U.S. patent application number 15/091148 was filed with the patent office on 2017-01-05 for controlled-release cns modulating compositions and methods for the treatment of otic disorders.
The applicant listed for this patent is Otonomy, Inc., The Regents of the University of California. Invention is credited to Luis A. Dellamary, Sergio G. Duron, Jeffrey P. Harris, Carl Lebel, Jay Lichter, Fabrice Piu, Michael Christopher Scaife, Andrew M. Trammel, Benedikt Vollrath, Qiang Ye.
Application Number | 20170000728 15/091148 |
Document ID | / |
Family ID | 41467161 |
Filed Date | 2017-01-05 |
United States Patent
Application |
20170000728 |
Kind Code |
A1 |
Lichter; Jay ; et
al. |
January 5, 2017 |
Controlled-Release CNS Modulating Compositions and Methods for the
Treatment of Otic Disorders
Abstract
Disclosed herein are compositions and methods for the treatment
of otic disorders with CNS modulating agent compositions and
compositions administered locally to an individual afflicted with
an otic disorder, through direct application of these compositions
and compositions onto or via perfusion into the targeted auris
structure(s).
Inventors: |
Lichter; Jay; (Rancho Santa
Fe, CA) ; Trammel; Andrew M.; (Olathe, KS) ;
Piu; Fabrice; (San Diego, CA) ; Ye; Qiang;
(San Diego, CA) ; Scaife; Michael Christopher;
(Los Altos, CA) ; Vollrath; Benedikt; (San Diego,
CA) ; Duron; Sergio G.; (San Diego, CA) ;
Dellamary; Luis A.; (San Marcos, CA) ; Lebel;
Carl; (Malibu, CA) ; Harris; Jeffrey P.; (La
Jolla, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Otonomy, Inc.
The Regents of the University of California |
San Diego
Oakland |
CA
CA |
US
US |
|
|
Family ID: |
41467161 |
Appl. No.: |
15/091148 |
Filed: |
April 5, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14300011 |
Jun 9, 2014 |
9333171 |
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15091148 |
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13425217 |
Mar 20, 2012 |
8852626 |
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14300011 |
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12494156 |
Jun 29, 2009 |
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13425217 |
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61076567 |
Jun 27, 2008 |
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61082450 |
Jul 21, 2008 |
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61094384 |
Sep 4, 2008 |
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61101112 |
Sep 29, 2008 |
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61140033 |
Dec 22, 2008 |
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61164812 |
Mar 30, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/5513 20130101;
A61K 47/44 20130101; A61K 31/197 20130101; A61K 31/167 20130101;
A61K 31/195 20130101; A61K 31/5513 20130101; A61K 9/06 20130101;
A61K 47/14 20130101; A61K 47/38 20130101; A61K 31/195 20130101;
A61K 47/10 20130101; A61K 9/0046 20130101; A61K 31/00 20130101;
A61K 2300/00 20130101; A61K 45/06 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; A61P 27/16 20180101; A61K 31/167
20130101 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 31/167 20060101 A61K031/167; A61K 31/197 20060101
A61K031/197; A61K 31/5513 20060101 A61K031/5513 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 24, 2009 |
GB |
0907070.7 |
Claims
1.-20. (canceled)
21. An intratympanic composition for use in the treatment of an
otic disease or condition by administration on or near the round
window membrane of the ear, the intratympanic composition
comprising a multiparticulate Central Nervous System (CNS)
modulator, or pharmaceutically acceptable salt thereof; and an
auris acceptable gel, wherein the multiparticulate Central Nervous
System (CNS) modulator, or pharmaceutically acceptable salt thereof
is not provided as polymer-containing particles, and is suspended
in the auris acceptable gel.
22. The intratympanic composition of claim 21, wherein the auris
acceptable gel is an auris acceptable hydrogel.
23. The intratympanic composition of claim 21, wherein the auris
acceptable gel has a gelation viscosity between about 15,000 cP and
about 1,000,000 cP.
24. The intratympanic composition of claim 21, wherein the auris
acceptable gel is capable of being injected by a narrow gauge
needle or cannula through the tympanic membrane to an area on or
near the round window membrane.
25. The intratympanic composition of claim 21, wherein the
intratympanic composition has an osmolarity of from about 150
mOsm/L to about 1000 mOsm/L.
26. The intratympanic composition of claim 21, wherein the
multiparticulate Central Nervous System (CNS) modulator is
micronized Central Nervous System (CNS) modulator.
27. The intratympanic composition of claim 21, wherein the
intratympanic composition has a pH between 7.0 and 8.0.
28. The intratympanic composition of claim 21, wherein the CNS
modulator is a GABA receptor modulator or an antihistamine.
29. The intratympanic composition of claim 28, wherein the
antihistamine is selected from meclizine, diphenhydramine,
dimenhydrinate, loratadine, quetiapine, mepyramine, piperoxan,
antazoline, carbinoxamine, doxylamine, clemastine, pheniramine,
chlorphenamine, chlorpheniramine, dexchlorpheniramine,
brompheniramine, triprolidine, cyclizine, chlorcyclizine,
hydroxyzine, promethazine, alimemazine, trimeprazine,
cyproheptadine, azatadine, ketotifen, oxatomide and
betahistine.
30. The intratympanic composition of claim 28, wherein the GABA
receptor modulator agonizes the activity of a GABA receptor.
31. The intratympanic composition of claim 28, wherein the GABA
receptor modulator partially or fully inhibits the repolarization
of a neuron.
32. The intratympanic composition of claim 28, wherein the GABA
receptor modulator is selected from a benzodiazepine, a loop
diuretic, or a GABA analogue.
33. The intratympanic composition of claim 28, wherein the GABA
receptor modulator is selected from alprazolam, bromazepam,
brotizolam, chlordiazepoxide, clonazepam, clorazepate, diazepam,
estazolam, flunitrazepam, flurazepam, loprazolam, lorazepam,
lormetazepam, idazolam, nimetazepam, nitrazepam, oxazepam,
prazepam, temazepam, and triazolam or combinations thereof.
34. The intratympanic composition of claim 21, wherein the otic
disease or condition is endolymphatic hydrops, kinetosis,
labyrinthitis, mal de debarquement, Meniere's disease, Meniere's
syndrome, Ramsay Hunt's syndrome (Herpes zoster infection),
recurrent vestibulopathy, tinnitus, vertigo, microvascular
compression syndrome, utricular dysfunction, vestibular neuronitis,
benign paroxysmal positional vertigo, or combinations thereof.
35. The intratympanic composition of claim 21, wherein the otic
disease or condition is tinnitus.
36. The intratympanic composition of claim 21, wherein sustained
release of the CNS modulator into the cochlea occurs for a period
of at least 5 days after a single administration.
37. The intratympanic composition of claim 21, wherein sustained
release of the CNS modulator into the cochlea occurs for a period
of at least 10 days after a single administration.
Description
CROSS-REFERENCE
[0001] This application is a continuation of U.S. patent
application Ser. No. 14/300,011, filed Jun. 9, 2014, which is a
continuation of U.S. patent application Ser. No. 13/425,217, filed
Mar. 20, 2012, now U.S. Pat. No. 8,852,626, which is a continuation
of of U.S. patent application Ser. No. 12/494,156, filed Jun. 29,
2009 (now abandoned), which claims the benefit of U.S. Provisional
Application No. 61/076,567, filed 27 Jun. 2008; U.S. Provisional
Application No. 61/082,450, filed 21 Jul. 2008; U.S. Provisional
Application No. 61/094,384, filed 4 Sep. 2008; U.S. Provisional
Application No. 61/101,112, filed 29 Sep. 2008; U.S. Provisional
Application No. 61/140,033, filed 22 Dec. 2008; U.S. Provisional
Application No. 61/164,812, filed 30 Mar. 2009; and UK Patent
Application No. 0907070.7, filed Apr. 24, 2009; all of that are
incorporated herein in their 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, in certain embodiments, are compositions,
compositions, manufacturing methods, therapeutic methods, uses,
kits, and delivery devices for the controlled-release of at least
one CNS modulating agent to at least one structure or region of the
ear. Disclosed herein, in certain embodiments, are
controlled-release compositions for delivering a CNS modulating
agent to the ear. In some embodiments, the target portion of the
ear is the middle ear (or auris media). In some embodiments, the
target portion of the ear is the inner ear (or auris interna). In
other embodiments, the target portion of the ear is both the auris
media and the auris interna. In some embodiments, the
controlled-release compositions further comprise a rapid or
immediate release component for delivering a CNS modulating agent
to the targeted auris structure. All compositions comprise
excipients that are auris-acceptable.
[0004] Also disclosed herein, in certain embodiments, are
compositions and devices for the treatment of otic disorders, said
compositions and devices comprising a CNS modulating agent. Further
disclosed herein, in certain embodiments, are methods for the
treatment of otic disorders by administration of a
controlled-release composition comprising a CNS modulating agent to
an individual in need thereof. In some embodiments, the otic
disorder is endolymphatic hydrops, kinetosis, labyrinthitis, mal de
debarquement, Meniere's disease, Meniere's syndrome, Ramsay Hunt's
syndrome (Herpes zoster infection), recurrent vestibulopathy,
tinnitus, vertigo, microvascular compression syndrome, utricular
dysfunction, vestibular neuronitis, benign paroxysmal positional
vertigo, or combinations thereof.
