U.S. patent application number 15/264107 was filed with the patent office on 2017-02-02 for methods for the treatment of pediatric otic disorders.
The applicant listed for this patent is Otonomy, Inc.. Invention is credited to Luis A. Dellamary, Carl Lebel, Fabrice Piu, Qiang Ye.
Application Number | 20170027930 15/264107 |
Document ID | / |
Family ID | 52587275 |
Filed Date | 2017-02-02 |
United States Patent
Application |
20170027930 |
Kind Code |
A1 |
Piu; Fabrice ; et
al. |
February 2, 2017 |
METHODS FOR THE TREATMENT OF PEDIATRIC OTIC DISORDERS
Abstract
Disclosed herein are methods for the treatment of pediatric otic
diseases or conditions with antimicrobial agent compositions and
formulations administered locally to an individual afflicted with
an otic disease or condition, through direct application of these
compositions and formulations onto or via perfusion into the
targeted auris structure(s).
Inventors: |
Piu; Fabrice; (San Diego,
CA) ; Ye; Qiang; (San Diego, CA) ; Dellamary;
Luis A.; (San Marcos, CA) ; Lebel; Carl;
(Malibu, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Otonomy, Inc. |
San Diego |
CA |
US |
|
|
Family ID: |
52587275 |
Appl. No.: |
15/264107 |
Filed: |
September 13, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14469408 |
Aug 26, 2014 |
9486405 |
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15264107 |
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61870318 |
Aug 27, 2013 |
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14469408 |
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61914904 |
Dec 11, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/496 20130101;
A61P 31/04 20180101; Y02A 50/473 20180101; A61P 27/16 20180101;
A61K 47/18 20130101; A61K 9/0046 20130101; A61K 9/0019 20130101;
A61K 9/06 20130101; A61K 47/10 20130101; Y02A 50/30 20180101; A61P
31/00 20180101 |
International
Class: |
A61K 31/496 20060101
A61K031/496; A61K 9/00 20060101 A61K009/00; A61K 47/18 20060101
A61K047/18; A61K 47/10 20060101 A61K047/10 |
Claims
1. A method of treating a pediatric otic disease or condition
associated with a microbial infection, the method comprising
administering into the middle ear of a pediatric patient in need
thereof an aqueous thermoreversible gel composition comprising
about 6.0% by weight of micronized ciprofloxacin and 15-17% by
weight of poloxamer 407.
2. The method of claim 1, wherein the composition comprises from
about 5 mg to about 7 mg by weight of micronized ciprofloxacin.
3. The method of claim 1, wherein the composition comprises
5.4-6.6% by weight of micronized ciprofloxacin.
4. The method of claim 1, wherein the composition is free of
butylated hydroxytoluene (BHT).
5. The method of claim 1, wherein the composition is
preservative-free.
6. The method of claim 1, wherein the composition further comprises
tromethamine.
7. The method of claim 1, wherein the composition has a pH of about
7.0 to about 8.0.
8. The method of claim 1, wherein the composition is administered
to the pediatric patient through a single, intratympanic injection
to each infected ear.
9. The method of claim 1, wherein the composition is administered
following myringotomy.
10. The method of claim 9, wherein the composition is administered
to the site of myringotomy of the pediatric patient.
11. The method of claim 9, wherein the composition is administered
before tympanostomy tube placement.
12. The method of claim 9, wherein the composition is administered
after tympanostomy tube placement.
13. The method of claim 1, wherein the pediatric otic disease or
condition is otitis externa or otitis media.
14. The method of claim 1, wherein the pediatric otic disease or
condition is otitis media with effusion.
15. The method of claim 1, wherein the pediatric otic disease or
condition is bilateral middle ear effusion.
16. The method of claim 1, wherein the pediatric patient is 6
months to 12 years old.
17. The method of claim 1, wherein the pediatric patient is 6
months to 2 years old.
18. The method of claim 1, wherein the pediatric patient is 2 years
to 12 years old.
19. The method of claim 1, wherein the pediatric otic disease or
condition is associated with a bacterial infection.
20. The method of claim 19, wherein the bacterial infection is
associated with Escherichia coli, Klebsiella pneumoniae,
Enterobacter cloacae, Proteus mirabilis, Proteus rettgeri, Proteus
vulgaris, Proteus morgani, Providencia stuartii, Morganella
morganii, Citrobacter freundii, Pseudomonas aeruginosa,
Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus
pyogenes, Streptococcus pneumoniae, Streptococcus faecalis,
Alcaligenes faecalis, Klebsiella aerogenes, Klebsiella pneumonia,
Haemophilus influenzae, Moraxella catarrhalis, or a combination
thereof.
Description
CROSS-REFERENCE
[0001] This application is a continuation of U.S. application Ser.
No. 14/469,408, filed Aug. 26, 2014, which claims the benefit of
U.S. Provisional Application No. 61/870,318 filed Aug. 27, 2013,
and U.S. Provisional Application No. 61/914,904 filed Dec. 11,
2013, each of which is hereby incorporated by reference in its
entirety.
BACKGROUND OF THE INVENTION
[0002] Vertebrates have a pair of ears, placed symmetrically on
opposite sides of the head. The ear serves as both the sense organ
that detects sound and the organ that maintains balance and body
position. The ear is generally divided into three portions: the
outer ear, auris media (or middle ear) and the auris interna (or
inner ear).
SUMMARY OF THE INVENTION
[0003] Described herein are compositions, formulations, therapeutic
methods, uses, and kits for the controlled release of desired
agents to at least one structure or region of the ear. Provided
herein in some embodiments are methods of treating a pediatric otic
disease or condition associated with a microbial infection, the
method comprising administering into the middle ear of a pediatric
patient in need thereof an aqueous thermoreversible gel composition
comprising micronized ciprofloxacin and poloxamer 407. In some
embodiments, the composition comprises 1.8 to 6.6% by weight of
micronized ciprofloxacin and 15-17% by weight of poloxamer 407. In
certain embodiments, the composition comprises 1.8-2.2% by weight
of micronized ciprofloxacin. In other embodiments, the composition
comprises 5.4-6.6% by weight of micronized ciprofloxacin.
[0004] In certain embodiments, the composition further comprises a
buffering agent. In some embodiments, the buffering agent comprises
tromethamine. In some embodiments, the composition further
comprises an osmolality modifier. In some embodiments, the
osmolality modifier comprises sodium chloride. In some embodiments,
the composition further comprises a pH adjusting agent. In some
embodiments, the composition has a pH of about 7.0 to about 8.0. In
some embodiments, the composition comprises micronized
ciprofloxacin, poloxamer 407, sodium chloride, tromethamine,
hydrochloric acid, and water. In some embodiments, the composition
consists essentially of micronized ciprofloxacin, poloxamer 407,
sodium chloride, tromethamine, hydrochloric acid, and water.
[0005] Some embodiments provided herein describe methods of
treating a pediatric otic disease or condition associated with a
microbial infection, the method comprising administering to a
pediatric patient a composition that is free of butylated
hydroxytoluene (BHT). In some embodiments, the composition is
preservative-free.
[0006] In some embodiments, any composition described herein is
administered to the pediatric patient through a single,
intratympanic injection to each infected ear. In some embodiments,
the composition is administered to a pediatric patient via an
intratympanic injection anterior to the round window membrane. In
some embodiments, the composition is administered to a pediatric
patient via an intratympanic injection into the middle ear. In some
embodiments, the composition is administered following myringotomy.
In some embodiments, the composition is administered to the site of
myringotomy of the pediatric patient. In certain embodiments, the
composition is administered before tympanostomy tube placement. In
other embodiments, the composition is administered after
tympanostomy tube placement.
[0007] In some embodiments, the pediatric otic disease or condition
is otitis externa or otitis media. In further or additional
embodiments, the pediatric otic disease or condition is otitis
media with effusion. In certain embodiments, the pediatric otic
disease or condition is bilateral middle ear effusion.
[0008] In some embodiments, the pediatric patient is 6 months to 12
years old. In certain embodiments, the pediatric patient is 6
months to 2 years old. In other embodiments, the pediatric patient
is 2 years to 12 years old.
[0009] In some embodiments, the pediatric otic disease or condition
is associated with a bacterial infection. In certain embodiments,
the bacterial infection is associated with Escherichia coli,
Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis,
Proteus rettgeri, Proteus vulgaris, Proteus morgani, Providencia
stuartii, Morganella morganii, Citrobacter freundii, Pseudomonas
aeruginosa, Staphylococcus aureus, Staphylococcus epidermidis,
Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus
faecalis, Alcaligenes faecalis, Klebsiella aerogenes, Klebsiella
pneumonia, Haemophilus influenzae, Moraxella catarrhalis, or a
combination thereof. In some embodiments, the pediatric otic
disease or condition is associated with Streptococcus pneumoniae,
Haemophilus influenzae, Moraxella catarrhalis, Streptococcus
pyogenes, Staphylococcus aureus, or a combination thereof. In some
embodiments, the pediatric otic disease or condition is associated
with Streptococcus pneumonia. In some embodiments, the pediatric
otic disease or condition is associated with Haemophilus
influenzae. In some embodiments, the pediatric otic disease or
condition is associated with Moraxella catarrhalis.
BRIEF DESCRIPTION OF FIGURES
[0010] FIG. 1 illustrates the anatomy of the ear
[0011] FIG. 2: Summary of Composition A, CIPRODEX.RTM. and
CETRAXAL.RTM. treatment regimens.
[0012] FIG. 3: Comparison of middle ear pharmacokinetic parameters
of ciprofloxacin following administration of Composition A,
CIPRODEX.RTM. or CETRAXAL.RTM.. AUC: Area under the curve; MRT:
Mean residence time; MIC: Minimum inhibitory concentration. A MIC
of 2 .mu.g/ml was defined based upon the breakpoint for bacteria of
intermediate susceptibility to ciprofloxacin.
[0013] FIG. 4A-4C: Middle ear free ciprofloxacin levels following
administration of Composition A, CIPRODEX.RTM. or CETRAXAL.RTM..
(FIG. 4A) Female guinea pigs received a single IT-ANT injection of
various doses of Composition A: 0.06% (closed inverted triangles),
0.2% (stars), 0.6% (closed circles), 2% (closed triangles), 6%
(closed squares) and 12% Composition A (closed diamonds). A
twice-daily one-week course of CIPRODEX.RTM. (FIG. 4B) or
CETRAXAL.RTM. (FIG. 4C) administered through a tympanostomy tube
was given. Free drug levels of ciprofloxacin, obtained by lavaging
the middle ear, were determined at the indicated times. (FIG. 4B
and FIG. 4C) Predicted profile of ciprofloxacin by combining peak
and trough levels. Left inset: peak levels; right inset: trough
levels. Data are presented as mean.+-.SEM (n=4 ears per group per
time point).
[0014] FIG. 5A-5C: Middle ear epithelium (tissue-bound)
ciprofloxacin levels following administration of Composition A,
CIPRODEX.RTM. or CETRAXAL.RTM.. (FIG. 5A) Female guinea pigs
received a single IT-ANT injection of various doses of Composition
A: 0.6% (closed circles), 2% (closed triangles), 6% (closed
squares) or 12% (closed diamonds). A twice-daily one-week course of
CIPRODEX.RTM. (FIG. 5B) or CETRAXAL.RTM. (FIG. 5C) administered
through a tympanostomy tube was given. Tissue-bound levels of
ciprofloxacin, obtained by harvesting the middle ear epithelium,
were determined at the indicated times. (FIG. 5B and FIG. 5C)
Predicted profile of ciprofloxacin by combining peak and trough
levels. Left inset: peak levels; right inset: trough levels. Data
are presented as mean.+-.SEM (n=4 ears per group per time
point).
[0015] FIG. 6A-6C: Inner ear ciprofloxacin levels following
administration of Composition A, CIPRODEX.RTM. or CETRAXAL.RTM..
(FIG. 6A) Guinea pigs received a single IT-ANT injection of various
doses of Composition A: 0.6% (closed circles), 2% (closed
triangles), 6% (closed squares) or 12% (closed diamonds). A
twice-daily one-week course of CIPRODEX.RTM. (FIG. 6B) or
CETRAXAL.RTM. (FIG. 6 C) administered through a tympanostomy tube
was given. Perilymph levels of ciprofloxacin were determined at the
indicated times. (FIG. 6B and FIG. 6C) Predicted profile of
ciprofloxacin by combining peak and trough levels. Left inset: peak
levels; right inset: trough levels. Data are presented as
mean.+-.SEM (n=4 ears per group per time point).
[0016] FIG. 7: Middle ear bacterial load and effusion volume in
chinchillas with otitis media treated with Composition A,
CIPRODEX.RTM. or CETRAXAL.RTM.. Otitis media was induced by middle
ear inoculation of S. pneumoniae. Immediately prior to drug
administration (at Day 3 post inoculation), the middle ear was
drained of effusion and a tympanostomy tube placed. Chinchillas
received either a single IT-ANT injection of various doses of
Composition A, or a twice daily for 3 days treatment course of
CIPRODEX.RTM. (CPD) or CETRAXAL.RTM. (CTX). The bacterial titer and
effusion volume in the middle ear were determined. Data are
presented as mean.+-.SEM (n=6-13 ears).
[0017] FIG. 8: Time to clinical cure in chinchillas with otitis
media treated with Composition A or CIPRODEX.RTM.. Otitis media was
induced by middle ear inoculation of S. pneumoniae. Immediately
prior to drug administration (at Day 3 post inoculation), the
middle ear was drained of effusion and a tympanostomy tube placed.
Chinchillas received either a single IT-ANT injection of various
doses of Composition A, or a twice daily for 3 days treatment
course of CIPRODEX.RTM.. The bacterial titer was determined at the
indicated times. Data are presented as mean.+-.SEM (n=6-10 ears).
Arrows refer to the time of administration of Composition A or
CIPRODEX.RTM..
[0018] FIG. 9: Middle ear ciprofloxacin levels in chinchillas with
otitis media treated with Composition A, CIPRODEX.RTM. or
CETRAXAL.RTM.. The levels of free ciprofloxacin in the middle ear
of treated chinchillas with OM was determined. Three days post
treatment initiation, middle ear samples were collected and the
concentration of ciprofloxacin determined. Data are presented as
mean.+-.SEM (n=6-13 ears). CPD: CIPRODEX.RTM., CTX:
CETRAXAL.RTM..
[0019] FIG. 10: Auditory function following administration of
Composition A or CETRAXAL.RTM.. The auditory function of male and
female guinea pigs was monitored using Auditory Brainstem Responses
at baseline and termination. Animals received a single IT-ANT
injection of poloxamer 407 vehicle, 2% or 6% Composition A, or a
twice daily for 7 days treatment course of CETRAXAL.RTM.. Hearing
threshold shifts were reported at low (4 kHz), medium (10 kHz) and
high (20 kHz) frequencies. Data are presented as mean.+-.SEM (n=5
per sex per group).
[0020] FIG. 11A-11E: Middle ear histology following administration
of Composition A, CIPRODEX.RTM. or CETRAXAL.RTM.. Male and female
guinea pigs (n=5 per sex, per group) received a single IT-ANT
injection of poloxamer 407 vehicle, 2% or 6% Composition A, or a
twice daily for 7 days treatment course of CIPRODEX.RTM. or
CETRAXAL.RTM.. Representative tissue sections of the middle ear (at
termination) from guinea pigs treated with saline (FIG. 11 A),
gentamicin (FIG. 11B), P407 vehicle (FIG. 11C), 2% Composition A
(FIG. 11D), 6% Composition A (FIG. 11E), CIPRODEX.RTM. (FIG. 11F)
and CETRAXAL.RTM. (FIG. 11G) are presented. Legend: M: malleus, S:
stapes, TM: tympanic membrane. Arrows make references of: (FIG.
11A) foamy macrophages; (FIG. 11B) upper arrow: fibroplasia and
inflammation, lower arrow: mixed cellular and proteinaceous debris;
(FIG. 11C) foamy macrophages; (FIG. 11D) foamy macrophages; (FIG.
11E) granulomatous inflammation; (FIG. 11F) reactive cells; (FIG.
11G) basophilic foamy macrophages.
[0021] FIG. 12A-12G: Inner ear cytocochleogram following
administration of Composition A, CIPRODEX.RTM. or CETRAXAL.RTM..
Male and female guinea pigs (n=5 per sex, per group) received a
single IT-ANT injection of poloxamer 407 vehicle, 2% or 6%
Composition A, or a twice daily for 7 days treatment course of
CIPRODEX.RTM. or CETRAXAL.RTM.. Representative cytocochleograms (at
termination) mapping the presence or absence of inner hair cells
(black line) and the three rows of outer hairs (row 1--red line;
row 2--blue line; row 3--green line) by position along the cochlear
spiral, with apex on the left and base on the right, from the
cochleae of treated guinea pigs having received saline (FIG. 12A),
gentamicin (FIG. 12B), P407 vehicle (FIG. 12C), 2% Composition A
(FIG. 12D), 6% Composition A (FIG. 12E), CIPRODEX.RTM. (FIG. 12F)
and CETRAXAL.RTM. (FIG. 12G).
[0022] FIG. 13: Tympanostomy tube patency. Pictures of the tympanic
membrane region depicting the patency at Day 1 and Day 3 following
IT-ANT administration in guinea pigs of poloxamer 407 vehicle (dyed
with Evans Blue), immediately prior to tympanostomy tube
placement.
[0023] FIG. 14: Design of an exemplary clinical trial in pediatric
patients (2 identical trials).
[0024] FIG. 15: Exemplary clinical trial results: Cumulative
proportion of treatment failures through Day 15 (all patients; "n"
denotes sample size per group).
[0025] FIG. 16: Exemplary clinical trial results: Cumulative
proportion of treatment through Day 15 (per-protocol analysis; "n"
denotes sample size per group).
[0026] FIG. 17: Exemplary clinical trial results: Cumulative
proportion of treatment failures due to otorrhea or rescue
antibiotic use for otorrhea or otitis media through Day 15 ("n"
denotes sample size per group).
DETAILED DESCRIPTION OF THE INVENTION
[0027] Provided herein are controlled release antimicrobial agent
compositions and formulations for the treatment of pediatric otic
disorders or conditions, including otitis externa, otitis media,
Ramsay Hunt syndrome, otosyphilis, AIED, Meniere's disease, and
vestibular neuronitis. In some embodiments, the antimicrobial agent
is ciprofloxacin. Compositions comprising combinations of
therapeutic agents useful for the treatment of otic disorders,
including combinations of different antimicrobial agents, as well
as combinations of antimicrobial agents with other therapeutic
agents, are also encompassed in certain embodiments disclosed
herein.
[0028] Otitis externa (OE), also referred to as swimmer's ear, is
an inflammation of the external ear and/or ear canal. OE is
primarily caused by bacteria (e.g., Pseudomonas aeruginosa and
Staphylococcus aureus) or fungi (e.g., Candida albicans and
Aspergillus) in the outer ear, which establish infection following
damage to the skin of the ear canal. Symptoms of OE include
otalgia, swelling, and otorrhea. If the condition progresses
significantly, OE may cause temporary conductive hearing loss as a
result of the swelling and discharge. Treatment of OE involves
eliminating the aggravating pathogen from the ear canal and
reducing inflammation, which is usually accomplished by
administering combinations of antimicrobial agents, e.g.,
antibacterial and antifungal agents, with anti-inflammatory agents,
e.g., steroids.
[0029] Otitis media (OM) is an inflammation of the middle ear.
Bacterial infection accounts for a large percentage of OM cases,
with more than 40% of cases attributed to Streptococcus pneumoniae
infection. However, viruses, as well as other microbes, may account
for OM conditions. Because OM can be caused by a virus, bacteria or
both, various antimicrobial agents are used to eliminate the
underlying pathogen.
[0030] Syphilis is a venereal disease, caused by the spirochete
Treponema pallidum, which may result in otic disorders,
particularly cochleovestibular disorders, due to membranous
labyrinthitis, and secondarily meningitis. Both acquired and
congenital syphilis can cause otic disorders. Symptoms of
cochleovestibular disorders resulting from syphilis are often
similar to those of other otic disorders, such as AIED and
Meniere's disease, and include tinnitus, deafness, vertigo,
malaise, sore throat, headaches, and skin rashes.
[0031] Treatment of otosyphilis (syphilis presenting otic symptoms)
typically includes a combination of steroids and antibacterial
agents. Such treatments may be effective in eradicating the
spirochete organism while reducing inflammation. However,
Treponemas may remain in the cochlear and vestibular endolymph even
after eradication from other sites in the body. Accordingly, long
term treatment with penicillins may be required to achieve complete
eradication of the spirochete organism from the endolymph
fluid.
[0032] Systemic antimicrobial administration for the treatment of
otic disorders, e.g., OE, OM and otosyphilis, may create a
potential inequality in drug concentration with higher circulating
levels in the serum, and lower levels in the target auris interna
organ structures. As a result, fairly large amounts of drug are
required to overcome this inequality in order to deliver
sufficient, therapeutically effective quantities to the inner ear.
Further, bioavailability is often decreased due to metabolism of
the drug by the liver. In addition, systemic drug administration
may increase the likelihood of systemic toxicities and adverse side
effects as a result of the high serum amounts required to
effectuate sufficient local delivery to the target site. Systemic
toxicities may also occur as a result of liver breakdown and
processing of the therapeutic agents, forming toxic metabolites
that effectively erase any benefit attained from the administered
therapeutic.
[0033] To overcome the toxic and attendant undesired side effects
of systemic delivery of antimicrobial agents (which are generally
understood to be toxic to cells), disclosed herein are methods and
compositions for local delivery of antimicrobial agents to auris
media structures. In some embodiments, the auris-acceptable
sustained-release formulations disclosed herein are capable of
being administered into the middle ear via intratympanic injection.
In some embodiments, the auris-acceptable sustained-release
formulations are administered into the middle ear through entry via
a myringotomy incision site. Alternatively, the auris-acceptable
sustained-release formulations is applied via syringe and needle,
wherein the needle is inserted through the tympanic membrane into
the middle ear.
[0034] In addition, localized treatment of the auris media
structures also affords the one or more benefit of improved pK
profiles, improved uptake, low systemic release, and/or improved
toxicity profile.
[0035] Because of the localized targeting of the antimicrobial
agent formulations and compositions, the risk of adverse effects
can be reduced as a result of treatment with previously
characterized toxic or ineffective antimicrobial agent. Localized
administration of antimicrobial agent compositions reduces the risk
of development of resistance to antibiotics compared to the risk
for development of antibiotic resistance when an antibiotic is
administered systemically. The compositions described herein are
effective for recurring otic diseases or conditions including, for
example, recurring ear infections in children without the need for
changing treatment regimens (e.g., in response to development of
antibiotic resistance). Accordingly, also contemplated within the
scope of the embodiments herein is the use of antimicrobial agents
in the treatment of otic diseases or conditions including otitis
externa, otitis media, Ramsay Hunt syndrome, otosyphilis, AIED,
Meniere's disease, and vestibular neuronitis, including therapeutic
agents that have been previously rejected by practitioners because
of adverse effects or ineffectiveness of the antimicrobial
agent(s).
[0036] Also included within the embodiments disclosed herein is the
use of additional auris media and/or auris interna-acceptable
agents in combination with the antimicrobial agent formulations and
compositions disclosed herein. When used, such agents assist in the
treatment of hearing or equilibrium loss or dysfunction resulting
from an autoimmune disorder, including vertigo, tinnitus, hearing
loss, balance disorders, infections, inflammatory response or
combinations thereof. Accordingly, agents that ameliorate or reduce
the effects of vertigo, tinnitus, hearing loss, balance disorders,
infections, inflammatory response or combinations thereof are also
contemplated to be used in combination with the antimicrobial
agent(s) described herein.
[0037] In some embodiments, the composition further comprises an
antimicrobial agent as an immediate release agent wherein the
immediate release antimicrobial agent is the same agent as the
controlled-release agent, a different antimicrobial agent, an
additional therapeutic agent, or a combination thereof. In some
embodiments, the composition further comprises an additional
therapeutic agent, including an additional antimicrobial agent, an
anti-inflammatory agent, a corticosteroid, a cytotoxic agent, an
anti-TNF agent, a collagen, a gamma-globulin, an interferon, a
platelet activator factor antagonist, a nitric oxide synthase
inhibitor, or combinations thereof. In another aspect, the
additional therapeutic agent is an immediate release or a
controlled release agent.
[0038] In some embodiments, the additional therapeutic agent is an
immediate release agent. In some embodiments, the additional
therapeutic agent is a controlled release agent.
[0039] Accordingly, provided herein are controlled release
antimicrobial agent formulations and compositions to locally treat
auris media and/or auris interna structures of pediatric patients,
thereby avoiding side effects as a result of systemic
administration of the antimicrobial agents. The locally applied
antimicrobial agent formulations and compositions are compatible
with auris media, and are administered either directly to the
desired auris media structure of a pediatric patient, e.g. the
tympanic cavity, or administered to a structure in direct
communication with areas of the auris media. By specifically
targeting the auris media structures of the pediatric patient,
adverse side effects as a result of systemic treatment are avoided.
Moreover, by providing a controlled release antimicrobial agent
formulation or composition to treat otic disorders, a constant
and/or extended source of antimicrobial agent is provided to the
pediatric patient suffering from an otic disorder, reducing or
eliminating the variability of treatment.
[0040] Intratympanic injection of therapeutic agents is the
technique of injecting a therapeutic agent behind the tympanic
membrane into the auris media and/or auris interna. Despite early
success with this technique (Schuknecht, Laryngoscope (1956) 66,
859-870) some challenges do remain. For example, access to the
auris media, the site of drug absorption into the auris media, can
be challenging.
[0041] In addition, intra-tympanic injections create several
unrecognized problems not addressed by currently available
treatment regimens, such as changing the osmolarity and pH of the
perilymph and endolymph, and introducing pathogens and endotoxins
that directly or indirectly damage inner ear structures. One of the
reasons the art may not have recognized these problems is that
there are no approved intra-tympanic compositions: the inner ear
provides sui generis formulation challenges. Thus, compositions
developed for other parts of the body have little to no relevance
for an intra-tympanic composition.
[0042] There is little guidance in the prior art regarding
requirements (e.g., level of sterility, pH, osmolarity) for otic
formulations that are suitable for administration to humans. There
is wide anatomical disparity between the ears of animals across
species. A consequence of the inter-species differences in auditory
structures is that animal models of inner ear disease are often
unreliable as a tool for testing therapeutics that are being
developed for clinical approval.
[0043] Provided herein are otic formulations that feature suitable
levels of pH, osmolarity, ionic balance, sterility, endotoxin
and/or pyrogen levels. The auris compositions described herein are
compatible with the microenvironment of the inner ear (e.g., the
perilymph) and are suitable for administration to humans. In some
embodiments, the formulations described herein aid visualization of
the administered compositions obviating the need for invasive
procedures (e.g., removal of perilymph) during preclinical and/or
clinical development of intratympanic therapeutics.
[0044] Provided herein are controlled release antimicrobial agent
formulations and compositions to locally treat targeted auris
structures of pediatric patients, thereby avoiding side effects as
a result of systemic administration of the antimicrobial agent
formulations and compositions. The locally applied antimicrobial
agent formulations and compositions and devices are compatible with
the targeted auris structures, and administered either directly to
the desired targeted auris structure, e.g. the tympanic cavity, or
administered to a structure in direct communication with areas of
the auris media. By specifically targeting an auris structure,
adverse side effects as a result of systemic treatment are avoided.
Moreover, clinical studies have shown the benefit of having
sustained exposure of drug to the perilymph of the cochlea, for
example with improved clinical efficacy of sudden hearing loss when
the therapeutic agent is given on multiple occasions. Thus, by
providing a controlled release antimicrobial agent formulation or
composition to treat otic disorders, a sustained, and/or extended
source of antimicrobial agent is provided to the individual or
patient suffering from an otic disorder, reducing or eliminating
variability in treatment. Accordingly, one embodiment disclosed
herein is to provide a composition that enables at least one
antimicrobial agent to be released in therapeutically effective
doses either at variable or constant rates such as to ensure a
sustained release of the at least one agent.
[0045] In addition, the auris-acceptable sustained-release
antimicrobial agent formulations and treatments described herein
are provided to the target ear region of the individual in need,
including the middle ear, and the individual in need is
additionally administered an oral dose of antimicrobial agent. In
some embodiments, the oral dose of antimicrobial agent is
administered prior to administration of the auris-acceptable
sustained-release antimicrobial agent formulation, and then the
oral dose is tapered off over the period of time that the
auris-acceptable sustained-release antimicrobial agent formulation
is provided. Alternatively, the oral dose of antimicrobial agent is
administered during administration of the auris-acceptable
controlled-release antimicrobial agent formulation, and then the
oral dose is tapered off over the period of time that the
auris-acceptable controlled-release antimicrobial agent formulation
is provided. Alternatively, the oral dose of antimicrobial agent is
administered after administration of the auris-acceptable
controlled-release antimicrobial agent formulation has been
initiated, and then the oral dose is tapered off over the period of
time that the auris-acceptable controlled-release antimicrobial
agent formulation is provided.
[0046] In addition, the antimicrobial agent pharmaceutical
compositions or formulations or devices included herein also
include carriers, adjuvants, such as preserving, stabilizing,
wetting or emulsifying agents, solution promoters, salts for
regulating the osmotic pressure, and/or buffers. Such carriers,
adjuvants, and other excipients will be compatible with the
environment in the targeted auris structure(s). Accordingly,
specifically contemplated for the compositions and devices
described herein are carriers, adjuvants and excipients that lack
ototoxicity or are minimally ototoxic in order to allow effective
treatment of the otic disorders contemplated herein with minimal
side effects in the targeted regions or areas.
[0047] Intratympanic injection of compositions or devices creates
several additional problems that must also be addressed before the
composition or device can be administered. For example, there are
many excipients that are ototoxic. While these excipients can be
used when formulating an active agent for delivery by another
method (e.g., topical), their use is generally limited, reduced or
eliminated when formulating a delivery device to be administered to
the ear due to their ototoxic effects.
[0048] By way of non-limiting example, the formulations disclosed
herein are free or substantially free of alcohols, propylene
glycol, and cyclohexane. In some embodiments, the formulations
disclosed herein comprise less than about 50 ppm, less than about
25 ppm, less than about 20 ppm, less than about 10 ppm, less than
about 5 ppm, less than about 1 ppm, of each of alcohols, propylene
glycol, and cyclohexane.
[0049] In some embodiment, the use of preservatives is limited,
reduced or eliminated when formulating the auris-acceptable
sustained release formulation disclosed herein. As a non-limiting
example, the use of the following commonly utilized preservatives
should be limited, reduced or eliminated when formulating agents
for administration to the ear: benzethonium chloride, benzalkonium
chloride, butylated hydroxytoluene (BHT), and thiomersal. Thus, in
some embodiments, the formulations disclosed herein are free or
substantially free of benzethonium chloride, benzalkonium chloride,
butylated hydroxytoluene (BHT), and thiomersal. In some
embodiments, the formulations disclosed herein comprise less than
about 50 ppm, less than about 25 ppm, less than about 20 ppm, less
than about 10 ppm, less than about 5 ppm, less than about 1 ppm, of
each of benzethonium chloride, benzalkonium chloride, butylated
hydroxytoluene (BHT), and thiomersal.
[0050] Certain antiseptics used to disinfect components of
therapeutic preparations (or the devices utilized to administer the
preparations) should be limited, reduced, or eliminated in otic
preparations. For example, acetic acid, iodine, and merbromin are
all known to be ototoxic. Additionally, chlorhexidene, a commonly
used antiseptic, should be limited, reduced or eliminated to
disinfect any component of an otic preparation (including devices
used to administer the preparation) as it is highly ototoxic in
minute concentrations (e.g., 0.05%). Thus, in some embodiments, the
formulations disclosed herein are free or substantially free of
acetic acid, iodine, merbromin, and chlorhexidene. In some
embodiments, the formulations disclosed herein comprise less than
about 50 ppm, less than about 25 ppm, less than about 20 ppm, less
than about 10 ppm, less than about 5 ppm, less than about 1 ppm, of
each of acetic acid, iodine, merbromin, and chlorhexidene.
[0051] Further, otic preparations require particularly low
concentrations of several potentially-common contaminants that are
known to be ototoxic. Other dosage forms, while seeking to limit
the contamination attributable to these compounds, do not require
the stringent precautions that otic preparations require. For
example, the following contaminants should be absent or nearly
absent from otic preparations: arsenic, lead, mercury, and tin.
