the formula (III]:
Ric
Ri.,
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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 Rll and R12 are independently hydrogen, halogen,
lower alkyl,
lower alkoxy, or aryl; and pharmaceutically acceptable salts thereof.
[0122] A particularly useful compound of formula (1I>] is (S)-6,8-dichloro-2-
(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid.
[0123] Another particularly preferred group 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.
[0124] Illustratively, celecoxib, 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-difluorophenyl)-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), tert-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, tert-butyl 1 benzyl-4-[(4-oxopiperidin-1-
yl}sulfonyl]piperidine-4-
carboxylate, and 4-[5-(phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-
yl]benzenesulfonamide
are useful in the method and composition of the invention.
[0125] Valdecoxib 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.
5,633,272 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
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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 in the 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.
[0126] Where the second agent is a selective COX-2 inhibitor a preferred
concentration range in a composition of the invention is about 0.01 to about
1000 mg/ml,
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.
[0127] 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
33
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thereof.
[0128] Preferred anesthetic agents include lidocaine, bupivacaine, prilocaine,
ropivacaine, and tautomers, stereoisomers, enantiomers, salts, hydrates,
prodrugs and
combinations thereof.
[0129] In another embodiment the second agent is a sodium channel blocker.
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
pain, reduction of edema, and the like.
[0130] Sodium channel blockers useful according to the invention can be
selected
from the following non-limiting list: NaV 1.8 (PN3) subtype sodium channel
blockers,
NaV 1.3 (Type ~ subtype sodium channel blockers, carboxamides, fenamates,
oxicams,
propanamides, pyrazinoylguanidine semicarbazones, semicarbazides, and the
like.
[0131] 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-pyrazole]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,
pancuronium,
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)-1,2,4triazin-5-ylamine, verapamil, zolamine, zonisamide, and
the like,
and combinations thereof.
[0132] Amphipathic oils applicable to the current invention include all
amphipathic
oils that are water dispersible and ethanol insoluble.
[0133] Preferred such amphipathic oils are polyglycolized glycerides prepared
by an
34
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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.
[0134] 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
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 and combinations thereof.
[0135] 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 oils or substantially equivalent
oils from
another manufacturer: LabrafilTM M-1944CS, LabrafilTM M-1966CS, LabrafilTM
M-1980CS and combinations thereof.
[0136] The most preferred amphipathic oil is pegicol 5-oleate, for example
LabrafilTM
M-1944CS of Gattfosse Corporation.
[0137] A preferred concentration range for the amphipathic oil in a
composition of the
invention is about 0.01 % to about 99% weightJvolume, more preferably about 1
% to
about 80% weightlvolume, and still more preferably about 3% to about 25%
weightlvolume.
[0138] Microcrystalline wax is as defined for example in Handbaok of
Pharmaceutical Excipients, 3rd ed. or in National Formulary, 19th ed. (NF 19)
and can
be obtained from a number of manufacturers including Witco Corporation.
[0139] A preferred concentration range for microcrystalline wax in a
composition of
the invention is about 0.001 % to about 50% weightlvolume, more preferably
about 0.1 %
to about 40% weight/volume, and still more preferably about 1% to about 15%
weight/volume.
[0140] Pharmaceutically acceptable non-aqueous carriers of the invention can
be fully
saturated, or partially or fully unsaturated. Examples of non-aqueous Garners
include, but
are not limited to, vegetable oils, mineral oils, synthetic oils and
combinations thereof.
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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
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 (capric), 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 and/or 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 earner in compositions of the
invention is
polyethylene glycol.
[0141] Preferred non-aqueous earners 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 earner is
cottonseed
oil. By way of example cottonseed oil is available in a preparation of 70%
unsaturated
fatty acids from Sigma Chemical Co.
[0142] A preferred concentration range for the non-aqueous earner in a
composition
of the invention is about 0.5% to about 99% weight/volume, more preferably
about 10%
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to about 95% weightlvolume, and still more preferably about 40% to about 90%
weight/volume.
[0143] 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, solubilization
agents, wetting
agents, lubricants, emulsifiers, salts for influencing osmotic pressure,
coloring agents,
alcohols, isotonic agents, permeation agents, anti-irritants, buffering agents
and
combinations thereof.