[0005] The auris compositions and therapeutic methods described
herein have numerous advantages that overcome the
previously-unrecognized limitations of compositions and therapeutic
methods described in prior art.
Sterility
[0006] The environment of the inner ear is an isolated environment.
The endolymph and the perilymph are static fluids and are not in
contiguous contact with the circulatory system. The
blood--labyrinth--barrier (BLB), which includes a blood-endolymph
barrier and a blood-perilymph barrier, consists of tight junctions
between specialized epithelial cells in the labyrinth spaces (i.e.,
the vestibular and cochlear spaces). The presence of the BLB limits
delivery of active agents (e.g., CNS modulating agents, aural
pressure modulators, antimicrobials) to the isolated
microenvironment of the inner ear. Auris hair cells are bathed in
endolymphatic or perilymphatic fluids and cochlear recycling of
potassium ions is important for hair cell function. When the inner
ear is infected, there is an influx of leukocytes and/or
immunoglobulins (e.g. in response to a microbial infection) into
the endolymph and/or the perilymph and the ionic composition of
inner ear fluids is upset by the influx of leukocytes and/or
immunoglobulins. In certain instances, a change in the ionic
composition of inner ear fluids results in hearing loss, loss of
balance and/or ossification of auditory structures. In certain
instances, trace amounts of pyrogens and/or microbes trigger
infections and related physiological changes in the isolated
microenvironment of the inner ear.
[0007] Due to the susceptibility of the inner ear to infections,
auris compositions require a level of sterility that has not been
recognized hitherto in prior art. Provided herein are auris
compositions that are sterilized with stringent sterility
requirements and are suitable for administration to the middle
and/or inner ear. In some embodiments, the auris compatible
compositions described herein are substantially free of pyrogens
and/or microbes.
Compatibility with Inner Ear Environment
[0008] Described herein are otic compositions with an ionic balance
that is compatible with the perilymph and/or the endolymph and does
not cause any change in cochlear potential. In specific
embodiments, osmolarity/osmolality of the present compositions is
adjusted, for example, by the use of appropriate salt
concentrations (e.g., concentration of sodium salts) or the use of
tonicity agents that render the compositions endolymph-compatible
and/or perilymph-compatible (i.e. isotonic with the endolymph
and/or perilymph). In some instances, the endolymph-compatible
and/or perilymph-compatible compositions described herein cause
minimal disturbance to the environment of the inner ear and cause
minimum discomfort (e.g., vertigo) to a subject (e.g., a human)
upon administration. Further, the compositions comprise polymers
that are biodegradable and/or dispersible, and/or otherwise
non-toxic to the inner ear environment. In some embodiments, the
compositions described herein are free of preservatives and cause
minimal disturbance (e.g., change in pH or osmolarity, irritation)
in auditory structures. In some embodiments, the compositions
described herein comprise antioxidants that are non-irritating
and/or non-toxic to otic structures.
Dosing Frequency
[0009] The current standard of care for auris compositions requires
multiple administrations of drops or injections (e.g. intratympanic
injections) over several days (e.g., up to two weeks), including
schedules of receiving multiple injections per day. In some
embodiments, auris compositions described herein are
controlled-release compositions and are administered at reduced
dosing frequency compared to the current standard of care. In
certain instances, when an auris composition is administered via
intratympanic injection, a reduced frequency of administration
alleviates discomfort caused by multiple intratympanic injections
in individuals undergoing treatment for a middle and/or inner ear
disease, disorder or condition. In certain instances, a reduced
frequency of administration of intratympanic injections reduces the
risk of permanent damage (e.g., perforation) to the tympanic
membrane. The compositions described herein provide a constant,
sustained, extended, delayed or pulsatile rate of release of an
active agent into the inner ear environment and thus avoid any
variability in drug exposure in treatment of otic disorders.
Therapeutic Index
[0010] Auris compositions described herein are administered into
the ear canal, or in the vestibule of the ear. In some embodiments,
access to the vestibular and cochlear apparatus occurs through the
auris media (e.g., the round window membrane, the oval
window/stapes footplate, the annular ligament and through the otic
capsule/temporal bone). Otic administration of the compositions
described herein avoids toxicity associated with systemic
administration (e.g., hepatotoxicity, cardiotoxicity,
gastrointestinal side effects, renal toxicity) of the active
agents. In some instances, localized administration in the ear
allows an active agent to reach a target (e.g., the inner ear) in
the absence of systemic accumulation of the active agent. In some
instances, local administration to the ear provides a higher
therapeutic index for an active agent that would otherwise have
dose-limiting systemic toxicity.
Prevention of Drainage into Eustachian Tube
[0011] In some instances, a disadvantage of liquid compositions is
their propensity to drip into the eustachian tube and cause rapid
clearance of the composition from the inner ear. Provided herein,
in certain embodiments, are auris compositions comprising polymers
that gel at body temperature and remain in contact with the target
auditory surfaces (e.g., the round window) for extended periods of
time. In some embodiments, the compositions further comprise a
mucoadhesive that allows the compositions to adhere to otic mucosal
surfaces. In some instances, the auris compositions described
herein avoid attenuation of therapeutic benefit due to drainage or
leakage of active agents via the eustachian tube.
DESCRIPTION OF CERTAIN EMBODIMENTS
[0012] Described herein, in certain embodiments, are
controlled-release compositions and devices for treating otic
disorders comprising a therapeutically-effective amount of a CNS
modulating agent, a controlled-release auris-acceptable excipient
and an auris-acceptable vehicle. In one aspect, the
controlled-release auris-acceptable excipient is chosen from an
auris-acceptable polymer, an auris-acceptable viscosity enhancing
agent, an auris-acceptable gel, an auris-acceptable paint, an
auris-acceptable foam, an auris-acceptable microsphere or
microparticle, an auris-acceptable hydrogel, an auris-acceptable in
situ forming spongy material, an auris-acceptable actinic radiation
curable gel, an auris-acceptable liposome, an auris-acceptable
nanocapsule or nanosphere, an auris-acceptable thermoreversible gel
or combinations thereof. In further embodiments, the
auris-acceptable viscosity enhancing agent is a cellulose, a
cellulose ether, alginate, polyvinylpyrrolidone, a gum, a
cellulosic polymer or combinations thereof. In yet another
embodiment, the auris-acceptable viscosity enhancing agent is
present in an amount sufficient to provide a viscosity of between
about 1000 to about 1,000,000 centipoise. In still another aspect,
the auris-acceptable viscosity enhancing agent is present in an
amount sufficient to provide a viscosity of between about 50,000 to
about 1,000,000 centipoise.
[0013] In some embodiments, the compositions disclosed herein are
formulated for a pH that ensures that they are compatible with the
targeted auris structure. In some embodiments, the compositions
disclosed herein are formulated for a practical osmolality and/or
osmolarity that ensures that homeostasis of the target auris
structure is maintained. A perilymph-suitable osmolarity/osmolality
is a practical osmolarity/osmolality that maintains the homeostasis
of the target auris structure during administration of the
pharmaceutical compositions described herein.
[0014] For example, the osmolarity of the perilymph is between
about 270-300 mOsm/L and the compositions described herein are
optionally formulated to provide a practical osmolarity of about
150 to about 1000 mOsm/L. In certain embodiments, the compositions
described herein provide a practical osmolarity within about 150 to
about 500 mOsm/L at the target site of action (e.g., the inner ear
and/or the perilymph and/or the endolymph). In certain embodiments,
the compositions described herein provide a practical osmolarity
within about 200 to about 400 mOsm/L at the target site of action
(e.g., the inner ear and/or the perilymph and/or the endolymph). In
certain embodiments, the compositions described herein provide a
practical osmolarity within about 250 to about 320 mOsm/L at the
target site of action (e.g., the inner ear and/or the perilymph
and/or the endolymph). In certain embodiments, the compositions
described herein provide a perilymph-suitable osmolarity within
about 150 to about 500 mOsm/L, about 200 to about 400 mOsm/L or
about 250 to about 320 mOsm/L at the target site of action (e.g.,
the inner ear and/or the perilymph and/or the endolymph). In
certain embodiments, the compositions described herein provide a
perilymph-suitable osmolality within about 150 to about 500
mOsm/kg, about 200 to about 400 mOsm/kg or about 250 to about 320
mOsm/kg at the target site of action (e.g., the inner ear and/or
the perilymph and/or the endolymph). Similarly, the pH of the
perilymph is about 7.2-7.4, and the pH of the present compositions
is formulated (e.g., with the use of buffers) to provide a
perilymph-suitable pH of about 5.5 to about 9.0, about 6.0 to about
8.0 or about 7.0 to about 7.6. In certain embodiments, the pH of
the compositions is within about 6.0 to about 7.6. In certain
instances, the pH of the endolymph is about 7.2-7.9, and the pH of
the present compositions is formulated (e.g., with the use of
buffers) to be within about 5.5 to about 9.0, within about 6.5 to
about 8.0 or within about 7.0 to about 7.6.