Thus, in some embodiments, a device disclosed herein is free or
substantially free of arsenic, lead, mercury, and tin. In some
embodiments, a device disclosed herein comprises less than about 50
ppm, less than about 25 ppm, less than about 20 ppm, less than
about 10 ppm, less than about 5 ppm, less than about 1 ppm, of each
of arsenic, lead, mercury, and tin.
CERTAIN DEFINITIONS
[0052] The term "auris-acceptable" with respect to a formulation,
composition or ingredient, as used herein, includes having no
persistent detrimental effect on the auris interna (or inner ear)
of the subject being treated. By "auris-pharmaceutically
acceptable," as used herein, refers to a material, such as a
carrier or diluent, which does not abrogate the biological activity
or properties of the compound in reference to the auris interna (or
inner ear), and is relatively or is reduced in toxicity to the
auris interna (or inner ear), i.e., the material is administered to
an individual without causing undesirable biological effects or
interacting in a deleterious manner with any of the components of
the composition in which it is contained.
[0053] As used herein, amelioration or lessening of the symptoms of
a particular otic disease, disorder or condition by administration
of a particular compound or pharmaceutical composition refers to
any decrease of severity, delay in onset, slowing of progression,
or shortening of duration, whether permanent or temporary, lasting
or transient that is attributed to or associated with
administration of the compound or composition.
[0054] The term "about" refers to a variation customarily
understood in the technical field of the present disclosure. In
some embodiment, the term "about" refers to a variation of .+-.20%.
In some embodiments, the term "about" refers to a variation of
.+-.15%. In some embodiments, the term "about" refers to a
variation of .+-.10%. In some embodiments, the term "about" refers
to a variation of .+-.5%. In some embodiments, the term "about"
refers to a variation of .+-.2%. In some embodiments, the term
"about" refers to a variation of .+-.1%.
[0055] "Auris media" refers to the middle ear, including the
tympanic cavity, auditory ossicles and oval window, which connects
the middle ear with the inner ear.
[0056] "Blood plasma concentration" refers to the concentration of
compounds provided herein in the plasma component of blood of a
subject.
[0057] The term "diluent" refers to chemical compounds that are
used to dilute the antimicrobial agent prior to delivery and which
are compatible with the auris interna.
[0058] "Drug absorption" or "absorption" refers to the process of
movement of the antimicrobial agents from the localized site of
administration, by way of example only, the round window membrane
of the inner ear, and across a barrier (the round window membranes,
as described below) into the auris interna or inner ear structures.
The terms "co-administration" or the like, as used herein, are
meant to encompass administration of the antimicrobial agents to a
single patient, and are intended to include treatment regimens in
which the antimicrobial agents are administered by the same or
different route of administration or at the same or different
time.
[0059] The terms "effective amount" or "therapeutically effective
amount," as used herein, refer to a sufficient amount of the active
agent or otic agent (e.g., an antimicrobial agent, an
anti-inflammatory agent) being administered that would be expected
to relieve to some extent one or more of the symptoms of the
disease or condition being treated. For example, the result of
administration of an antimicrobial agent disclosed herein is
reduction and/or alleviation of the signs, symptoms, or causes of
tinnitus or balance disorders. For example, an "effective amount"
for therapeutic uses is the amount of antimicrobial agent,
including a formulation as disclosed herein required to provide a
decrease or amelioration in disease symptoms without undue adverse
side effects. The term "therapeutically effective amount" includes,
for example, a prophylactically effective amount. An "effective
amount" of an antimicrobial agent disclosed herein is an amount
effective to achieve a desired pharmacologic effect or therapeutic
improvement without undue adverse side effects. It is understood
that "an effective amount" or "a therapeutically effective amount"
varies, in some embodiments, from subject to subject, due to
variation in metabolism of the compound administered, age, weight,
general condition of the subject, the condition being treated, the
severity of the condition being treated, and the judgment of the
prescribing physician. It is also understood that "an effective
amount" in an extended-release dosing format may differ from "an
effective amount" in an immediate release dosing format based upon
pharmacokinetic and pharmacodynamic considerations.
[0060] The terms "enhance" or "enhancing" refers to an increase or
prolongation of either the potency or duration of a desired effect
of antimicrobial agent, or a diminution of any adverse
symptomatology that is consequent upon the administration of the
therapeutic agent. Thus, in regard to enhancing the effect of the
antimicrobial agents disclosed herein, the term "enhancing" refers
to the ability to increase or prolong, either in potency or
duration, the effect of other therapeutic agents that are used in
combination with the antimicrobial agent disclosed herein. An
"enhancing-effective amount," as used herein, refers to an amount
of antimicrobial agent or other therapeutic agent which is adequate
to enhance the effect of another therapeutic agent or antimicrobial
agent of the target auris structure in a desired system. When used
in a patient, amounts effective for this use will depend on the
severity and course of the disease, disorder or condition, previous
therapy, the patient's health status and response to the drugs, and
the judgment of the treating physician.
[0061] The term "inhibiting" includes preventing, slowing, or
reversing the development of a condition, for example, or
advancement of a condition in a patient necessitating
treatment.
[0062] The terms "kit" and "article of manufacture" are used as
synonyms.
[0063] "Pharmacodynamics" refers to the factors which determine the
biologic response observed relative to the concentration of drug at
the desired site within the auris media and/or auris interna.
[0064] "Pharmacokinetics" refers to the factors which determine the
attainment and maintenance of the appropriate concentration of drug
at the desired site within the auris media and/or auris
interna.
[0065] As used herein, the term "antimicrobial agent" refers to
compounds that inhibit the growth, proliferation, or multiplication
of microbes, or that kill microbes. "Antimicrobial agents" may work
by any suitable mechanism against the microbes, including by being
toxic or cytostatic.
[0066] The term "otic intervention" means an external insult or
trauma to one or more auris structures and includes implants, otic
surgery, injections, cannulations, or the like. Implants include
auris-interna or auris-media medical devices, examples of which
include cochlear implants, hearing sparing devices,
hearing-improvement devices, tympanostomy tubes, short electrodes,
micro-prostheses or piston-like prostheses; needles; stem cell
transplants; drug delivery devices; any cell-based therapeutic; or
the like. Otic surgery includes middle ear surgery, inner ear
surgery, tympanostomy, cochleostomy, labyrinthotomy, mastoidectomy,
stapedectomy, stapedotomy, endolymphatic sacculotomy or the like.
Injections include intratympanic injections, intracochlear
injections, injections across the round window membrane or the
like. Cannulations include intratympanic, intracochlear,
endolymphatic, perilymphatic or vestibular cannulations or the
like.
[0067] In prophylactic applications, compositions comprising the
antimicrobial agents described herein are administered to a patient
susceptible to or otherwise at risk of a particular disease,
disorder or condition. For example, such conditions include and are
not limited to otitis externa, otitis media, Ramsay Hunt syndrome,
otosyphilis, AIED, Meniere's disease, and vestibular neuronitis.
Such an amount is defined to be a "prophylactically effective
amount or dose." In this use, the precise amounts also depend on
the patient's state of health, weight, and the like.
[0068] As used herein "micronized ciprofloxacin" includes, by way
of example only, greater than 70% by weight of the active agent is
in the form of micronized particles of the active agent. In further
embodiments, the term means greater than 80% by weight of the
active agent is in the form of micronized particles of the active
agent. In yet further embodiments, the term means greater than 90%
by weight of the active agent is in the form of micronized
particles of the active agent. In some embodiment, the "micronized
ciprofloxacin" refers to micronized particles that are
non-microencapsulated.
[0069] The mean residence time (MRT) is the average time that
molecules of an active agent (e.g., a microbial agent) reside in an
otic structure after a dose.
[0070] As used herein, the term "subject" is used to mean an
animal, preferably a mammal, including a human or non-human. The
terms patient and subject may be used interchangeably.
[0071] The terms "treat," "treating" or "treatment," as used
herein, include alleviating, abating or ameliorating a disease or
condition, for example tinnitus, symptoms, preventing additional
symptoms, ameliorating or preventing the underlying metabolic
causes of symptoms, inhibiting the disease or condition, e.g.,
arresting the development of the disease or condition, relieving
the disease or condition, causing regression of the disease or
condition, relieving a condition caused by the disease or
condition, or stopping the symptoms of the disease or condition
either prophylactically and/or therapeutically.
[0072] Other objects, features, and advantages of the methods and
compositions described herein will become apparent from the
following detailed description. It should be understood, however,
that the detailed description and the specific examples, while
indicating specific embodiments, are given by way of illustration
only.
Methods
[0073] Provided herein in some embodiments are methods of treating
a pediatric otic disease or condition associated with a microbial
infection. In some embodiments, the method comprises administering
to a pediatric patient a composition comprising micronized
ciprofloxacin and poloxamer 407. In some embodiments, the pediatric
patient is 6 months to 12 years old. In certain embodiments, the
pediatric patient is 6 months to 2 years old. In other embodiments,
the pediatric patient is 2 years to 12 years old.
[0074] In some embodiments, the pediatric otic disease or condition
is associated with a bacterial infection. In certain embodiments,
the pediatric otic disease or condition is associated with
Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae,
Proteus mirabilis, Proteus rettgeri, Proteus vulgaris, Proteus
morgani, Providencia stuartii, Morganella morganii, Citrobacter
freundii, Pseudomonas aeruginosa, Staphylococcus aureus,
Staphylococcus epidermidis, Streptococcus pyogenes, Streptococcus
pneumoniae, Streptococcus faecalis, Alcaligenes faecalis,
Klebsiella aerogenes, Klebsiella pneumonia, Haemophilus influenzae,
Moraxella catarrhalis, or a combination thereof. In some
embodiments, the pediatric otic disease or condition is associated
with Streptococcus pneumoniae, Haemophilus influenzae, Moraxella
catarrhalis, Streptococcus pyogenes, Staphylococcus aureus, or a
combination thereof. In some embodiments, the pediatric otic
disease or condition is associated with Streptococcus pneumonia. In
some embodiments, the pediatric otic disease or condition is
associated with Haemophilus influenzae. In some embodiments, the
pediatric otic disease or condition is associated with Moraxella
catarrhalis.
[0075] In some embodiments, the compositions described herein treat
a pediatric otic disease or condition associated with traditionally
resistant bacterial strains. In some embodiments, the compositions
described herein treat a pediatric otic disease or condition
associated with intermediate and resistant bacterial strains to
ciprofloxacin. In some embodiments, the intermediate and resistant
bacterial strains to ciprofloxacin exhibit a MIC above 2 .mu.g/mL,
above 25 .mu.g/mL, above 50 .mu.g/mL, or above 75 .mu.s/mL.
[0076] In some embodiments, use of the compositions described
herein provide adequate clinical cure against resistant
microorganisms. In some embodiments, the time to clinical cure is 6
h, 8 h, 10 h, 12 h, 14 h, 16 h, 18 h, 20 h, 22 h, 24 h, 26 h, 28 h,
30 h, 32 h, 34 h, 36 h, 38 h, 40 h, 42 h, 44 h, 48 h, 50 h, 52 h,
54 h, 56 h, 58 h, 60 h, 64 h, 68 h, or 72 h. In certain
embodiments, the time to clinical cure is about 12 h. In some
embodiments, the time to clinical cure is less than 12 h. In
certain embodiments, the time to clinical cure is about 18 h. In
some embodiments, the time to clinical cure is less than 18 h. In
certain embodiments, the time to clinical cure is about 24 h. In
some embodiments, the time to clinical cure is less than 24 h. In
certain embodiments, the time to clinical cure is about 36 h. In
some embodiments, the time to clinical cure is less than 36 h. In
certain embodiments, the time to clinical cure is about 48 h. In
some embodiments, the time to clinical cure is less than 48 h. In
certain embodiments, the resistant microorganisms are resistant to
ciprofloxacin. In some embodiments, the methods described herein
prevent or alleviate the potential for antibiotic resistance. In
some embodiments, the use of the compositions described herein
provides bacterial eradication. In certain embodiments, the methods
described herein eradicate pretherapy bacteria in the middle ear.
In some embodiments, the use of the compositions described herein
reduces middle ear effusion.
[0077] In some embodiments, the use of the compositions provided
herein provides antimicrobial protection against biofilms. In some
embodiments, the biofilms are present on tympanostomy tubes placed
in a pediatric patient. In some embodiments, the compositions
provided herein disrupt biofilms.
[0078] Some embodiments provided herein describe a method of
treating or preventing post-surgical otorrhea. In some embodiments,
the method comprises administering to a pediatric patient a
composition comprising micronized ciprofloxacin and poloxamer 407.
In some embodiments, the composition is administered to the
myringotomy site prior to tympanostomy tube placement. In some
embodiments, there is no visible otorrhea 3 days post-surgery. In
other embodiments, there is no visible otorrhea 5 days
post-surgery. In other embodiments, there is no visible otorrhea 7
days post-surgery. In other embodiments, there is no visible
otorrhea 10 days post-surgery. In other embodiments, there is no
visible otorrhea 14 days post-surgery.
[0079] In some embodiments, the methods described herein treat
pediatric otic diseases or conditions without causing or leading to
ototoxicity. In some embodiments, treatment of a pediatric otic
disease or condition with a composition described herein provides
minimal functional changes in hearing. In some embodiments,
treatment of a pediatric otic disease or condition with a
composition described herein provides no evidence of cochlear
pathology. In some embodiments, treatment of a pediatric otic
disease or condition with a composition described herein provides
minimal threshold shifts. In some embodiments, treatment of a
pediatric otic disease or condition with a composition described
herein does not change or influence cochlear pathology. In some
embodiments, treatment of a pediatric otic disease or condition
with a composition described herein is not associated with cochlear
toxicity. In some embodiments, treatment of a pediatric otic
disease or condition with a composition described herein does not
induce hair cell loss of the cochlea. In some embodiments,
treatment of a pediatric otic disease or condition with a
composition described herein does not affect the patency of
tympanostomy tubes.
Anatomy of the Ear
[0080] As shown in FIG. 1, the outer ear is the external portion of
the organ and is composed of the pinna (auricle), the auditory
canal (external auditory meatus) and the outward facing portion of
the tympanic membrane, also known as the ear drum. The pinna, which
is the fleshy part of the external ear that is visible on the side
of the head, collects sound waves and directs them toward the
auditory canal. Thus, the function of the outer ear, in part, is to
collect and direct sound waves towards the tympanic membrane and
the middle ear.
[0081] The middle ear is an air-filled cavity, called the tympanic
cavity, behind the tympanic membrane. The tympanic membrane, also
known as the ear drum, is a thin membrane that separates the
external ear from the middle ear. The middle ear lies within the
temporal bone, and includes within this space the three ear bones
(auditory ossicles): the malleus, the incus and the stapes. The
auditory ossicles are linked together via tiny ligaments, which
form a bridge across the space of the tympanic cavity. The malleus,
which is attached to the tympanic membrane at one end, is linked to
the incus at its anterior end, which in turn is linked to the
stapes. The stapes is attached to the oval window, one of two
windows located within the tympanic cavity. A fibrous tissue layer,
known as the annular ligament connects the stapes to the oval
window. Sound waves from the outer ear first cause the tympanic
membrane to vibrate. The vibration is transmitted across to the
cochlea through the auditory ossicles and oval window, which
transfers the motion to the fluids in the auris interna. Thus, the
auditory ossicles are arranged to provide a mechanical linkage
between the tympanic membrane and the oval window of the
fluid-filled auris interna, where sound is transformed and
transduced to the auris interna for further processing. Stiffness,
rigidity or loss of movement of the auditory ossicles, tympanic
membrane or oval window leads to hearing loss, e.g. otosclerosis,
or rigidity of the stapes bone.
[0082] The tympanic cavity also connects to the throat via the
eustachian tube. The eustachian tube provides the ability to
equalize the pressure between the outside air and the middle ear
cavity. The round window, a component of the auris interna but
which is also accessible within the tympanic cavity, opens into the
cochlea of the auris interna. The round window is covered by round
window membrane, which consists of three layers: an external or
mucous layer, an intermediate or fibrous layer, and an internal
membrane, which communicates directly with the cochlear fluid. The
round window, therefore, has direct communication with the auris
interna via the internal membrane.
[0083] Movements in the oval and round window are interconnected,
i.e. as the stapes bone transmits movement from the tympanic
membrane to the oval window to move inward against the auris
interna fluid, the round window (round window membrane) is
correspondingly pushed out and away from the cochlear fluid. This
movement of the round window allows movement of fluid within the
cochlea, which leads in turn to movement of the cochlear inner hair
cells, allowing hearing signals to be transduced. Stiffness and
rigidity in round window membrane leads to hearing loss because of
the lack of ability of movement in the cochlear fluid. Recent
studies have focused on implanting mechanical transducers onto the
round window, which bypasses the normal conductive pathway through
the oval window and provides amplified input into the cochlear
chamber.
[0084] Auditory signal transduction takes place in the auris
interna. The fluid-filled auris interna, or inner ear, consists of
two major components: the cochlear and the vestibular apparatus.
The auris interna is located in part within the osseous or bony
labyrinth, an intricate series of passages in the temporal bone of
the skull. The vestibular apparatus is the organ of balance and
consists of the three semi-circular canals and the vestibule. The
three semi-circular canals are arranged relative to each other such
that movement of the head along the three orthogonal planes in
space can be detected by the movement of the fluid and subsequent
signal processing by the sensory organs of the semi-circular
canals, called the crista ampullaris. The crista ampullaris
contains hair cells and supporting cells, and is covered by a
dome-shaped gelatinous mass called the cupula. The hairs of the
hair cells are embedded in the cupula. The semi-circular canals
detect dynamic equilibrium, the equilibrium of rotational or
angular movements.
[0085] When the head turns rapidly, the semicircular canals move
with the head, but endolymph fluid located in the membranous
semi-circular canals tends to remain stationary. The endolymph
fluid pushes against the cupula, which tilts to one side. As the
cupula tilts, it bends some of the hairs on the hair cells of the
crista ampullaris, which triggers a sensory impulse. Because each
semicircular canal is located in a different plane, the
corresponding crista ampullaris of each semi-circular canal
responds differently to the same movement of the head. This creates
a mosaic of impulses that are transmitted to the central nervous
system on the vestibular branch of the vestibulocochlear nerve. The
central nervous system interprets this information and initiates
the appropriate responses to maintain balance. Of importance in the
central nervous system is the cerebellum, which mediates the sense
of balance and equilibrium.
[0086] The vestibule is the central portion of the auris interna
and contains mechanoreceptors bearing hair cells that ascertain
static equilibrium, or the position of the head relative to
gravity. Static equilibrium plays a role when the head is
motionless or moving in a straight line. The membranous labyrinth
in the vestibule is divided into two sac-like structures, the
utricle and the saccule. Each structure in turn contains a small
structure called a macula, which is responsible for maintenance of
static equilibrium. The macula consists of sensory hair cells,
which are embedded in a gelatinous mass (similar to the cupula)
that covers the macula. Grains of calcium carbonate, called
otoliths, are embedded on the surface of the gelatinous layer.
[0087] When the head is in an upright position, the hairs are
straight along the macula. When the head tilts, the gelatinous mass
and otoliths tilts correspondingly, bending some of the hairs on
the hair cells of the macula. This bending action initiates a
signal impulse to the central nervous system, which travels via the
vestibular branch of the vestibulocochlear nerve, which in turn
relays motor impulses to the appropriate muscles to maintain
balance.
[0088] The cochlea is the portion of the auris interna related to
hearing. The cochlea is a tapered tube-like structure which is
coiled into a shape resembling a snail. The inside of the cochlea
is divided into three regions, which is further defined by the
position of the vestibular membrane and the basilar membrane. The
portion above the vestibular membrane is the scala vestibuli, which
extends from the oval window to the apex of the cochlea and
contains perilymph fluid, an aqueous liquid low in potassium and
high in sodium content. The basilar membrane defines the scala
tympani region, which extends from the apex of the cochlea to the
round window and also contains perilymph. The basilar membrane
contains thousands of stiff fibers, which gradually increase in
length from the round window to the apex of the cochlea. The fibers
of the basement membrane vibrate when activated by sound. In
between the scala vestibuli and the scala tympani is the cochlear
duct, which ends as a closed sac at the apex of the cochlea. The
cochlear duct contains endolymph fluid, which is similar to
cerebrospinal fluid and is high in potassium.
[0089] The organ of Corti, the sensory organ for hearing, is
located on the basilar membrane and extends upward into the
cochlear duct. The organ of Corti contains hair cells, which have
hairlike projections that extend from their free surface, and
contacts a gelatinous surface called the tectorial membrane.
Although hair cells have no axons, they are surrounded by sensory
nerve fibers that form the cochlear branch of the vestibulocochlear
nerve (cranial nerve VIII).
[0090] As discussed, the oval window, also known as the elliptical
window communicates with the stapes to relay sound waves that
vibrate from the tympanic membrane. Vibrations transferred to the
oval window increases pressure inside the fluid-filled cochlea via
the perilymph and scala vestibuli/scala tympani, which in turn
causes the round window membrane to expand in response. The
concerted inward pressing of the oval window/outward expansion of
the round window allows for the movement of fluid within the
cochlea without a change of intra-cochlear pressure. However, as
vibrations travel through the perilymph in the scala vestibuli,
they create corresponding oscillations in the vestibular membrane.
These corresponding oscillations travel through the endolymph of
the cochlear duct, and transfer to the basilar membrane. When the
basilar membrane oscillates, or moves up and down, the organ of
Corti moves along with it. The hair cell receptors in the Organ of
Corti then move against the tectorial membrane, causing a
mechanical deformation in the tectorial membrane. This mechanical
deformation initiates the nerve impulse which travels via the
vestibulocochlear nerve to the central nervous system, mechanically
transmitting the sound wave received into signals that are
subsequently processed by the central nervous system.
Diseases
[0091] Pediatric otic disorders, including auris interna, auris
media, and auris externa disorders, produce symptoms which include
but are not limited to hearing loss, nystagmus, vertigo, tinnitus,
inflammation, swelling, infection and congestion. These disorders
may have many causes, such as infection, injury, inflammation,
tumors and adverse response to drugs or other chemical agents.
[0092] Inflammatory Disorders of the Ear
[0093] Otitis externa (OE), also referred to as swimmer's ear, is
an inflammation and/or infection of the external ear. OE is often
caused by bacteria in the outer ear, which establish infection
following damage to the skin of the ear canal. Primary bacterial
pathogens that cause OE are Pseudomonas aeruginosa and
Staphylococcus aureus, but the condition is associated with the
presence of many other strains of gram positive and negative
bacteria. OE is also sometimes caused by fungal infection in the
outer ear, including Candida albicans and Aspergillus. Symptoms of
OE include otalgia, swelling, and otorrhea. If the condition
progresses significantly, OE may cause temporary conductive hearing
loss as a result of the swelling and discharge.
[0094] Treatment of OE involves eliminating the aggravating
pathogen from the ear canal and reducing inflammation, which is
usually accomplished by administering combinations of antimicrobial
agents, e.g., antibacterial and antifungal agents, with
anti-inflammatory agents, e.g., steroids. Typical antibacterial
agents for the treatment of OE include aminoglycosides (e.g.,
neomycin, gentamycin, and tobramycin), polymyxins (e.g., polymyxin
B), fluoroquinolone (e.g., ofloxacin, ciprofloxacin, levofloxacin,
trovafloxacin), cephalosporins (e.g., cefuroxime, ceflacor,
cefprozil, loracarbef, cefindir, cefixime, cefpodoxime proxetil,
cefibuten, and ceftriaxone), penicillins (e.g., amoxicillin,
amoxicillin-clavulanate, and penicillinase-resistant penicillins),
and combinations thereof. Typical antifungal agents for the
treatment of OE include clotrimazole, thimerasol, M-cresyl acetate,
tolnaftate, itraconazole, and combinations thereof. Acetic acid is
also administered to the ear, alone and in combination with other
agents, to treat bacterial and fungal infections. Ear drops are
often used as the vehicle for administration of the active agents.
In the case that ear swelling has progressed substantially and ear
drops do not penetrate significantly into the ear canal, a wick can
be inserted into the ear canal to facilitate penetration of the
treatment solutions. Oral antibiotics are also administered in the
case of extensive soft tissue swelling that extends to the face and
neck. When the pain of OE is extremely severe such that it
interferes with normal activity, e.g., sleeping, pain relievers
such as topical analgesics or oral narcotics may be given until the
underlying inflammation and infection are alleviated.
[0095] Notably, some types of topical ear drops, such as ear drops
containing neomycin, are safe and effective for use in the ear
canal, but can be irritating and even ototoxic to the auris media,
prompting concern that such topical preparations should not be used
unless the tympanic membrane is known to be intact. Utilization of
the formulations disclosed herein for the treatment of OE allows
for use of active agents that are potentially damaging to the auris
media, even when the tympanic membrane is not intact. Specifically,
the controlled release formulations disclosed herein can be applied
locally in the external ear with improved retention time, thus
eliminating concern that the active agents will leak out of the ear
canal into the auris media. Furthermore, otoprotectants can be
added when ototoxic agents, such as neomycin, are used.
[0096] Treatment of severe OE with the antimicrobial compositions
disclosed herein, particularly highly viscous and/or mucoadhesive
formulations, also obviates the need for extended use of an ear
wick. Specifically, the compositions disclosed herein have
increased retention time in the ear canal as a result of the
formulation technology, thus eliminating the need for a device to
maintain their presence in the outer ear. The formulations can be
applied in the outer ear with a needle or an ear dropper, and the
active agents can be maintained at the site of inflammation without
the aid of an ear wick. In some embodiments, antimicrobial agent
compositions described herein further comprise anti-inflammatory
agents and are useful in the treatment of otitis externa.
[0097] In some embodiments, the treatment of OE with antimicrobial
formulations disclosed herein encompasses the treatment of granular
myringitis, a specific form of OE characterized by chronic
inflammation of the pars tensa of the tympanic membrane. The outer
epithelial and underlying fibrous layers of the tympanic membrane
are replaced by a proliferating granulation tissue. The predominant
symptom is foul-smelling otorrhea. A variety of bacteria and fungi
cause the condition, including Proteus and Psuedomonas species.
Accordingly, antimicrobial agent formulations disclosed herein
comprising antibacterial or antifungal agents are useful for the
treatment of granular myringitis.
[0098] In some embodiments, the treatment of OE with antimicrobial
formulations disclosed herein encompasses the treatment of chronic
stenosing otitis externa. Chronic stenosing otitis externa is
characterized by repeated infections, typically caused by bacteria
or fungi. The primary symptoms are pruritus in the ear canal,
otorrhea, and chronic swelling. Antimicrobial agent formulations
disclosed herein comprising antibacterial or antifungal agents are
useful for the treatment of chronic stenosing otitis externa.
[0099] In some embodiments, the treatment of OE with antimicrobial
formulations disclosed herein encompasses the treatment of
malignant or necrotizing external otitis, an infection involving
the temporal and adjacent bones. Malignant external otitis is
typically a complication of external otitis. It occurs primarily in
persons with compromised immunity, especially in older persons with
diabetes mellitus. Malignant external otitis is often caused by the
bacteria Pseudomonas aeruginosa. Treatment typically involves
correction of immunosuppression when possible, in conjunction with
antibacterial therapy and pain relievers. According, antimicrobial
agent formulations disclosed herein are useful for the treatment of
malignant or necrotizing external otitis.
[0100] Otitis media (OM), which includes acute otitis media (AOM),
chronic otitis media, otitis media with effusion (OME), recurrent
acute otitis media (RAOM), chronic otitis media with effusion
(COME), secretory otitis media, and chronic secretory otitis media
as examples, is a condition affecting both adults and children. OM
susceptibility is multifactorial and complex, including
environmental, microbial and host factors. Bacterial infection
accounts for a large percentage of OM cases, with more than 40% of
cases attributed to Streptococcus pneumoniae infection. However,
viruses, as well as other microbes, may also account for OM
conditions. In some instances, otitis media is associated with
eustachian tube dysfunction that is caused by, for example,
anatomic blockage to inflammation, secondary to allergies, upper
respiratory tract infection (URTI), trauma or the like.
[0101] Otitis media with effusion (OME) is characterized by a
nonpurulent effusion of the middle ear that may be either mucoid or
serous. Symptoms usually involve hearing loss or aural fullness. In
children, hearing loss is generally mild and is often detected only
with an audiogram. Serous otitis media is a specific type of OME
caused by transudate formation as a result of a rapid decrease in
middle ear pressure relative to the atmospheric pressure.
[0102] Because OM can be caused by a virus, bacteria or both, it is
often difficult to identify the exact cause and thus the most
appropriate treatment. Treatment options for OM include
antibiotics, such as penicillins (e.g., amoxicillin and
amoxicillin-clavulanate), clavulanate acid,
trimethoprim-sulfamethoxazole, fluoroquinolone (e.g., ofloxacin,
ciprofloxacin, levofloxacin, trovafloxacin), cephalosporins (e.g.,
cefuroxime, ceflacor, cefprozil, loracarbef, cefindir, cefixime,
cefpodoxime proxetil, cefibuten, and ceftriaxone), macrolides and
azalides (e.g., erythromycin, clarithromycin, and azithromycin),
sulfonamides, and combinations thereof. Surgical intervention is
also available, including myringotomy, an operation to insert a
tympanostomy tube through the tympanic membrane and into the
patient's middle ear to drain the fluid and balance the pressure
between the outer and middle ear. Antipyretics and analgesics,
including benzocaine, ibuprofen and acetaminophen, may also be
prescribed to treat accompanying fever or pain effects.
Antimicrobial agent compositions disclosed herein comprising
antibacterial or antifungal agents are useful for the treatment of
pediatric otitis media (OM), which includes acute otitis media
(AOM), chronic otitis media, otitis media with effusion (OME),
recurrent acute otitis media (RAOM), chronic otitis media with
effusion (COME), secretory otitis media, and chronic secretory
otitis media or the like. In some embodiments, antimicrobial agent
compositions described herein further comprise anti-inflammatory
agents and are useful in the treatment of pediatric otitis media
(OM), which includes acute otitis media (AOM), chronic otitis
media, otitis media with effusion (OME), recurrent acute otitis
media (RAOM), chronic otitis media with effusion (COME), secretory
otitis media, and chronic secretory otitis media or the like. In
some embodiments, the compositions disclosed herein comprising
ciprofloxacin are useful for the treatment of pediatric otitis
media with effusion. In some embodiments, the compositions
disclosed herein comprising ciprofloxacin are useful for the
treatment of pediatric bilateral middle ear effusion.
[0103] Regardless of the causative agent, increases in cytokine
production, including interleukins and TNF, have been observed in
the effluent media of individuals afflicted with OM. IL-1.beta.,
IL-6 and TNF-.alpha. are acute-phase cytokines that promote acute
inflammatory response after infection with viruses and bacteria.
Moreover, higher TNF-.alpha. levels have been associated with a
history of multiple tympanostomy tube placements, indicating a role
for TNF-.alpha. in chronic OM cases. Finally, direct injection of
TNF-.alpha. and interleukins has been shown to induce middle ear
inflammation in a guinea pig model. These studies support the role
that cytokines may play in the origin and maintenance of OM in the
auris media. Thus, treatment of OM includes the use of
antimicrobial agents in conjunction with anti-inflammatory agents
to eliminate the pathogen and treat the symptoms of inflammation.
Such treatments include use of steroids, TNF-.alpha. inhibitors,
platelet activating factor antagonists, nitric oxide synthase
inhibitors, histamine antagonists, and combinations thereof in
conjunction with the antimicrobial formulations disclosed
herein.
[0104] Mastoiditis is an infection of the mastoid process, which is
the portion of the temporal bone behind the ear. It is typically
caused by untreated acute otitis media. Mastoiditis may be acute or
chronic. Symptoms include pain, swelling, and tenderness in the
mastoid region, as well as otalgia, erythematous, and otorrhea.
Mastoiditis typically occurs as bacteria spread from the middle ear
to the mastoid air cells, where the inflammation causes damage to
the bony structures. The most common bacterial pathogens are
Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus
aureus, and gram-negative bacilli. Accordingly, antimicrobial agent
formulations disclosed herein comprising antibacterial agents
effective against the bacteria are useful for the treatment of
mastoiditis, including acute mastoiditis and chronic
mastoiditis.