[0144] The composition comprising the antibacterial agent and optionally the
second
agent can be administered for treatment or prevention 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.
[0145] The composition comprising the antibacterial agent and optionally the
second
agent 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 device into
the external auditory canal of the ear of a subject and infusing the
composition into the
ear.
[0146] 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 fox 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.
[0147] An illustrative suspension composition of the invention containing an
antibacterial agent, e.g., ceftiofur hydrochloride and a second agent, e.g.,
the selective
CQX-2 inhibitor deracoxib, has the following composition:
antibacterial agent 1-150 mg/ml
second agent 1-350 mg/ml
LabrafilTM M-1944CS 1-75%
microcrystalline wax 0.1-25%
37
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WO 2005/009472 PCT/IB2004/002474
cottonseed oil q.s. to 100%
(all percentages are weight/volume).
EXAMPLES
[0148] The following examples illustrate aspects of the present invention but
should
not be construed as limitations.
Example 1
[0149] A suspension to be administered by intramammary infusion was prepared
having the following composition:
ceftiofur hydrochloride (micronized) 12.5 mg/ml
LabrafilTM M-1944CS 50 mg/ml
microcrystalline wax NE 70 mg/ml
cottonseed oil NF q,s,
[0150] The microcrystalline wax and approximately 27% of the total amount of
the
cottonseed oil were heated to 85-98°C with mixing, in a kettle. The
balance of the
cottonseed oil was heated to 85-98°C with mixing, in a manufacturing
tank. After the
microcrystalline wax was completely melted the microcrystalline wax/cottonseed
oil
mixture in the kettle was transferred to the manufacturing tank containing
cottonseed oil
and mixed thoroughly. The resulting mixture was cooled to 38-45°C and
the LabrafilTM
M-1944CS was added to the manufacturing tank with mixing to form a vehicle.
The
ceftiofur hydrochloride was then added to the vehicle and the resulting
composition was
mixed to form a uniform suspension. The suspension was screened and filled
into 12 ml
high density polyethylene mastitis syringes. The packaged product was
terminally
sterilized by gamma irradiation at a dose of 25-40 kGy.
[0151] The interfacial tension of the above suspension was determined using
the drop
volume technique with deionized water at 39°C by comparison with that
of a reference
suspension prepared with 70 mg/ml microcrystalline wax in cottonseed oil but
without
LabrafilTM M-1944CS.
[0152] The interfacial tension of the suspension containing both LabrafilTM
M-1944CS and microcrystalline wax in cottonseed oil was 6.5 dyne%m, about 3.4
times
lower than that of the reference suspension (22.5 dyne/cm).
[0153] The above suspension is administered at a dose of 125 mg/quarter/day
(for
38
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from 2 to 8 days) by intramammary infusion to a lactating cow, in combination
therapy
with a parenteral injection of 100 mg/ml parecoxib sodium in a vehicle of
phosphate
buffered saline administered at a dose of 4 mglkg of body weight/day. The
combination
therapy is effective in treatment of lactating cow mastitis.
Example 2
[0154] A suspension to be administered by intramammary infusion was prepared
having the following composition:
ceftiofur hydrochloride (micronized) 12.5 mglml
Labrafil ~ M-1944CS 50 mglml
microcrystalline wax NF 100 mg/ml
cottonseed oil NF q.s.
[0155] The microcrystalline wax and cottonseed oil were heated to 85-
98°C with
mixing, in a manufacturing tank. After the microcrystalline wax was completely
melted
the mixture was cooled to 38-45°C and the LabrafilTM M-1944CS was added
to the
manufacturing tank with mixing to form the vehicle. Ceftiofur hydrochloride
was added
to the resulting vehicle and mixed to form a uniform suspension. The
suspension was
screened and filled into 12 ml high density polyethylene mastitis syringes.
The packaged
product was terminally sterilized by gamma irradiation at a dose of 25-40 kGy.
[0156] The interfacial tension of the above suspension was determined using
the drop
volume technique with deionized water at 39°C by comparison with that
of a reference
suspension prepared with 100 mg/ml microcrystalline wax in cottonseed oil but
without
Labrafil ~ M-1944CS.
[0157] The interfacial tension of the suspension containing both LabrafilTM
M-1944CS and microcrystalline wax in cottonseed oil was 7.1 dyne/cm, about 4.0
times
lower than that of the reference suspension (28.1 dynelcm).