[0015] In some aspects, the controlled-release auris-acceptable
excipient is biodegradable and/or bioeliminated (e.g., degraded
and/or eliminated through urine, feces or other routes of
elimination). In another aspect, the controlled-release composition
further comprises an auris-acceptable mucoadhesive, an
auris-acceptable penetration enhancer or an auris-acceptable
bioadhesive.
[0016] In one aspect, the controlled-release composition is
delivered using a drug delivery device, which is a needle and
syringe, a pump, a microinjection device, and in situ forming
spongy material or combinations thereof. In some embodiments, the
CNS modulating agent of the controlled-release composition has
limited or no systemic release, is toxic when administered
systemically, has poor pK characteristics, or combinations
thereof.
[0017] In some embodiments, the CNS modulating agent is a CNS
inhibitory agent. In some embodiments, the CNS inhibitory agent
inhibits the transmission of a nerve impulse. In some embodiments,
the CNS inhibitory agent inhibits the release of a
neurotransmitter. In some embodiments, the CNS inhibitory agent
agonizes the activity of a GABA receptor. In some embodiments, the
CNS inhibitory agent partially or fully inhibits the repolarization
of a neuron. In some embodiments, the CNS inhibitory agent disrupts
the conduction of an ion channel.
[0018] In some embodiments, the CNS modulating agent is an
antihistamine, a GABA receptor modulator, a neurotransmitter
reuptake inhibitor, a local anesthetic, an anticholinergic, a
sodium channel blocker, a calcium channel blocker, a
thyrotropin-releasing hormone, or combinations thereof. In another
aspect, the CNS modulating agent is a salt or prodrug of the CNS
modulating agent. In other aspects, the CNS modulating agent is
meclizine, diphenhydramine, dimenhydrinate, loratadine, quetiapine,
mepyramine, piperoxan, antazoline, carbinoxamine, doxylamine,
clemastine, pheniramine, chlorphenamine, chlorpheniramine,
dexchlorpheniramine, brompheniramine, triprolidine, cyclizine,
chlorcyclizine, hydroxyzine, promethazine, alimemazine,
trimeprazine, cyproheptadine, azatadine, ketotifen, oxatomide,
meclizine hydrochloride, promethazine hydrochloride, cinnarizine,
hydroxyzine pamoate, betahistine dihydrochloride, alprazolam,
bromazepam, brotizolam, chlordiazepoxide, clonazepam, clorazepate,
diazepam, estazolam, flunitrazepam, flurazepam, loprazolam,
lorazepam, lormetazepam, idazolam, nimetazepam, nitrazepam,
oxazepam, prazepam, temazepam, triazolam, clonazepam, diazepam,
lorazepam, furosemide, bumetanide, ethacrynic acid, gab apentin,
pregabalin, muscimol, baclofen, amitriptyline, nortriptyline,
trimipramine, fluoxetine, paroxetine, sertraline, glycopyrrolate,
homatropine, scopolamine, atropine, benzocaine, carticaine,
cinchocaine, cyclomethycaine, lidocaine, prilocaine, propxycaine,
proparacaine, tetracaine, tocainide, trimecaine, carbamazepine,
oxcarbazepine, phenytein, valproic acid, sodium valproate,
cinnarizine, flunarizine, nimodipine, thyrotropin-releasing
hormone, or combinations thereof.
[0019] Also disclosed herein, in certain embodiments, is a method
for treating an otic disorder comprising administering a
composition disclosed herein at least once every 3, 4, 5, 6, 7, 8,
9, 10, 11, 12, 13, 14, or 15 days; at least once a week, once every
two weeks, once every three weeks, once every four weeks, once
every five weeks, or once every six weeks; or at least once a
month, once every two months, once every three months, once every
four months, once every five months, once every six months, once
every seven months, once every eight months, once every nine
months, once every ten months, once every eleven months, or once
every twelve months. In particular embodiments, the
controlled-release compositions described herein provide a
sustained dose of a CNS modulating agent to the inner ear between
subsequent doses of the controlled-release composition. That is,
taking one example only, if new doses of the CNS modulating agent
controlled-release composition are administered via intratympanic
injection to the round window membrane every 10 days, then the
controlled-release composition provides an effective dose of a CNS
modulating agent to the inner ear (e.g., across the round window
membrane) during that 10-day period.
[0020] In one aspect, the composition is administered so that the
composition is in contact with the crista fenestrae cochleae, the
round window membrane or the tympanic cavity. In one aspect the
composition is administered by intratympanic injection.
[0021] Provided herein are pharmaceutical compositions or devices,
comprising: a therapeutically effective amount of a CNS inhibitory
agent having substantially low degradation products; and wherein
the composition or device comprises two or more characteristics
selected from: [0022] (i) between about 0.1% to about 10% by weight
of the CNS modulating agent, or pharmaceutically acceptable prodrug
or salt thereof; [0023] (ii) between about 14% to about 21% by
weight of a polyoxyethylene-polyoxypropylene triblock copolymer of
general formula E106 P70 E106; [0024] (iii) sterile water, q.s.,
buffered to provide a pH between about 5.5 and about 8.0; [0025]
(iv) multiparticulate CNS modulating agent; [0026] (v) a gelation
temperature between about 19.degree. C. to about 42.degree. C.;
[0027] (vi) less than about 50 colony forming units (cfu) of
microbiological agents per gram of composition, and [0028] (vii)
less than about 5 endotoxin units (EU) per kg of body weight of a
subject.
[0029] In some embodiments, a pharmaceutical composition or device
described herein comprises: [0030] (i) between about 0.1% to about
10% by weight of the CNS modulating agent, or pharmaceutically
acceptable prodrug or salt thereof; [0031] (ii) between about 14%
to about 21% by weight of a polyoxyethylene-polyoxypropylene
triblock copolymer of general formula E106 P70 E106; and [0032]
(iii) multiparticulate CNS modulating agent.
[0033] In some embodiments, a pharmaceutical composition or device
described herein comprises: [0034] (i) between about 0.1% to about
10% by weight of the CNS modulating agent, or pharmaceutically
acceptable prodrug or salt thereof; [0035] (ii) between about 14%
to about 21% by weight of a polyoxyethylene-polyoxypropylene
triblock copolymer of general formula E106 P70 E106; [0036] (iii)
multiparticulate CNS modulating agent; and [0037] (iv) a gelation
temperature between about 19.degree. C. to about 42.degree. C.
[0038] In some embodiments, a pharmaceutical composition or device
described above provides a practical osmolarity between about 150
and 500 mOsm/L. In some embodiments, a pharmaceutical composition
or device described above provides a practical osmolarity between
about 200 and 400 mOsm/L. In some embodiments, a pharmaceutical
composition or device described above provides a practical
osmolarity between about 250 and 320 mOsm/L.
[0039] In some embodiments, the CNS modulating agent is released
from the pharmaceutical composition or device described above for a
period of at least 3 days. In some embodiments, the CNS modulating
agent is released from the pharmaceutical composition or device
described above for a period of at least 5 days. In some
embodiments, the CNS modulating agent is released from the
pharmaceutical composition or device described above for a period
of at least 10 days. In some embodiments, the CNS modulating agent
is released from the pharmaceutical composition or device described
above for a period of at least 14 days. In some embodiments, the
CNS modulating agent is released from the pharmaceutical
composition or device described above for a period of at least one
month.
[0040] In some embodiments, a pharmaceutical composition or device
described above comprises a CNS modulating agent as a neutral
molecule, a free acid, a free base, a salt or a prodrug. In some
embodiments, a pharmaceutical composition or device described above
comprises a CNS modulating agent as a neutral molecule, a free
acid, a free base, a salt or a prodrug, or a combination
thereof.
[0041] In some embodiments, a pharmaceutical composition or device
described above comprises a CNS modulating agent as
multiparticulates. In some embodiments, a pharmaceutical
composition or device described above comprises a CNS modulating
agent in the form of micronized particles. In some embodiments, a
pharmaceutical composition or device described above comprises a
CNS modulating agent as micronized powders.
[0042] In some embodiments, a pharmaceutical composition or device
described above comprises about 10% of a
polyoxyethylene-polyoxypropylene triblock copolymer of general
formula E106 P70 E106 by weight of the composition. In some
embodiments, a pharmaceutical composition or device described above
comprises about 15% of a polyoxyethylene-polyoxypropylene triblock
copolymer of general formula E106 P70 E106 by weight of the
composition. In some embodiments, a pharmaceutical composition or
device described above comprises about 20% of a
polyoxyethylene-polyoxypropylene triblock copolymer of general
formula E106 P70 E106 by weight of the composition. In some
embodiments, a pharmaceutical composition or device described above
comprises about 25% of a polyoxyethylene-polyoxypropylene triblock
copolymer of general formula E106 P70 E106 by weight of the
composition.