[0105] Bullous myringitis is an infection of the tympanic membrane,
caused by a variety of bacteria and viruses, including Mycoplasma
bacteria. The infection leads to inflammation of the tympanic
membrane and nearby canal, and causes the formation of blisters on
the ear drum. The primary symptom of Bullous myringitis is pain,
which may be relieved through the administration of analgesics.
Antimicrobial formulations disclosed herein comprising
antibacterial and antiviral agents are useful for the treatment of
Bullous myringitis.
[0106] Eustachian tubal catarrh, or Eustachian salpingitis, is
caused from inflammation and swelling of the Eustachian tubes,
resulting in a build-up of catarrh. Accordingly, antimicrobial
formulations disclosed herein are useful for the treatment of
Eustachian salpingitis.
[0107] Labyrinthitis, e.g., serous labyrinthitis, is an
inflammation of the inner ear that involves one or more labyrinths
housing the vestibular system. The primary symptom is vertigo, but
the condition is also characterized by hearing loss, tinnitus, and
nystagmus. Labrynthitis maybe acute, lasting for one to six weeks
and being accompanied by severe vertigo and vomiting, or chronic,
with symptoms lasting for months or even years. Labyrinthitis is
typically caused by viral or bacterial infection. Accordingly,
antimicrobial formulations disclosed herein comprising
antibacterial and antiviral agents are useful for the treatment of
labyrinthitis.
[0108] Facial nerve neuritis is a form of neuritis, an inflammation
of the peripheral nervous system, afflicting the facial nerve. The
primary symptoms of the condition are a tingling and burning
sensation, and stabbing pains in the affected nerves. In severe
cases, there may be numbness, loss of sensation, and paralysis of
the nearby muscles. The condition is typically caused by herpes
zoster or herpes simplex viral infection, but has also been
associated with bacterial infection, e.g., leprosy. Accordingly,
antimicrobial formulations disclosed herein comprising
antibacterial and antiviral agents are useful for the treatment of
facial nerve neuritis.
[0109] In some embodiments, antimicrobial formulations disclosed
herein are also useful for the treatment of temporal bone
osteoradionecrosis.
[0110] Ramsay Hunt Syndrome (Herpes Zoster Oticus)
[0111] Ramsay Hunt syndrome is caused by a herpes zoster infection
of the auditory nerve. The infection may cause severe ear pain,
hearing loss, vertigo, blisters on the outer ear, in the ear canal,
as well as on the skin of the face or neck supplied by the nerves.
Facial muscles may also become paralyzed if the facial nerves are
compressed by the swelling. Hearing loss may be temporary or
permanent, with vertigo symptoms usually lasting from several days
to weeks.
[0112] Treatment of Ramsay Hunt's syndrome includes administration
of antiviral agents, such as ganciclovir, acyclovir, famciclovir
and valacyclovir. Antiviral agents may be given in combination with
agents that treat symptoms of the infection, such as
corticosteroids, analgesics and narcotics to relieve the pain, and
scopolamine, diazempam, or other central nervous system agents to
suppress vertigo. Capsaicin, lidocaine patches and nerve blocks may
also be used. Surgery may be performed on compressed facial nerves
to relieve facial paralysis.
[0113] Otosyphilis
[0114] Syphilis is a venereal disease, caused by the spirochete
Treponema pallidum, which in its secondary and tertiary stages may
result in otic disorders, particularly cochleovestibular disorders,
due to membranous labyrinthitis, and secondarily meningitis. Both
acquired and congenital syphilis can cause otic disorders. Symptoms
of cochleovestibular disorders resulting from syphilis are often
similar to those of other otic disorders, such as AIED and
Meniere's disease, and include tinnitus, deafness, vertigo,
malaise, sore throat, headaches, and skin rashes. Syphilis
infection may lead to congenital prenatal hearing loss, affecting
approximately 11.2 per 100,000 live births in the United States, as
well as sudden hearing loss in adults.
[0115] Treatment of otosyphilis (syphilis presenting otic symptoms)
typically includes a combination of steroids (e.g., prednisilone)
and antibacterial agents (e.g., benzathine penicillin G (BICILLIN
LA.RTM.), penicillin G procaine, doxycycline, tetracycline,
ceftriaxone, azithromycin). Such treatments may be effective in
eradicating the spirochete organism. However, Treponemas may remain
in the cochlear and vestibular endolymph even after eradication
from other sites in the body. Accordingly, long term treatment with
penicillins may be required to achieve complete eradication of the
spirochete organism from the endolymph fluid. Also, in the case of
a severe or advanced case of syphilis, a uricosuric drug, such as
probenecid, may be administered in conjunction with the
antibacterial agent to increase its efficacy.
[0116] Other Microbial Infections Causing Cochleovestibular
Disorders
[0117] Other microbial infections are known to cause
cochleovestibular disorders, including hearing loss. Such
infections include rubella, cytomegalovirus, mononucleosis,
varicella zoster (chicken pox), pneumonia, Borrelia species of
bacteria (Lyme disease), and certain fungal infections.
Accordingly, controlled release antimicrobial agent formulations
disclosed herein are also used for localized treatment of these
infections in the ear.
[0118] Autoimmune Inner Ear Disease
[0119] Autoimmune inner ear disease (AIED) is one of the few
reversible causes of sensorineural hearing loss. It is a disorder
appearing in both adults and children that often involves a
bilateral disturbance of the audio and vestibular functions of the
auris interna. In many cases, AIED occurs without systemic
autoimmune symptoms, but up to one-third of patients also suffer
from a systemic autoimmune illness, such as inflammatory bowel
disease, rheumatoid arthritis, Ankylosing spondylitis, Systemic
Lupus Erythematosus (SLE), Sjogren's Syndrome, Cogan's disease,
ulcerative colitis, Wegener's granulomatosis and scleroderma.
Behcet's disease, a multisystem disease, also commonly has
audiovestibular problems. A classification scheme for AIED has been
developed (Harris and Keithley Otorhinolaryngology Head and Neck
Surgery (2002) 91, 18-32).
[0120] The immune system normally performs a crucial role in
protecting the inner ear from invasive pathogens such as bacteria
and viruses. However, in AIED the immune system itself begins to
damage the delicate inner ear tissues. The inner ear is fully
capable of mounting a localized immune response to foreign
antigens. When a foreign antigen enters the inner ear, it is first
processed by immunocompetent cells which reside in and around the
endolymphatic sac. Once the foreign antigen has been processed by
these immunocompetent cells, these cells secrete various cytokines
which modulate the immune response of the inner ear. One result of
this cytokine release is to facilitate the influx of inflammatory
cells, which are recruited from the systemic circulation. These
systemic inflammatory cells enter the cochlea via diapedesis
through the spiral modiolar vein and its tributaries, and begin to
participate in antigen uptake and deregulation just as it occurs in
other parts of the body. Interleukin 1 (IL-1) plays an important
role in modulating the innate (nonspecific) immune response and is
a known activator of resting T helper cells and B-cells. T helper
cells, once activated by IL-1, produce IL-2. IL-2 secretion results
in differentiation of pluripotent T-cells into helper, cytotoxic
and suppressor T-cell subtypes. IL-2 also assists T helper cells in
the activation of B lymphocytes and probably plays a pivotal role
in the immunoregulation of the immune response of the vestibular
and cochlear regions. IL-2 is within the perilymph of the auris
interna as early as 6 h after antigen challenge with peak levels at
18 h after antigen challenge. The perilymphatic levels of IL-2 then
dissipate, and it is no longer present within the perilymph at 120
hours post antigen challenge.
[0121] Both IL-1.beta. and tumor necrosis factor-.alpha.
(TNF-.alpha.) may play a key role in the initiation and
amplification of the immune response. IL-1.beta. is expressed by
the fibrocytes of the spiral ligament in the presence of trauma
such as surgical trauma or acoustic trauma in a nonspecific
response. TNF-.alpha. is expressed either by infiltrating systemic
cells or by resident cells contained within the endolymphatic sac
in the presence of antigen. TNF-.alpha. is released as part of the
adaptive (specific) immune response in animal models. When antigen
is injected into the auris interna of mice, IL-1.beta. and
TNF-.alpha. are both expressed and a vigorous immune response
occurs. However, when antigen is introduced to the auris interna
via the cerebral spinal fluid in the absence of trauma, only
TNF-.alpha. is expressed and the immune response in minimal.
Importantly, cochlear trauma in isolation also results in a minimal
immune response. These results suggest that both the nonspecific
and specific components of the immune response act in concert in
the auris interna to achieve a maximal response.
[0122] Thus, if the cochlea is traumatized and an antigen is
injected (or in the case of autoimmune disease, the patient has
immune cells directed against inner ear antigens), both the
nonspecific and the specific immune responses can be activated
simultaneously. This results in the concurrent production of
IL-1.beta. as well as TNF-.alpha. which causes a greatly amplified
level of inflammation leading to substantial damage to the auris
interna.
[0123] Certain evidence suggests that viral infection is a factor
in the initiation of the inflammatory response that results in
AIED. Various autoimmune conditions are induced or enhanced by a
variety of DNA and RNA virus infections. Acute or persistent viral
infections induce or enhance autoimmune diseases in animal models
as well. Similar antigenic determinants have also been observed on
viruses and host components. Oldstone, M. B. A. J. Autoimmun.
(1989) 2(suppl): 187-194. Further, serological tests have
identified viral infection in at least one patient diagnosed with a
systemic autoimmune disorder that is often associated with AIED
(Cogan's syndrome). Garcia-Berrocal, et al. O.R.L. (2008) 70:
16-20.
[0124] Accordingly, in some embodiments, controlled release
antimicrobial agent compositions and formulations disclosed herein
are administered for the treatment of AIED. Particularly, in
certain embodiments, formulations disclosed herein comprising
antiviral agents are administered for treatment of AIED. In other
embodiments, the antimicrobial agent formulations disclosed herein
are administered for the treatment of AIED in conjunction with
other pharmaceutical agents useful for treating the same conditions
or symptoms of the same conditions, including steroids, cytotoxic
agents, collagen, gamma globulin infusion, or other immune
modulating drugs. Steroids include, e.g., prednisone or decadron.
Cytotoxic agents for the treatment of AIED include, e.g.,
methotrexate, cyclophosphamide, and thalidomide. Plasmapheresis
procedures are optionally used. Treatment with oral collagen, gamma
globulin infusions, or other immune modulating drugs (e.g.
beta-interferon, alpha-interferon or copaxone) is also optionally
used in combination with the antimicrobial agent formulations
disclosed herein. The additional pharmaceutical agents are
optionally administered together with the controlled release
formulations disclosed herein, or through other modes of
administration, e.g., orally, by injection, topically, nasally or
through any other suitable means. The additional pharmaceutical
agents are optionally co-administered, or administered at different
time periods.
[0125] Meniere's Disease
[0126] Meniere's disease is characterized by sudden attacks of
vertigo, nausea and vomiting that may last for 3 to 24 hours, and
may subside gradually. Progressive hearing loss, tinnitus and a
sensation of pressure in the ears accompanies the disease through
time. The cause of symptoms associated with Meniere's disease is
likely an imbalance of inner ear fluid homeostasis, including an
increase in production or a decrease in reabsorption of inner ear
fluid.
[0127] Although the cause of Meniere's disease is unknown, certain
evidence suggests a viral etiology for the disease. Specifically,
histopathologic analysis of temporal bones in patients with
Meniere's disease revealed viral ganglionitis. Also, viral DNA has
been observed in the ganglia of patients with Meniere's disease at
a higher rate than in healthy patients. Oliveira et al. ORL (2008)
70: 42-51. Based on these studies, a pilot study of intratympanic
injection of the antiviral agent ganciclovir was conducted,
resulting in an improvement of patients suffering from Meniere's
disease. Guyot et al. ORL (2008) 70: 21-27. Accordingly, controlled
release formulations disclosed herein comprising antiviral agents,
e.g., ganciclvir, acyclovir, famovir, and valgancyclovir, can be
administered to the ear for localized treatment of Meniere's
disease.
[0128] Other treatments of Meniere's disease are aimed at dealing
with the immediate symptoms and prevention of recurrence.
Low-sodium diets, avoidance of caffeine, alcohol, and tobacco have
been advocated. Medications that temporarily relieve vertigo
attacks include antihistamines (e.g., meclizine), and central
nervous system agents, including barbiturates and/or
benzodiazepines (e.g., lorazepam or diazepam). Other examples of
drugs that may be useful in relieving symptoms include muscarinic
antagonists, including scopolamine. Nausea and vomiting may be
relieved by suppositories containing antipsychotic agents,
including the phenothiazine agent prochlorperazine (Compazine.RTM.,
Buccastem, Stemetil and Phenotil). Thus, other treatments of
Meniere's disease are optionally used in combination with the
controlled release formulations disclosed herein for the treatment
of Meniere's disease.
[0129] Surgical procedures have also been used to relieve symptoms
of Meniere's disease, including destruction of vestibular function
to relieve vertigo symptoms. These procedures aim to either reduce
fluid pressure in the inner ear and/or to destroy inner ear balance
function. An endolymphatic shunt procedure, which relieves fluid
pressure, may be placed in the inner ear to relieve symptoms of
vestibular dysfunction. Severing of the vestibular nerve may also
be employed, which may control vertigo while preserving
hearing.
[0130] Another approach to destruction of vestibular function for
the treatment of severe Meniere's disease is intratympanic
application of an agent that destroys sensory hair cell function in
the vestibular system, thereby eradicating inner ear balance
function. Various antimicrobial agents are used in the procedure,
including aminoglycosides such as gentamicin and streptomycin. The
agents are injected through the tympanic membrane using a small
needle, a tympanostomy tube with or without a wick, or surgical
catheters. Various dosing regimens are used to administer the
antimicrobial agents, including a low dose method in which less of
the agents are administered over longer periods of time (e.g., one
month between injections), and high dose methods in which more of
the agents are administered over a shorter time frame (e.g., every
week). Although the high dose method is typically more effective,
it is more risky, as it may result in hearing loss.
[0131] Accordingly, formulations disclosed herein are also useful
for administration of antimicrobial agents, e.g., gentamicin and
streptomycin, for disabling the vestibular apparatus to treat
Meniere's disease. The formulations disclosed herein can be used to
maintain a steady release of the active agents inside the tympanic
membrane, thereby avoiding the need for multiple injections or the
insertion of a tympanostomy tube. Further, by keeping the active
agents localized in the vestibular system, the formulations
disclosed herein can also be used to administer higher doses of the
antimicrobial agents with a decreased risk of hearing loss.
[0132] Meniere's Syndrome
[0133] Meniere's syndrome, which displays similar symptoms as
Meniere's disease, is attributed as a secondary affliction to
another disease process, e.g. thyroid disease or inner ear
inflammation due to syphilis infection. Meniere's syndrome is thus
a collection of secondary effects to various processes that
interfere with normal production or resorption of endolymph,
including microbial infection. Treatment of patients afflicted with
Meniere's syndrome is similar to Meniere's disease.
[0134] Vestibular Neuronitis
[0135] Vestibular neuronitis is characterized by sudden vertigo
attacks, which may present as a single attack of vertigo, a series
of attacks, or a persistent condition which diminishes over a
matter of weeks. Symptoms typically include nausea, vomiting, and
previous upper respiratory tract infections, although there are
generally no auditory symptoms. Vestibular neuronitis may also be
associated with eye nystagmus, a condition characterized by
flickering of the eyes involuntarily toward the affected side. It
is caused by inflammation of the vestibular nerve, the nerve that
connects the inner ear to the brain, and is likely caused by viral
infection. Diagnosis of vestibular neuronitis usually involves
tests for nystagmus using electronystamography, a method of
electronically recording eye movements. Magnetic resonance imaging
may also be performed to determine if other causes may play a role
in the vertigo symptoms.
[0136] Treatment of vestibular neuronitis typically involves
alleviating the symptoms of the condition, primarily vertigo, until
the condition clears on its own. Treatment of vertigo is often
identical to Meniere's disease, and may include meclizine,
lorazepam, prochlorperazine, or scopolamine. Fluids and
electrolytes may also be intravenously administered if the vomiting
is severe. Corticosteroids, such as prednisilone, are also given if
the condition is detected early enough.
[0137] Compositions disclosed herein comprising an antiviral agent
can be administered for the treatment of vestibular neuronitis.
Further, the compositions may be administered with other agents
that are typically used to treat symptoms of the condition,
including anticholinergics, antihistamines, benzodiazepines, or
steroids.
[0138] Postural Vertigo
[0139] Postural vertigo, otherwise known as positional vertigo, is
characterized by sudden violent vertigo that is triggered by
certain head positions. This condition may be caused by damaged
semicircular canals caused by physical injury to the inner ear,
otitis media, ear surgery or blockage of the artery to the inner
ear.
[0140] Vertigo onset in patients with postural vertigo usually
develops when a person lies on one ear or tilts the head back to
look up. Vertigo may be accompanied by nystagmus. Treatment of
postural vertigo often involves the same treatment as in Meniere's
disease. In severe cases of postural vertigo, the vestibular nerve
is severed to the affected semicircular canal. Treatment of vertigo
is often identical to Meniere's disease, and may include meclizine,
lorazepam, prochlorperazine or scopolamine. Fluids and electrolytes
may also be intravenously administered if the vomiting is
severe.
[0141] Sensorineural Hearing Loss
[0142] Sensorineural hearing loss occurs when the components of the
inner ear or accompanying neural components are affected, and may
contain a neural (i.e., the auditory nerve or auditory nerve
pathways in the brain are affected) or sensory component. Sensory
hearing loss may be hereditary, or it may be caused by acoustic
trauma (i.e. very loud noises), a viral infection, drug-induced or
Meniere's disease. In some instances, noise induced hearing loss is
caused by loud noises, for example, gun fire, loud music or other
human-based noise. Neural hearing loss may occur as a result of
brain tumors, infections, or various brain and nerve disorders,
such as stroke. Some hereditary diseases, such as Refsum's disease
(defective accumulation of branched fatty acids), may also cause
neural disorders affecting hearing loss. Auditory nerve pathways
may be damaged by demyelinating diseases, e.g. idiopathic
inflammatory demyelinating disease (including multiple sclerosis),
transverse myelitis, Devic's disease, progressive multifocal
leukoencephalopathy, Guillain-Barre syndrome, chronic inflammatory
demyelinating polyneuropathy and anti-MAG perpheral neuropathy.
[0143] The incidence of sudden deafness, or sensorineural hearing
loss, occurs in about 1 in 5,000 individuals, and may be caused by
viral or bacterial infections, e.g. mumps, measles, influenza,
chickenpox, cytomegalovirus, syphilis or infectious mononucleosis,
or physical injury to the inner ear organ. In some cases, no cause
can be identified. Tinnitus and vertigo may accompany sudden
deafness, which subsides gradually. Oral corticosteroids are
frequently prescribed to treat sensorineural hearing loss. In some
cases, surgical intervention may be necessary.
[0144] Hereditary Disorders
[0145] Hereditary disorders, including Scheibe, Mondini-Michelle,
Waardenburg's, Michel, Alexander's ear deformity, hypertelorism,
Jervell-Lange Nielson, Refsum's and Usher's syndromes, are found in
approximately 20% of patients with sensorineural hearing loss.
Congenital ear malformations may result from defects in the
development of the membranous labyrinthine, the osseous
labyrinthine, or both. Along with profound hearing loss and
vestibular function abnormalities, hereditary deformities may also
be associated with other dysfunctions, including development of
recurring meningitis, cerebral spinal fluid (CSF) leaks, as well as
perilymphatic fistulas. Treatment of chronic infections may be
necessitated in hereditary disorder patients.
Pharmaceutical Agents
[0146] Provided herein are antimicrobial agent compositions and
formulations that treat otic disorders and/or their attendant
symptoms, including but not limited to infection, hearing loss,
nystagmus, vertigo, tinnitus, inflammation, swelling, and
congestion. Otic disorders, including AIED, otitis media, otitis
externa, Meniere's disease, Ramsay Hunt syndrome, otosyphilis,
hereditary disorders and vestibular neuronitis, have causes and
symptoms that are responsive to the pharmaceutical agents disclosed
herein, or other pharmaceutical agents. Antimicrobial agents that
are not disclosed herein but which are useful for the amelioration
or eradication of otic disorders are expressly included and
intended within the scope of the embodiments presented. In some
embodiments, pharmaceutically active metabolites, salts,
polymorphs, prodrugs, analogues, and derivatives of the
antimicrobial agents disclosed herein that retain the ability of
the parent antimicrobial agents to treat otic disorders are useful
in the formulations.
[0147] Moreover, pharmaceutical agents which have been previously
shown to be excessively toxic, harmful or non-effective during
systemic or localized application in other organ systems, for
example through toxic metabolites formed after hepatic processing,
toxicity of the drug in particular organs, tissues or systems,
through high levels needed to achieve efficacy, through the
inability to be released through systemic pathways, or through poor
PK characteristics, are useful in some embodiments. Accordingly,
pharmaceutical agents which have limited or no systemic release,
systemic toxicity, poor PK characteristics or combinations thereof
are contemplated within the scope of the embodiments disclosed
herein.
[0148] The antimicrobial agent formulations disclosed herein are
optionally targeted directly to otic structures where treatment is
needed. For example, one embodiment contemplated is the direct
application of the antimicrobial agent formulations disclosed
herein to the auris media through piercing of the intratympanic
membrane and applying the antimicrobial agent formulation directly
to the auris media structures affected, including the walls of the
tympanic cavity or auditory ossicles. By doing so, the
antimicrobial agent formulations disclosed herein are confined to
the targeted auris media structure, and will not be lost, for
example, through leakage through the eustachian tube or pierced
tympanic membrane. In some embodiments, the antimicrobial agent
formulations are targeted to specific regions of the auris media by
application with a needle and syringe, a pump, a microinjection
device, or any combination thereof.
[0149] Antimicrobial Agent
[0150] Some embodiments provided herein describe composition
comprising an antimicrobial agent. In some embodiments, the
antimicrobial agent is an antibacterial agent. In some embodiments,
the antibacterial agent treats infections caused by gram positive
bacteria. In some embodiments, the antibacterial agent treats
infections caused by gram negative bacteria. In some embodiments,
the antibacterial agent treats infections caused by mycobacteria.
In some embodiments, the antibacterial agent treats infections
caused by giardia. In some embodiments, the antibacterial agent
(e.g., ciprofloxacin) treats infections caused by Escherichia coli,
Klebsiella pneumoniae, Enterobacter cloacae, Proteus mirabilis,
Proteus rettgeri, Proteus vulgaris, Proteus morgani, Providencia
stuartii, Morganella morganii, Citrobacter freundii, Pseudomonas
aeruginosa, Staphylococcus aureus, Staphylococcus epidermidis,
Streptococcus pyogenes, Streptococcus pneumoniae, Streptococcus
faecalis, Alcaligenes faecalis, Klebsiella aerogenes, Klebsiella
pneumonia, Haemophilus influenzae, Moraxella catarrhalis, or a
combination thereof. In some embodiments, the antibacterial agent
(e.g., ciprofloxacin) treats infections caused by Streptococcus
pneumoniae, Haemophilus influenzae, Moraxella catarrhalis,
Streptococcus pyogenes, Staphylococcus aureus, or a combination
thereof. In some embodiments, the antibacterial agent (e.g.,
ciprofloxacin) treats infections caused by Streptococcus pneumonia.
In some embodiments, the antibacterial agent (e.g., ciprofloxacin)
treats infections caused by Haemophilus influenzae. In some
embodiments, the antibacterial agent (e.g., ciprofloxacin) treats
infections caused by Moraxella catarrhalis.
[0151] In some embodiments, the antibacterial agent treats
infections by inhibiting bacterial protein synthesis. In some
embodiments, the antibacterial agent treats infections by
disrupting synthesis of bacterial cell wall. In some embodiments,
the antibacterial agent treats infections by changing permeability
of bacterial cell membranes. In some embodiments, the antibacterial
agent treats infections by disrupting DNA replication in
bacteria.
[0152] In some embodiments, the antibacterial agent is an
antibiotic. In some embodiments, the antibiotic is a quinolone. In
specific embodiments, the antibiotic is ciprofloxacin. In some
embodiments, the antibiotic is micronized ciprofloxacin. In some
embodiments, an antibiotic compatible with the compositions
described herein is a broad spectrum antibiotic. In some
embodiments, an antibiotic compatible with the compositions
described herein is effective in treating infections that are
resistant to other classes of antibiotics. In some embodiments,
intratympanic administration of an antibiotic composition described
herein reduces the risk of development of antibiotic resistance
that is seen with systemic treatments.
[0153] Concentration of Active Agent
[0154] In some embodiments, the compositions described herein have
a concentration of active pharmaceutical ingredient between about
0.01% to about 90%, between about 0.01% to about 50%, between about
0.1% to about 70%, between about 0.1% to about 50%, between about
0.1% to about 40%, between about 0.1% to about 30%, between about
0.1% to about 20%, between about 0.1% to about 10%, or between
about 0.1% to about 5%, of the active ingredient, or
pharmaceutically acceptable prodrug or salt thereof, by weight of
the composition. In some embodiments, the compositions described
herein have a concentration of active pharmaceutical agent, or
pharmaceutically acceptable prodrug or salt thereof, between about
1% to about 50%, between about 5% to about 50%, between about 10%
to about 40%, or between about 10% to about 30%, of the active
ingredient, or pharmaceutically acceptable prodrug or salt thereof,
by weight of the composition. In some embodiments, formulations
described herein comprise about 70% by weight of an antimicrobial
agent, or pharmaceutically acceptable prodrug or salt thereof, by
weight of the formulation. In some embodiments, formulations
described herein comprise about 60% by weight of an antimicrobial
agent, or pharmaceutically acceptable prodrug or salt thereof, by
weight of the formulation. In some embodiments, formulations
described herein comprise about 50% by weight of an antimicrobial
agent, or pharmaceutically acceptable prodrug or salt thereof, by
weight of the formulation. In some embodiments, formulations
described herein comprise about 40% by weight of an antimicrobial
agent, or pharmaceutically acceptable prodrug or salt thereof, by
weight of the formulation. In some embodiments, formulations
described herein comprise about 30% by weight, or pharmaceutically
acceptable prodrug or salt thereof, of an antimicrobial agent by
weight of the formulation. In some embodiments, formulations
described herein comprise about 20% by weight of an antimicrobial
agent, or pharmaceutically acceptable prodrug or salt thereof, by
weight of the formulation. In some embodiments, formulations
described herein comprise about 15% by weight of an antimicrobial
agent, or pharmaceutically acceptable prodrug or salt thereof, by
weight of the formulation. In some embodiments, formulations
described herein comprise about 10% by weight of an antimicrobial
agent by weight of the formulation. In some embodiments,
formulations described herein comprise about 5% by weight of an
antimicrobial agent, or pharmaceutically acceptable prodrug or salt
thereof, by weight of the formulation. In some embodiments,
formulations described herein comprise about 2.5% by weight of an
antimicrobial agent, or pharmaceutically acceptable prodrug or salt
thereof, by weight of the formulation. In some embodiments,
formulations described herein comprise about 1% by weight of an
antimicrobial agent, or pharmaceutically acceptable prodrug or salt
thereof, by weight of the formulation. In some embodiments,
formulations described herein comprise about 0.5% by weight of an
antimicrobial agent, or pharmaceutically acceptable prodrug or salt
thereof, by weight of the formulation. In some embodiments,
formulations described herein comprise about 0.1% by weight of an
antimicrobial agent, or pharmaceutically acceptable prodrug or salt
thereof, by weight of the formulation. In some embodiments,
formulations described herein comprise about 0.01% by weight of an
antimicrobial agent, or pharmaceutically acceptable prodrug or salt
thereof, by weight of the formulation. In some embodiments, the
formulations described herein have a concentration of active
pharmaceutical ingredient, or pharmaceutically acceptable prodrug
or salt thereof, between about 0.1 to about 70 mg/mL, between about
0.5 mg/mL to about 70 mg/mL, between about 0.5 mg/mL to about 50
mg/mL, between about 0.5 mg/mL to about 20 mg/mL, between about 1
mg to about 70 mg/mL, between about 1 mg to about 50 mg/mL, between
about 1 mg/mL and about 20 mg/mL, between about 1 mg/mL to about 10
mg/mL, or between about 1 mg/mL to about 5 mg/mL, of the active
agent, or pharmaceutically acceptable prodrug or salt thereof, by
volume of the formulation.
[0155] In some embodiments, the composition comprises 1-8% by
weight of micronized ciprofloxacin. In some embodiments, the
composition comprises 1.8 to 6.6% by weight of micronized
ciprofloxacin. In some embodiments, the composition comprises
1.8-2.2% by weight of micronized ciprofloxacin. In other
embodiments, the composition comprises 5.4-6.6% by weight of
micronized ciprofloxacin. In some embodiments, the composition
comprises about 1%, about 1.1% about 1.2%, about 1.3%, about 1.4%,
about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about
2.0%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%,
about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3.0%, about
3.1%, about 3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%,
about 3.7%, about 3.8%, about 3.9%, about 4.0%, about 4.1%, about
4.2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%,
about 4.8%, about 4.9%, about 5.0%, about 5.1%, about 5.2%, about
5.3%, about 5.4%, about 5.5%, about 5.6%, about 5.7%, about 5.8%,
about 5.9%, about 6.0%, about 6.1%, about 6.2%, about 6.3%, about
6.4%, about 6.5%, about 6.6%, about 6.7%, about 6.8%, about 6.9%,
about 7.0%, about 7.1%, about 7.2%, about 7.3%, about 7.4%, about
7.5%, about 7.6%, about 7.7%, about 7.8%, about 7.9%, about 8.0% by
weight of micronized ciprofloxacin. In some specific embodiments,
the composition comprises about 1.8% by weight of micronized
ciprofloxacin. In some specific embodiments, the composition
comprises about 1.9% by weight of micronized ciprofloxacin. In some
specific embodiments, the composition comprises about 2.0% by
weight of micronized ciprofloxacin. In some specific embodiments,
the composition comprises about 2.1% by weight of micronized
ciprofloxacin. In some specific embodiments, the composition
comprises 2.2% by weight of micronized ciprofloxacin. In some
specific embodiments, the composition comprises 5.4% by weight of
micronized ciprofloxacin. In some specific embodiments, the
composition comprises 5.5% by weight of micronized ciprofloxacin.
In some specific embodiments, the composition comprises 5.6% by
weight of micronized ciprofloxacin. In some specific embodiments,
the composition comprises 5.7% by weight of micronized
ciprofloxacin. In some specific embodiments, the composition
comprises 5.8% by weight of micronized ciprofloxacin. In some
specific embodiments, the composition comprises 5.9% by weight of
micronized ciprofloxacin. In some specific embodiments, the
composition comprises 6.0% by weight of micronized ciprofloxacin.
In some specific embodiments, the composition comprises 6.1% by
weight of micronized ciprofloxacin. In some specific embodiments,
the composition comprises 6.2% by weight of micronized
ciprofloxacin. In some specific embodiments, the composition
comprises 6.3% by weight of micronized ciprofloxacin. In some
specific embodiments, the composition comprises 6.4% by weight of
micronized ciprofloxacin. In some specific embodiments, the
composition comprises 6.5% by weight of micronized ciprofloxacin.
In some specific embodiments, the composition comprises 6.6% by
weight of micronized ciprofloxacin.
Pharmaceutical Formulations
[0156] Provided herein are pharmaceutical compositions or devices
that include at least one antimicrobial agent (e.g., ciprofloxacin)
and a pharmaceutically acceptable diluent(s), excipient(s), or
carrier(s). In some embodiments, the pharmaceutical compositions
include other medicinal or pharmaceutical agents, carriers,
adjuvants, such as salts for regulating the osmotic pressure,
and/or buffers. In other embodiments, the pharmaceutical
compositions also contain other therapeutic substances. In some
embodiments, the pharmaceutical compositions are
preservative-free.
[0157] In some embodiments, the auris-compatible formulations
described herein are free of preservatives. In some embodiments,
any of the formulations described herein are free of sodium
bisulfite, sodium thiosulfate, ascorbate, chorobutanol, thimerosal,
parabens, benzyl alcohol, Butylated hydroxytoluene (BHT), and
phenylethanol. In certain embodiments, any of the formulations
described herein are free of BHT.