[0158] The above suspension is administered by intramammary infusion at a dose
of
125 mg/quarter/day (for 2 to 8 days) to a lactating cow, in combination
therapy with a
parenteral injection of 200 mg/ml parecoxib sodium in a vehicle of phosphate
buffered
saline administered at a dose of 4 mg/kg of body weight/day. The combination
therapy is
effective in treatment of lactating cow mastitis.
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Example 3
[0159] A suspension to be administered by intramammary infusion was prepared
having the following composition:
ceftiofur hydrochloride (micronized) 12.5 mglml
LabrafilTM M-1944CS 200 mg/ml
microcrystalline wax NF 100 mglml
cottonseed oil NF q.s.
[0160] The microcrystalline wax and cottonseed oil were heated to 85-
98°C with
mixing, in a manufacturing tank. After the microcrystalline wax was completely
melted
the mixture was cooled to 38-45°C and LabrafilTM M-1944CS was added to
the
manufacturing tank with mixing to form the vehicle. The ceftiofur
hydrochloride was
then added to the resulting vehicle and mixed to form a uniform suspension.
The
suspension was screened and filled into 12 ml high density polyethylene
mastitis syringes.
The packaged product was terminally sterilized by gamma irradiation at a dose
of 25-40
kGy.
[0161] The interfacial tension of the above suspension was determined using
the drop
volume technique with deionized water at 39°C by comparison with that
of a reference
suspension prepared with 100 mg/ml microcrystalline wax in cottonseed oil but
without
Labrafil~ M-1944CS.
[0162] The interfacial tension of the suspension containing both LabrafilTM
M-1944CS and microcrystalline wax in cottonseed oil was <1 dyne/cm, more than
28
times lower than that of the reference suspension (28.1 dyne/cm).
[0163] The above suspension is administered at a dose of 125 mglquarterlday
(for 2 to
8 days) by intramammary infusion to a lactating cow, in combination therapy
with a
parenteral injection of 100 mg/ml parecoxib sodium in a vehicle of
15°Io polyethylene
glycol in phosphate buffered saline administered at a dose of 4 mg/kg of body
weight/day.
The combination therapy is effective in treatment of lactating cow mastitis.
Example 4
[0164] A suspension to be administered by intramammary infusion is prepared
having
the following composition:
ceftiofur crystalline free acid (micronized) 25 mg/ml
deracoxib 170 mglml
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LabrafilTM M-1966CS 100 mg/ml
microcrystalline wax NF 50 mg/ml
corn oil NF q.s.
[0165] 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
is cooled to 305°C and the LabrafilTM M-1966CS is added to the
manufacturing tank
with mixing to form a vehicle. The ceftiofur crystalline free acid and the
deracoxib are
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.
[0166] The above suspension is administered to all four quarters of a dry cow
at a
dose of 500 mg ceftiofur crystalline free acidlquarter and 3,400 mg
deracoxiblquarter by
intramammary infusion. The suspension is effective in treatment of dry cow
mastitis.
Example 5
[0167] A suspension to be administered by otic infusion is prepared having the
following composition:
pirlimycin 25 mglml
rofecoxib 25 mg/ml
Labrafil ~ M-1980CS 500 mg/ml
microcrystalline wax NF 0.10 mglml
propyl gallate 1.0 mg/ml
mineral oil q.s.
[0168] 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 waxlmineral oil mixture in the
kettle is
transferred to the manufacturing tank containing mineral oil and nuxed
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 pirlimycin and the rofecoxib are added to
the
resulting vehicle and mixed to form a uniform suspension. The suspension is
screened
and filled into 20 ml polypropylene containers.
41
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[0169] The above suspension is administered at a dose of 2.5 mg pirlimycin/kg
body
weight and 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 6
[0170] A suspension to be administered by intramammary infusion is prepared
having
the following composition:
ceftiofur hydrochloride (micronized) 50 mg/ml
deracoxib 300 mg/ml
LabrafilTM M-1944CS 50 mg/ml
microcrystalline wax NF 70 mg/ml
cottonseed oil NF q,s,
[0171] 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
M-1944CS is added to the manufacturing tank with mixing to form the vehicle.
The
ceftiofur hydrochloride and deracoxib are 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.