[0043] In some embodiments, a pharmaceutical composition or device
described herein comprises about 1% of a CNS modulating agent, or
pharmaceutically acceptable prodrug or salt thereof, by weight of
the composition. In some embodiments, a pharmaceutical composition
or device described above comprises about 2% of a CNS modulating
agent, or pharmaceutically acceptable prodrug or salt thereof, by
weight of the composition. In some embodiments, a pharmaceutical
composition or device described herein comprises about 3% of a CNS
modulating agent, or pharmaceutically acceptable prodrug or salt
thereof, by weight of the composition. In some embodiments, a
pharmaceutical composition or device described herein comprises
about 4% of a CNS modulating agent, or pharmaceutically acceptable
prodrug or salt thereof, by weight of the composition. In some
embodiments, a pharmaceutical composition or device described above
comprises about 5% of a CNS modulating agent, or pharmaceutically
acceptable prodrug or salt thereof, by weight of the composition.
In some embodiments, a pharmaceutical composition or device
described above comprises about 10% of a CNS modulating agent, or
pharmaceutically acceptable prodrug or salt thereof, by weight of
the composition. In some embodiments, a pharmaceutical composition
or device described above comprises about 15% of a CNS modulating
agent, or pharmaceutically acceptable prodrug or salt thereof, by
weight of the composition. In some embodiments, a pharmaceutical
composition or device described above comprises about 20% of a CNS
modulating agent, or pharmaceutically acceptable prodrug or salt
thereof, by weight of the composition. In some embodiments, a
pharmaceutical composition or device described above comprises
about 25% of a CNS modulating agent, or pharmaceutically acceptable
prodrug or salt thereof, by weight of the composition. In some
embodiments, a pharmaceutical composition or device described above
comprises about 30% of a CNS modulating agent, or pharmaceutically
acceptable prodrug or salt thereof, by weight of the composition.
In some embodiments, a pharmaceutical composition or device
described above comprises about 40% of a CNS modulating agent, or
pharmaceutically acceptable prodrug or salt thereof, by weight of
the composition. In some embodiments, a pharmaceutical composition
or device described above comprises about 50% of a CNS modulating
agent, or pharmaceutically acceptable prodrug or salt thereof, by
weight of the composition. In some embodiments, a pharmaceutical
composition or device described above comprises about 60% of a CNS
modulating agent, or pharmaceutically acceptable prodrug or salt
thereof, by weight of the composition. In some embodiments, a
pharmaceutical composition or device described above comprises
about 70% of a CNS modulating agent, or pharmaceutically acceptable
prodrug or salt thereof, by weight of the composition. In some
embodiments, a pharmaceutical composition or device described above
comprises about 80% of a CNS modulating agent, or pharmaceutically
acceptable prodrug or salt thereof, by weight of the composition.
In some embodiments, a pharmaceutical composition or device
described above comprises about 90% of a CNS modulating agent, or
pharmaceutically acceptable prodrug or salt thereof, by weight of
the composition.
[0044] In some embodiments, a pharmaceutical composition or device
described above has a pH between about 5.5 and about 8.0. In some
embodiments, a pharmaceutical composition or device described above
has a pH between about 6.0 and about 8.0. In some embodiments, a
pharmaceutical composition or device described above has a pH
between about 6.0 and about 7.6.
[0045] In some embodiments, a pharmaceutical composition or device
described above contains less than 100 colony forming units (cfu)
of microbiological agents per gram of composition. In some
embodiments, a pharmaceutical composition or device described above
contains less than 50 colony forming units (cfu) of microbiological
agents per gram of composition. In some embodiments, a
pharmaceutical composition or device described above contains less
than 10 colony forming units (cfu) of microbiological agents per
gram of composition.
[0046] In some embodiments, a pharmaceutical composition or device
described above contains less than 5 endotoxin units (EU) per kg of
body weight of a subject. In some embodiments, a pharmaceutical
composition or device described above contains less than 4
endotoxin units (EU) per kg of body weight of a subject.
[0047] In some embodiments, a pharmaceutical composition or device
described above provides a gelation temperature between about
between about 19.degree. C. to about 42.degree. C. In some
embodiments, a pharmaceutical composition or device described above
provides a gelation temperature between about between about
19.degree. C. to about 37.degree. C. In some embodiments, a
pharmaceutical composition or device described above provides a
gelation temperature between about between about 19.degree. C. to
about 30.degree. C.
[0048] In some embodiments, the pharmaceutical composition or
device is an auris-acceptable thermoreversible gel. In some
embodiments, the polyoxyethylene-polyoxypropylene triblock
copolymer is biodegradable and/or bioeliminated (e.g., the
copolymer is eliminated from the body by a biodegradation process,
e.g., elimination in the urine, the feces or the like). In some
embodiments, a pharmaceutical composition or device described
herein further comprises a mucoadhesive. In some embodiments, a
pharmaceutical composition or device described herein further
comprises a penetration enhancer. In some embodiments, a
pharmaceutical composition or device described herein further
comprises a thickening agent. In some embodiments, a pharmaceutical
composition or device described herein further comprises a dye.
[0049] In some embodiments, a pharmaceutical composition or device
described herein further comprises a drug delivery device selected
from a needle and syringe, a pump, a microinjection device, a wick,
an in situ forming spongy material or combinations thereof.
[0050] In some embodiments, a pharmaceutical composition or device
described herein is a pharmaceutical composition or device wherein
the CNS modulating agent, or pharmaceutically acceptable salt
thereof, has limited or no systemic release, systemic toxicity,
poor PK characteristics, or combinations thereof. In some
embodiments, of the pharmaceutical compositions or devices
described herein, the CNS modulating agent is in the form of a
neutral molecule, a free base, a free acid, a salt, a prodrug, or a
combination thereof. In some embodiments, of the pharmaceutical
compositions or devices described herein, the CNS modulating agent
is administered in the form of a phosphate or ester prodrug. In
some embodiments, pharmaceutical compositions or devices described
herein comprise one or more CNS modulating agent, or
pharmaceutically acceptable salt thereof, prodrug or combination
thereof as an immediate release agent.
[0051] In some embodiments, pharmaceutical compositions or devices
described herein further comprise an additional therapeutic agent.
In some embodiments, the additional therapeutic agent is a an
acidifying agent, an anesthetic, an analgesic, an antibiotic,
antiemetic, an antifungal, an anti-microbial agent, an
antipsychotic (especially those in the phenothiazine class), an
antiseptic, an antiviral, an astringent, a chemotherapeutic agent,
a collagen, a corticosteroid, a diuretic, a keratolytic agent, a
nitric oxide synthase inhibitor, combinations thereof.
[0052] In some embodiments, pharmaceutical compositions or devices
described herein are pharmaceutical compositions or devices wherein
the pH of the pharmaceutical composition or device is between about
6.0 to about 7.6.
[0053] In some embodiments, of the pharmaceutical compositions or
devices described herein, the ratio of a
polyoxyethylene-polyoxypropylene triblock copolymer of general
formula E106 P70 E106 to a thickening agent is from about 40:1 to
about 5:1. In some embodiments, the thickening agent is
carboxymethyl cellulose, hydroxypropyl cellulose or hydroxypropyl
methylcellulose.
[0054] In some embodiments, the otic disease or condition is
endolymphatic hydrops, kinetosis, labyrinthitis, mal de
debarquement, Meniere's disease, Meniere's syndrome, Ramsay Hunt's
syndrome (Herpes zoster infection), recurrent vestibulopathy,
tinnitus, vertigo, microvascular compression syndrome, utricular
dysfunction, vestibular neuronitis, benign paroxysmal positional
vertigo, or combinations thereof.
[0055] Also provided herein is a method of treating an otic disease
or condition characterized by an excess of nerve impulses
comprising administering to an individual in need thereof an
intratympanic composition or device comprising a therapeutically
effective amount of a CNS inhibitory agent, wherein the CNS
inhibitory agent is in the form of a substantially low degradation
product; and wherein the composition or device comprises two or
more characteristics selected from: [0056] (i) between about 0.1%
to about 10% by weight of the CNS modulating agent, or
pharmaceutically acceptable prodrug or salt thereof; [0057] (ii)
between about 14% to about 21% by weight of a
polyoxyethylene-polyoxypropylene triblock copolymer of general
formula E106 P70 E106; [0058] (iii) sterile water, q.s., buffered
to provide a pH between about 5.5 and about 8.0; [0059] (iv)
multiparticulate CNS modulating agent; [0060] (v) a gelation
temperature between about 19.degree. C. to about 42.degree. C.;
[0061] (vi) less than about 50 colony forming units (cfu) of
microbiological agents per gram of composition, and [0062] (vii)
less than about 5 endotoxin units (EU) per kg of body weight of a
subject.
[0063] In some embodiments of the methods described herein, the CNS
modulating agent is released from the composition or devices for a
period of at least 3 days. In some embodiments of the methods
described herein, the CNS modulating agent is released from the
composition or device for a period of at least 4 days. In some
embodiments of the methods described herein, the CNS modulating
agent is released from the composition or device for a period of at
least 5 days. In some embodiments of the methods described herein,
the CNS modulating agent is released from the composition or device
for a period of at least 6 days. In some embodiments of the methods
described herein, the CNS modulating agent is released from the
composition or device for a period of at least 7 days. In some
embodiments of the methods described herein, the CNS modulating
agent is released from the composition or device for a period of at
least 8 days. In some embodiments of the methods described herein,
the CNS modulating agent is released from the composition or device
for a period of at least 9 days. In some embodiments of the methods
described herein, the CNS modulating agent is released from the
composition or device for a period of at least 10 days. In some
embodiments of the method described above, the CNS modulating agent
is essentially in the form of micronized particles.