[0158] pH and Practical Osmolarity
[0159] In some embodiments, an otic composition or device disclosed
herein is formulated to provide an ionic balance that is compatible
with inner ear fluids (e.g., endolymph and/or perilymph).
[0160] In certain instances, the ionic composition of the endolymph
and perilymph regulate the electrochemical impulses of hair cells
and thus hearing. In certain instances, changes in the conduction
of electrochemical impulses along otic hair cells results in
hearing loss. In certain instances, changes in the ionic balance of
the endolymph or perilymph results in complete hearing loss. In
certain instances, changes in the ionic balance of the endolymph or
perilymph results in partial hearing loss. In certain instances,
changes in the ionic balance of the endolymph or perilymph results
in permanent hearing loss. In certain instances, changes in the
ionic balance of the endolymph or perilymph results in temporary
hearing loss.
[0161] In some embodiments, a composition or device disclosed
herein is formulated in order to not disrupt the ionic balance of
the endolymph. In some embodiments, a composition or device
disclosed herein has an ionic balance that is the same as or
substantially the same as the endolymph. In some embodiments, a
composition or device disclosed herein does not does not disrupt
the ionic balance of the endolymph so as to result in partial or
complete hearing loss. In some embodiments, a composition or device
disclosed herein does not does not disrupt the ionic balance of the
endolymph so as to result in temporary or permanent hearing
loss.
[0162] In some embodiments, a composition or device disclosed
herein does not substantially disrupt the ionic balance of the
perilymph. In some embodiments, a composition or device disclosed
herein has an ionic balance that is the same as or substantially
the same as the perilymph. In some embodiments, a composition or
device disclosed herein does not result in partial or complete
hearing loss as the composition or device does not disrupt the
ionic balance of the perilymph. In some embodiments, a composition
or device disclosed herein does not result in temporary or
permanent hearing loss as the composition or device does not
disrupt the ionic balance of the perilymph.
[0163] As used herein, "practical osmolarity/osmolality" or
"deliverable osmolarity/osmolality" means the osmolarity/osmolality
of a composition or device as determined by measuring the
osmolarity/osmolality of the active agent and all excipients except
the gelling and/or the thickening agent (e.g.,
polyoxyethylene-polyooxypropylene copolymers,
carboxymethylcellulose or the like). The practical osmolarity of a
composition or device disclosed herein is measured by a suitable
method, e.g., a freezing point depression method as described in
Viegas et. al., Int. J. Pharm., 1998, 160, 157-162. In some
instances, the practical osmolarity of a composition or device
disclosed herein is measured by vapor pressure osmometry (e.g.,
vapor pressure depression method) that allows for determination of
the osmolarity of a composition or device at higher temperatures.
In some instances, vapor pressure depression method allows for
determination of the osmolarity of a composition or device
comprising a gelling agent (e.g., a thermoreversible polymer) at a
higher temperature wherein the gelling agent is in the form of a
gel.
[0164] In some embodiments, the osmolarity at a target site of
action (e.g., the perilymph) is about the same as the delivered
osmolarity (i.e., osmolarity of materials that cross or penetrate
the round window membrane) of a composition or device described
herein. In some embodiments, a composition or device described
herein has a deliverable osmolarity of about 150 mOsm/L to about
500 mOsm/L, about 250 mOsm/L to about 500 mOsm/L, about 250 mOsm/L
to about 350 mOsm/L, about 280 mOsm/L to about 370 mOsm/L or about
250 mOsm/L to about 320 mOsm/L.
[0165] The practical osmolality of an otic composition or device
disclosed herein is from about 100 mOsm/kg to about 1000 mOsm/kg,
from about 200 mOsm/kg to about 800 mOsm/kg, from about 250 mOsm/kg
to about 500 mOsm/kg, or from about 250 mOsm/kg to about 320
mOsm/kg, or from about 250 mOsm/kg to about 350 mOsm/kg or from
about 280 mOsm/kg to about 320 mOsm/kg. In some embodiments, a
composition or device described herein has a practical osmolarity
of about 100 mOsm/L to about 1000 mOsm/L, about 200 mOsm/L to about
800 mOsm/L, about 250 mOsm/L to about 500 mOsm/L, about 250 mOsm/L
to about 350 mOsm/L, about 250 mOsm/L to about 320 mOsm/L, or about
280 mOsm/L to about 320 mOsm/L.
[0166] The main cation present in the endolymph is potassium. In
addition the endolymph has a high concentration of positively
charged amino acids. The main cation present in the perilymph is
sodium. In certain instances, the ionic composition of the
endolymph and perilymph regulate the electrochemical impulses of
hair cells. In certain instances, any change in the ionic balance
of the endolymph or perilymph results in a loss of hearing due to
changes in the conduction of electrochemical impulses along otic
hair cells. In some embodiments, a composition disclosed herein
does not disrupt the ionic balance of the perilymph. In some
embodiments, a composition disclosed herein has an ionic balance
that is the same as or substantially the same as the perilymph. In
some embodiments, a composition disclosed herein does not disrupt
the ionic balance of the endolymph. In some embodiments, a
composition disclosed herein has an ionic balance that is the same
as or substantially the same as the endolymph. In some embodiments,
an otic formulation described herein is formulated to provide an
ionic balance that is compatible with inner ear fluids (e.g.,
endolymph and/or perilymph).
[0167] The endolymph and the perilymph have a pH that is close to
the physiological pH of blood. The endolymph has a pH range of
about 7.2-7.9; the perilymph has a pH range of about 7.2-7.4. The
in situ pH of the proximal endolymph is about 7.4 while the pH of
distal endolymph is about 7.9.
[0168] In some embodiments, the pH of a composition described
herein is adjusted (e.g., by use of a buffer) to an
endolymph-compatible pH range of about 5.5 to 9.0. In specific
embodiments, the pH of a composition described herein is adjusted
to a perilymph-suitable pH range of about 5.5 to about 9.0. In some
embodiments, the pH of a composition described herein is adjusted
to a perilymph-suitable range of about 5.5 to about 8.0, about 6 to
about 8.0 or about 6.6 to about 8.0. In some embodiments, the pH of
a composition described herein is adjusted to a perilymph-suitable
pH range of about 7.0-7.6.
[0169] In some embodiments, useful formulations also include one or
more pH adjusting agents or buffering agents. Suitable pH adjusting
agents or buffers include, but are not limited to acetate,
bicarbonate, ammonium chloride, citrate, phosphate,
pharmaceutically acceptable salts thereof and combinations or
mixtures thereof
[0170] Some embodiments provided herein describe an antimicrobial
composition further comprising an osmolality modifier, pH adjusting
agent, and a buffering agent. In some embodiments, the
antimicrobial composition comprises hydrochloric acid as a pH
adjusting agent. In some embodiments, the antimicrobial composition
comprises tromethamine as a buffering agent. In some embodiments,
the antimicrobial composition comprises sodium chloride as an
osmolality modifier. In certain embodiments, the antimicrobial
composition consists of ciprofloxacin, poloxamer 407, water, an
osmolality modifier (e.g., sodium chloride), a pH adjusting agent
(e.g., hydrochloric acid), and a buffering agent (e.g.,
tromethamine).
[0171] In one embodiment, when one or more buffers are utilized in
the formulations of the present disclosure, they are combined,
e.g., with a pharmaceutically acceptable vehicle and are present in
the final formulation, e.g., in an amount ranging from about 0.1%
to about 20%, from about 0.5% to about 10%. In certain embodiments
of the present disclosure, the amount of buffer included in the gel
formulations are an amount such that the pH of the gel formulation
does not interfere with the body's natural buffering system.
[0172] In one embodiment, diluents are also used to stabilize
compounds because they can provide a more stable environment. Salts
dissolved in buffered solutions (which also can provide pH control
or maintenance) are utilized as diluents in the art, including, but
not limited to a phosphate buffered saline solution.
[0173] In some embodiments, any gel formulation described herein
has a pH that allows for sterilization (e.g., by filtration or
aseptic mixing or heat treatment and/or autoclaving (e.g., terminal
sterilization) of a gel formulation without degradation of the
pharmaceutical agent (e.g., antimicrobial agent) or the polymers
comprising the gel. In order to reduce hydrolysis and/or
degradation of the otic agent and/or the gel polymer during
sterilization, the buffer pH is designed to maintain pH of the
formulation in the 7-8 range during the process of sterilization
(e.g., high temperature autoclaving).
[0174] In specific embodiments, any gel formulation described
herein has a pH that allows for sterilization (e.g., by heat
treatment and/or autoclaving) of a gel formulation without
degradation of the pharmaceutical agent (e.g., antimicrobial agent)
or the polymers comprising the gel. For example, in order to reduce
hydrolysis and/or degradation of the otic agent and/or the gel
polymer during autoclaving, the buffer pH is designed to maintain
pH of the formulation in the 7-8 range at elevated temperatures.
Any appropriate buffer is used depending on the otic agent used in
the formulation. In some instances, since pK.sub.a of TRIS
decreases as temperature increases at approximately -0.03/.degree.
C. and pK.sub.a of PBS increases as temperature increases at
approximately 0.003/.degree. C., autoclaving at 250.degree. F.
(121.degree. C.) results in a significant downward pH shift (i.e.
more acidic) in the TRIS buffer whereas a relatively much less
upward pH shift in the PBS buffer and therefore much increased
hydrolysis and/or degradation of an otic agent in TRIS than in PBS.
Degradation of an otic agent is reduced by the use of an
appropriate combination of a buffer and polymeric additives (e.g.
CMC) as described herein.
[0175] In some embodiments, a formulation pH of between about 5.0
and about 9.0, between about 5.5 and about 8.5, between about 6.0
and about 7.6, between about 7 and about 7.8, between about 7.0 and
about 7.6, between about 7.2 and 7.6, or between about 7.2 and
about 7.4 is suitable for sterilization (e.g., by filtration or
aseptic mixing or heat treatment and/or autoclaving (e.g., terminal
sterilization)) of auris formulations described herein. In specific
embodiments a formulation pH of about 6.0, about 6.5, about 7.0,
about 7.1, about 7.2, about 7.3, about 7.4, about 7.5, or about 7.6
is suitable for sterilization (e.g., by filtration or aseptic
mixing or heat treatment and/or autoclaving (e.g., terminal
sterilization)) of any composition described herein.
[0176] In some embodiments, the pharmaceutical formulations
described herein are stable with respect to pH over a period of any
of at least about 1 day, at least about 2 days, at least about 3
days, at least about 4 days, at least about 5 days, at least about
6 days, at least about 1 week, at least about 2 weeks, at least
about 3 weeks, at least about 4 weeks, at least about 5 weeks, at
least about 6 weeks, at least about 7 weeks, at least about 8
weeks, at least about 1 month, at least about 2 months, at least
about 3 months, at least about 4 months, at least about 5 months,
or at least about 6 months. In other embodiments, the formulations
described herein are stable with respect to pH over a period of at
least about 1 week. Also described herein are formulations that are
stable with respect to pH over a period of at least about 1
month.
[0177] Tonicity Agents
[0178] In general, the endolymph has a higher osmolality than the
perilymph. For example, the endolymph has an osmolality of about
304 mOsm/kg H.sub.2O while the perilymph has an osmolality of about
294 mOsm/kg H.sub.2O. In certain embodiments, tonicity agents are
added to the formulations described herein in an amount as to
provide a practical osmolality of an otic formulation of about 100
mOsm/kg to about 1000 mOsm/kg, from about 200 mOsm/kg to about 800
mOsm/kg, from about 250 mOsm/kg to about 500 mOsm/kg, or from about
250 mOsm/kg to about 350 mOsm/kg or from about 280 mOsm/kg to about
320 mOsm/kg. In some embodiments, the formulations described herein
have a practical osmolarity of about 100 mOsm/L to about 1000
mOsm/L, about 200 mOsm/L to about 800 mOsm/L, about 250 mOsm/L to
about 500 mOsm/L, about 250 mOsm/L to about 350 mOsm/L, about 280
mOsm/L to about 320 mOsm/L or about 250 mOsm/L to about 320
mOsm/L.
[0179] In some embodiments, the deliverable osmolarity of any
formulation described herein is designed to be isotonic with the
targeted otic structure (e.g., endolymph, perilymph or the like).
In specific embodiments, auris compositions described herein are
formulated to provide a delivered perilymph-suitable osmolarity at
the target site of action of about 250 to about 320 mOsm/L; and
preferably about 270 to about 320 mOsm/L. In specific embodiments,
auris compositions described herein are formulated to provide a
delivered perilymph-suitable osmolality at the target site of
action of about 250 to about 320 mOsm/kg H.sub.2O; or an osmolality
of about 270 to about 320 mOsm/kg H.sub.2O. In specific
embodiments, the deliverable osmolarity/osmolality of the
formulations (i.e., the osmolarity/osmolality of the formulation in
the absence of gelling or thickening agents (e.g., thermoreversible
gel polymers) is adjusted, for example, by the use of appropriate
salt concentrations (e.g., concentration of potassium or sodium
salts) or the use of tonicity agents which renders the formulations
endolymph-compatible and/or perilymph-compatible (i.e. isotonic
with the endolymph and/or perilymph) upon delivery at the target
site. The osmolarity of a formulation comprising a thermoreversible
gel polymer is an unreliable measure due to the association of
varying amounts of water with the monomeric units of the polymer.
The practical osmolarity of a formulation (i.e., osmolarity in the
absence of a gelling or thickening agent (e.g. a thermoreversible
gel polymer) is a reliable measure and is measured by any suitable
method (e.g., freezing point depression method, vapor depression
method). In some instances, the formulations described herein
provide a deliverable osmolarity (e.g., at a target site (e.g.,
perilymph) that causes minimal disturbance to the environment of
the inner ear and causes minimum discomfort (e.g., vertigo and/or
nausea) to a mammal upon administration.
[0180] In some embodiments, any formulation described herein is
isotonic with the perilymph and/or endolymph. Isotonic formulations
are provided by the addition of a tonicity agent. Suitable tonicity
agents include, but are not limited to any pharmaceutically
acceptable sugar, salt or any combinations or mixtures thereof,
such as, but not limited to dextrose, glycerin, mannitol, sorbitol,
sodium chloride, and other electrolytes. In some embodiments,
tonicity agents are non-ototoxic.
[0181] Useful auris compositions include one or more salts in an
amount required to bring osmolality of the composition into an
acceptable range. Such salts include those having sodium, potassium
or ammonium cations and chloride, citrate, ascorbate, borate,
phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions;
suitable salts include sodium chloride, potassium chloride, sodium
thiosulfate, sodium bisulfite and ammonium sulfate.
[0182] In some embodiments, the formulations described herein have
a pH and/or practical osmolarity as described herein, and have a
concentration of active pharmaceutical ingredient between about 1
.mu.M and about 10 .mu.M, between about 1 mM and about 100 mM,
between about 0.1 mM and about 100 mM, between about 0.1 mM and
about 100 nM. In some embodiments, the formulations described
herein have a pH and/or practical osmolarity as described herein,
and have a concentration of active pharmaceutical ingredient
between about 0.01% about 20%, between about 0.01% about 10%,
between about 0.01% about 7.5%, between about 0.01% 6%, between
about 0.01-5%, between about 0.1 about 10%, or between about 0.1
about 6% of the active ingredient by weight of the formulation. In
some embodiments, the formulations described herein have a pH
and/or practical osmolarity as described herein, and have a
concentration of active pharmaceutical ingredient between about 0.1
and about 70 mg, between about 1 mg and about 70 mg/mL, between
about 1 mg and about 50 mg/mL, between about 1 mg/mL and about 20
mg/mL, between about 1 mg/mL to about 10 mg/mL, between about 1
mg/mL to about 5 mg/mL, or between about 0.5 mg/mL to about 5 mg/mL
of the active agent by volume of the formulation. In some
embodiments, the formulations described herein have a pH and/or
practical osmolarity as described herein, and have a concentration
of active pharmaceutical ingredient between about 1 .mu.g/mL and
about 500 .mu.g/mL, between about 1 .mu.g/mL and about 250
.mu.s/mL, between about 1 .mu.g and about 100 .mu.g/mL, between
about 1 .mu.g/mL and about 50 .mu.g/mL, or between about 1 .mu.g/mL
and about 20 .mu.g/mL of the active agent by volume of the
formulation.
[0183] Particle Size
[0184] Size reduction is used to increase surface area and/or
modulate formulation dissolution properties. It is also used to
maintain a consistent average particle size distribution (PSD)
(e.g., micrometer-sized particles, nanometer-sized particles or the
like) for any formulation described herein. In some embodiments,
any formulation described herein comprises multiparticulates, i.e.,
a plurality of particle sizes (e.g., micronized particles,
nano-sized particles, non-sized particles, colloidal particles);
i.e., the formulation is a multiparticulate formulation. In some
embodiments, any formulation described herein comprises one or more
multiparticulate (e.g., micronized) therapeutic agents.
Micronization is a process of reducing the average diameter of
particles of a solid material. Micronized particles are from about
micrometer-sized in diameter to about nanometer sized in diameter.
In some embodiments, the average diameter of particles in a
micronized solid is from about 0.5 .mu.m to about 500 .mu.m. In
some embodiments, the average diameter of particles in a micronized
solid is from about 1 .mu.m to about 200 .mu.m. In some
embodiments, the average diameter of particles in a micronized
solid is from about 2 .mu.m to about 100 .mu.m. In some
embodiments, the average diameter of particles in a micronized
solid is from about 3 .mu.m to about 50 .mu.m. In some embodiments,
a particulate micronized solid comprises particle sizes of less
than about 5 microns, less than about 20 microns and/or less than
about 100 microns. In some embodiments, the use of particulates
(e.g., micronized particles) of antimicrobial agent allows for
extended and/or sustained release of the antimicrobial agent from
any formulation described herein compared to a formulation
comprising non-multiparticulate (e.g., non-micronized)
antimicrobial agent. In some instances, formulations containing
multiparticulate (e.g. micronized) antimicrobial agent are ejected
from a 1 mL syringe adapted with a 27G needle without any plugging
or clogging.
[0185] In some instances, any particle in any formulation described
herein is a coated particle (e.g., a coated micronized particle,
nano-particle) and/or a microsphere and/or a liposomal particle.
Particle size reduction techniques include, by way of example,
grinding, milling (e.g., air-attrition milling (jet milling), ball
milling), coacervation, complex coacervation, high pressure
homogenization, spray drying and/or supercritical fluid
crystallization. In some instances, particles are sized by
mechanical impact (e.g., by hammer mills, ball mill and/or pin
mills). In some instances, particles are sized via fluid energy
(e.g., by spiral jet mills, loop jet mills, and/or fluidized bed
jet mills). In some embodiments formulations described herein
comprise crystalline particles and/or isotropic particles. In some
embodiments, formulations described herein comprise amorphous
particles and/or anisotropic particles. In some embodiments,
formulations described herein comprise therapeutic agent particles
wherein the therapeutic agent is a free base, or a salt, or a
prodrug of a therapeutic agent, or any combination thereof
[0186] In some embodiments, a formulation described herein
comprises one or more antimicrobial agents wherein the
antimicrobial agent comprises nanoparticulates. In some
embodiments, a formulation described herein comprises antimicrobial
agent beads (e.g., vancomycin beads) that are optionally coated
with controlled release excipients. In some embodiments, a
formulation described herein comprises an antimicrobial agent that
is granulated and/or reduced in size and coated with controlled
release excipients; the granulated coated antimicrobial agent
particulates are then optionally micronized and/or formulated in
any of the compositions described herein.
[0187] In some instances, a combination of an antimicrobial agent
as a neutral molecule, free acid or free base and/or a salt of the
antimicrobial agent is used to prepare pulsed release otic agent
formulations using the procedures described herein. In some
formulations, a combination of a micronized antimicrobial agent
(and/or salt or prodrug thereof) and coated particles (e g,
nanoparticles, liposomes, microspheres) is used to prepare pulsed
release otic agent formulations using any procedure described
herein. Alternatively, a pulsed release profile is achieved by
solubilizing up to 20% of the delivered dose of the antimicrobial
agent (e.g., micronized antimicrobial agent, free base, free acid
or salt or prodrug thereof; multiparticulate antimicrobial agent,
free base, free acid or salt or prodrug thereof) with the aid of
cyclodextrins, surfactants (e.g., poloxamers (407, 338, 188), tween
(80, 60, 20, 81), PEG-hydrogenated castor oil, cosolvents like
N-methyl-2-Pyrrolidone or the like and preparing pulsed release
formulations using any procedure described herein.
[0188] In specific embodiments, any auris-compatible formulation
described herein comprises one or more micronized pharmaceutical
agents (e.g., antimicrobial agents). In some of such embodiments, a
micronized pharmaceutical agent comprises micronized particles,
coated (e.g., with an extended release coat) micronized particles,
or a combination thereof. In some of such embodiments, a micronized
pharmaceutical agent comprising micronized particles, coated
micronized particles, or a combination thereof, comprises an
antimicrobial agent as a neutral molecule, a free acid, a free
base, a salt, a prodrug or any combination thereof. In certain
embodiments, a pharmaceutical composition described herein
comprises an antimicrobial agent as a micronized powder. In certain
embodiments, a pharmaceutical composition described herein
comprises an antimicrobial agent in the form of a micronized
antimicrobial agent powder.
[0189] The multiparticulates and/or micronized antimicrobial agents
described herein are delivered to an auris structure (e.g., inner
ear) by means of any type of matrix including solid, liquid or gel
matrices. In some embodiments, the multiparticulates and/or
micronized antimicrobial agents described herein are delivered to
an auris structure (e.g., inner ear) by means of any type of matrix
including solid, liquid or gel matrices via intratympanic
injection.
[0190] Tunable Release Characteristics
[0191] The release of active agent from any formulation,
composition or device described herein is optionally tunable to the
desired release characteristics. In some embodiments, a composition
described herein is a solution that is substantially free of
gelling components. In such instances, the composition provides
essentially immediate release of an active agent. In some of such
embodiments, the composition is useful in perfusion of otic
structures, e.g., during surgery.
[0192] In some embodiments, a composition described herein is a
solution that is substantially free of gelling components and
comprises micronized otic agent (e.g., a corticosteroid, an
antimicrobial agent or the like). In some of such embodiments, the
composition provides release of an active agent from about 2 days
to about 4 days.
[0193] In some embodiments, a composition described herein
comprises a gelling agent (e.g., poloxamer 407) and provides
release of an active agent over a period of from about 1 day to
about 3 days. In some embodiments, a composition described herein
comprises a gelling agent (e.g., poloxamer 407) and provides
release of an active agent over a period of from about 1 day to
about 5 days. In some embodiments, a composition described herein
comprises a gelling agent (e.g., poloxamer 407) and provides
release of an active agent over a period of from about 2 days to
about 7 days.
[0194] In some embodiments, a composition described herein
comprises a thermoreversible polymer (e.g., poloxamer 407) in
combination with micronized otic agent (e.g., ciprofloxacin) and
provides extended sustained release over a longer period of time.
In some embodiments, a composition described herein comprises about
14-17% of a thermoreversible polymer (e.g., poloxamer 407) and
micronized otic agent (e.g., ciprofloxacin), and provides extended
sustained release over a period of from about 1 week to about 3
weeks. In some embodiments, a composition described herein
comprises about 18-21% of a thermoreversible polymer (e.g.,
poloxamer 407) and micronized otic agent (e.g., ciprofloxacin), and
provides extended sustained release over a period of from about 3
weeks to about 6 weeks. In some embodiments, a composition
described herein comprises about 15-17% by weight of a
thermoreversible polymer (e.g., poloxamer 407). In some
embodiments, a composition described herein comprises about
14.4-17.6% by weight of a thermoreversible polymer (e.g., poloxamer
407). In some embodiments, a composition described herein comprises
about 15.5-16.5% by weight of a thermoreversible polymer (e.g.,
poloxamer 407). In some embodiments, a composition described herein
comprises about 14.4%, about 14.6%, about 14.8%, about 15%, about
15.1%, about 15.2%, about 15.3%, about 15.4%, about 15.5%, about
15.6%, about 15.7%, about 15.8%, about 15.9%, about 16%, about
16.1%, about 16.2%, about 16.3%, about 16.4%, about 16.5%, about
16.6%, about 16.7%, about 16.8%, about 16.9%, about 17%, about
17.2%, about 17.4%, about 17.6%, about 17.8%, about 18% by weight
of a thermoreversible polymer (e.g., poloxamer 407). In some
embodiments, a composition described herein comprises about 15% by
weight of a thermoreversible polymer (e.g., poloxamer 407). In some
embodiments, a composition described herein comprises about 15.5%
by weight of a thermoreversible polymer (e.g., poloxamer 407). In
some embodiments, a composition described herein comprises about
16% by weight of a thermoreversible polymer (e.g., poloxamer 407).
In some embodiments, a composition described herein comprises about
16.5% by weight of a thermoreversible polymer (e.g., poloxamer
407). In some embodiments, a composition described herein comprises
about 17% by weight of a thermoreversible polymer (e.g., poloxamer
407).
[0195] Accordingly, the amount of gelling agent in a composition,
and the particle size of an otic agent are tunable to the desired
release profile of an otic agent from the composition.
[0196] As described herein, compositions comprising micronized otic
agents (e.g., ciprofloxacin) provide extended release over a longer
period of time compared to compositions comprising non-micronized
otic agents. In some instances, the micronized otic agent (e.g.,
ciprofloxacin) provides a steady supply (e.g., +/-20%) of active
agent via slow degradation and serves as a depot for the active
agent; such a depot effect increases residence time of the otic
agent in the ear. In specific embodiments, selection of an
appropriate particle size of the active agent (e.g., micronized
active agent) in combination with the amount of gelling agent in
the composition provides tunable extended release characteristics
that allow for release of an active agent over a period of hours,
days, weeks or months.
[0197] In some embodiments, the viscosity of any formulation
described herein is designed to provide a suitable rate of release
from an auris compatible gel. In some embodiments, the
concentration of a thickening agent (e.g., gelling components such
as polyoxyethylene-polyoxypropylene copolymers) allows for a
tunable mean dissolution time (MDT). The MDT is inversely
proportional to the release rate of an active agent from a
composition or device described herein. Experimentally, the
released otic agent is optionally fitted to the Korsmeyer-Peppas
equation
Q Q .alpha. = k t n + b ##EQU00001##
[0198] where Q is the amount of otic agent released at time t,
Q.alpha. is the overall released amount of otic agent, k is a
release constant of the nth order, n is a dimensionless number
related to the dissolution mechanism and b is the axis intercept,
characterizing the initial burst release mechanism wherein n=1
characterizes an erosion controlled mechanism. The mean dissolution
time (MDT) is the sum of different periods of time the drug
molecules stay in the matrix before release, divided by the total
number of molecules and is optionally calculated by:
M D T = n k - 1 / n n + 1 ##EQU00002##
[0199] For example, a linear relationship between the mean
dissolution time (MDT) of a composition or device and the
concentration of the gelling agent (e.g., poloxamer) indicates that
the otic agent is released due to the erosion of the polymer gel
(e.g., poloxamer) and not via diffusion. In another example, a
non-linear relationship indicates release of otic agent via a
combination of diffusion and/or polymer gel degradation. In another
example, a faster gel elimination time course of a composition or
device (a faster release of active agent) indicates lower mean
dissolution time (MDT). The concentration of gelling components
and/or active agent in a composition are tested to determine
suitable parameters for MDT. In some embodiments, injection volumes
are also tested to determine suitable parameters for preclinical
and clinical studies. The gel strength and concentration of the
active agent affects release kinetics of an otic agent from the
composition. At low poloxamer concentration, elimination rate is
accelerated (MDT is lower). An increase in otic agent concentration
in the composition or device prolongs residence time and/or MDT of
the otic agent in the ear.
[0200] In some embodiments, the MDT for poloxamer from a
composition or device described herein is at least 6 hours. In some
embodiments, the MDT for poloxamer from a composition or device
described herein is at least 10 hours.
[0201] In some embodiments, the MDT for an active agent from a
composition or device described herein is from about 30 hours to
about 48 hours. In some embodiments, the MDT for an active agent
from a composition or device described herein is from about 30
hours to about 96 hours. In some embodiments, the MDT for an active
agent from a composition or device described herein is from about
30 hours to about 1 week. In some embodiments, the MDT for a
composition or device described herein is from about 1 week to
about 6 weeks.
[0202] In some embodiments, the mean residence time (MRT) for an
active agent in a composition or device described herein is from
about 20 hours to about 48 hours. In some embodiments, the MRT for
an active agent from a composition or device described herein is
from about 20 hours to about 96 hours. In some embodiments, the MRT
for an active agent from a composition or device described herein
is from about 20 hours to about 1 week.
[0203] In some embodiments, the MRT for an active agent is about 20
hours. In some embodiments, the MRT for an active agent is about 30
hours. In some embodiments, the MRT for an active agent is about 40
hours. In some embodiments, the MRT for an active agent is about 50
hours. In some embodiments, the MRT for an active agent is about 60
hours. In some embodiments, the MRT for an active agent is about 70
hours. In some embodiments, the MRT for an active agent is about 80
hours. In some embodiments, the MRT for an active agent is about 90
hours. In some embodiments, the MRT for an active agent is about 1
week. In some embodiments, the MRT for an active agent is about 90
hours. In some embodiments, the MRT for a composition or device
described herein is from about 1 week to about 6 weeks. In some
embodiments, the MRT for an active agent is about 1 week. In some
embodiments, the MRT for an active agent is about 2 weeks. In some
embodiments, the MRT for an active agent is about 3 weeks. In some
embodiments, the MRT for an active agent is about 4 weeks. In some
embodiments, the MRT for an active agent is about 5 weeks. The half
life of an otic agent and mean residence time of the otic agent are
determined for each formulation by measurement of concentration of
the otic agent in the perilymph using procedures described
herein.
[0204] In some embodiments, the use of a composition comprising
micronized ciprofloxacin described herein for the treatment of
middle ear effusion provides a middle ear MRT of 150 to 300 h. In
some embodiments, the use of a composition comprising micronized
ciprofloxacin described herein for the treatment of middle ear
effusion provides a middle ear MRT of 175 to 275 h. In some
embodiments, the use of a composition comprising micronized
ciprofloxacin described herein for the treatment of middle ear
effusion provides a middle ear MRT of 200 to 250 h. In some
embodiments, the use of a composition comprising micronized
ciprofloxacin described herein for the treatment of middle ear
effusion provides a middle ear MRT of 160 to 190 h. In some
embodiments, the use of a composition comprising micronized
ciprofloxacin described herein for the treatment of middle ear
effusion provides a middle ear MRT of 170 to 180 h. In some
embodiments, the use of a composition comprising micronized
ciprofloxacin described herein for the treatment of middle ear
effusion provides a middle ear MRT of 250 to 300 h. In some
embodiments, the use of a composition comprising micronized
ciprofloxacin described herein for the treatment of middle ear
effusion provides a middle ear MRT of 265 to 285 h. In some
embodiments, the use of a composition comprising micronized
ciprofloxacin described herein for the treatment of middle ear
effusion provides a middle ear MRT of about 175 h, about 180 h,
about 185 h, about 190 h, about 195 h, about 200 h, about 210 h,
about 220 h, about 225 h, about 230 h, about 240 h, about 250 h,
about 260 h, about 270 h, or about 275 h.
[0205] In certain embodiments, any controlled release otic
formulation described herein increases the exposure of an otic
agent and increases the Area Under the Curve (AUC) in otic fluids
(e.g., endolymph and/or perilymph) by about 30%, about 40%, about
50%, about 60%, about 70%, about 80% or about 90% compared to a
formulation that is not a controlled release otic formulation.
[0206] In certain embodiments, any controlled release otic
formulation described herein increases the exposure time of an otic
agent and decreases the Cmax in otic fluids (e.g., endolymph and/or
perilymph) by about 40%, about 30%, about 20%, or about 10%,
compared to a formulation that is not a controlled release otic
formulation. In certain embodiments, any controlled release otic
formulation described herein alters (e.g. reduces) the ratio of
Cmax to Cmin compared to a formulation that is not a controlled
release otic formulation. In certain embodiments, any controlled
release otic formulation described herein increases the exposure of
an otic agent and increases the length of time that the
concentration of an otic agent is above Cmin by about 30%, about
40%, about 50%, about 60%, about 70%, about 80% or about 90%
compared to a formulation that is not a controlled release otic
formulation. In certain instances, controlled release formulations
described herein delay the time to Cmax. In certain instances, the
controlled steady release of a drug prolongs the time the
concentration of the drug will stay above the Cmin. In some
embodiments, auris compositions described herein prolong the
residence time of a drug in the inner ear and provide a stable drug
exposure profile. In some instances, an increase in concentration
of an active agent in the composition saturates the clearance
process and allows for a more rapid and stable steady state to be
reached.