[0172] The above suspension is administered to all four quarters of a dry cow
at a
dose of 500 mg ceftiofur hydrochloride/quarter and 12,000 mg deracoxib/quarter
by
intramammary infusion. The suspension is effective in treatment of dry cow
mastitis.
Example 7
[0173] A suspension to be administered by intramammary infusion is prepared
having
the following composition:
ceftiofur sodium (micronized) 25 mg/ml
valdecoxib 1.5 mg/ml
Labrafil ~ WL-2609BS 75 mg/ml
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microcrystalline wax NF 100 mg/ml
Miglyol ~ 812 q.s.
[0174] The microcrystalline wax and approximately 30% 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
812 and mixed thoroughly. The resulting mixture is cooled to 38-45°C
and the
LabrafilTM WL-2609BS is added to the manufacturing tank with mixing to form
the
vehicle. The ceftiofur sodium and the valdecoxib are 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.
[0175] The above suspension is administered to all four quarters of a dry cow
at a
dose of 500 mg ceftiofur sodium/quarter and 30 mg valdecoxib/quarter by
intramammary
infusion. The suspension is effective in treatment of dry cow mastitis.
Example 8
[0176] A suspension to be administered by otic infusion is prepared having the
following composition:
ceftiofur hydrochloride (micronized) 100 mg/ml
deracoxib 100 mglml
Labrafil ~ M-1944CS 700 mg/ml
microcrystalline wax NF 0.05 mg/ml
mineral oil q.s.
[0177] 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 38-4.5°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.
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The suspension is screened and filled into 50 ml polypropylene containers.
[0178] 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 9
[0179] A suspension to be administered by otic infusion is prepared having the
following composition:
ceftiofur hydrochloride (micronized) 100 mg/ml
LabrafilTM M-1944CS 700 mg/ml
microcrystalline wax NF 0.1 mgiml
cottonseed oil NF q.s.
[0180] 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 is added to
the
resulting vehicle and mixed to form a uniform suspension. The suspension is
screened
and filled into 60 ml polypropylene containers.
[0181] The above suspension is administered at a dose of 4 mg ceftiofur
hydrochloride/kg body weight by infusion into the ear of a subject, in
combination therapy
with oral administration of a 200 mg CelebrexC~ (celecoxib) capsule given
twice per day.
The combination therapy is effective in treatment and/or prevention of otitis
externs.
[0182] A suspension to be administered by otic infusion is prepared having the
following composition:
ceftiofur hydrochloride (micronized) 75 mg/ml
LabrafilTM M-1944C5 750 mg/ml
microcrystalline wax NF 0.05 mg/ml
mineral oil q.s.
[0183] The microcrystalline wax and mineral 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 is added to the
resulting
44
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vehicle and mixed to form a uniform suspension. The suspension is screened and
filled
into a 20 ml polypropylene delivery device.
[0184] The above suspension is administered at a dose of 2 mg ceftiofur
hydrochloride/kg body weight by infusion into the ear of a subject, in
combination therapy
with oral administration of a 10 mg Bextra~ (valdecoxib) tablet given once a
day. The
combination therapy is effective in treatment of infectious myringitis.
E,xamnle 11
[0185] A suspension to be administered by otic infusion is prepared having the
following composition:
ceftiofur hydrochloride (micronized)100 mg/ml
parecoxib free acid 100 mgiml
LabrafilTM M-1944CS 700 mg/ml
microcrystalline wax NF 0.1 mglml
cottonseed oil NF q.s.
[0186] 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.
[0187] The above suspension is administered at a dose of 4 mg ceftiofur
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 and/or
prevention of
otitis externs.
Example 12
[0188] A suspension to be administeredtic infusion is prepared
by o having the
following composition:
lidocaine 100 mg/ml
linezolid 100 mg/ml
parecoxib free acid 100 mglml
LabrafilTM M-1944CS 700 mglml
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WO 2005/009472 PCT/IB2004/002474
microcrystalline wax NF 0.1 mglml
cottonseed oil NF q.s.
[0189] 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 linezolid, 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.
[0190] The above suspension is administered at a dose of 4 mg linezolid/kg
body
weight, 4 mg lidocaine/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
and/or
prevention of otitis externs.
[0191] 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.
46