[0064] In some embodiments of the methods described herein, the
composition is administered across the round window. In some
embodiments of the methods described herein, the otic disease or
condition is endolymphatic hydrops, kinetosis, labyrinthitis, mal
de debarquement, Meniere's disease, Meniere's syndrome, Ramsay
Hunt's syndrome (Herpes zoster infection), recurrent
vestibulopathy, tinnitus, vertigo, microvascular compression
syndrome, utricular dysfunction, vestibular neuronitis, benign
paroxysmal positional vertigo, or combinations thereof.
BRIEF DESCRIPTION OF FIGURES
[0065] FIG. 1 illustrates a comparison of non-sustained release and
sustained release compositions.
[0066] FIG. 2 illustrates the effect of concentration on the
viscosity of aqueous solutions of Blanose refined CMC.
[0067] FIG. 3 illustrates the effect of concentration on the
viscosity of aqueous solutions of Methocel.
[0068] FIG. 4 provides an illustrative representation of the
anatomy of the ear.
DETAILED DESCRIPTION OF THE INVENTION
[0069] Provided herein are controlled-release CNS modulating agent
compositions and compositions to treat (e.g., ameliorate or reduce
the effects of) an otic disease, disorder, or condition
characterized by an excess of nerve impulses. In some embodiments,
the CNS modulating agent is a CNS inhibitory agent. In some
embodiments, the otic disease, disorder, or condition is
endolymphatic hydrops, kinetosis, labyrinthitis, mal de
debarquement, Meniere's disease, Meniere's syndrome, Ramsay Hunt's
syndrome (Herpes zoster infection), recurrent vestibulopathy,
tinnitus, vertigo, microvascular compression syndrome, utricular
dysfunction, vestibular neuronitis, benign paroxysmal positional
vertigo, or combinations thereof.
[0070] A few therapeutic products are available for the treatment
of otic disorders; however, systemic routes via oral, intravenous
or intramuscular routes are currently used to deliver these
therapeutic agents. In some instances, systemic drug administration
creates a potential inequality in drug concentration with higher
circulating levels in the serum, and lower levels in the target
auris media and 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. 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.
[0071] To overcome the toxic and attendant side effects of systemic
delivery, disclosed herein are methods and compositions and devices
for local delivery of therapeutic agents to targeted auris
structures. Access to, for example, the vestibular and cochlear
apparatus will occur through the auris media including round window
membrane, the oval window/stapes footplate, the annular ligament
and through the otic capsule/temporal bone.
[0072] 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. This technique
presents several challenges; for example, access to the round
window membrane, the site of drug absorption into the auris
interna, is challenging.
[0073] Further, 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 composition challenges. Thus, compositions
developed for other parts of the body have little to no relevance
for an intra-tympanic composition.
[0074] There is no guidance in the prior art regarding requirements
(e.g., level of sterility, pH, osmolarity) for otic compositions
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.
[0075] Provided herein are otic compositions that meet stringent
criteria for 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 compositions described herein comprise dyes and
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.
[0076] Provided herein are controlled-release CNS modulating agent
compositions and compositions to locally treat targeted auris
structures, thereby avoiding side effects as a result of systemic
administration of the CNS modulating agent compositions and
compositions. The locally applied CNS modulating agent compositions
and compositions and devices are compatible with the targeted auris
structures, and administered either directly to the desired
targeted auris structure (e.g., the cochlear region, the tympanic
cavity or the external ear), or administered to a structure in
direct communication with areas of the auris interna (e.g., the
round window membrane, the crista fenestrae cochleae or the oval
window membrane). 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 long
term 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 CNS modulating composition or
composition to treat otic disorders, a constant, variable and/or
extended source of a CNS modulating agent is provided to the
subject suffering from an otic disorder, reducing or eliminating
uncertainty in treatment. Accordingly, one embodiment disclosed
herein is to provide a composition that enables at least one CNS
modulating agent to be released in therapeutically effective doses
either at variable or constant rates such as to ensure a continuous
release of a CNS modulating agent. In some embodiments, a CNS
modulating agent disclosed herein is administered as an immediate
release composition or composition. In other embodiments, a CNS
modulating agent is administered as a sustained release
composition, released either continuously, variably or in a
pulsatile manner, or variants thereof. In still other embodiments,
a CNS modulating agent composition is administered as both an
immediate release and sustained release composition, released
either continuously, variably or in a pulsatile manner, or variants
thereof. The release is optionally dependent on environmental or
physiological conditions, for example, the external ionic
environment (see, e.g. Oros.RTM. release system, Johnson &
Johnson).
[0077] In addition, localized treatment of the targeted auris
structure also affords the use of previously undesired therapeutic
agents, including agents with poor pK profiles, poor uptake, low
systemic release and/or toxicity issues. Because of the localized
targeting of the CNS modulating agent compositions and compositions
and devices, as well as the biological blood barrier present in the
auris interna, the risk of adverse effects will be reduced as a
result of treatment with previously characterized toxic or
ineffective CNS modulating agents. Accordingly, also contemplated
within the scope of the embodiments herein is the use of a CNS
modulating agents in the treatment of disorders that have been
previously rejected by practitioners because of adverse effects or
ineffectiveness of the CNS modulating agent.
[0078] Also included within the embodiments disclosed herein is the
use of additional auris-compatible agents in combination with the
CNS modulating agent compositions and compositions and devices
disclosed herein. When used, such agents assist in the treatment of
hearing or equilibrium loss or dysfunction as a result of
endolymphatic hydrops, kinetosis, labyrinthitis, mal de
debarquement, Meniere's disease, Meniere's syndrome, Ramsay Hunt's
syndrome (Herpes zoster infection), recurrent vestibulopathy,
tinnitus, vertigo, microvascular compression syndrome, utricular
dysfunction, vestibular neuronitis, benign paroxysmal positional
vertigo, or combinations thereof. Accordingly, additional agents
that ameliorate or reduce the effects of endolymphatic hydrops,
kinetosis, labyrinthitis, mal de debarquement, Meniere's disease,
Meniere's syndrome, Ramsay Hunt's syndrome (Herpes zoster
infection), recurrent vestibulopathy, tinnitus, vertigo,
microvascular compression syndrome, utricular dysfunction,
vestibular neuronitis, benign paroxysmal positional vertigo, or
combinations thereof are also contemplated to be used in
combination with a CNS modulating agent. In some embodiments, the
additional agent is an acidifying agent, an anesthetic, an
analgesic, an antibiotic, antiemetic, an antifungal, an
anti-microbial agent, an antipsychotic (especially those in the
phenothiazine class), an antiseptic, an antiviral, an astringent, a
chemotherapeutic agent, a collagen, a corticosteroid, a diuretic, a
keratolytic agent, a nitric oxide synthase inhibitor, or
combinations thereof.
[0079] In some embodiments, an auris-acceptable controlled-release
CNS modulating composition described herein is administered to the
target ear region and an oral dose of a CNS modulating agent is
additionally administered. In some embodiments, an oral dose of a
CNS modulating agent is administered before administration of the
auris-acceptable controlled-release CNS modulating composition, and
then the oral dose is tapered off over the period of time that the
controlled-release CNS modulating composition is provided.
Alternatively, an oral dose of a CNS modulating agent is
administered during administration of the controlled-release CNS
modulating composition, and then the oral dose is tapered off over
the period of time that the controlled-release CNS modulating
composition is provided. Alternatively, an oral dose of a CNS
modulating agent is administered after administration of the
controlled-release CNS modulating composition, and then the oral
dose is tapered off over the period of time that the
controlled-release CNS modulating composition is provided.
[0080] In addition, the CNS modulating agent pharmaceutical
compositions or compositions or devices included herein also
include carriers, adjuvants (e.g., 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). Specifically contemplated 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. To prevent ototoxicity, CNS modulating
agent pharmaceutical compositions or compositions or devices
disclosed herein are optionally targeted to distinct regions of the
targeted auris structures, including but not limited to the
tympanic cavity, vestibular bony and membranous labyrinths,
cochlear bony and membranous labyrinths and other anatomical or
physiological structures located within the auris interna.
CERTAIN DEFINITIONS
[0081] The term "auris-acceptable" with respect to a composition,
composition or ingredient, as used herein, includes having no
persistent detrimental effect on the auris media (or middle ear)
and 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 media (or middle ear) and the auris interna (or inner
ear), and is relatively or is reduced in toxicity to the auris
media (or middle ear) and 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 that it is
contained.
[0082] 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.
[0083] "Antioxidants" are auris-pharmaceutically acceptable
antioxidants, and include, for example, butylated hydroxytoluene
(BHT), sodium ascorbate, ascorbic acid, sodium metabisulfite and
tocopherol. In certain embodiments, antioxidants enhance chemical
stability where required. Antioxidants are also used to counteract
the ototoxic effects of certain therapeutic agents, including
agents that are used in combination with the CNS modulating agents
disclosed herein.