[0207] In some embodiments, the use of a composition comprising
micronized ciprofloxacin described herein for the treatment of
middle ear effusion provides exposure to high and stable
ciprofloxacin concentrations in the middle ear compartment. In some
embodiments, the use of a composition comprising micronized
ciprofloxacin described herein for the treatment of middle ear
effusion provides a middle ear ciprofloxacin C.sub.max of 50 to 125
.mu.g/mL. In some embodiments, the use of a composition comprising
micronized ciprofloxacin described herein for the treatment of
middle ear effusion provides a middle ear ciprofloxacin C.sub.max
of 75 to 100 .mu.g/mL. In some embodiments, the use of a
composition comprising micronized ciprofloxacin described herein
for the treatment of middle ear effusion provides a middle ear
ciprofloxacin C.sub.max of about 75 .mu.g/mL, about 80 .mu.g/mL,
about 85 .mu.g/mL, about 90 .mu.g/mL, about 95 .mu.g/mL, or about
100 .mu.g/mL. In some embodiments, the use of a composition
comprising micronized ciprofloxacin described herein for the
treatment of middle ear effusion provides a middle ear
ciprofloxacin C.sub.max of at least 50 .mu.g/mL, at least 75
.mu.g/mL, at least 80 .mu.g/mL, at least 85 .mu.g/mL, at least 90
.mu.g/mL, at least 95 .mu.g/mL, or at least 100 .mu.g/mL. In some
embodiments, the use of a composition comprising micronized
ciprofloxacin described herein for the treatment of middle ear
effusion provides a middle ear ciprofloxacin C.sub.max of at least
50 .mu.g/mL. In some embodiments, the use of a composition
comprising micronized ciprofloxacin described herein for the
treatment of middle ear effusion provides a middle ear
ciprofloxacin C.sub.max of at least 60 .mu.g/mL. In some
embodiments, the use of a composition comprising micronized
ciprofloxacin described herein for the treatment of middle ear
effusion provides a middle ear ciprofloxacin C.sub.max of at least
75 .mu.g/mL.
[0208] In some embodiments, the use of a composition comprising
micronized ciprofloxacin described herein for the treatment of
middle ear effusion provides a middle ear ciprofloxacin AUC of
7,500 to 50,000 .mu.gh/mL. In certain embodiments, the use of a
composition comprising micronized ciprofloxacin described herein
for the treatment of middle ear effusion provides a middle ear
ciprofloxacin AUC of 10,000 to 25,000 .mu.gh/mL. In certain
embodiments, the use of a composition comprising micronized
ciprofloxacin described herein for the treatment of middle ear
effusion provides a middle ear ciprofloxacin AUC of about 10,000
.mu.gh/mL, 12,000 .mu.gh/mL, about 15,000 .mu.gh/mL, about 17,000
.mu.gh/mL, about 20,000 .mu.gh/mL, about 22,000 .mu.gh/mL, or about
25,000 .mu.gh/mL. In certain embodiments, the use of a composition
comprising micronized ciprofloxacin described herein for the
treatment of middle ear effusion provides a middle ear
ciprofloxacin AUC of about 10,000 .mu.gh/mL. In certain
embodiments, the use of a composition comprising micronized
ciprofloxacin described herein for the treatment of middle ear
effusion provides a middle ear ciprofloxacin AUC of about 15,000
.mu.gh/mL. In certain embodiments, the use of a composition
comprising micronized ciprofloxacin described herein for the
treatment of middle ear effusion provides a middle ear
ciprofloxacin AUC of about 17,000 .mu.gh/mL. In certain
embodiments, the use of a composition comprising micronized
ciprofloxacin described herein for the treatment of middle ear
effusion provides a middle ear ciprofloxacin AUC of about 20,000
.mu.gh/mL. In certain embodiments, the use of a composition
comprising micronized ciprofloxacin described herein for the
treatment of middle ear effusion provides a middle ear
ciprofloxacin AUC of about 25,000 .mu.gh/mL.
[0209] In some embodiments, the use of a composition comprising
micronized ciprofloxacin described herein for the treatment of
middle ear effusion provides a middle ear ciprofloxacin
AUC.sub.0-24 of 1,000 to 3,000 .mu.gh/mL. In certain embodiments,
the use of a composition comprising micronized ciprofloxacin
described herein for the treatment of middle ear effusion provides
a middle ear ciprofloxacin AUC.sub.0-24 of 2,000 to 2,500
.mu.gh/mL. In certain embodiments, the use of a composition
comprising micronized ciprofloxacin described herein for the
treatment of middle ear effusion provides a middle ear
ciprofloxacin AUC.sub.0-24 of about 1,000 .mu.gh/mL, 1,200
.mu.gh/mL, about 1,400 .mu.gh/mL, about 1,600 .mu.gh/mL, about
1,800 .mu.gh/mL, about 2,000 .mu.gh/mL, about 2,100 .mu.gh/mL,
about 2,200 .mu.gh/mL, about 2,300 .mu.gh/mL, about 2,400
.mu.gh/mL, about 2,500 .mu.gh/mL, about 2,600 .mu.gh/mL, about
2,700 .mu.gh/mL, about 2,800 .mu.gh/mL, or about 3,000 .mu.gh/mL.
In certain embodiments, the use of a composition comprising
micronized ciprofloxacin described herein for the treatment of
middle ear effusion provides a middle ear ciprofloxacin
AUC.sub.0-24 of about 2,000 .mu.gh/mL. In certain embodiments, the
use of a composition comprising micronized ciprofloxacin described
herein for the treatment of middle ear effusion provides a middle
ear ciprofloxacin AUC.sub.0-24 of about 2,100 .mu.gh/mL. In certain
embodiments, the use of a composition comprising micronized
ciprofloxacin described herein for the treatment of middle ear
effusion provides a middle ear ciprofloxacin AUC.sub.0-24 of about
2,200 .mu.gh/mL. In certain embodiments, the use of a composition
comprising micronized ciprofloxacin described herein for the
treatment of middle ear effusion provides a middle ear
ciprofloxacin AUC.sub.0-24 of about 2,300 .mu.gh/mL. In certain
embodiments, the use of a composition comprising micronized
ciprofloxacin described herein for the treatment of middle ear
effusion provides a middle ear ciprofloxacin AUC.sub.0-24 of about
2,400 .mu.gh/mL. In certain embodiments, the use of a composition
comprising micronized ciprofloxacin described herein for the
treatment of middle ear effusion provides a middle ear
ciprofloxacin AUC.sub.0-24 of about 2,500 .mu.gh/mL.
[0210] In some embodiments, the use of a composition comprising
micronized ciprofloxacin described herein for the treatment of
middle ear effusion provides a middle ear ciprofloxacin T>MIC
(time of ciprofloxacin above minimum inhibitory concentration) of
about 350 to 800 h. In some embodiments, the use of a composition
comprising micronized ciprofloxacin described herein for the
treatment of middle ear effusion provides a middle ear
ciprofloxacin T>MIC of about 400 to 730 h. In some embodiments,
the use of a composition comprising micronized ciprofloxacin
described herein for the treatment of middle ear effusion provides
a middle ear ciprofloxacin T>MIC of about 400 h, about 425 h,
about 450 h, about 475 h, about 500 h, about 525 h, about 550 h,
about 575 h, about 600 h, about 625 h, about 650 h, about 675 h,
about 700 h, about 725 h, or about 730 h. In some embodiments, the
use of a composition comprising micronized ciprofloxacin described
herein for the treatment of middle ear effusion provides a middle
ear ciprofloxacin T>MIC of about 450 h. In some embodiments, the
use of a composition comprising micronized ciprofloxacin described
herein for the treatment of middle ear effusion provides a middle
ear ciprofloxacin T>MIC of about 500 h. In some embodiments, the
use of a composition comprising micronized ciprofloxacin described
herein for the treatment of middle ear effusion provides a middle
ear ciprofloxacin T>MIC of about 550 h. In some embodiments, the
use of a composition comprising micronized ciprofloxacin described
herein for the treatment of middle ear effusion provides a middle
ear ciprofloxacin T>MIC of about 600 h. In some embodiments, the
use of a composition comprising micronized ciprofloxacin described
herein for the treatment of middle ear effusion provides a middle
ear ciprofloxacin T>MIC of about 650 h.
[0211] In some embodiments, the use of a composition comprising
micronized ciprofloxacin described herein for the treatment of
middle ear effusion provides a middle ear ciprofloxacin
C.sub.max/MIC (minimum inhibitory concentration) ratio of 40 to 50.
In some embodiments, the use of a composition comprising micronized
ciprofloxacin described herein for the treatment of middle ear
effusion provides a middle ear ciprofloxacin C.sub.max/MIC ratio of
about 40. In some embodiments, the use of a composition comprising
micronized ciprofloxacin described herein for the treatment of
middle ear effusion provides a middle ear ciprofloxacin
C.sub.max/MIC ratio of about 42. In some embodiments, the use of a
composition comprising micronized ciprofloxacin described herein
for the treatment of middle ear effusion provides a middle ear
ciprofloxacin C.sub.max/MIC ratio of about 44. In some embodiments,
the use of a composition comprising micronized ciprofloxacin
described herein for the treatment of middle ear effusion provides
a middle ear ciprofloxacin C.sub.max/MIC ratio of about 46. In some
embodiments, the use of a composition comprising micronized
ciprofloxacin described herein for the treatment of middle ear
effusion provides a middle ear ciprofloxacin C.sub.max/MIC ratio of
about 48. In some embodiments, the use of a composition comprising
micronized ciprofloxacin described herein for the treatment of
middle ear effusion provides a middle ear ciprofloxacin
C.sub.max/MIC ratio of about 50. In some embodiments, the use of a
composition comprising micronized ciprofloxacin described herein
for the treatment of middle ear effusion provides a middle ear
ciprofloxacin C.sub.max/MIC (minimum inhibitory concentration)
ratio of at least 10. In some embodiments, the use of a composition
comprising micronized ciprofloxacin described herein for the
treatment of middle ear effusion provides a middle ear
ciprofloxacin C.sub.max/MIC (minimum inhibitory concentration)
ratio of at least 20. In some embodiments, the use of a composition
comprising micronized ciprofloxacin described herein for the
treatment of middle ear effusion provides a middle ear
ciprofloxacin C.sub.max/MIC (minimum inhibitory concentration)
ratio of at least 30. In some embodiments, the use of a composition
comprising micronized ciprofloxacin described herein for the
treatment of middle ear effusion provides a middle ear
ciprofloxacin C.sub.max/MIC (minimum inhibitory concentration)
ratio of at least 40.
[0212] In some embodiments, the use of a composition comprising
micronized ciprofloxacin described herein for the treatment of
middle ear effusion provides a middle ear ciprofloxacin
AUC.sub.0-24/MIC (minimum inhibitory concentration) ratio of 1000
to 1200. In some embodiments, the use of a composition comprising
micronized ciprofloxacin described herein for the treatment of
middle ear effusion provides a middle ear ciprofloxacin
AUC.sub.0-24/MIC ratio of about 900. In some embodiments, the use
of a composition comprising micronized ciprofloxacin described
herein for the treatment of middle ear effusion provides a middle
ear ciprofloxacin AUC.sub.0-24/MIC ratio of about 1000. In some
embodiments, the use of a composition comprising micronized
ciprofloxacin described herein for the treatment of middle ear
effusion provides a middle ear ciprofloxacin AUC.sub.0-24/MIC ratio
of about 1050. In some embodiments, the use of a composition
comprising micronized ciprofloxacin described herein for the
treatment of middle ear effusion provides a middle ear
ciprofloxacin AUC.sub.0-24/MIC ratio of about 1100. In some
embodiments, the use of a composition comprising micronized
ciprofloxacin described herein for the treatment of middle ear
effusion provides a middle ear ciprofloxacin AUC.sub.0-24/MIC ratio
of about 1150. In some embodiments, the use of a composition
comprising micronized ciprofloxacin described herein for the
treatment of middle ear effusion provides a middle ear
ciprofloxacin AUC.sub.0-24/MIC ratio of about 1200. In some
embodiments, the use of a composition comprising micronized
ciprofloxacin described herein for the treatment of middle ear
effusion provides a middle ear ciprofloxacin AUC.sub.0-24/MIC
(minimum inhibitory concentration) ratio of at least 100. In some
embodiments, the use of a composition comprising micronized
ciprofloxacin described herein for the treatment of middle ear
effusion provides a middle ear ciprofloxacin AUC.sub.0-24/MIC
(minimum inhibitory concentration) ratio of at least 250. In some
embodiments, the use of a composition comprising micronized
ciprofloxacin described herein for the treatment of middle ear
effusion provides a middle ear ciprofloxacin AUC.sub.0-24/MIC
(minimum inhibitory concentration) ratio of at least 500. In some
embodiments, the use of a composition comprising micronized
ciprofloxacin described herein for the treatment of middle ear
effusion provides a middle ear ciprofloxacin AUC.sub.0-24/MIC
(minimum inhibitory concentration) ratio of at least 1000.
[0213] In certain instances, once drug exposure (e.g.,
concentration in the endolymph or perilymph) of a drug reaches
steady state, the concentration of the drug in the endolymph or
perilymph stays at or about the therapeutic dose for an extended
period of time (e.g., one day, 2 days, 3 days, 4 days, 5 days, 6
days, or 1 week, 3 weeks, 6 weeks, 2 months). In some embodiments,
the steady state concentration of active agent released from a
controlled release formulation described herein is about 5 to about
20 times the steady state concentration of an active agent released
from a formulation that is not a controlled release formulation. In
some embodiments, the steady state concentration of active agent
released from a controlled release formulation described herein is
about 20 to about 50 times the steady state concentration of an
active agent released from a formulation that is not a controlled
release formulation.
[0214] Controlled Release Formulations
[0215] In general, controlled release drug formulations impart
control over the release of drug with respect to site of release
and time of release within the body. As discussed herein,
controlled release refers to immediate release, delayed release,
sustained release, extended release, variable release, pulsatile
release and bi-modal release. Many advantages are offered by
controlled release. First, controlled release of a pharmaceutical
agent allows less frequent dosing and thus minimizes repeated
treatment. Second, controlled release treatment results in more
efficient drug utilization and less of the compound remains as a
residue. Third, controlled release offers the possibility of
localized drug delivery by placement of a delivery device or
formulation at the site of disease. Still further, controlled
release offers the opportunity to administer and release two or
more different drugs, each having a unique release profile, or to
release the same drug at different rates or for different
durations, by means of a single dosage unit.
[0216] Auris-Acceptable Gels
[0217] Gels, sometimes referred to as jellies, have been defined in
various ways. For example, the United States Pharmacopoeia defines
gels as semisolid systems consisting of either suspensions made up
of small inorganic particles or large organic molecules
interpenetrated by a liquid. Gels include a single-phase or a
two-phase system. A single-phase gel consists of organic
macromolecules distributed uniformly throughout a liquid in such a
manner that no apparent boundaries exist between the dispersed
macromolecules and the liquid. Some single-phase gels are prepared
from synthetic macromolecules (e.g., carbomer) or from natural
gums, (e.g., tragacanth). In some embodiments, single-phase gels
are generally aqueous, but will also be made using alcohols and
oils. Two-phase gels consist of a network of small discrete
particles.
[0218] Gels can also be classified as being hydrophobic or
hydrophilic. In certain embodiments, the base of a hydrophobic gel
consists of a liquid paraffin with polyethylene or fatty oils
gelled with colloidal silica, or aluminum or zinc soaps. In
contrast, the base of hydrophobic gels usually consists of water,
glycerol, or propylene glycol gelled with a suitable gelling agent
(e.g., tragacanth, starch, cellulose derivatives,
carboxyvinylpolymers, and magnesium-aluminum silicates). In certain
embodiments, the rheology of the compositions or devices disclosed
herein is pseudo plastic, plastic, thixotropic, or dilatant.
[0219] In one embodiment the enhanced viscosity auris-acceptable
formulation described herein is not a liquid at room temperature.
In certain embodiments, the enhanced viscosity formulation is
characterized by a phase transition between room temperature and
body temperature (including an individual with a serious fever,
e.g., up to about 42.degree. C.). In some embodiments, the phase
transition occurs at 1.degree. C. below body temperature, at
2.degree. C. below body temperature, at 3.degree. C. below body
temperature, at 4.degree. C. below body temperature, at 6.degree.
C. below body temperature, at 8.degree. C. below body temperature,
or at 10.degree. C. below body temperature. In some embodiments,
the phase transition occurs at about 15.degree. C. below body
temperature, at about 20.degree. C. below body temperature or at
about 25.degree. C. below body temperature. In specific
embodiments, the gelation temperature (Tgel) of a formulation
described herein is about 20.degree. C., about 25.degree. C., or
about 30.degree. C. In certain embodiments, the gelation
temperature (Tgel) of a formulation described herein is about
35.degree. C., or about 40.degree. C. In one embodiment,
administration of any formulation described herein at about body
temperature reduces or inhibits vertigo associated with
intratympanic administration of otic formulations. Included within
the definition of body temperature is the body temperature of a
healthy individual, or an unhealthy individual, including an
individual with a fever (up to 42.degree. C.). In some embodiments,
the pharmaceutical compositions or devices described herein are
liquids at about room temperature and are administered at or about
room temperature, reducing or ameliorating side effects such as,
for example, vertigo.
[0220] Polymers composed of polyoxypropylene and polyoxyethylene
form thermoreversible gels when incorporated into aqueous
solutions. These polymers have the ability to change from the
liquid state to the gel state at temperatures close to body
temperature, therefore allowing useful formulations that are
applied to the targeted auris structure(s). The liquid state-to-gel
state phase transition is dependent on the polymer concentration
and the ingredients in the solution.
[0221] Poloxamer 407 (PF-127) is a nonionic surfactant composed of
polyoxyethylene-polyoxypropylene copolymers. Other poloxamers
include 188 (F-68 grade), 237 (F-87 grade), 338 (F-108 grade).
Aqueous solutions of poloxamers are stable in the presence of
acids, alkalis, and metal ions. PF-127 is a commercially available
polyoxyethylene-polyoxypropylene triblock copolymer of general
formula E106 P70 E106, with an average molar mass of 13,000. The
polymer can be further purified by suitable methods that will
enhance gelation properties of the polymer. It contains
approximately 70% ethylene oxide, which accounts for its
hydrophilicity. It is one of the series of poloxamer ABA block
copolymers, whose members share the chemical formula shown
below.
##STR00001##
[0222] PF-127 is of particular interest since concentrated
solutions (>20% w/w) of the copolymer are transformed from low
viscosity transparent solutions to solid gels on heating to body
temperature. This phenomenon, therefore, suggests that when placed
in contact with the body, the gel preparation will form a
semi-solid structure and a sustained release depot. Furthermore,
PF-127 has good solubilizing capacity, low toxicity and is,
therefore, considered a good medium for drug delivery systems.
[0223] In an alternative embodiment, the thermogel is a
PEG-PLGA-PEG triblock copolymer (Jeong et al, Nature (1997),
388:860-2; Jeong et al, J. Control. Release (2000), 63:155-63;
Jeong et al, Adv. Drug Delivery Rev. (2002), 54:37-51). The polymer
exhibits sol-gel behavior over a concentration of about 5% w/w to
about 40% w/w. Depending on the properties desired, the
lactide/glycolide molar ratio in the PLGA copolymer ranges from
about 1:1 to about 20:1. The resulting copolymers are soluble in
water and form a free-flowing liquid at room temperature, but form
a hydrogel at body temperature. A commercially available
PEG-PLGA-PEG triblock copolymer is RESOMER RGP t50106 manufactured
by Boehringer Ingelheim. This material is composed of a PGLA
copolymer of 50:50 poly(DL-lactide-co-glycolide) and is 10% w/w of
PEG and has a molecular weight of about 6000.
[0224] ReGel.RTM. is a tradename of MacroMed Incorporated for a
class of low molecular weight, biodegradable block copolymers
having reverse thermal gelation properties as described in U.S.
Pat. Nos. 6,004,573, 6,117,949, 6,201,072, and 6,287,588. It also
includes biodegradable polymeric drug carriers disclosed in pending
U.S. patent application Ser. Nos. 09/906,041, 09/559,799 and
10/919,603. The biodegradable drug carrier comprises ABA-type or
BAB-type triblock copolymers or mixtures thereof, wherein the
A-blocks are relatively hydrophobic and comprise biodegradable
polyesters or poly(orthoester)s, and the B-blocks are relatively
hydrophilic and comprise polyethylene glycol (PEG), said copolymers
having a hydrophobic content of between 50.1 to 83% by weight and a
hydrophilic content of between 17 to 49.9% by weight, and an
overall block copolymer molecular weight of between 2000 and 8000
Daltons. The drug carriers exhibit water solubility at temperatures
below normal mammalian body temperatures and undergo reversible
thermal gelation to then exist as a gel at temperatures equal to
physiological mammalian body temperatures. The biodegradable,
hydrophobic A polymer block comprises a polyester or poly(ortho
ester), in which the polyester is synthesized from monomers
selected from the group consisting of D,L-lactide, D-lactide,
L-lactide, D,L-lactic acid, D-lactic acid, L-lactic acid,
glycolide, glycolic acid, .epsilon.-caprolactone,
.epsilon.-hydroxyhexanoic acid, .gamma.-butyrolactone,
.gamma.-hydroxybutyric acid, .delta.-valerolactone,
.delta.-hydroxyvaleric acid, hydroxybutyric acids, malic acid, and
copolymers thereof and having an average molecular weight of
between about 600 and 3000 Daltons. The hydrophilic B-block segment
is preferably polyethylene glycol (PEG) having an average molecular
weight of between about 500 and 2200 Daltons.
[0225] Additional biodegradable thermoplastic polyesters include
AtriGel.RTM. (provided by Atrix Laboratories, Inc.) and/or those
disclosed, e.g., in U.S. Pat. Nos. 5,324,519; 4,938,763; 5,702,716;
5,744,153; and 5,990,194; wherein the suitable biodegradable
thermoplastic polyester is disclosed as a thermoplastic polymer.
Examples of suitable biodegradable thermoplastic polyesters include
polylactides, polyglycolides, polycaprolactones, copolymers
thereof, terpolymers thereof, and any combinations thereof. In some
such embodiments, the suitable biodegradable thermoplastic
polyester is a polylactide, a polyglycolide, a copolymer thereof, a
terpolymer thereof, or a combination thereof. In one embodiment,
the biodegradable thermoplastic polyester is 50/50
poly(DL-lactide-co-glycolide) having a carboxy terminal group; is
present in about 30 wt. % to about 40 wt. % of the composition; and
has an average molecular weight of about 23,000 to about 45,000.
Alternatively, in another embodiment, the biodegradable
thermoplastic polyester is 75/25 poly (DL-lactide-co-glycolide)
without a carboxy terminal group; is present in about 40 wt. % to
about 50 wt. % of the composition; and has an average molecular
weight of about 15,000 to about 24,000. In further or alternative
embodiments, the terminal groups of the
poly(DL-lactide-co-glycolide) are either hydroxyl, carboxyl, or
ester depending upon the method of polymerization. Polycondensation
of lactic or glycolic acid provides a polymer with terminal
hydroxyl and carboxyl groups. Ring-opening polymerization of the
cyclic lactide or glycolide monomers with water, lactic acid, or
glycolic acid provides polymers with the same terminal groups.
However, ring-opening of the cyclic monomers with a monofunctional
alcohol such as methanol, ethanol, or 1-dodecanol provides a
polymer with one hydroxyl group and one ester terminal groups.
Ring-opening polymerization of the cyclic monomers with a diol such
as 1,6-hexanediol or polyethylene glycol provides a polymer with
only hydroxyl terminal groups.
[0226] Since the polymer systems of thermoreversible gels dissolve
more completely at reduced temperatures, methods of solubilization
include adding the required amount of polymer to the amount of
water to be used at reduced temperatures. Generally after wetting
the polymer by shaking, the mixture is capped and placed in a cold
chamber or in a thermostatic container at about 0-10.degree. C. in
order to dissolve the polymer. The mixture is stirred or shaken to
bring about a more rapid dissolution of the thermoreversible gel
polymer. The antimicrobial agent and various additives such as
buffers, salts, and preservatives are subsequently added and
dissolved. In some instances the antimicrobial agent and/or other
pharmaceutically active agent is suspended if it is insoluble in
water. The pH is modulated by the addition of appropriate buffering
agents. round window membrane mucoadhesive characteristics are
optionally imparted to a thermoreversible gel by incorporation of
round window membrane mucoadhesive carbomers, such as Carbopol.RTM.
934P, to the composition (Majithiya et al, AAPS PharmSciTech
(2006), 7(3), p. E1; EP0551626, both of which is incorporated
herein by reference for such disclosure).
[0227] In one embodiment are auris-acceptable pharmaceutical gel
formulations which do not require the use of an added viscosity
enhancing agent. Such gel formulations incorporate at least one
pharmaceutically acceptable buffer. In one aspect is a gel
formulation comprising an antimicrobial agent and a
pharmaceutically acceptable buffer. In another embodiment, the
pharmaceutically acceptable excipient or carrier is a gelling
agent.
[0228] In other embodiments, useful antimicrobial agent
auris-acceptable pharmaceutical formulations also include one or
more pH adjusting agents or buffering agents to provide an
endolymph or perilymph suitable pH. Suitable pH adjusting agents or
buffers include, but are not limited to acetate, bicarbonate,
ammonium chloride, citrate, phosphate, pharmaceutically acceptable
salts thereof and combinations or mixtures thereof. Such pH
adjusting agents and buffers are included in an amount required to
maintain pH of the composition between a pH of about 5 and about 9,
in one embodiment a pH between about 6.5 to about 7.5, and in yet
another embodiment at a pH of about 6.5, 6.6, 6.7, 6.8, 6.9, 7.0,
7.1, 7.2, 7.3, 7.4, 7.5. In one embodiment, when one or more
buffers are utilized in the formulations of the present disclosure,
they are combined, e.g., with a pharmaceutically acceptable vehicle
and are present in the final formulation, e.g., in an amount
ranging from about 0.1% to about 20%, from about 0.5% to about 10%.
In certain embodiments of the present disclosure, the amount of
buffer included in the gel formulations are an amount such that the
pH of the gel formulation does not interfere with the auris media
or auris interna's natural buffering system, or does not interfere
with the natural pH of the endolymph or perilymph: depending on
where in the cochlea the antimicrobial agent formulation is
targeted. In some embodiments, from about 10 .mu.M to about 200 mM
concentration of a buffer is present in the gel formulation. In
certain embodiments, from about a 5 mM to about a 200 mM
concentration of a buffer is present. In certain embodiments, from
about a 20 mM to about a 100 mM concentration of a buffer is
present. In one embodiment is a buffer such as acetate or citrate
at slightly acidic pH. In one embodiment the buffer is a sodium
acetate buffer having a pH of about 4.5 to about 6.5. In one
embodiment the buffer is a sodium citrate buffer having a pH of
about 5.0 to about 8.0, or about 5.5 to about 7.0.
[0229] In an alternative embodiment, the buffer used is
tris(hydroxymethyl)aminomethane, bicarbonate, carbonate or
phosphate at slightly basic pH. In one embodiment, the buffer is a
sodium bicarbonate buffer having a pH of about 6.5 to about 8.5, or
about 7.0 to about 8.0. In another embodiment the buffer is a
sodium phosphate dibasic buffer having a pH of about 6.0 to about
9.0.
[0230] Also described herein are aqueous thermoreversible gel
formulations comprising an antimicrobial agent and a
thermoreversible polymer, such as a poloxamer (e.g. Poloxamer 407).
In some embodiments, the concentration of the thermoreversible
polymer in the water being sufficient to provide a final viscosity
(after intratympanic injection) from about 100 to about 100,000 cP.
In certain embodiments, the viscosity of the gel is in the range
from about 100 to about 50,000 cP, about 100 cP to about 1,000 cP,
about 500 cP to about 1500 cP, about 1000 cP to about 3000 cP,
about 2000 cP to about 8,000 cP, about 4,000 cP to about 50,000 cP,
about 10,000 cP to about 500,000 cP, about 15,000 cP to about
1,000,000 cP.
[0231] In some embodiments, the viscosity of the gel formulations
presented herein is measured by any means described. For example,
in some embodiments, an LVDV-II+CP Cone Plate Viscometer and a Cone
Spindle CPE-40 are used to calculate the viscosity of the gel
formulation described herein. In other embodiments, a Brookfield
(spindle and cup) viscometer is used to calculate the viscosity of
the gel formulation described herein. In some embodiments, the
viscosity ranges referred to herein are measured at room
temperature. In other embodiments, the viscosity ranges referred to
herein are measured at body temperature (e.g., at the average body
temperature of a healthy human).
[0232] If desired, the auris-acceptable pharmaceutical gels also
contain osmolality adjustors and other excipients in addition,
buffering agents, and pH adjusting agents. Suitable
auris-acceptable water soluble buffering agents are alkali or
alkaline earth metal carbonates, phosphates, bicarbonates,
citrates, borates, acetates, succinates and the like, such as
sodium phosphate, citrate, borate, acetate, bicarbonate, carbonate
and tromethamine (TRIS). These agents are present in amounts
sufficient to maintain the pH of the system at about 7.0 to about
8.0. In some embodiments, the buffering agent (e.g. tromethamine)
is included at a concentration of about 0.4% to about 0.6% on a
weight basis of the total composition.
[0233] General Methods of Sterilization
[0234] Provided herein are otic compositions that ameliorate or
lessen pediatric otic disorders described herein. Further provided
herein are methods comprising the administration of said otic
compositions. In some embodiments, the compositions or devices are
sterilized. Included within the embodiments disclosed herein are
means and processes for sterilization of a pharmaceutical
composition or device disclosed herein for use in humans. The goal
is to provide a safe pharmaceutical product, relatively free of
infection causing micro-organisms. The U. S. Food and Drug
Administration has provided regulatory guidance in the publication
"Guidance for Industry: Sterile Drug Products Produced by Aseptic
Processing" available at:
http://www.fda.gov/cder/guidance/5882fnl.htm, which is incorporated
herein by reference in its entirety.
[0235] As used herein, sterilization means a process used to
destroy or remove microorganisms that are present in a product or
packaging. Any suitable method available for sterilization of
objects and compositions is used. Available methods for the
inactivation of microorganisms include, but are not limited to, the
application of extreme heat, lethal chemicals, or gamma radiation.
In some embodiments is a process for the preparation of an otic
therapeutic formulation comprising subjecting the formulation to a
sterilization method selected from heat sterilization, chemical
sterilization, radiation sterilization or filtration sterilization.
The method used depends largely upon the nature of the device or
composition to be sterilized. Detailed descriptions of many methods
of sterilization are given in Chapter 40 of Remington: The Science
and Practice of Pharmacy published by Lippincott, Williams &
Wilkins, and is incorporated by reference with respect to this
subject matter.
[0236] Sterilization by Heat
[0237] Many methods are available for sterilization by the
application of extreme heat. One method is through the use of a
saturated steam autoclave. In this method, saturated steam at a
temperature of at least 121.degree. C. is allowed to contact the
object to be sterilized. The transfer of heat is either directly to
the microorganism, in the case of an object to be sterilized, or
indirectly to the microorganism by heating the bulk of an aqueous
solution to be sterilized. This method is widely practiced as it
allows flexibility, safety and economy in the sterilization
process.
[0238] Dry heat sterilization is a method which is used to kill
microorganisms and perform depyrogenation at elevated temperatures.
This process takes place in an apparatus suitable for heating
HEPA-filtered microorganism-free air to temperatures of at least
130-180.degree. C. for the sterilization process and to
temperatures of at least 230-250.degree. C. for the depyrogenation
process. Water to reconstitute concentrated or powdered
formulations is also sterilized by autoclave. In some embodiments,
the formulations described herein comprise micronized antimicrobial
agents (e.g., micronized ciprofloxacin) that are sterilized by dry
heating, e.g., heating for about 7-11 hours at internal powder
temperatures of 130-140.degree. C., or for 1-2 hours at internal
temperatures of 150-180.degree. C.
[0239] Chemical Sterilization
[0240] Chemical sterilization methods are an alternative for
products that do not withstand the extremes of heat sterilization.
In this method, a variety of gases and vapors with germicidal
properties, such as ethylene oxide, chlorine dioxide, formaldehyde
or ozone are used as the anti-apoptotic agents. The germicidal
activity of ethylene oxide, for example, arises from its ability to
serve as a reactive alkylating agent. Thus, the sterilization
process requires the ethylene oxide vapors to make direct contact
with the product to be sterilized.
[0241] Radiation Sterilization
[0242] One advantage of radiation sterilization is the ability to
sterilize many types of products without heat degradation or other
damage. The radiation commonly employed is beta radiation or
alternatively, gamma radiation from a .sup.60Co source. The
penetrating ability of gamma radiation allows its use in the
sterilization of many product types, including solutions,
compositions and heterogeneous mixtures. The germicidal effects of
irradiation arise from the interaction of gamma radiation with
biological macromolecules. This interaction generates charged
species and free radicals. Subsequent chemical reactions, such as
rearrangements and cross-linking processes, result in the loss of
normal function for these biological macromolecules. The
formulations described herein are also optionally sterilized using
beta irradiation.
[0243] Filtration
[0244] Filtration sterilization is a method used to remove but not
destroy microorganisms from solutions. Membrane filters are used to
filter heat-sensitive solutions. Such filters are thin, strong,
homogenous polymers of mixed cellulosic esters (MCE),
polyvinylidene fluoride (PVF; also known as PVDF), or
polytetrafluoroethylene (PTFE) and have pore sizes ranging from 0.1
to 0.22 .mu.m. Solutions of various characteristics are optionally
filtered using different filter membranes. For example, PVF and
PTFE membranes are well suited to filtering organic solvents while
aqueous solutions are filtered through PVF or MCE membranes. Filter
apparatus are available for use on many scales ranging from the
single point-of-use disposable filter attached to a syringe up to
commercial scale filters for use in manufacturing plants. The
membrane filters are sterilized by autoclave or chemical
sterilization. Validation of membrane filtration systems is
performed following standardized protocols (Microbiological
Evaluation of Filters for Sterilizing Liquids, Vol 4, No. 3.
Washington, D.C.: Health Industry Manufacturers Association, 1981)
and involve challenging the membrane filter with a known quantity
(ca. 10.sup.7/cm.sup.2) of unusually small microorganisms, such as
Brevundimonas diminuta (ATCC 19146).
[0245] Pharmaceutical compositions are optionally sterilized by
passing through membrane filters. Formulations comprising
nanoparticles (U.S. Pat. No. 6,139,870) or multilamellar vesicles
(Richard et al., International Journal of Pharmaceutics (2006),
312(1-2):144-50) are amenable to sterilization by filtration
through 0.22 .mu.m filters without destroying their organized
structure.
[0246] In some embodiments, the methods disclosed herein comprise
sterilizing the formulation (or components thereof) by means of
filtration sterilization. In another embodiment the
auris-acceptable otic therapeutic agent formulation comprises a
particle wherein the particle formulation is suitable for
filtration sterilization. In a further embodiment said particle
formulation comprises particles of less than 300 nm in size, of
less than 200 nm in size, of less than 100 nm in size. In another
embodiment the auris-acceptable formulation comprises a particle
formulation wherein the sterility of the particle is ensured by
sterile filtration of the precursor component solutions. In another
embodiment the auris-acceptable formulation comprises a particle
formulation wherein the sterility of the particle formulation is
ensured by low temperature sterile filtration. In a further
embodiment, low temperature sterile filtration is carried out at a
temperature between 0 and 30.degree. C., between 0 and 20.degree.
C., between 0 and 10.degree. C., between 10 and 20.degree. C., or
between 20 and 30.degree. C.
[0247] In another embodiment is a process for the preparation of an
auris-acceptable particle formulation comprising: filtering the
aqueous solution containing the particle formulation at low
temperature through a sterilization filter; lyophilizing the
sterile solution; and reconstituting the particle formulation with
sterile water prior to administration. In some embodiments, a
formulation described herein is manufactured as a suspension in a
single vial formulation containing the micronized active
pharmaceutical ingredient. A single vial formulation is prepared by
aseptically mixing a sterile poloxamer solution with sterile
micronized active ingredient (e.g., ciprofloxacin) and transferring
the formulation to sterile pharmaceutical containers. In some
embodiments, a single vial containing a formulation described
herein as a suspension is resuspended before dispensing and/or
administration.
[0248] In specific embodiments, filtration and/or filling
procedures are carried out at about 5.degree. C. below the gel
temperature (Tgel) of a formulation described herein and with
viscosity below a theoretical value of 100 cP to allow for
filtration in a reasonable time using a peristaltic pump.
[0249] In another embodiment the auris-acceptable otic therapeutic
agent formulation comprises a nanoparticle formulation wherein the
nanoparticle formulation is suitable for filtration sterilization.
In a further embodiment the nanoparticle formulation comprises
nanoparticles of less than 300 nm in size, of less than 200 nm in
size, or of less than 100 nm in size. In another embodiment the
auris-acceptable formulation comprises a microsphere formulation
wherein the sterility of the microsphere is ensured by sterile
filtration of the precursor organic solution and aqueous solutions.
In another embodiment the auris-acceptable formulation comprises a
thermoreversible gel formulation wherein the sterility of the gel
formulation is ensured by low temperature sterile filtration. In a
further embodiment, the low temperature sterile filtration occurs
at a temperature between 0 and 30.degree. C., or between 0 and
20.degree. C., or between 0 and 10.degree. C., or between 10 and
20.degree. C., or between 20 and 30.degree. C. In another
embodiment is a process for the preparation of an auris-acceptable
thermoreversible gel formulation comprising: filtering the aqueous
solution containing the thermoreversible gel components at low
temperature through a sterilization filter; lyophilizing the
sterile solution; and reconstituting the thermoreversible gel
formulation with sterile water prior to administration.
[0250] In some instances, the active ingredients are sterilized
separately in a dry state. In some instances, the active
ingredients are sterilized as a suspension or as a colloidal
suspension. The remaining excipients (e.g., fluid gel components
present in auris formulations) are sterilized in a separate step by
a suitable method (e.g. filtration and/or irradiation of a cooled
mixture of excipients); the two solutions that are separately
sterilized are then mixed aseptically to provide a final auris
formulation. In some instances, the final aseptic mixing is
performed just prior to administration of a formulation described
herein.
[0251] In some instances, conventionally used methods of
sterilization (e.g., heat treatment (e.g., in an autoclave), gamma
irradiation, filtration) lead to degradation of polymeric
components (e.g., thermosetting, gelling or mucoadhesive polymer
components) and/or the active agent in the formulation. In some
instances, sterilization of an auris formulation by filtration
through membranes (e.g., 0.2 .mu.M membranes) is not possible if
the formulation comprises thixotropic polymers that gel during the
process of filtration.
[0252] Accordingly, provided herein are methods for sterilization
of auris formulations that prevent degradation of polymeric
components (e.g., thermosetting and/or gelling and/or mucoadhesive
polymer components) and/or the active agent during the process of
sterilization. In some embodiments, degradation of the active agent
(e.g., any therapeutic otic agent described herein) is reduced or
eliminated through the use of specific pH ranges for buffer
components and specific proportions of gelling agents in the
formulations. In some embodiments, the choice of an appropriate
gelling agent and/or thermosetting polymer allows for sterilization
of formulations described herein by filtration. In some
embodiments, the use of an appropriate thermosetting polymer and an
appropriate copolymer (e.g., a gelling agent) in combination with a
specific pH range for the formulation allows for high temperature
sterilization of formulations described with substantially no
degradation of the therapeutic agent or the polymeric excipients.
An advantage of the methods of sterilization provided herein is
that, in certain instances, the formulations are subjected to
terminal sterilization via autoclaving without any loss of the
active agent and/or excipients and/or polymeric components during
the sterilization step and are rendered substantially free of
microbes and/or pyrogens.
[0253] Microorganisms
[0254] Provided herein are auris-acceptable compositions or devices
that ameliorate or lessen otic disorders described herein. Further
provided herein are methods comprising the administration of said
otic compositions. In some embodiments, the compositions or devices
are substantially free of microorganisms. Acceptable bioburden or
sterility levels are based on applicable standards that define
therapeutically acceptable compositions, including but not limited
to United States Pharmacopeia Chapters <1111> et seq. For
example, acceptable sterility (e.g., bioburden) levels include
about 10 colony forming units (cfu) per gram of formulation, about
50 cfu per gram of formulation, about 100 cfu per gram of
formulation, about 500 cfu per gram of formulation or about 1000
cfu per gram of formulation. In some embodiments, acceptable
bioburden levels or sterility for formulations include less than 10
cfu/mL, less that 50 cfu/mL, less than 500 cfu/mL or less than 1000
cfu/mL microbial agents. In addition, acceptable bioburden levels
or sterility include the exclusion of specified objectionable
microbiological agents. By way of example, specified objectionable
microbiological agents include but are not limited to Escherichia
coli (E. coli), Salmonella sp., Pseudomonas aeruginosa (P.
aeruginosa) and/or other specific microbial agents.
[0255] Sterility of the auris-acceptable otic therapeutic agent
formulation is confirmed through a sterility assurance program in
accordance with United States Pharmacopeia Chapters <61>,
<62> and <71>. A key component of the sterility
assurance quality control, quality assurance and validation process
is the method of sterility testing. Sterility testing, by way of
example only, is performed by two methods. The first is direct
inoculation wherein a sample of the composition to be tested is
added to growth medium and incubated for a period of time up to 21
days. Turbidity of the growth medium indicates contamination.
Drawbacks to this method include the small sampling size of bulk
materials which reduces sensitivity, and detection of microorganism
growth based on a visual observation. An alternative method is
membrane filtration sterility testing. In this method, a volume of
product is passed through a small membrane filter paper. The filter
paper is then placed into media to promote the growth of
microorganisms. This method has the advantage of greater
sensitivity as the entire bulk product is sampled. The commercially
available Millipore Steritest sterility testing system is
optionally used for determinations by membrane filtration sterility
testing. For the filtration testing of creams or ointments
Steritest filter system No. TLHVSL210 are used. For the filtration
testing of emulsions or viscous products Steritest filter system
No. TLAREM210 or TDAREM210 are used. For the filtration testing of
pre-filled syringes Steritest filter system No. TTHASY210 are used.
For the filtration testing of material dispensed as an aerosol or
foam Steritest filter system No. TTHVA210 are used. For the
filtration testing of soluble powders in ampoules or vials
Steritest filter system No. TTHADA210 or TTHADV210 are used.
[0256] Testing for E. coli and Salmonella includes the use of
lactose broths incubated at 30-35.degree. C. for 24-72 hours,
incubation in MacConkey and/or EMB agars for 18-24 hours, and/or
the use of Rappaport medium. Testing for the detection of P.
aeruginosa includes the use of NAC agar. United States Pharmacopeia
Chapter <62> further enumerates testing procedures for
specified objectionable microorganisms.
[0257] In certain embodiments, any controlled release formulation
described herein has less than about 60 colony forming units (CFU),
less than about 50 colony forming units, less than about 40 colony
forming units, or less than about 30 colony forming units of
microbial agents per gram of formulation. In certain embodiments,
the otic formulations described herein are formulated to be
isotonic with the endolymph and/or the perilymph.
[0258] Endotoxins
[0259] Provided herein are otic compositions that ameliorate or
lessen otic disorders described herein. Further provided herein are
methods comprising the administration of said otic compositions. In
some embodiments, the compositions or devices are substantially
free of endotoxins. An additional aspect of the sterilization
process is the removal of by-products from the killing of
microorganisms (hereinafter, "Product"). The process of
depyrogenation removes pyrogens from the sample. Pyrogens are
endotoxins or exotoxins which induce an immune response. An example
of an endotoxin is the lipopolysaccharide (LPS) molecule found in
the cell wall of gram-negative bacteria. While sterilization
procedures such as autoclaving or treatment with ethylene oxide
kill the bacteria, the LPS residue induces a proinflammatory immune
response, such as septic shock. Because the molecular size of
endotoxins can vary widely, the presence of endotoxins is expressed
in "endotoxin units" (EU). One EU is equivalent to 100 picograms of
E. coli LPS. Humans can develop a response to as little as 5 EU/kg
of body weight. The bioburden (e.g., microbial limit) and/or
sterility (e.g., endotoxin level) is expressed in any units as
recognized in the art. In certain embodiments, otic compositions
described herein contain lower endotoxin levels (e.g. <4 EU/kg
of body weight of a subject) when compared to conventionally
acceptable endotoxin levels (e.g., 5 EU/kg of body weight of a
subject). In some embodiments, the auris-acceptable otic
therapeutic agent formulation has less than about 5 EU/kg of body
weight of a subject. In other embodiments, the auris-acceptable
otic therapeutic agent formulation has less than about 4 EU/kg of
body weight of a subject. In additional embodiments, the
auris-acceptable otic therapeutic agent formulation has less than
about 3 EU/kg of body weight of a subject. In additional
embodiments, the auris-acceptable otic therapeutic agent
formulation has less than about 2 EU/kg of body weight of a
subject.
[0260] In some embodiments, the auris-acceptable otic therapeutic
agent formulation or device has less than about 5 EU/kg of
formulation. In other embodiments, the auris-acceptable otic
therapeutic agent formulation has less than about 4 EU/kg of
formulation. In additional embodiments, the auris-acceptable otic
therapeutic agent formulation has less than about 3 EU/kg of
formulation. In some embodiments, the auris-acceptable otic
therapeutic agent formulation has less than about 5 EU/kg Product.
In other embodiments, the auris-acceptable otic therapeutic agent
formulation has less than about 1 EU/kg Product. In additional
embodiments, the auris-acceptable otic therapeutic agent
formulation has less than about 0.2 EU/kg Product. In some
embodiments, the auris-acceptable otic therapeutic agent
formulation has less than about 5 EU/g of unit or Product. In other
embodiments, the auris-acceptable otic therapeutic agent
formulation has less than about 4 EU/g of unit or Product. In
additional embodiments, the auris-acceptable otic therapeutic agent
formulation has less than about 3 EU/g of unit or Product. In some
embodiments, the auris-acceptable otic therapeutic agent
formulation has less than about 5 EU/mg of unit or Product. In
other embodiments, the auris-acceptable otic therapeutic agent
formulation has less than about 4 EU/mg of unit or Product. In
additional embodiments, the auris-acceptable otic therapeutic agent
formulation has less than about 3 EU/mg of unit or Product. In
certain embodiments, otic compositions described herein contain
from about 1 to about 5 EU/mL of formulation. In certain
embodiments, otic compositions described herein contain from about
2 to about 5 EU/mL of formulation, from about 3 to about 5 EU/mL of
formulation, or from about 4 to about 5 EU/mL of formulation.
[0261] In certain embodiments, otic compositions or devices
described herein contain lower endotoxin levels (e.g. <0.5 EU/mL
of formulation) when compared to conventionally acceptable
endotoxin levels (e.g., 0.5 EU/mL of formulation). In some
embodiments, the auris-acceptable otic therapeutic agent
formulation or device has less than about 0.5 EU/mL of formulation.
In other embodiments, the auris-acceptable otic therapeutic agent
formulation has less than about 0.4 EU/mL of formulation. In
additional embodiments, the auris-acceptable otic therapeutic agent
formulation has less than about 0.2 EU/mL of formulation.
[0262] Pyrogen detection, by way of example only, is performed by
several methods. Suitable tests for sterility include tests
described in United States Pharmacopoeia (USP) <71> Sterility
Tests (23rd edition, 1995). The rabbit pyrogen test and the Limulus
amebocyte lysate test are both specified in the United States
Pharmacopeia Chapters <85> and <151> (USP23/NF 18,
Biological Tests, The United States Pharmacopeial Convention,
Rockville, Md., 1995). Alternative pyrogen assays have been
developed based upon the monocyte activation-cytokine assay.
Uniform cell lines suitable for quality control applications have
been developed and have demonstrated the ability to detect
pyrogenicity in samples that have passed the rabbit pyrogen test
and the Limulus amebocyte lysate test (Taktak et al, J. Pharm.
Pharmacol. (1990), 43:578-82). In an additional embodiment, the
auris-acceptable otic therapeutic agent formulation is subject to
depyrogenation. In a further embodiment, the process for the
manufacture of the auris-acceptable otic therapeutic agent
formulation comprises testing the formulation for pyrogenicity. In
certain embodiments, the formulations described herein are
substantially free of pyrogens.
Methods of Treatment
[0263] Administration--Otic Surgery
[0264] In some embodiments, administration of an antimicrobial
composition or device described herein in combination with an otic
intervention (e.g., an intratympanic injection, a stapedectomy,
myringotomy, tympanostomy tube surgery, a medical device implant or
a cell-based transplant) delays or prevents collateral damage to
auris structures, e.g., irritation, inflammation and/or infection,
caused by the external otic intervention (e.g., installation of an
external device and/or cells in the ear). In some embodiments,
administration of an antimicrobial composition or device described
herein in combination with an implant allows for a more effective
restoration of hearing loss compared to an implant alone.
[0265] In some embodiments, administration of an antimicrobial
composition or device described herein reduces damage to cochlear
structures caused by underlying conditions (e.g., bacterial
meningitis, autoimmune ear disease (AIED)) allowing for successful
cochlear device implantation. In some embodiments, administration
of a composition or device described herein, in conjunction with
otic surgery, medical device implantation and/or cell
transplantation, reduces or prevents cell damage and/or
inflammation associated with otic surgery, medical device
implantation and/or cell transplantation.
[0266] In some embodiments, administration of an antimicrobial
composition or device described herein (e.g., a composition or
device comprising ciprofloxacin) in conjunction with a cochlear
implant or stem cell transplant has a trophic effect (e.g.,
promotes healthy growth of cells and/or healing of tissue in the
area of an implant or transplant). In some embodiments, a trophic
effect is desirable during otic surgery or during intratympanic
injection procedures. In some embodiments, a trophic effect is
desirable after installation of a medical device or after a cell
transplant. In some of such embodiments, the antimicrobial
compositions or devices described herein are administered via
direct cochlear injection, through a chochleostomy or via
deposition on the round window. In some embodiments, a medical
device is coated with a composition described herein prior to
implantation in the ear.
[0267] In one aspect, the formulations described herein, and modes
of administration thereof, are applicable to methods of direct
injection into the middle ear. Thus, the formulations described
herein are useful in combination with otic interventions. In some
embodiments, an otic intervention is an implantation procedure
(e.g., implantation of a hearing device in the cochlea). In some
embodiments, an otic intervention is a surgical procedure
including, by way of non-limiting examples, cochleostomy,
labyrinthotomy, mastoidectomy, stapedectomy, stapedotomy,
myringotomy, tympanostomy tube surgery, endolymphatic sacculotomy
or the like. In some embodiments, the inner ear compartments are
perfused with a formulation described herein prior to otic
intervention, during otic intervention, or after otic intervention,
or a combination thereof
[0268] In some embodiments, the auris gel formulations are capable
of being administered into the middle ear via intratympanic
injection. In other embodiments, the auris gel formulations are
administered into the middle ear via a post-auricular incision.
Alternatively, the auris gel formulation is applied via syringe and
needle, wherein the needle is inserted through the tympanic
membrane and into the middle ear. The auris gel formulations are
then deposited into the middle ear for localized treatment of otic
disorders. In other embodiments, the auris gel formulations are
applied via microcathethers implanted into the patient, and in yet
further embodiments the formulations are administered via a pump
device through the surgical incision on the tympanic membrane. In
still further embodiments, the auris gel formulations are
administered into the middle ear via a microinjection device. In
yet other embodiments, the auris gel formulations are administered
into the tympanic cavity. In some embodiments, the auris gel
formulations are applied on the tympanic membrane. In still other
embodiments, the auris gel formulations are applied onto or in the
auditory canal.
[0269] In certain embodiments, a composition described herein is
administered before a pediatric otic intervention (e.g., before
implantation of a medical device or a cell-based therapeutic). In
certain embodiments, a composition described herein is administered
during a pediatric otic intervention (e.g., during implantation of
a medical device or a cell-based therapeutic). In other
embodiments, a composition described herein is administered after a
pediatric otic intervention (e.g., after implantation of a medical
device or a cell-based therapeutic). In some of such embodiments, a
composition described herein that is administered after the
pediatric otic intervention is an intermediate release or extended
release composition (e.g., a composition comprising an antibiotic
and optionally comprising an anti-inflammatory agent) and contains
gelling components as described herein. In some embodiments, an
implant (e.g., a tympanostomy tube) is coated with a composition or
device described herein prior to insertion in the ear.
[0270] In some embodiments, a composition described herein
comprising micronized ciprofloxacin is administered to a pediatric
patient via an intratympanic injection anterior to the round window
membrane. In some embodiments, a composition described herein
comprising micronized ciprofloxacin is administered to a pediatric
patient at the site of myringotomy. In some embodiments, a
composition described herein comprising micronized ciprofloxacin is
administered to a pediatric patient before myringotomy. In other
embodiments, a composition described herein comprising micronized
ciprofloxacin is administered to a pediatric patient after
myringotomy. In some embodiments, a composition described herein
comprising micronized ciprofloxacin is administered to a pediatric
patient before tympanostomy tube placement. In other embodiments, a
composition described herein comprising micronized ciprofloxacin is
administered to a pediatric patient after tympanostomy tube
placement. In some embodiments, a composition described herein
comprising micronized ciprofloxacin is administered to a pediatric
patient after myringotomy and before tympanostomy tube placement.
In some embodiments, a composition described herein comprising
micronized ciprofloxacin is administered to a pediatric patient
before myringotomy and before tympanostomy tube placement. In some
embodiments, a composition described herein comprising micronized
ciprofloxacin is administered to a pediatric patient after
myringotomy and after tympanostomy tube placement.
[0271] Dosing Methods and Schedules
[0272] Drugs delivered to the inner ear have been administered
systemically via oral, intravenous or intramuscular routes.
However, systemic administration for pathologies local to the inner
ear increases the likelihood of systemic toxicities and adverse
side effects and creates a non-productive distribution of drug in
which high levels of drug are found in the serum and
correspondingly lower levels are found at the inner ear.
[0273] Intratympanic injection of therapeutic agents is the
technique of injecting a therapeutic agent behind the tympanic
membrane into the middle and/or inner ear. In one embodiment, the
formulations described herein are administered directly onto the
round window membrane via transtympanic injection. In another
embodiment, the antimicrobial agent auris-acceptable formulations
described herein are administered onto the round window membrane
via a non-transtympanic approach to the inner ear. In additional
embodiments, the formulation described herein is administered onto
the round window membrane via a surgical approach to the round
window membrane comprising modification of the crista fenestrae
cochleae.
[0274] In one embodiment the delivery system is a syringe and
needle apparatus that is capable of piercing the tympanic membrane
and directly accessing the round window membrane or crista
fenestrae cochleae of the auris interna. In some embodiments, the
needle on the syringe is wider than a 18 gauge needle. In another
embodiment, the needle gauge is from 18 gauge to 31 gauge. In a
further embodiment, the needle gauge is from 25 gauge to 30 gauge.
Depending upon the thickness or viscosity of the antimicrobial
agent compositions or formulations, the gauge level of the syringe
or hypodermic needle may be varied accordingly. In another
embodiment, the internal diameter of the needle can be increased by
reducing the wall thickness of the needle (commonly referred as
thin wall or extra thin wall needles) to reduce the possibility of
needle clogging while maintaining an adequate needle gauge.
[0275] In another embodiment, the needle is a hypodermic needle
used for instant delivery of the gel formulation. The hypodermic
needle may be a single use needle or a disposable needle. In some
embodiments, a syringe may be used for delivery of the
pharmaceutically acceptable gel-based antimicrobial
agent-containing compositions as disclosed herein wherein the
syringe has a press-fit (Luer) or twist-on (Luer-lock) fitting. In
one embodiment, the syringe is a hypodermic syringe. In another
embodiment, the syringe is made of plastic or glass. In yet another
embodiment, the hypodermic syringe is a single use syringe. In a
further embodiment, the glass syringe is capable of being
sterilized. In yet a further embodiment, the sterilization occurs
through an autoclave. In another embodiment, the syringe comprises
a cylindrical syringe body wherein the gel formulation is stored
before use. In other embodiments, the syringe comprises a
cylindrical syringe body wherein the antimicrobial agent
pharmaceutically acceptable gel-based compositions as disclosed
herein is stored before use which conveniently allows for mixing
with a suitable pharmaceutically acceptable buffer. In other
embodiments, the syringe may contain other excipients, stabilizers,
suspending agents, diluents or a combination thereof to stabilize
or otherwise stably store the antimicrobial agent or other
pharmaceutical compounds contained therein.
[0276] In some embodiments, the syringe comprises a cylindrical
syringe body wherein the body is compartmentalized in that each
compartment is able to store at least one component of the
auris-acceptable antimicrobial agent gel formulation. In a further
embodiment, the syringe having a compartmentalized body allows for
mixing of the components prior to injection into the auris media or
auris interna. In other embodiments, the delivery system comprises
multiple syringes, each syringe of the multiple syringes contains
at least one component of the gel formulation such that each
component is pre-mixed prior to injection or is mixed subsequent to
injection. In a further embodiment, the syringes disclosed herein
comprise at least one reservoir wherein the at least one reservoir
comprises an antimicrobial agent, or a pharmaceutically acceptable
buffer, or a viscosity enhancing agent, such as a gelling agent or
a combination thereof. Commercially available injection devices are
optionally employed in their simplest form as ready-to-use plastic
syringes with a syringe barrel, needle assembly with a needle,
plunger with a plunger rod, and holding flange, to perform an
intratympanic injection.
[0277] In some embodiments, the delivery device is an apparatus
designed for administration of therapeutic agents to the middle
and/or inner ear. By way of example only: GYRUS Medical Gmbh offers
micro-otoscopes for visualization of and drug delivery to the round
window niche; Arenberg has described a medical treatment device to
deliver fluids to inner ear structures in U.S. Pat. Nos. 5,421,818;
5,474,529; and 5,476,446, each of which is incorporated by
reference herein for such disclosure. U.S. patent application Ser.
No. 08/874,208, which is incorporated herein by reference for such
disclosure, describes a surgical method for implanting a fluid
transfer conduit to deliver therapeutic agents to the inner ear.
U.S. Patent Application Publication 2007/0167918, which is
incorporated herein by reference for such disclosure, further
describes a combined otic aspirator and medication dispenser for
intratympanic fluid sampling and medicament application.
[0278] In some embodiments, the auris-acceptable composition
described herein is administered through a single intratypanic
injection, wherein the composition contains from about 2 mg to
about 14 mg, from about 2 mg to about 12 mg, from about 4 mg to
about 12 mg, from about 4 mg to about 10 mg, from about 4 mg to
about 8 mg, from about 5 mg to about 8 mg, from about 5 mg to about
7 mg, or from about 5.5 mg to about 6.5 mg, of the antimicrobial
agent, such as ciprofloxacin. In some embodiments, those dosages
are in the form of a composition comprising 15-17% by weight of
poloxamer 407 and 5.4-6.6% by weight of micronized ciprofloxacin.
In some embodiments, those dosages are in the form of a composition
comprising 15-17% by weight of poloxamer 407 and 1.8-2.2% by weight
of micronized ciprofloxacin. In some embodiment, 200 .mu.L of a
composition containing 4 mg of ciprofloxacin is administered to an
ear through intratympanic injection. In some embodiment, 200 .mu.L
of a composition containing 12 mg of ciprofloxacin is administered
to an ear through intratympanic injection. In some embodiment, 100
.mu.L of a composition containing 6 mg of ciprofloxacin is
administered to an ear through intratympanic injection
[0279] The auris-acceptable compositions or formulations containing
the antimicrobial agent compound(s) described herein are
administered for prophylactic and/or therapeutic treatments. In
therapeutic applications, the antimicrobial agent compositions are
administered to a patient already suffering from an autoimmune
disease, condition or disorder, in an amount sufficient to cure or
at least partially arrest the symptoms of the disease, disorder or
condition. Amounts effective for this use will depend on the
severity and course of the disease, disorder or condition, previous
therapy, the patient's health status and response to the drugs, and
the judgment of the treating physician.
[0280] Frequency of Administration
[0281] In some embodiments, a composition disclosed herein is
administered to an individual in need thereof once. In some
embodiments, a composition disclosed herein is administered to a
pediatric patient in a single injection to the patient's infected
ear. In some embodiments, a composition disclosed herein is
administered to an individual in need thereof more than once.
[0282] The number of times a composition is administered to an
individual in need thereof depends on the discretion of a medical
professional, the disorder, the severity of the disorder, and the
individual's response to the formulation. In some embodiments, a
composition disclosed herein is administered once to an individual
in need thereof with a mild acute condition. In some embodiments, a
composition disclosed herein is administered more than once to an
individual in need thereof with a moderate or severe acute
condition. In the case wherein the patient's condition does not
improve, upon the doctor's discretion the administration of an
antimicrobial may be administered chronically, that is, for an
extended period of time, including throughout the duration of the
patient's life in order to ameliorate or otherwise control or limit
the symptoms of the patient's disease or condition.
[0283] In the case wherein the patient's condition does not
improve, upon the doctor's discretion the administration of the
antimicrobial agent compounds may be administered chronically, that
is, for an extended period of time, including throughout the
duration of the patient's life in order to ameliorate or otherwise
control or limit the symptoms of the patient's disease or
condition.
[0284] The amount of antimicrobial agent that will correspond to
such an amount will vary depending upon factors such as the
particular compound, disease condition and its severity, according
to the particular circumstances surrounding the case, including,
e.g., the specific antimicrobial agent being administered, the
route of administration, the autoimmune condition being treated,
the target area being treated, and the subject or host being
treated.
Pharmacokinetics of Controlled Release Formulations
[0285] In some embodiments, the formulation provides an
extended/sustained release formulation of at least one
antimicrobial agent. In certain embodiments, diffusion of at least
one antimicrobial agent from the formulation occurs for a time
period exceeding 5 days, or 6 days, or 7 days, or 10 days, or 12
days, or 14 days, or 18 days, or 21 days, or 25 days, or 30 days,
or 45 days, or 2 months or 3 months or 4 months or 5 months or 6
months or 9 months or 1 year. In other embodiments, a
therapeutically effective amount of at least one antimicrobial
agent is released from the formulation for a time period exceeding
5 days, or 6 days, or 7 days, or 10 days, or 12 days, or 14 days,
or 18 days, or 21 days, or 25 days, or 30 days, or 45 days, or 2
months or 3 months or 4 months or 5 months or 6 months or 9 months
or 1 year.
[0286] In a specific embodiment the formulation provides a
therapeutically effective amount of at least one antimicrobial
agent at the site of disease with essentially no systemic exposure.
In an additional embodiment the formulation provides a
therapeutically effective amount of at least one antimicrobial
agent at the site of disease with essentially no detectable
systemic exposure. In other embodiments, the formulation provides a
therapeutically effective amount of at least one antimicrobial
agent at the site of disease with little or no detectable systemic
exposure.
[0287] The combination of immediate release, delayed release and/or
extended release antimicrobial agent compositions or formulations
may be combined with other pharmaceutical agents, as well as the
excipients, diluents, stabilizers, tonicity agents and other
components disclosed herein. As such, depending upon the
antimicrobial agent used, the thickness or viscosity desired, or
the mode of delivery chosen, alternative aspects of the embodiments
disclosed herein are combined with the immediate release, delayed
release and/or extended release embodiments accordingly.
Kits/Articles of Manufacture
[0288] The disclosure also provides kits for preventing, treating
or ameliorating the symptoms of a disease or disorder in a mammal.
Such kits generally will comprise one or more of the antimicrobial
agent controlled-release compositions or devices disclosed herein,
and instructions for using the kit. The disclosure also
contemplates the use of one or more of the antimicrobial agent
controlled-release compositions, in the manufacture of medicaments
for treating, abating, reducing, or ameliorating the symptoms of a
disease, dysfunction, or disorder in a mammal, such as a human that
has, is suspected of having, or at risk for developing an inner ear
disorder.
[0289] In some embodiments, kits include a carrier, package, or
container that is compartmentalized to receive one or more
containers such as vials, tubes, and the like, each of the
container(s) including one of the separate elements to be used in a
method described herein. Suitable containers include, for example,
bottles, vials, syringes, and test tubes. In other embodiments, the
containers are formed from a variety of materials such as glass or
plastic.