[0084] "Auris interna" refers to the inner ear, including the
cochlea and the vestibular labyrinth, and the round window that
connects the cochlea with the middle ear.
[0085] "Auris-bioavailability" or "Auris-interna bioavailability"
or "Auris-media bioavailability" or "Auris-externa bioavailability"
refers to the percentage of the administered dose of compounds
disclosed herein that becomes available in the targeted auris
structure of the animal or human being studied.
[0086] "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.
[0087] "Auris externa" refers to the outer ear, including the
pinna, the auditory canal, and the tympanic membrane, which
connects the outer ear with the middle ear.
[0088] "Balance disorder" refers to a disorder, illness, or
condition that causes a subject to feel unsteady, or to have a
sensation of movement. Included in this definition are dizziness,
vertigo, disequilibrium, and pre-syncope. Diseases that are
classified as balance disorders include, but are not limited to,
Ramsay Hunt's Syndrome, Meniere's Disease, mal de debarquement,
benign paroxysmal positional vertigo, and labyrinthitis.
[0089] "Blood plasma concentration" refers to the concentration of
compounds provided herein in the plasma component of blood of a
subject.
[0090] "Carrier materials" are excipients that are compatible with
CNS modulating agent(s), the targeted auris structure(s) and the
release profile properties of the auris-acceptable pharmaceutical
compositions. Such carrier materials include, e.g., binders,
suspending agents, disintegration agents, filling agents,
surfactants, solubilizers, stabilizers, lubricants, wetting agents,
diluents, and the like. "Auris-pharmaceutically compatible carrier
materials" include, but are not limited to, acacia, gelatin,
colloidal silicon dioxide, calcium glycerophosphate, calcium
lactate, maltodextrin, glycerine, magnesium silicate,
polyvinylpyrrolidone (PVP), cholesterol, cholesterol esters, sodium
caseinate, soy lecithin, taurocholic acid, phosphatidylcholine,
sodium chloride, tricalcium phosphate, dipotassium phosphate,
cellulose and cellulose conjugates, sugars sodium stearoyl
lactylate, carrageenan, monoglyceride, diglyceride, pregelatinized
starch, and the like.
[0091] "CNS modulator" and "CNS modulating agent" are synonyms.
They refer to agents that decrease, diminish, partially suppress,
fully suppress, ameliorate, antagonize, agonize, stimulate or
increase the activity of the CNS. For example, they may increase
the activity of GABA by, for example, increasing the sensitivity of
the GABA receptors, or they may alter the depolarization in
neurons.
[0092] The term "diluent" refers to chemical compounds that are
used to dilute the CNS modulating agent prior to delivery and that
are compatible with the targeted auris structure(s).
[0093] "Dispersing agents," and/or "viscosity modulating agents"
are materials that control the diffusion and homogeneity of the CNS
modulating agent through liquid media. Examples of diffusion
facilitators/dispersing agents include but are not limited to
hydrophilic polymers, electrolytes, Tween.RTM. 60 or 80, PEG,
polyvinylpyrrolidone (PVP; commercially known as Plasdone.RTM.),
and the carbohydrate-based dispersing agents such as, for example,
hydroxypropyl celluloses (e.g., HPC, HPC-SL, and HPC-L),
hydroxypropyl methylcelluloses (e.g., HPMC K100, HPMC K4M, HPMC
K15M, and HPMC K100M), carboxymethylcellulose sodium,
methylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose,
hydroxypropylmethylcellulose phthalate,
hydroxypropylmethylcellulose acetate stearate (HPMCAS),
noncrystalline cellulose, magnesium aluminum silicate,
triethanolamine, polyvinyl alcohol (PVA), vinyl pyrrolidone/vinyl
acetate copolymer (S630), 4-(1,1,3,3-tetramethylbutyl)-phenol
polymer with ethylene oxide and formaldehyde (also known as
tyloxapol), poloxamers (e.g., Pluronic F127, Pluronics F68.RTM.,
F88.RTM., and F108.RTM., which are block copolymers of ethylene
oxide and propylene oxide); and poloxamines (e.g., Tetronic
908.RTM., also known as Poloxamine 908.RTM., which is a
tetrafunctional block copolymer derived from sequential addition of
propylene oxide and ethylene oxide to ethylenediamine (BASF
Corporation, Parsippany, N.J.)), polyvinylpyrrolidone K12,
polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or
polyvinylpyrrolidone K30, polyvinylpyrrolidone/vinyl acetate
copolymer (S-630), polyethylene glycol, e.g., the polyethylene
glycol has a molecular weight of about 300 to about 6000, or about
3350 to about 4000, or about 7000 to about 5400, sodium
carboxymethylcellulose, methylcellulose, polysorbate-80, sodium
alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar
gum, xanthans, including xanthan gum, sugars, cellulosics, such as,
e.g., sodium carboxymethylcellulose, methylcellulose, sodium
carboxymethylcellulose, polysorbate-80, sodium alginate,
polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan
monolaurate, povidone, carbomers, polyvinyl alcohol (PVA),
alginates, chitosans and combinations thereof. Plasticizers such as
cellulose or triethyl cellulose are also be used as dispersing
agents. Optional dispersing agents useful in liposomal dispersions
and self-emulsifying dispersions of the CNS modulating agents
disclosed herein are dimyristoyl phosphatidyl choline, phosphatidyl
cholines (c8-c18), phosphatidylethanolamines (c8-c18), phosphatidyl
glycerols (c8-c18), natural phosphatidyl choline from eggs or soy,
natural phosphatidyl glycerol from eggs or soy, cholesterol and
isopropyl myristate.
[0094] "Drug absorption" or "absorption" refers to the process of
movement of the CNS modulating agent(s) 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 CNS modulating agents to a
single patient, and are intended to include treatment regimens in
that the CNS modulating agents are administered by the same or
different route of administration or at the same or different
time.
[0095] The terms "effective amount" or "therapeutically effective
amount," as used herein, refer to a sufficient amount of the CNS
modulating agents 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 the CNS modulating agents disclosed herein is
reduction and/or alleviation of the signs, symptoms, or causes of
Meniere's disease. For example, an "effective amount" for
therapeutic uses is the amount of the CNS modulating agent,
including a composition 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 a CNS modulating agent composition 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.
[0096] The terms "enhance" or "enhancing" refers to an increase or
prolongation of either the potency or duration of a desired effect
of the CNS modulating agent, or a diminution of any adverse
symptoms such as localized pain that is consequent upon
administration of the therapeutic agent. Thus, in regard to
enhancing the effect of the CNS modulating 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 CNS modulating agents
disclosed herein. An "enhancing-effective amount," as used herein,
refers to an amount of a CNS modulating agents, or other
therapeutic agent, which is adequate to enhance the effect of
another therapeutic agent or CNS modulating agents 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.
[0097] The term "inhibiting" includes preventing, slowing, or
reversing the development of a condition, for example, Meniere's
disease, or advancement of a condition in a patient necessitating
treatment.
[0098] The terms "kit" and "article of manufacture" are used as
synonyms.
[0099] "Modulator of the GABA.sub.A receptor," "modulator of the
GABA receptor," "GABA.sub.A receptor modulator," and "GABA receptor
modulator," are synonyms. They refer to substances that modulate
the activity of the GABA neurotransmitter, by, for example,
increasing the sensitivity of the GABA receptor to GABA.
"Pharmacodynamics" refers to the factors that determine the
biologic response observed relative to the concentration of drug at
the desired site within the targeted auris structure.
[0100] "Pharmacokinetics" refers to the factors that determine the
attainment and maintenance of the appropriate concentration of drug
at the desired site within the targeted auris structure.
[0101] In prophylactic applications, compositions containing the
CNS modulators described herein are administered to a patient
susceptible to or otherwise at risk of a particular disease,
disorder or condition, for example, tinnitus, or patients that are
suffering from diseases associated with tinnitus, including by way
of example only, benign paroxysmal positions vertigo,
labyrinthitis, 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. As used herein, a
"pharmaceutical device" includes any composition described herein
that, upon administration to an ear, provides a reservoir for
extended release of an active agent described herein.
[0102] A "prodrug" refers to the CNS modulating agent that is
converted into the parent drug in vivo. In certain embodiments, a
prodrug is enzymatically metabolized by one or more steps or
processes to the biologically, pharmaceutically or therapeutically
active form of the compound. To produce a prodrug, a
pharmaceutically active compound is modified such that the active
compound will be regenerated upon in vivo administration. In one
embodiment, the prodrug is designed to alter the metabolic
stability or the transport characteristics of a drug, to mask side
effects or toxicity, or to alter other characteristics or
properties of a drug. Compounds provided herein, in some
embodiments, are derivatized into suitable prodrugs.
[0103] "Round window membrane" is the membrane in humans that
covers the fenestrae cochlea (also known as the circular window,
fenestrae rotunda, or round window). In humans, the thickness of
round window membrane is about 70 micron.