[0290] The articles of manufacture provided herein contain
packaging materials. Packaging materials for use in packaging
pharmaceutical products are also presented herein. See, e.g., U.S.
Pat. Nos. 5,323,907, 5,052,558 and 5,033,252. Examples of
pharmaceutical packaging materials include, but are not limited to,
blister packs, bottles, tubes, inhalers, pumps, bags, vials,
containers, syringes, bottles, and any packaging material suitable
for a selected formulation and intended mode of administration and
treatment. A wide array of antimicrobial agent formulations
compositions provided herein are contemplated as are a variety of
treatments for any disease, disorder, or condition that would
benefit by controlled release administration of an antimicrobial
agent to the inner ear.
[0291] In some embodiments, a kit includes one or more additional
containers, each with one or more of various materials (such as
reagents, optionally in concentrated form, and/or devices)
desirable from a commercial and user standpoint for use of a
formulation described herein. Non-limiting examples of such
materials include, but not limited to, buffers, diluents, filters,
needles, syringes; carrier, package, container, vial and/or tube
labels listing contents and/or instructions for use and package
inserts with instructions for use. A set of instructions is
optionally included. In a further embodiment, a label is on or
associated with the container. In yet a further embodiment, a label
is on a container when letters, numbers or other characters forming
the label are attached, molded or etched into the container itself;
a label is associated with a container when it is present within a
receptacle or carrier that also holds the container, e.g., as a
package insert. In other embodiments a label is used to indicate
that the contents are to be used for a specific therapeutic
application. In yet another embodiment, a label also indicates
directions for use of the contents, such as in the methods
described herein.
[0292] In certain embodiments, the pharmaceutical compositions are
presented in a pack or dispenser device which contains one or more
unit dosage forms containing a compound provided herein. In another
embodiment, the pack for example contains metal or plastic foil,
such as a blister pack. In a further embodiment, the pack or
dispenser device is accompanied by instructions for administration.
In yet a further embodiment, the pack or dispenser is also
accompanied with a notice associated with the container in form
prescribed by a governmental agency regulating the manufacture,
use, or sale of pharmaceuticals, which notice is reflective of
approval by the agency of the form of the drug for human or
veterinary administration. In another embodiment, such notice, for
example, is the labeling approved by the U.S. Food and Drug
Administration for prescription drugs, or the approved product
insert. In yet another embodiment, compositions containing a
compound provided herein formulated in a compatible pharmaceutical
carrier are also prepared, placed in an appropriate container, and
labeled for treatment of an indicated condition.
EXAMPLES
Example 1
Preparation of a Thermoreversible Gel Ciprofloxacin Composition
Comprising Micronized Ciprofloxacin Powder (Composition A)
TABLE-US-00001 [0293] Ingredient Quantity (mg/mL of formulation)
ciprofloxacin 60.0 Poloxamer 407 157 Sodium Chloride 4.5
Tromethamine 5.8 Hydrochloric acid (37.5% w/w) QS for pH adjustment
(pH 7.0-8.0) Water for injection QS to 1040
[0294] Ciprofloxacin was purchased from Neuland Laboratories.
CIPRODEX.RTM. Otic (0.3% ciprofloxacin and 0.1% dexamethasone
suspension) and CETRAXAL.RTM. Otic (0.2% ciprofloxacin solution)
were obtained from MWI Veterinary. Acepromazine, ketamine and
xylazine were also from MWI Veterinary. Poloxamer 407 was purchased
from BASF. Ciprofloxacin was heat sterilized and combined with a
heat or filtration sterilized diluent comprising the Poloxamer 407
and other ingredients to form the finalized formulation. Other
Composition As (with different ciprofloxacin concentrations) were
prepared similarly.
Example 2
In Vivo Testing of Intratympanic Injection of Composition a in
Guinea Pigs
[0295] Male and female guinea pigs (Hartley HA:Crl, Charles River
Laboratories, n=4-5 per sex, per group) weighing 200-300 g, of
approximately 6-8 weeks of age were used for the pharmacokinetic
and toxicology experiments. Prior to any procedure, animals were
anesthetized either using a combination of xylazine (10 mg/kg),
ketamine (40 mg/kg), and acepromazine (0.75 mg/kg) for up to an
hour via the intramuscular route, or using isoflurane to effect via
inhalation. During the procedure and until recovery, animals were
placed on a temperature controlled (40.degree. C.) heating pad.
After consciousness was regained, animals were returned to the
vivarium.
[0296] Intratympanic injection of Composition A anterior to the
round window membrane (IT-ANT)--
[0297] All animals were injected bilaterally. Each animal was
positioned so that the head was tilted at an angle to favor
injection away from the round window niche to the middle ear
cavity. Briefly, under visualization with an operating microscope,
50 .mu.l of Composition A was injected using a 22G needle through
the tympanic membrane into the inferior anterior quadrant.
[0298] Tympanostomy Tube Placement--While the animal was
anesthetized, a 27G needle was used to create a pinhole
(myringotomy) in the lower anterior portion of the tympanic
membrane. A ventilation tube (FEP, internal diameter 0.56 mm, wall
thickness 0.15 mm, length 2.5-3.0 mm) was inlayed through the
hole.
[0299] CIPRODEX.RTM. and CETRAXAL.RTM. Treatment Course--
[0300] Awake guinea pigs were manually restrained for a short
period of time while the otic drops (10 .mu.l auris utraque (AU)
for CIPRODEX.RTM., 15 .mu.l AU for CETRAXAL.RTM.) were administered
into the external ear canal in proximity to the tympanostomy tube.
Tragal pumping was then performed several times to ensure
penetration of the drug into the middle ear cavity. Drugs were
administered twice daily (9 AM and 5 PM) for 7 consecutive
days.
[0301] Free Ciprofloxacin (Middle Ear Lavage) and Tissue-Bound
Ciprofloxacin (Epithelium) Collections--
[0302] For the middle ear lavage, the lower anterior and posterior
portion of the tympanic membrane was removed, with an attempt to
prevent disturbing the upper anterior and upper posterior portions
of the tympanum. Using a 27 gauge blunt needle, the middle ear
cavity was lavaged twice in the following manner: 100 .mu.l of
sterile water was placed into the middle ear and then extracted
using the same syringe. Both washes (totaling about 200 .mu.l) were
collected into a single tube for subsequent analysis. The lavage
volume was chosen as it represents the average volume capacity of
the guinea pig middle ear. Free drug concentration data were
normalized to a hypothetical middle ear volume of 250 .mu.l. For
the middle ear epithelium collection, the bulla from each guinea
pig was removed and extensively flushed with sterile water. The
bulla was then slightly surgically exposed, the middle epithelium
layer dissected from the bulla and weighed and stored for analysis.
Tissue-bound drug concentration data were expressed as .mu.g
ciprofloxacin per gram of tissue weight.
[0303] Ossicle Mobility Assessment--
[0304] At necropsy, using a dissecting microscope, the middle ear
was opened, and the ossicles revealed by removing regions of the
temporal bone. A forceps was used to gently apply pressure to the
ossicles to determine mobility.
Example 2A
Middle Ear Free Ciprofloxacin Levels
[0305] Female guinea pigs received a single IT-ANT injection of
various doses of Composition A: 0.06% (closed inverted triangles),
0.2% (stars), 0.6% (closed circles), 2% (closed triangles), 6%
(closed squares) and 12% Composition A (closed diamonds). A
twice-daily one-week course of CIPRODEX.RTM. (B) or CETRAXAL.RTM.
(C) administered through a tympanostomy tube was given. Free drug
levels of ciprofloxacin, obtained by lavaging the middle ear, were
determined at the indicated times. (B and C) Predicted profile of
ciprofloxacin by combining peak and trough levels.
[0306] Determination of free ciprofloxacin concentrations was
performed using high pressure liquid chromatography (HPLC). The
limit of detection of the method was 100 ng/ml. Middle ear lavage
samples were centrifuged 10 min at 15000 rpm and the supernatant
collected. Extraction of ciprofloxacin was performed by a 1:1
dilution using acetonitrile:TEA phosphate buffer (40:60 v/v, pH
3.0) followed by centrifugation. Middle ear epithelium samples were
extracted using acetonitrile:TEA phosphate buffer (20:80 v/v, pH
3.0) and submitted to sonication and vortexing. The samples were
analyzed by reverse phase HPLC (1200 series, Agilent) equipped with
UV detection (278 nm) using a phenyl-hexyl Luna column (3 .mu.m;
250.times.4.6 mm). A flow rate of 0.7 ml/min was applied with the
following gradient method: isocratic (20:80
acetonitrile:TEA-phosphate buffer) the first 8 minutes followed by
a gradient from 8-10 min up to a ratio of 50:50
acetonitrile:TEA-phosphate buffer, isocratic up to 24 min then a
gradient from min 24-26 to the original conditions. Quantification
was performed against an external standard. Sample ciprofloxacin
concentrations were interpolated based upon from the calibration
curves.
[0307] Administration of Composition A:
[0308] The levels of free ciprofloxacin in the middle ear were
determined following a single IT-ANT injection of various doses of
Composition A, ranging from 0.06% to 12% (FIG. 4A). Depending on
the dose given, ciprofloxacin levels peaked at Day 1 between
45.4.+-.22.1 and 99.9.+-.5.6 .mu.g/ml. Disappearance from the
middle ear compartment was strongly dependent upon the Composition
A dose, with drug levels dropping below 2 .mu.g/ml in as little as
3 days with 0.06% Composition A, approximately 7 days with 0.2%
Composition A, but remaining on or above these levels for 28 days
with higher Composition A doses. Overall, a single intratympanic
injection of Composition A provided high C.sub.max and steady dose,
with progressive decline over time.
[0309] Administration of CIPRODEX.RTM.:
[0310] Following a single application of CIPRODEX.RTM. drops,
ciprofloxacin peak levels reached 22.6.+-.5.9 .mu.g/ml within 3
hours, then declined sharply to 7.8.+-.2.2 .mu.g/ml by 6 hours
(FIG. 4B). During the twice daily for 7 days regimen, the trough
levels were determined 16 hours post the second daily
administration from the preceding day. Ciprofloxacin levels varied
from 2.6.+-.0.4 .mu.g/ml at Day 1, immediately before the 3.sup.rd
dose, to 8.6.+-.0.4 .mu.g/ml at treatment completion. By compiling
the data from peak and trough levels, the predicted middle ear free
ciprofloxacin profile following CIPRODEX.RTM. treatment was
derived. The pulsatile nature of CIPRODEX.RTM. administration was
quite evident, with free ciprofloxacin levels in the middle ear
cycling rapidly between each otic drop application. The amplitude
between the lowest and highest drug levels within each cycle varied
by almost 10-fold, from 2.6.+-.0.4 to 22.6.+-.5.9 .mu.g/ml. There
was a noted drug accumulation during the treatment course reaching
8.6.+-.0.4 .mu.g/ml at Day 7. Following the completion of the twice
daily for 7 days dosing regimen, ciprofloxacin levels slowly
decreased, reaching 1.3.+-.0.9 .mu.g/ml by Day 28.
[0311] Administration of CETRAXAL.RTM.:
[0312] (FIG. 4C). Ciprofloxacin free middle ear levels reached
24.1.+-.12.2 .mu.g/ml at 1 hour, decreasing to 14.0.+-.2.4 .mu.g/ml
by 6 hours. Drug accumulation during the twice daily for 7 days
treatment was pronounced, increasing from 5.3.+-.0.8 .mu.g/ml at
Day 1 to 18.6.+-.4.1 .mu.g/ml at Day 7. Thereafter, elimination was
slow with levels declining to 1.8.+-.0.8 .mu.g/ml by Day 28.
[0313] A compilation of the middle ear ciprofloxacin
pharmacokinetic parameters is presented in FIG. 3. The
administration of Composition A yielded significantly higher
C.sub.max values, ranging from 45.4 to 99.9 .mu.g/ml, than either
CIPRODEX.RTM. or CETRAXAL.RTM., 22.6 .mu.g/ml and 24.1 .mu.g/ml,
respectively. Consequently, the degree of exposure (as measured by
AUC) following Composition A administration was comparable to that
of CIPRODEX.RTM. and CETRAXAL.RTM. at low Composition A doses (0.06
to 0.6%), but significantly larger at higher Composition A doses,
being 6- to 10-fold higher at 12% Composition A. Measures of
predicted antimicrobial clinical efficacy were determined and based
upon a MIC of 2 .mu.g/ml, which defines the breakpoint for bacteria
of intermediate susceptibility to ciprofloxacin. Three parameters
were considered: time of ciprofloxacin above MIC (T>MIC),
C.sub.max/MIC and AUC.sub.0-24/MIC ratios. For both CIPRODEX.RTM.
and CETRAXAL.RTM., T>MIC is of 25 days, specifically 601 and 611
hours, respectively. The different Composition A doses bracket
these values, with a T>MIC of 2.6 days (63 h) at 0.06%
Composition A to 30.0 days (721 h) at 12% Composition A. Both
CIPRODEX.RTM. and CETRAXAL.RTM. exhibit good predicted clinical
efficacy values, typically 1-2 fold above the proposed limits.
Composition A values are excellent with C.sub.max/MIC ratios 2-5
fold and AUC.sub.0-24/MIC 5-12 fold above the recommended values,
respectively.
Example 2B
Middle Ear Epithelium (Tissue-Bound) Ciprofloxacin
[0314] Administration of Composition A:
[0315] Female guinea pigs received a single IT-ANT injection of
various doses of Composition A: 0.6% (closed circles), 2% (closed
triangles), 6% (closed squares) or 12% (closed diamonds). A single
IT-ANT injection of Composition A (0.6% to 12%) resulted in
tissue-bound drug levels reaching 37.0.+-.10.2 to 586.+-.309
.mu.g/ml at Day 1, depending on the dose (FIG. 5A). These values
were 1-6 fold higher than the free ciprofloxacin concentrations
noted in the middle ear. Ciprofloxacin elimination from the middle
ear epithelium was limited, with concentrations remaining between
7.0.+-.2.1 .mu.g/ml and 103.8.+-.72.4 .mu.g/ml at Day 14, at the
0.6% and 12% Composition A doses, respectively.
[0316] Administration of CIPRODEX.RTM. or CETRAXAL.RTM.:
[0317] A twice-daily one-week course of CIPRODEX.RTM. or
CETRAXAL.RTM. was administered to female guinea pigs through a
tympanostomy tube. Tissue-bound levels of ciprofloxacin, obtained
by harvesting the middle ear epithelium, were determined at the
indicated times. (FIGS. 5B and 5C) Following administration of
CIPRODEX.RTM., tissue-bound ciprofloxacin peaked at 10.5.+-.3.5
.mu.g/ml within 1 hour decreasing to 1.0.+-.0.3 .mu.g/ml within 6
hours (FIG. 5B). Drug accumulation was marked during the treatment
course reaching 34.4.+-.16.3 .mu.g/ml at Day 7. Over the next 7
days, ciprofloxacin levels decreased sharply to 8.0.+-.2.2 .mu.g/ml
by Day 14. Following administration of CETRAXAL.RTM. (FIG. 5C),
middle ear epithelium ciprofloxacin levels reached a maximum of
5.1.+-.1.8 .mu.g/ml at 1 hour decreasing to 0.5.+-.0.3 .mu.g/ml by
6 hours. Over the twice daily for 7 days treatment course,
tissue-bound ciprofloxacin accumulated to 3.7.+-.0.7 .mu.g/ml at
Day 7 from 1.5.+-.1.1 .mu.g/ml at Day 1, but decreased rapidly to
0.1.+-.0.1 .mu.g/ml by Day 14.
Example 2C
Inner Ear Ciprofloxacin Levels
[0318] Perilymph Collection--
[0319] The skin behind the ear of anesthetized guinea pigs was
shaved and disinfected with povidone-iodine. An incision was then
made behind the ear, and muscles were carefully retracted from over
the bulla. A hole was drilled though the bulla using a dental burr
so that the middle ear was exposed and accessible. The cochlea and
the round window membrane were visualized under a stereo surgical
microscope. Mucosal tissues of the cochlea were removed and the
area washed carefully to remove any potential drug contaminants. A
unique microhole was hand drilled through the bony shell of the
cochlea (otic capsule) adjacent to the round window. Perilymph (5
.mu.l) was then collected using a microcapillary inserted into the
cochlear scala tympani.
[0320] Perilymphatic Ciprofloxacin--
[0321] Determination of ciprofloxacin concentrations was performed
using HPLC combined with mass spectrometry detection (MS/MS). The
limit of detection of the method was 1 ng/ml. Samples were
extracted by protein precipitation using acetonitrile and the
organic supernatant was diluted in aqueous solution (1:2 v/v) prior
to analysis. The samples were analyzed by reversed phase HPLC (1200
series, Agilent) using an ACE C18 column (3 .mu.m; 50.times.2.1 mm)
at room temperature. The compound was ionized by electrospray and
detected using MS/MS in positive mode (Tandem quadrupole mass
spectrometer, API4000, Applied Biosystems). Peak areas of
ciprofloxacin were determined using Analyst 1.5 software (Applied
Biosystems). The calibration curves were obtained by fitting the
peak area ratios of analyte/internal standard and the nominal
standard concentrations to a suitable equation using Analyst.
Sample ciprofloxacin concentrations were then interpolated using
the equations derived from the calibration curves.
[0322] Administration of Composition A:
[0323] Guinea pigs received a single IT-ANT injection of various
doses of Composition A: 0.6% (closed circles), 2% (closed
triangles), 6% (closed squares) or 12% (closed diamonds). One day
post administration of Composition A (FIG. 6A), perilymph
concentrations of ciprofloxacin ranged from 3.1.+-.1.8 .mu.g/ml at
0.6% Composition A to a maximum of 19.0.+-.9.2 .mu.g/ml at 12%
Composition A. These values were 5 to 25-fold lower than the levels
observed in the middle ear, depending on the dose. Elimination from
this compartment was relatively rapid, with ciprofloxacin
concentrations dropping below 2 .mu.g/ml within 1-2 weeks.
[0324] Administration of CIPRODEX.RTM. or CETRAXAL.RTM.:
[0325] A twice-daily one-week course of CIPRODEX.RTM. (B) or
CETRAXAL.RTM. (C) administered through a tympanostomy tube was
given. Perilymph levels of ciprofloxacin were determined at the
indicated times. (FIGS. 6B and 6C) Following administration of
CIPRODEX.RTM. (FIG. 6B), levels of ciprofloxacin in the perilymph
cycled rapidly and extensively between each dose from 7.0.+-.4.2
.mu.g/ml to 0.9.+-.0.3 .mu.g/ml. No drug accumulation was evident
in the inner ear compartment during the treatment course. By Day
14, ciprofloxacin levels were below 0.1.+-.0.1 .mu.g/ml. When
CETRAXAL.RTM. was given (FIG. 6C), perilymph ciprofloxacin
concentrations fluctuated from 0.3.+-.0.1 .mu.g/ml to 7.1.+-.4.6
.mu.g/ml. At Day 7, upon completion of treatment, drug levels were
of 0.7.+-.0.3 .mu.g/ml, declining to 0.2.+-.0.2 .mu.g/ml by Day
14.
Example 3
Intratympanic Injection of Composition A in Chinchillas Otitis
Media Model
[0326] Otitis media was induced in chinchillas by middle ear
inoculation of S. pneumoniae. Three days later, when otitis media
was well established, the middle ear effusion was drained, a
tympanostomy tube placed and the therapeutic agent applied.
[0327] Male chinchillas (chinchilla laniger, Moulton Chinchilla
Ranch, n=6-13 per group) weighing 400-700 g, 4 months to 4 years of
age were used for the otitis media experiments. Prior to any
procedure, animals were anesthetized for a period of up to an hour
using a cocktail of xylazine (2 mg/kg), ketamine (40 mg/kg), and
acepromazine (0.5 mg/kg) administered intramuscularly. During the
procedure and until recovery, animals were placed on a temperature
controlled (40.degree. C.) heating pad. After consciousness was
regained, animals were returned to the vivarium.
[0328] Bacterial Inoculum--
[0329] The inoculum was always generated from a freshly grown
isolated colony from the original bacterial stock (Streptococcus
pneumoniae serotype 6C variant 10AR004), to minimize genetic drift.
The clinical isolate strain was obtained from a patient with
documented otitis media, and generously provided by Dr. Stephen
Pelton. A starter culture of 10 ml Brain Heart Infusion (BHI) media
was inoculated with one isolated colony and grown for 10 h at
31.degree. C. to prevent autolyzing activity. One ml of the starter
culture was used to seed a 100 ml BHI flask and grown at 37.degree.
C. until mid-log phase. The mid-log phase was previously determined
to be optimal at an optical density of 0.3 arbitrary units when
determined at 600 nm. Typically the mid-log phase was reached
within 3-4 h. The bacterial culture was centrifuged (5000 rpm, 15
min) and the pellet resuspended in 10 ml BHI. Subsequently, serial
dilutions were made to obtain inoculum at 2000 CFU/ml. Calculations
were based on previously established growth titration curves. The
inoculum was used immediately to inoculate chinchilla ears.
Aliquots of serial dilutions were immediately plated onto chocolate
agar plates (1.0% bovine hemoglobin) in duplicates, and incubated
overnight at 37.degree. C. in 5% CO.sub.2 to confirm the titer of
the inoculum.
[0330] Induction of Otitis Media--
[0331] Anesthetized chinchillas received a bilateral middle ear
injection of the bacterial inoculate (100 .mu.l of a solution
containing 200 CFUs of exponentially-growing S. pneumoniae). The
inoculum was injected directly into the middle ear via the
intratympanic route using a 27G or 30G needle. Otitis media was
evident in the large majority of animals by Day 3 post inoculation,
as documented by the high bacterial titer and presence of effusion
in the middle ear.
[0332] Intratympanic Injection of Composition a Anterior to the
Round Window Membrane (IT-ANT)--
[0333] All animals were treated bilaterally. Each animal was
positioned so that the head was tilted at an angle to favor
visualization of the tympanic membrane. A 27G or 30G needle was
used to drain the middle ear effusion by aspiration through the
tympanic membrane. The procedure was conducted under visualization
with an operating microscope. Immediately after, 50 .mu.l of
Composition A was injected intratympanically using a 22G needle
through the tympanic membrane into the posterior superior quadrant,
through the same pinhole used for drainage. Then, a ventilation
tube (FEP, internal diameter 0.81 mm, wall thickness 0.15 mm,
length 3.5-4.0 mm) was placed opposite of the site of intratympanic
injection to limit the risk of the hydrogel formulation interfering
with tube patency.
[0334] CIPRODEX.RTM. and CETRAXAL.RTM. Treatment Course--
[0335] All animals were treated bilaterally. Each animal was
positioned so that the head was tilted at an angle to favor
visualization of the tympanic membrane. At time of treatment
initiation, the middle ear was drained of any effusion and
immediately thereafter a tympanostomy tube was placed as described
above. The otic drops (10 .mu.l AU for CIPRODEX.theta., 15 .mu.l AU
for CETRAXAL.RTM.) were administered into the external ear canal in
proximity to the tympanostomy tube and the tragus pumped several
times to ensure penetration of the drug into the middle ear cavity.
Drugs were administered twice daily (9 AM and 5 PM) for 3
consecutive days. The initial dosing occurred while the chinchillas
were anesthetized. For the subsequent applications, chinchillas
were manually restrained for a short period of time.
[0336] Determination of Middle Ear Effusion Volumes, Bacterial
Titer and Ciprofloxacin Levels--
[0337] Middle ear effusion volumes were collected at Day 6 (3 days
post treatment initiation and 6 days post bacterial inoculation),
quantified and split in two. For the determination of the bacterial
titer, the middle ear effusion volumes were adjusted to an
arbitrary volume of 1 ml from which serial dilutions of 10-fold
increments were conducted up to the 10.sup.8 dilution. Aliquots of
100 .mu.l of each serial dilution were plated onto chocolate agar
plates (1.0% bovine hemoglobin) in duplicates, and incubated
overnight at 37.degree. C. in 5% CO.sub.2. Bacterial titer was
determined by counting the number of colonies present, corrected
for the different dilution factors and presented as CFU/ml. Only S.
pneumoniae colonies were counted, reflecting the initial otitis
media with effusion infection. For the determination of
ciprofloxacin concentrations, the middle ear effusion aliquots were
submitted to HPLC analysis.
Example 3A
Middle Ear Bacterial Load and Effusion Volume in Chinchillas with
Otitis Media
[0338] Administration of Composition A:
[0339] Chinchillas received a single IT-ANT injection of various
doses of Composition A as a single IT-ANT injection immediately
prior to tympanostomy tube placement. A summary of the treatment
regimens is presented in FIG. 2. The bacterial titer and effusion
volume in the middle ear were determined (FIG. 7).
[0340] Various doses of Composition A were evaluated, ranging from
0.06% to 6%. All doses were effective in reducing the middle ear
bacterial load by 6-8 log orders of magnitude, depending on the
dose. Values ranged from 1.1.times.10.sup.2 CFU/ml to
2.2.times.10.sup.4 CFU/ml. All doses, with the exception of 0.06%
Composition A, were also effective in reducing the middle ear
effusion to the levels seen with either CIPRODEX.RTM. and
CETRAXAL.RTM.. The middle ear effusion volume in the 0.06%
Composition A treatment group was 198.+-.66 .mu.l, not
significantly different than the control group. For the other doses
that were effective, the volumes ranged from 16.+-.9 .mu.l to
73.+-.35 .mu.l.
[0341] Administration of CIPRODEX.RTM. and CETRAXAL.RTM.:
[0342] CIPRODEX.RTM. and CETRAXAL.RTM. were administered twice
daily for 3 days to chinchillas following tympanostomy tube
placement. A summary of the treatment regimens is presented in FIG.
2. The bacterial titer and effusion volume in the middle ear were
determined. CIPRODEX.RTM. reduced the bacterial load in the middle
ear by more than 6 log orders of magnitude relative to untreated
subjects, to 3.2.times.10.sup.3 CFU/ml from 4.0.times.10.sup.10
CFU/ml, respectively (FIG. 7). A significant decrease in the extent
of the middle ear effusion was also noted, with volumes of 55.+-.23
.mu.l relative to the control 228.+-.53 .mu.l. Following treatment
with CETRAXAL.RTM., the bacterial titer was decreased by about 5
logs to 2.1.times.10.sup.5 CFU/ml and the middle ear effusion
volume to 70.+-.47 .mu.l.
Example 3B
Time to Clinical Cure in Chinchillas with Otitis Media
[0343] Administration of Composition A:
[0344] Chinchillas received a single IT-ANT injection of various
doses of Composition A as a single IT-ANT injection immediately
prior to tympanostomy tube placement. The bacterial titer was
determined at the indicated times (FIG. 8). The single IT-ANT
administration of Composition A yielded rapid clinical cure, with a
bacterial titer dropping to 9.2.times.10.sup.5 CFU/ml at 6 h from
1.8.times.10.sup.11 CFU/ml. Clinical cure was present within 18 h
of Composition A treatment, as evidenced by a bacterial load of
2.2.times.10.sup.3 CFU/ml.
[0345] Administration of CIPRODEX.RTM.:
[0346] Chinchillas received a twice daily for 3 days treatment
course of CIPRODEX.RTM. following tympanostomy tube placement. The
bacterial titer was determined at the indicated times (FIG. 8).
Following the first application of CIPRODEX.theta., the bacterial
titer dropped by about 4 logs within the first 6 h of treatment,
from 1.2.times.10.sup.10 CFU/ml to 1.0.times.10.sup.6 CFU/ml.
However, evidence of intermittent bacterial growth was evident in
between CIPRODEX.RTM. applications: at 24 h, the bacterial load was
of 2.2.times.10.sup.4 CFU/ml while at 30 h it had increased to
1.2.times.10.sup.6 CFU/ml. By 72 h, clinical cure was evident with
a bacterial titer of 8.7.times.10.sup.3 CFU/ml, i.e. a 6-Log
reduction compared to pre-treatment levels.
Example 3C
Middle Ear Ciprofloxacin Levels in Chinchillas with Otitis
Media
[0347] Three days post treatment initiation, middle ear samples
were collected and the concentrations of free ciprofloxacin in the
middle ear were determined (FIG. 9).
[0348] Administration of Composition A:
[0349] Chinchillas received a single IT-ANT injection of various
doses of Composition A as a single IT-ANT injection immediately
prior to tympanostomy tube placement. A summary of the treatment
regimens is presented in FIG. 2. Following the single IT-ANT
administration of Composition A, ciprofloxacin concentrations were
relatively low when 0.06% and 0.2% Composition A were given, at
0.1.+-.0.0 .mu.g/ml and 0.4.+-.0.2 .mu.g/ml, respectively. At
higher Composition A doses, concentrations of ciprofloxacin were
significant higher, from 16.4.+-.5.4 .mu.g/ml to 112.0.+-.27.4
.mu.g/ml. The concentrations observed were 2 to 13-fold higher than
the ones reached with administration of CIPRODEX.RTM. or
CETRAXAL.RTM..
[0350] Administration of CIPRODEX.RTM. and CETRAXAL.RTM.:
[0351] CIPRODEX.RTM. and CETRAXAL.RTM. were administered twice
daily for 3 days to chinchillas. A summary of the treatment
regimens is presented in FIG. 2. Following the twice daily for 3
days treatment course of CIPRODEX.RTM. or CETRAXAL.theta.,
ciprofloxacin levels were significant with values of 8.4.+-.2.1
.mu.g/ml and 13.2.+-.8.3 .mu.g/ml, respectively.
Example 4
Otic Tissue Assessments of Intratympanic Injection of Composition A
in Guinea Pigs
[0352] A one-month acute ototoxicity study was conducted in guinea
pigs to compare the toxicological potential of Composition A to
that of CIPRODEX.RTM. and CETRAXAL.RTM.. At termination, functional
and anatomic assessments of the middle and inner ear compartments
were conducted. Saline and the known ototoxicant gentamicin, both
administered as a single IT-ANT injection, were included as
negative and positive controls, respectively.
Example 4A
Auditory Brainstem Responses (ABR) Assessment
[0353] ABRs were recorded in an electrically and acoustically
shielded chamber. Needle electrodes were placed at the vertex
(active) and immediately below the pinna of the test ear
(reference) and contralateral ear (ground). TDT System III hardware
and SigGen/BioSig software (Tucker Davis Technologies) were used to
present the stimulus and record the ABR responses. Tones were
delivered through a Tucker-Davis EC1 driver (aluminum-shielded
enclosure made in house), with the speculum placed just inside the
tragus. Acoustic calibration was performed with TDT software
(SigCal) and thresholds are expressed as dB SPL. Stimulus
presentation (15 ms tone bursts, with 1 ms rise/fall times) was
presented 10 per second. Up to 1024 responses were averaged for
each stimulus level. Responses were collected for stimulus levels
in 10 dB steps at higher stimulus levels, with additional 5 dB
steps near threshold. Thresholds were interpolated between the
lowest stimulus level where a response was observed, and 5 dB
lower, where no response was observed.
[0354] The auditory function of male and female guinea pigs was
monitored using Auditory Brainstem Responses at baseline and
termination (FIG. 10). Animals received a single IT-ANT injection
of poloxamer 407 vehicle, 2% or 6% Composition A, or a twice daily
for 7 days treatment course of CETRAXAL.RTM.. Hearing threshold
shifts were reported at low (4 kHz), medium (10 kHz) and high (20
kHz) frequencies.
[0355] The variability of the baseline ABR thresholds was similar
between guinea pigs assigned to the different treatment groups at
each tested frequency. Mean ABR thresholds in the saline group
increased marginally from baseline upon study completion across
frequencies (.ltoreq.10 dB SPL). IT-ANT administration of the known
ototoxicant gentamicin (400 mg/ml) resulted in severe ABR threshold
shifts (.gtoreq.40-60 dB SPL) across frequencies. Following
administration of the vehicle P407, minimal elevations in ABR
threshold were observed across frequencies (.ltoreq.10 dB SPL),
comparable to that seen with saline. In the Composition A treatment
groups (2% and 6%), a dose-dependent mild ABR threshold shift was
evident at termination (10-20 dB SPL) across the frequencies
tested, with 2% Composition A exhibiting ABR shifts comparable to
saline. The twice daily for 7 days CETRAXAL.RTM. treatment course
generally resulted in mild to moderate hearing loss at termination
(20-30 dB SPL) across frequencies. Overall, Composition A treatment
was associated with minimal to mild ABR threshold shift across the
frequencies tested, and compared favorably to CETRAXAL.RTM.
treatment, which was associated with mild to moderate hearing
loss.
Example 4B
Middle Ear Histology
[0356] Male and female guinea pigs (n=5 per sex, per group)
received a single IT-ANT injection of poloxamer 407 vehicle, 2% or
6% Composition A, or a twice daily for 7 days treatment course of
CIPRODEX.RTM. or CETRAXAL.RTM.. Histological analysis of middle ear
paraffin sections was conducted at termination.
[0357] Middle Ear Histology--
[0358] Guinea pigs received vascular perfusion through the heart
with an isotonic saline solution followed by fixative containing 4%
paraformaldehyde (PFA) in phosphate buffer. Left and right temporal
bones were removed and trimmed. Left ear cochleae were designated
for inner ear assessment and the right ear cochleae for middle ear
histology. Cochleae of the left ear were fixed by intrascalar
perfusion of 4% PFA. The temporal bones were then placed in 4% PFA
for approximately 1 hour and transferred to a vial containing 0.5%
PFA in phosphate buffer. The right temporal bones were trimmed, and
then each was placed in a cassette containing 5% EDTA in phosphate
buffer. The cassettes were placed into a PELCO 3451 Microwave
System, running constantly for 3-5 days. Ears were then dehydrated
in EtOH and processed in JB-4 Glycol Methacrylate resin, placed
into molds containing the resin and polymerized at 4.degree. C. for
12 h. Blocks containing temporal bones were trimmed and 5 .mu.m
sections were cut with a Leica RM2165 Microtome and stained with
Paragon stain. Sections were examined under bright field optics.
Middle ear sections were assessed for tissue reaction and
inflammatory response. Mild tissue reaction was defined as small
increases in the thickness of the tissue associated with mucosal
linings with some possible vesiculation. Mild-moderate tissue
reaction was defined as small regions of new tissue growth or
inflammatory response. Moderate tissue reaction was defined as
larger tissue growth often associated with an inflammatory
response. Moderate to large tissue reaction was defined as several
regions with large amounts of new tissue growth and cells
associated with inflammatory response. Large response was defined
as a large tissue growth and inflammatory response associated with
much to all of the middle ear often with new bone growth.
[0359] Assessments focused on tissue reaction and inflammatory
response in the region of the tympanic membrane and the middle ear.
Histology of the middle ear revealed the presence of minimal
subacute inflammation in the vast majority of animals treated with
saline, poloxamer 407 vehicle, Composition A (2% and 6%),
CIPRODEX.RTM. and CETRAXAL.RTM. (FIG. 11). The known ototoxicant
gentamicin caused moderate chronic inflammation in all treated
ears, and associated moderate to severe fibroplasia, mild
hemorrhage and bone remodeling. The findings observed in all
treatment groups, with the exception of gentamicin, were considered
secondary to the intratympanic injection procedure and tympanostomy
tube placement.
Example 4C
Inner Ear Cytocochleogram
[0360] Male and female guinea pigs (n=5 per sex, per group)
received a single IT-ANT injection of poloxamer 407 vehicle, 2% or
6% Composition A, or a twice daily for 7 days treatment course of
CIPRODEX.RTM. or CETRAXAL.RTM..
[0361] Inner Ear Cytocochleogram--
[0362] The left ear cochleae were carefully removed from the
temporal bones and then further dissected, first removing the bony
otic capsule, followed by removal of lateral wall tissues,
including spiral ligament and stria vascularis. The tectorial
membrane was then removed and the cochleae placed in a solution of
rhodamine labeled phalloidin, diluted 1:100 in phosphate buffered
saline (PBS), for 30-120 min, in the dark, followed by two washes
in PBS. The cochlear sensory neural epithelium was then dissected
away from the modiolus, starting at the apex, to produce surface
preparations of the cochlear spiral. Each segment was mapped for
location and placed on a slide. A quantitative assessment of
presence or absence of hair cells was then carried out, beginning
at apex and proceeding to the base, to produce a cytocochleogram,
with presence or absence or hair cells mapped by position along the
cochlear spiral.
[0363] The integrity of the sensorineural epithelium was examined
in a quantitative assessment of inner and outer hair cells from
surface preparations of the cochlear spiral generating
cytocochleograms (FIG. 12). IT-ANT administration of saline was not
associated with hair cell loss in any of the treated animals, while
administration of the known ototoxicant gentamicin resulted in
profound to complete hair cell loss. IT-ANT administration of
poloxamer 407 vehicle was not associated with hair cell loss in any
of the treated animals, similarly to saline. OTO 201 at doses of 2%
and 6% did not produce otopathology, with no evidence of outer and
inner hair cell loss. In contrast, both CIPRODEX.RTM. and
CETRAXAL.RTM. group produced mild to moderate hair cell loss (outer
only), primarily confined to the apical half of the cochlea.
Example 4D
Tympanostomy Tube Patency
[0364] Tympanostomy tube patency was examined. The presence or
absence of clogging of the ventilation tube by the P407 hydrogel
was evaluated by visualization under a surgical microscope.
Following IT-ANT administration of poloxamer 407 vehicle to the
middle ear of guinea pigs immediately prior to ventilation tube
placement, there was no evidence of tube clogging at Day 1 and Day
3 post-treatment (FIG. 13). Thus, the presence of poloxamer 407
hydrogel in the middle ear does not affect the patency of
ventilation tubes inlayed through the tympanic membrane.
Example 5
Clinical Trial of Antimicrobial Agent Formulations in Combination
with Tympanostomy for Treatment of Pediatric Otitis Media with
Effusion
[0365] The purpose of this study is to determine if a composition
comprising Ciprofloxacin and poloxamer 407 administered in
combination with a tympanostomy is safe and effective in preventing
and/or treating middle ear infections in pediatric patients with
ear tubes.
[0366] Study Type:
[0367] Interventional
[0368] Study Design:
[0369] This is a randomized, double-blind, placebo- and
sham-controlled, multicenter, dose escalation Phase 1b study of
Composition A administered intra-operatively in pediatric subjects
with bilateral middle ear effusion who require tympanostomy tube
placement. Two dose levels of Composition A are evaluated relative
to placebo (vehicle only) and sham (no vehicle). Within each dose
cohort, subjects are randomized to either Composition A, placebo or
sham using a 2:1:1 allocation ratio; the cohorts will be stratified
by age: 1) 6 months to 2 years, or 2) greater than 2 years.
Cohort 1:
[0370] Diluted Composition A 4 mg; single 200 .mu.L intratympanic
injection in each ear [0371] Placebo (Vehicle) for Composition A;
single 200 .mu.L intratympanic injection in each ear [0372] Sham
Injection
Cohort 2:
[0372] [0373] Composition A 12 mg; single 200 .mu.L intratympanic
injection in each ear [0374] Placebo (Vehicle) for Composition A;
single 200 .mu.L intratympanic injection in each ear [0375] Sham
Injection
[0376] Dose and Mode of Administration: [0377] 4 mg Diluted
Composition A (4 mg ciprofloxacin in 16% poloxamer 407), single
bilateral 200 .mu.L intratympanic injections
[0378] The 4 mg Diluted Composition A final product suspension for
dosing is prepared on site at the clinic from two separate vials,
6% Composition A Drug Product and Composition A Diluent. An
appropriate volume of both 6% Composition A Drug Product and
Composition A Diluent is withdrawn and added to an empty vial and
mixed to achieve a visually homogeneous suspension of the target
drug concentration. [0379] 12 mg Composition A (12 mg ciprofloxacin
in 16% poloxamer 407), single bilateral 200 .mu.L intratympanic
injections.
[0380] The 12 mg Composition A is supplied from one vial (6%
Composition A Drug Product).
[0381] Placebo consists of the vehicle used to formulate
Composition A and is supplied from one vial (Composition A
Diluent). Subjects assigned to sham receive a sham injection with
an empty syringe.
[0382] Each dose of Composition A or placebo is administered as a
single, intratympanic injection into each ear. The recommended
injection procedure for intratympanic administration of Composition
A, placebo or sham is as follows:
1. Place myringotomy site where clinically indicated 2. Collect
culture specimen and remove remaining middle ear fluid 3. Using a
tuberculin syringe, direct 200 .mu.L of Diluted Composition A,
Composition A or placebo anterior and inferior to the myringotomy
site through the open tympanic membrane
[0383] a. For sham injections, the syringe is prepped to the 200
.mu.L graduation on the syringe; however, the syringe will not
contain any material
4. Place ventilation tube after administration of Composition A,
placebo or sham
[0384] Duration of Treatment:
[0385] Single bilateral 200 .mu.L intratympanic injection
[0386] Methodology:
[0387] Subjects have a clinical diagnosis of bilateral middle ear
effusion requiring tympanostomy tube (TT) placement. On the day of
surgery, prior to surgery, eligible subjects entering the first
cohort are examined to confirm bilateral middle ear effusion.
Subjects with bilateral middle ear effusion are randomized to
either 4 mg Diluted Composition A, placebo or sham. When at least
18 subjects in the 4 mg dose cohort have completed the Day 15
visit, a Data Review Group (DRG) reviews all safety data to date.
If no safety issues are identified by the DRG, enrollment of
eligible subjects with bilateral middle ear effusion into the
second dose cohort begins. Subjects in the second dose cohort with
bilateral middle ear effusion on the day of surgery, prior to
surgery, are randomized to either 12 mg Composition A, placebo or
sham. When both cohorts are enrolling simultaneously, subjects are
first randomized to one of the two cohorts and then to either
Composition A, placebo or sham. Subjects without bilateral effusion
on day of surgery are not randomized.
[0388] Within each dose cohort, 40 subjects are randomized to
Composition A, placebo or sham using a 2:1:1 allocation ratio.
Randomization to study drug within each cohort is stratified by
age: 1) 6 months to 2 years, or 2) greater than 2 years.
[0389] During surgery, a culture of the effusion from each ear is
obtained prior to Composition A, placebo or sham injection.
Composition A, placebo or sham is administered in both ears
following myringotomy. All syringes, including sham, are prepared
to maintain the blind. Following administration of Composition A,
placebo or sham and subsequent TT placement, caregivers and
subjects receive standard post-operative instructions.
[0390] Composition A, placebo or sham syringes are prepared by an
unblinded qualified health care professional at the investigative
site not otherwise associated with the trial. The pediatric
otolaryngologist becomes unblinded at the time of Composition A,
placebo or sham administration based on the appearance of the
treatment being administered. Caregivers, subjects, and study staff
are blinded to treatment.
[0391] During Days 1 through 29, caregivers report the presence of
otorrhea daily using an interactive voice response system (IVRS).
In addition, caregivers are instructed to bring the subject to the
study site for examination if otorrhea in one or both ears is
observed on or after 3 days post-surgery (Day 4). A blinded
investigator who was not involved in the administration of study
drug assesses the presence of otorrhea, and if present, a specimen
is collected for culture.
[0392] Subjects visit the study site on Days 4, 8, 15 and 29 for
safety assessments and otoscopic examination. The assessment of
otorrhea for the clinical activity endpoint occurs on Days 4, 8,
and 15 by the blinded investigator. Subjects with visible otorrhea
in the auditory canal on external examination by the blinded
investigator are considered "treatment failures" if otorrhea is
observed on or after 3 days post-surgery (Day 4) through Day 15.
Treatment failures are eligible for rescue medication and are
considered treatment failures for the remainder of the study.
Subjects designated as treatment failures are asked to remain
on-study and continue to be monitored for safety.
[0393] Inclusion Criteria:
Subjects meeting all of the following criteria may be eligible for
the study: 1. Subject is a male or female aged 6 months to 12
years, inclusive 2. Subject has a clinical diagnosis of bilateral
middle ear effusion requiring tympanostomy tube placement 3.
Subject's caregiver is willing to comply with the protocol and
attend all study visits 4. Subject's caregiver is able to use the
telephone and understand and respond to English or Spanish 5.
Subject's caregiver is able to provide written informed consent and
Health Insurance Portability and Accountability Act (HIPAA) of 1996
documents before the initiation of any study-related procedures 6.
Subject of appropriate age is able to provide assent for
participation in the study
[0394] Exclusion Criteria:
Subjects meeting any of the following criteria are not eligible for
participation: 1. Subject has a history of prior ear or mastoid
surgery, not including myringotomy or myringotomy with TT placement
2. Subject has been designated for any other surgical procedure
that would occur concurrently with TT placement, such as, but not
limited to adenoidectomy or tonsillectomy 3. Subject has a history
of sensorineural hearing loss 4. Subject has a history of chronic
or recurrent bacterial infections other than otitis media that
likely will require treatment with antibiotics during the course of
the study 5. Subject has tympanic membrane perforation 6. Subject
has a history of known immunodeficiency disease 7. Subject has an
abnormality of the tympanic membrane or middle ear that would
preclude precise placement of study drug or intratympanic injection
8. Use of topical nonsteroidal otic agents within 1 day of
randomization 9. Use of topical or otic corticosteroids within 3
days of randomization or systemic corticosteroids within 7 days of
randomization 10. Presence of any infection requiring systemic
antimicrobial or antifungal agents 11. Use of topical or systemic
antimicrobial or antifungal agents; amoxicillin, Augmentin.RTM.,
Omnicef.RTM., ceftriaxone, and cephalexin within 3 days of
randomization; doxycycline and fluoroquinolones within 7 days and
Zithromax.RTM. within 14 days of randomization 12. Concurrent use
of oral anti-inflammatory agents 13. Subject has a history of
allergy to ciprofloxacin or any of the components of Composition A
14. Subject has any other clinically significant illness or medical
condition that, in the opinion of either the investigator or
medical monitor, would prohibit the subject from participating in
the study 15. Subject has used an investigational drug or device in
the month prior to screening 16. Subject has been previously
exposed to Composition A 17. Subject is a menarcheal or
post-menarcheal female 18. Subject is not able to complete all
baseline assessments. For subjects 4 years or younger, the subject
must complete, at a minimum, DPOAE in both ears and VRA in one ear
at two frequencies, using both air and bone conduction in order to
be eligible for enrollment.
[0395] Outcome Measures for Evaluation:
Safety Endpoints:
[0396] Safety assessments include: [0397] Adverse events [0398]
Otoscopic examinations [0399] Tympanometry assessments [0400]
Audiometry assessments--Conventional audiometry assessments,
including air conduction and bone conduction, are performed on
subjects that are mature enough to participate, as determined by
the investigator, typically age 4 years and older. [0401] Visual
Reinforcement Audiometry (VRA), using air conduction and bone
conduction, and distortion product otoacoustic emission (DPOAE)
assessments are performed on all subjects not mature enough for
conventional audiometry, typically below the age of 4 years. [0402]
Vital sign measurements [0403] Physical examinations
Clinical Activity Endpoints:
[0404] Clinical activity assessments include: [0405] The proportion
of treatment failures defined as any subject receiving rescue
medications at any time post-surgery or having physician documented
otorrhea at any time on or after 3 days post-surgery in one or both
ears through each of the following time points: [0406] Day 4 [0407]
Day 8 [0408] Day 15 [0409] Time-to-otorrhea based on caregiver
diaries, defined as: [0410] The time-to-caregiver observed otorrhea
on or after 3 days post-surgery through Day 15 [0411] The
time-to-caregiver observed otorrhea beginning on the first calendar
day post-surgery through Day 15 [0412] Receipt of rescue medication
as defined above applies for this endpoint. [0413] Microbiological
eradication (absence, presumed or documented) of pretherapy
bacteria based on comparison to any bacteria in otorrhea present at
any visit, Day 4 through Day 15 inclusive. [0414] Day 29
Evaluations: Exploratory analyses also examine each of the clinical
activity endpoints noted above through Day 29.
[0415] Safety
[0416] Safety is assessed through Day 29. Safety endpoints are
summarized for each Composition A dose group as well as the placebo
and sham control groups for both the individual cohorts and pooled
across cohorts. Examination of any potential dose-response
relationship with respect to safety outcomes are also assessed. If
no significant adverse event (AE) is observed, a sample size of 20
subjects per dose cohort receiving Composition A (4 mg or 12 mg in
each ear, total dose of 8 mg or 24 mg) would be expected to
"rule-out" an AE with a subject incidence rate of approximately
0.14 or more with 95% confidence. Although this quantitative
information is helpful in assessing potential safety issues,
decisions with regard to dose escalation are based on expert
medical review of the emerging safety profile.
[0417] Clinical Activity
[0418] The primary clinical activity endpoint is the proportion of
treatment failures defined as any subject receiving rescue
medications at any time post-surgery or having physician documented
otorrhea at any time on or after 3 days post-surgery in one or both
ears. For this Phase 1b study, three separate time points are
examined: Days 4, 8 and 15. Subjects with physician documented
otorrhea in either ear 3 days post-surgery or receiving rescue
medications at any time post-surgery are defined as a treatment
failure from the earliest time point of either event through all
subsequent time points.
[0419] Additional exploratory analyses examine clinical activity
endpoints in the subset of subjects who were culture positive at
the time of TT placement. Analyses explore differences between
Composition A, placebo and sham control groups, both within
individual dose cohorts as well as comparisons of the two
Composition A doses to the pooled placebo group and the pooled sham
group across cohorts.
[0420] Given the primary safety objective, the study is not
designed to provide adequate power for statistical hypothesis
testing. Therefore, the analysis of clinical activity is primarily
descriptive and considered exploratory.
Example 6
Clinical Trial of Antimicrobial Agent Formulations in Combination
with Tympanostomy for Treatment of Pediatric Otitis Media with
Effusion
[0421] The purpose of this study is to determine if a composition
comprising Ciprofloxacin and poloxamer 407 administered in
combination with a tympanostomy is safe and effective in preventing
and/or treating middle ear infections in pediatric patients with
ear tubes.
[0422] Study Type:
[0423] Interventional
[0424] Study Design:
[0425] This is a randomized, double-blind, sham-controlled,
multicenter, Phase 3 study of 6 mg Composition A administered
intra-operatively in pediatric subjects with bilateral middle ear
effusion who require tympanostomy tube placement. One dose level of
Composition A (6 mg ciprofloxacin, 100 .mu.L) is evaluated relative
to sham (empty syringe). Subjects are randomized to either 6 mg
Composition A (6 mg ciprofloxacin, 100 .mu.L), or sham using a 2:1
allocation ratio; the subjects are be stratified by age: 1) 6
months to 2 years, or 2) greater than 2 years. [0426] Composition A
(6 mg ciprofloxacin); single 100 .mu.L intratympanic injection in
each ear [0427] Sham Injection
[0428] Dose: [0429] 6 mg Composition A (6 mg ciprofloxacin in 16%
poloxamer 407), single bilateral 100 .mu.L intratympanic
injections.
[0430] Duration of Treatment:
[0431] Single bilateral 100 .mu.L intratympanic injection
[0432] Methodology:
[0433] Subjects have a clinical diagnosis of bilateral middle ear
effusion requiring tympanostomy tube (TT) placement. On the day of
surgery, prior to surgery, eligible subjects entering the first
cohort are examined to confirm bilateral middle ear effusion.
Subjects with bilateral middle ear effusion are randomized to
either 6 mg Composition A or sham. Subjects without bilateral
effusion on day of surgery are not randomized.
[0434] Subjects are randomized to 6 mg Composition A or sham using
a 2:1 allocation ratio. Randomization to study drug is stratified
by age: 1) 6 months to 2 years, or 2) greater than 2 years.
[0435] During surgery, a culture of the effusion from each ear is
obtained prior to 6 mg Composition A or sham injection. 6 mg
Composition A or sham is administered in both ears following
myringotomy. All syringes, including sham, are prepared to maintain
the blind. Following administration of 6 mg Composition A or sham
and subsequent TT placement, caregivers and subjects receive
standard post-operative instructions.
[0436] 6 mg Composition A or sham syringes are prepared by an
unblinded qualified health care professional at the investigative
site not otherwise associated with the trial. The pediatric
otolaryngologist becomes unblinded at the time of 6 mg Composition
A or sham administration based on the appearance of the treatment
being administered. Caregivers, subjects, and study staff are
blinded to treatment.
[0437] Caregivers are instructed to bring the subject to the study
site for examination if otorrhea in one or both ears is observed on
or after 3 days post-surgery (Day 4). A blinded investigator who
was not involved in the administration of study drug assesses the
presence of otorrhea, and if present, a specimen is collected for
culture.
[0438] Subjects visit the study site on Days 4, 8, 15 and 29 for
safety assessments and otoscopic examination. The assessment of
otorrhea for the clinical activity endpoint occurs on Days 4, 8,
and 15 by the blinded investigator who looks for visible otorrhea
in the auditory canal on external examination. Once the blinder
investigator determines the presence of visible otorrhea, subjects
are eligible for rescue medication.
[0439] The primary efficacy endpoint is the cumulative proportions
for otic treatment failures through the Day 15 visit. An otic
treatment failure is defined as any subject receiving otic
antibiotic drops at any time post-surgery or having documented
otorrhea by the blinded investigator at any time on or after 3 days
post-surgery (Day 4) in one or both ears through the Day 15 visit.
Subjects are defined as an otic treatment failure from the earliest
time point of either event as defined above and considered an otic
treatment failure for the remainder of the study. Subjects
designated as treatment failures are asked to remain on-study and
continue to be monitored for safety.
[0440] Inclusion Criteria:
Subjects meeting all of the following criteria may be eligible for
the study: 1. Subject is a male or female aged 6 months to 12
years, inclusive 2. Subject has a clinical diagnosis of bilateral
middle ear effusion requiring tympanostomy tube placement 3.
Subject's caregiver is willing to comply with the protocol and
attend all study visits 4. Subject's caregiver is able to provide
written informed consent and Health Insurance Portability and
[0441] Accountability Act (HIPAA) documents before the initiation
of any study-related procedures
5. Subject of appropriate age is able to provide assent for
participation in the study
[0442] Exclusion Criteria:
Subjects meeting any of the following criteria are not eligible for
participation: 1. Subject has a history of prior ear or mastoid
surgery, not including myringotomy or myringotomy with TT placement
2. Subject has been designated for any other surgical procedure
that would occur concurrently with TT placement, such as, but not
limited to adenoidectomy or tonsillectomy 3. Subject has a history
of sensorineural hearing loss 4. Subject has a history of chronic
or recurrent bacterial infections other than otitis media that
likely will require treatment with antibiotics during the course of
the study 5. Subject has tympanic membrane perforation 6. Subject
has a history of known immunodeficiency disease 7. Subject has an
abnormality of the tympanic membrane or middle ear that would
preclude precise placement of study drug or intratympanic injection
8. Use of topical nonsteroidal otic agents within 1 day of
randomization 9. Use of topical or otic corticosteroids within 3
days of randomization or systemic corticosteroids within 7 days of
randomization 10. Presence of any infection requiring systemic
antimicrobial or antifungal agents 11. Use of topical or systemic
antimicrobial or antifungal agents; amoxicillin, Augmentin.RTM.,
Omnicef.RTM., ceftriaxone, and cephalexin within 3 days of
randomization; doxycycline and fluoroquinolones within 7 days and
Zithromax.RTM. within 14 days of randomization 12. Concurrent use
of oral anti-inflammatory agents 13. Subject has a history of
allergy to ciprofloxacin or any of the components of Composition A
14. Subject has any other clinically significant illness or medical
condition that, in the opinion of either the investigator or
medical monitor, would prohibit the subject from participating in
the study 15. Subject has used an investigational drug or device in
the month prior to screening 16. Subject has been previously
exposed to Composition A 17. Subject is a menarcheal or
post-menarcheal female 18. Subject is not able to complete all
baseline assessments.
Outcome Measures for Evaluation:
Safety Endpoints:
[0443] Safety assessments include: [0444] Adverse events [0445]
Otoscopic examinations [0446] Tympanometry assessments [0447]
Audiometry assessments Conventional audiometry assessments,
including air conduction and bone conduction, are performed on
subjects that are mature enough to participate, as determined by
the investigator, typically age 4 years and older. [0448] Vital
sign measurements [0449] Physical examinations
Primary Efficacy Endpoints:
[0449] [0450] The primary efficacy endpoint is the cumulative
proportion of otic treatment failures through the Day 15 visit. An
otic treatment failure is defined as any subject receiving otic
antibiotic drops at any time post-surgery or having documented
otorrhea by the blinded assessor at any time on or after 3 days
post-surgery (Day 4) in one or both ears through the Day 15 visit.
Subjects will be defined as an otic treatment failure from the
earliest time point of either event as defined above and considered
an otic treatment failure for the remainder of the study. Subjects
whose treatment failure status is unknown at the scheduled Day 15
visit due to loss-to-followup, study termination, or a missed
visit, will be classified as a treatment failure for the primary
analysis. The test of efficacy will be the difference between the
proportion of otic treatment failures through the Day 15 visit
between the 6 mg Composition A group and the sham group.
Secondary Efficacy Endpoints:
[0450] [0451] The cumulative proportion of otorrhea at any time on
or after 3 days post-surgery in one or both ears through Day 15.
The cumulative proportion of treatment failures defined as any
subject receiving otic rescue medications and/or systemic
antibiotic medication at any time post-surgery or having physician
documented otorrhea at any time on or after 3 days post-surgery in
one or both ears through Day 15. Microbiological eradication
(absence, presumed or documented) of pretherapy bacteria based on
comparison to any bacteria in otorrhea present at any visit, Day 4
through Day 15 inclusive.
[0452] Statistical Methods:
Sample Size:
[0453] To estimate the sample size for the current trial several
assumptions were made. First, to account for sampling variability
in the P1b trial, a treatment effect was assumed that was smaller
than that observed in the P1b. Second, a lost-to-follow-up rate
resulting in unknown Day 15 treatment failure status due to early
withdrawal or missed visits was estimated to be 5%. Assuming
subjects with an unknown treatment failure status would be analyzed
as a treatment failure for the primary analysis, a dilution of the
estimated treatment effect was incorporated. Lastly, due to revised
entry criteria, it is anticipated that the mix of younger subjects
(6-months to 2 years) will comprise approximately 60% of the total
sample size with subjects greater than 2 years comprising the
remaining 40% of the sample. Although the P1b trial had a 50:50 mix
of younger to older subjects, the data suggested the possibility of
a larger treatment effect for younger subjects, albeit older
subjects were also observed to benefit from treatment with OTO-201.
As such, an adjustment to the overall treatment effect based on an
enriched sample with approximately 60% younger subjects was also
incorporated into the sample size calculations. [0454] In a
non-limiting example, the 6 mg Composition A treatment effect based
on the difference between the 6 mg Composition A and sham otic
treatment failure proportions is estimated to be -0.21 and is based
on treatment failure rates in the 6 mg Composition A and sham
groups of 0.25 and 0.46, respectively. A Z-test for the difference
between two independent proportions using a pooled variance
estimate with a two-tailed alpha level of 0.05 and a 2:1 allocation
ratio was used to estimate power and sample size. The study has an
approximate power of 93% to reject the null hypothesis of no
difference. The current sample size would also yield a power, 88%,
if the lost-to-follow-up rate increases to 10% and would provide
additional power if the mix of younger subjects is greater than
60%.
Safety:
[0455] Safety will be assessed through Day 29. Safety endpoints
will be summarized for the 6 mg Composition A dose group as well as
the sham control group for the safety population subjects receiving
at least one dose of study drug or a sham injection.
Primary Efficacy Endpoint:
[0456] The proportion of otic treatment failures between the 6 mg
Composition A and sham groups will be compared using a Ztest for
independent proportions at a two-tailed alpha level of 0.05 using
the Intent-to-Treat (ITT) population. Specific details of handling
missing data and sensitivity analyses will be provided in the
Statistical Analysis Plan which will be finalized prior to
unblinding and database lock.
[0457] FIG. 14 schematically illustrates an exemplar clinical trial
according to the present disclosure. The exemplary clinical trial
program consists of two identical prospective, randomized,
double-blind, sham-controlled, multicenter, studies of Composition
A given as a single IT injection for intra-operative treatment of
middle ear effusion in pediatric patients requiring TTP surgery. As
shown in FIG. 14, each trial consists of two treatment arms of
Composition A as Arm 2 and no treatment (sham) as Arm 1, with
patients randomized 2 to 1, respectively.
[0458] The primary endpoint of the exemplary clinical trials is the
cumulative proportion of treatment failures defined as otorrhea
(fluid draining through the tube) observed by a blinded assessor
from Day 4 through the Day 15 visit, or use of rescue antibiotics
from Day 1 through the Day 15 visit, whichever occurred first.
Patients ages six months to 17 years are eligible for the clinical
trial if they presented with effusion (fluid) in both ears
(bilateral) at the time of TTP surgery. Following randomization,
patients receive either Composition A or no treatment (sham).
Treatment is administered in the operating room following the
myringotomy (a small incision in the ear drum) and suctioning, and
before the placement of the tube. As is customary in pediatric
patients, all patients are under general anesthesia for the
procedure. Follow-up visits occur on Day 4, 8, 15 and 29 after
surgery.
[0459] A total of 532 pediatric patients at 60 trial sites in the
United States and Canada have been enrolled across the two clinical
trials designated as Study 302 and Study 303. An analysis of the
baseline patient demographics data from both trials suggests
reasonable balance with no notable differences between the
treatment groups. All enrolled patients have completed the Day 15
study visit, except for one patient in a sham group and one patient
in an Composition A group who were randomized but not treated.
[0460] The exemplary clinical trial has demonstrated that
Composition A achieves its primary efficacy endpoint as well as
several secondary endpoints and is well tolerated. As shown in FIG.
15, Composition A has demonstrated a reduction for the primary
efficacy endpoint, the incidence of treatment failures through Day
15 in all randomized patients, which averaged 49% across the two
trials, in each case as compared to sham. This effect on the
incidence of treatment failures is statistically significant
(p<0.001) for both trials. The p-value is the probability that
the reported result was achieved purely by chance (e.g., a p-value
.ltoreq.0.001 means that there is a 0.1% or less probability that
the difference between the sham group and the treatment group is
purely due to chance). A p-value .ltoreq.0.05 is a commonly used
criterion for statistical significance and may be supportive of a
finding of efficacy by regulatory authorities.
[0461] One sensitivity analysis performed on the primary endpoint,
the per-protocol analysis, evaluates the incidence of treatment
failures in all enrolled patients who did not have a major protocol
deviation. More than 80% of patients in each trial and treatment
group qualified for this analysis. As shown in FIG. 16, Composition
A provides a reduction in the rate of treatment failure through Day
15 in the per-protocol population averaging more than 60% across
the two trials, in each case as compared to sham. This effect is
statistically significant (p<0.001) for both trials.
[0462] A post-hoc analysis has been conducted that evaluated the
cumulative proportion of patients in the exemplary trials
considered treatment failures due to observation of otorrhea by the
blinded observer or use of either otic or systemic antibiotics with
documentation of otorrhea or otitis media through Day 15. FIG. 17
presents this data for the Phase 3 trials which indicate that
Composition A reduces the rate of post-operative otorrhea or use of
rescue antibiotics for documented otorrhea or otitis media by more
than 60% when averaged across both trials, in each case as compared
to sham. This effect is statistically significant in both trials
(p.ltoreq.0.004).
[0463] Composition A has been well tolerated in the exemplary
clinical trials. No deaths, no serious adverse events related to
Composition A occurred in the exemplary clinical trial, and no
subjects were discontinued due to adverse events. There were no
adverse findings demonstrated on physical examination or vital
signs. Most adverse events were mild or moderate in severity.
Safety assessments included treatment-emergent adverse events, or
TEAEs, hearing function testing and tympanometry (middle ear
function). Results for TEAEs are presented in the table below.
Overall, there are no observed differences between AuriPro and sham
treatment. Additionally, treatment with Composition was not found
to have a negative impact on hearing, tympanometry or otoscopy
(general examination of the ear), and there was no increase in the
incidence of tube clogging with AuriPro.
[0464] While preferred embodiments of the present invention have
been shown and described herein, such embodiments are provided by
way of example only. Various alternatives to the embodiments
described herein are optionally employed in practicing the
inventions. It is intended that the following claims define the
scope of the invention and that methods and structures within the
scope of these claims and their equivalents be covered thereby.
* * * * *
References