[0104] "Solubilizers" refers to auris-acceptable compounds such as
triacetin, triethylcitrate, ethyl oleate, ethyl caprylate, sodium
lauryl sulfate, sodium caprate, sucrose esters, alkylglucosides,
sodium doccusate, vitamin E TPGS, dimethylacetamide,
N-methylpyrrolidone, N-hydroxyethylpyrrolidone,
polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl
cyclodextrins, ethanol, n-butanol, isopropyl alcohol, cholesterol,
bile salts, polyethylene glycol 200-600, glycofurol, transcutol,
propylene glycol, and dimethyl isosorbide and the like.
[0105] "Stabilizers" refers to compounds such as any antioxidation
agents, buffers, acids, preservatives and the like that are
compatible with the environment of the targeted auris structure.
Stabilizers include but are not limited to agents that will do any
of (1) improve the compatibility of excipients with a container, or
a delivery system, including a syringe or a glass bottle, (2)
improve the stability of a component of the composition, or (3)
improve composition stability.
[0106] As used herein, the term "subtantially low degradation
products" means less than 5% by weight of the active agent are
degradation products of the active agent. In further embodiments,
the term means less than 3% by weight of the active agent are
degradation products of the active agent. In yet further
embodiments, the term means less than 2% by weight of the active
agent are degradation products of the active agent. In further
embodiments, the term means less than 1% by weight of the active
agent are degradation products of the active agent.
[0107] "Steady state," as used herein, is when the amount of drug
administered to the targeted auris structure is equal to the amount
of drug eliminated within one dosing interval resulting in a
plateau or constant levels of drug exposure within the targeted
structure.
[0108] As used herein, the term "subject" is used to mean any
animal, preferably a mammal, including a human or non-human. The
terms patient and subject may be used interchangeably. Neither term
is to be interpreted as requiring the supervision of a medical
professional (e.g., a doctor, nurse, physician's assistant,
orderly, hospice worker).
[0109] "Surfactants" refers to compounds that are auris-acceptable,
such as sodium lauryl sulfate, sodium docusate, Tween.RTM. 60 or
80, triacetin, vitamin E TPGS, sorbitan monooleate, polyoxyethylene
sorbitan monooleate, polysorbates, polaxomers, bile salts, glyceryl
monostearate, copolymers of ethylene oxide and propylene oxide,
e.g., Pluronic.RTM. (BASF), and the like. Some other surfactants
include polyoxyethylene fatty acid glycerides and vegetable oils,
e.g., polyoxyethylene (60) hydrogenated castor oil; and
polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol
10, octoxynol 40. In some embodiments, surfactants are included to
enhance physical stability or for other purposes.
[0110] The terms "treat," "treating" or "treatment," as used
herein, include alleviating, abating or ameliorating a disease or
condition 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.
[0111] 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,
which the detailed description and the specific examples, while
indicating specific embodiments, are given by way of illustration
only.
Anatomy of the Ear
[0112] As shown in FIG. 4, 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.
[0113] 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.
[0114] 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 that
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.
[0115] 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.
[0116] 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.
[0117] 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.
[0118] 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.
[0119] 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.
[0120] The cochlea is the portion of the auris interna related to
hearing. The cochlea is a tapered tube-like structure that 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.
[0121] 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).
[0122] 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 that 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
[0123] Otic disorders, including auris interna and auris media
disorders, produce symptoms that 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.
Endolymphatic Hydrops
[0124] Endolymphatic hydrops refers to an increase in the hydraulic
pressure within the endolymphatic system of the inner ear. The
endolymph and perilymph are separated by thin membranes that
contain multiple nerves. Fluctuation in the pressure stresses the
membranes and the nerves they house. If the pressure is great
enough, disruptions may form in the membranes. This results in a
mixing of the fluids that can lead to a depolarization blockade and
transient loss of function. Changes in the rate of vestibular nerve
firing often lead to vertigo. Further, the organ of Corti may also
be affected. Distortions of the basilar membrane and the inner and
outer hair cells can lead to hearing loss and/or tinnitus.
[0125] Causes include metabolic disturbances, hormonal imbalances,
autoimmune disease, and viral, bacterial, or fungal infections.
Symptoms include hearing loss, vertigo, tinnitus, and aural
fullness. Nystagmus may also be present.
Kinetosis
[0126] Kinetosis, also known as motion sickness, is a condition in
that there is a disconnection between visually perceived movement
and the vestibular system's sense of movement. Dizziness, fatigue,
and nausea are the most common symptoms of kinetosis.
Labyrinthitis
[0127] Labyrinthitis is an inflammation of the labyrinths of the
ear that contain the vestibular system of the inner ear. Causes
include bacterial, viral, and fungal infections. It may also be
caused by a head injury or allergies. Symptoms of labyrinthitis
include difficulty maintaining balance, dizziness, vertigo,
tinnitus, and hearing loss. Recovery may take one to six weeks;
however, chronic symptoms may be present for years.
Mal de Debarquement
[0128] Mal de debarquement is a condition that usually occurs
subsequent to a sustained motion event, for example, a cruise, car
trip, or airplane ride. It is characterized by a persistent sense
of motion, difficulty maintaining balance, fatigue, and cognitive
impairment. Symptoms may also include dizziness, headaches,
hyperacusis, and/or tinnitus. Symptoms often last in excess of a
month.
Meniere's Disease
[0129] Meniere's Disease is an idiopathic condition 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 Meniere's disease is likely
related to an imbalance of inner ear fluid homeostasis, including
an increase in production or a decrease in reabsorption of inner
ear fluid.
[0130] Studies of the vasopressin (VP)-mediated aquaporin 2 (AQP2)
system in the inner ear suggest a role for VP in inducing endolymph
production, thereby increasing pressure in the vestibular and
cochlear structures. VP levels were found to be upregulated in
endolymphatic hydrops (Meniere's Disease) cases, and chronic
administration of VP in guinea pigs was found to induce
endolymphatic hydrops. Treatment with VP antagonists, including
infusion of OPC-31260 (a competitive antagonist of V.sub.2-R) into
the scala tympani resulted in a marked reduction of Meniere's
disease symptoms. Other VP antagonists include WAY-140288,
CL-385004, tolvaptan, conivaptan, SR 121463A and VPA 985. (Sanghi
et al. Eur. Heart J. (2005) 26:538-543; Palm et al. Nephrol. Dial
Transplant (1999) 14:2559-2562).
[0131] Other studies suggest a role for estrogen-related receptor
.beta./NR3B2 (ERR/Nr3b2) in regulating endolymph production, and
therefore pressure in the vestibular/cochlear apparatus. Knock-out
studies in mice demonstrate the role of the protein product of the
Nr3b2 gene in regulating endolymph fluid production. Nr3b2
expression has been localized in the endolymph-secreting strial
marginal cells and vestibular dark cells of the cochlea and
vestibular apparatus, respectively. Moreover, conditional knockout
of the Nr3b2 gene results in deafness and diminished endolymphatic
fluid volume.
Meniere's Syndrome
[0132] 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, thus,
are secondary effects to various process that interfere with normal
production or reabsorption of endolymph, including endocrine
abnormalities, electrolyte imbalance, autoimmune dysfunction,
medications, infections (e.g. parasitic infections) or
hyperlipidemia.
Ramsay Hunt's Syndrome (Herpes Zoster Infection)
[0133] Ramsay Hunt's Syndrome is caused by a herpes zoster
infection of the auditory nerve. The infection may cause severe ear
pain, hearing loss, vertigo, as well as 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.
Recurrent Vestibulopathy
[0134] Recurrent vestibulopathy is a condition wherein the subject
experiences multiple episodes of severe vertigo. The episodes of
vertigo may last for minutes or hours. Unlike Meniere's Disease, it
is not accompanied by hearing loss. In some cases it may develop
into Meniere's Disease or Benign Paroxysmal Positional Vertigo.
Tinnitus
[0135] Tinnitus is defined as the perception of sound in the
absence of any external stimuli. It may occur in one or both ears,
continuously or sporadically, and is most often described as a
ringing sound. It is most often used as a diagnostic symptom for
other diseases. There are two types of tinnitus: objective and
subjective. The former is a sound created in the body that is
audible to anyone. The latter is audible only to the affected
individual. Studies estimate that over 50 million Americans
experience some form of tinnitus. Of those 50 million, about 12
million experience severe tinnitus.
Vertigo
[0136] Vertigo is described as a feeling of spinning or swaying
while the body is stationary. There are two types of vertigo.
Subjective vertigo is the false sensation of movement of the body.
Objective vertigo is the perception that one's surrounding are in
motion. It is often accompanied by nausea, vomiting, and difficulty
maintaining balance.
[0137] While not wishing to be bound by any one theory, it is
hypothesized that vertigo is caused by an over-accumulation of
endolymph. This fluid imbalance results in increased pressure on
the cells of the inner ear that leads to the sensation of movement.
The most common cause of vertigo is benign paroxysmal positional
vertigo, or BPPV. It can also be brought on by a head injury, or a
sudden change of blood pressure. It is a diagnostic symptom of
several diseases including superior canal dehiscence syndrome and
Meniere's disease.
Microvascular Compression Syndrome
[0138] Microvascular compression syndrome (MCS), also called also
called "vascular compression" and "neurovascular compression, is a
disorder characterized by vertigo and tinnitus. It is caused by the
irritation of the VII Cranial Nerve (also know as the
vestibulocochlear nerve) by a blood vessel. Other symptoms found in
subjects with MCS include, but are not limited to, severe motion
intolerance, and neuralgic like "quick spins".
Utricular Dysfunction
[0139] The utricle is one of the two otoliths found in the
vestibular labyrinth. It is responsive to both gravity and linear
acceleration along the horizontal plane. Utricular dysfunction is a
disorder caused by damage to the utricle. It is often characterized
by a subject's perception of tilting or imbalance.
Vestibular Neuronitis
[0140] Vestibular neuronitis, or vestibular neuropathy, is an
acute, sustained dysfunction of the peripheral vestibular system.
It is theorized that vestibular neuronitis is caused by a
disruption of afferent neuronal input from one or both of the
vestibular apparatuses. Sources of this disruption include viral
infection, and acute localized ischemia of the vestibular nerve
and/or labyrinth.
[0141] The most significant finding when diagnosing vestibular
neuronitis is spontaneous, unidirectional, horizontal nystagmus. It
is often accompanied by nausea, vomiting, and vertigo. It is,
generally, not accompanied by hearing loss or other auditory
symptoms.
Benign Paroxysmal Positional Vertigo
[0142] Benign paroxysmal positional vertigo is caused by the
movement of free floating calcium carbonate crystals (otoliths)
from the utricle to one of the semicircular canals, most often the
posterior semicircular canal. Movement of the head results in the
movement of the otoliths causing abnormal endolymph displacement
and a resultant sensation of vertigo. The episodes of vertigo
usually last for about a minute and are rarely accompanied by other
auditory symptoms.
Pharmaceutical Agents
[0143] Provided herein are CNS modulating compositions or
compositions that ameliorate or lessen balance disorders and/or
tinnitus. Otic disorders have causes and symptoms that are
responsive to the pharmaceutical agents disclosed herein, or other
pharmaceutical agents. CNS modulating agents that are not disclosed
herein but that are useful for the amelioration or eradication of
otic disorders are expressly included and intended within the scope
of the embodiments presented.
[0144] In some embodiments, the CNS modulating agent is a CNS
inhibitory agent. In some embodiments, the CNS inhibitory agent
inhibits the transmission of a nerve impulse. In some embodiments,
the CNS inhibitory agent inhibits the release of a
neurotransmitter. In some embodiments, the CNS inhibitory agent
agonizes the activity of a GABA receptor. In some embodiments, the
CNS inhibitory agent partially or fully inhibits the repolarization
of a neuron. In some embodiments, the CNS inhibitory agent disrupts
the conduction of an ion channel.
[0145] Moreover, pharmaceutical agents that have been previously
shown to be toxic, harmful or non-effective during systemic or
localized application in other organ systems (e.g., 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
contemplated for use with any of the compositions disclosed herein.
Accordingly, pharmaceutical agents that have limited or no systemic
release, systemic toxicity, poor pK characteristics or combinations
thereof are contemplated within the scope of the embodiments
disclosed herein.
[0146] The CNS modulating compositions disclosed herein are
optionally targeted directly to otic structures where treatment is
needed; for example, one embodiment contemplated is the direct
application of the CNS modulating compositions disclosed herein
onto the round window membrane or the crista fenestrae cochlea of
the auris interna, allowing direct access and treatment of the
auris interna, or inner ear components. In other embodiments, the
CNS modulating composition disclosed herein is applied directly to
the oval window. In yet other embodiments, direct access is
obtained through microinjection directly into the auris interna,
for example, through cochlear microperfusion. Such embodiments also
optionally comprise a drug delivery device, wherein the drug
delivery device delivers the CNS modulating compositions through
use of a needle and syringe, a pump, a microinjection device or any
combination thereof. In still other embodiments, application of the
CNS modulating composition is targeted to the auris media through
piercing of the intratympanic membrane and applying the CNS
modulating composition directly to the auris media structures
affected, including the walls of the tympanic cavity or auditory
ossicles. By doing so, the CNS modulating compositions disclosed
herein are confined to the targeted auris media structure, and will
not be lost, for example, through diffusion or leakage through the
eustachian tube or pierced tympanic membrane.
[0147] Some pharmaceutical agents, either alone or in combination,
are ototoxic. The localized application of the potentially ototoxic
drug lessens the toxic effects that occur through systemic
application (e.g., through the use of lower amounts with maintained
efficacy or the use of targeted amounts for a shorter period of
time).
Antihistamines
[0148] Contemplated for use with the compositions disclosed herein
are agents that ameliorate otic disorders, including vestibular
disorders and/or tinnitus, through local modulation of central
nervous system (CNS) activity. Accordingly, some embodiments
incorporate the use of agents that block the action of
neurotransmitters in the CNS. Histamine is a neurotransmitter in
the CNS. Accordingly, some embodiments incorporate the use of
agents that modulate histamine receptors (e.g. the H.sub.1
receptor, H.sub.2 receptor, and/or the H.sub.3 receptor).
[0149] Antihistamines that target the H.sub.1 receptor include, but
are not limited to, meclizine, diphenhydramine, dimenhydrinate,
loratadine and quetiapine. Other antihistamines include mepyramine,
piperoxan, antazoline, carbinoxamine, doxylamine, clemastine,
pheniramine, chlorphenamine, chlorpheniramine, dexchlorpheniramine,
brompheniramine, triprolidine, cyclizine, chlorcyclizine,
hydroxyzine, promethazine, alimemazine, trimeprazine,
cyproheptadine, azatadine, ketotifen, oxatomide and combinations
thereof. In some embodiments, the H.sub.1 receptor antagonist is
meclizine hydrochloride. In some embodiments, the H.sub.1 receptor
antagonist is promethazine hydrochloride. In some embodiments, the
H.sub.1 receptor antagonist is dimenhydrinate. In some embodiments,
the H.sub.1 receptor antagonist is diphenhydramine. In some
embodiments, the H.sub.1 receptor antagonist is cinnarizine. In
some embodiments, the H.sub.1 receptor antagonist is hydroxyzine
pamoate.
[0150] Antihistamines that target the H.sub.3 receptor include, but
are not limited to, betahistine dihydrochloride.
GABA Receptor Modulators
[0151] Contemplated for use with the compositions disclosed herein
are agents that ameliorate otic disorders, including vestibular
disorders and/or tinnitus, through local modulation of central
nervous system (CNS) activity. Accordingly, some embodiments
incorporate the use of agents that modulate the action of GABA
receptors in the CNS. GABA, or .gamma.-aminobutyric acid, is an
inhibitory neurotransmitter in the CNS. It acts at inhibitory
synapses of both pre- and postsynaptic neuronal processes. The
binding of GABA to its receptors (the GABA.sub.A receptor, the
GABA.sub.B receptor, and the GABA.sub.C receptor) results in the
opening of ion channels, and the flow of Cl.sup.- into the cell
and/or K.sup.+ out of the neuron. The result is hyperpolarization
of the neuron. Accordingly, some embodiments incorporate the use of
agents that increase or decrease the sensitivity of the GABA
receptors, or activate the GABA receptors by mimicking GABA.
[0152] The benzodiazepines are agonists of the GABA.sub.A receptor.
When a benzodiazepine binds to the GABA.sub.A receptor it induces a
conformational change that increases the affinity of GABA for its
receptor. The result of the increase in the binding of GABA is an
increase in the frequency with that the Cl.sup.- channels in the
neurons open. This causes hyperpolarization of the neural membrane.
In some embodiments, the benzodiazepine is selected from the group
consisting of: alprazolam, bromazepam, brotizolam,
chlordiazepoxide, clonazepam, clorazepate, diazepam, estazolam,
flunitrazepam, flurazepam, loprazolam, lorazepam, lormetazepam,
idazolam, nimetazepam, nitrazepam, oxazepam, prazepam, temazepam,
triazolam or combinations thereof. In some embodiments, the
benzodiazepine is clonazepam, diazepam, lorazepam, or combinations
thereof. In some embodiments, the benzodiazepine is diazepam.
[0153] In some embodiments, the GABA receptor modulator is a loop
diuretic. In some embodiments, the loop diuretic is furosemide,
bumetanide, or ethacrynic acid. In some embodiments, the loop
diuretic is furosemide. In some embodiments, the loop diuretic is
bumetanide. In some embodiments, the loop diuretic is ethacrynic
acid. Furosemide, for example, binds to the GABA.sub.A receptor and
reversibly antagonizes GABA-evoked currents of the .alpha.6,
.beta.2, and .gamma.2 receptors. By way of example only, useful
loop diuretics include, but are not limited to, furosemide,
bumetanide, and ethacrynic acid.
[0154] In some embodiments, the modulator of a GABA receptor is a
GABA analogue. GABA analogues mimic GABA. Thus, when they bind to a
GABA receptor, the receptor acts as though GABA is binding to it
and the receptor is activated. In some embodiments, the GABA analog
is gabapentin, pregabalin, muscimol, or baclofen. In some
embodiments, the GABA analog is gabapentin. In some embodiments,
the GABA analog is pregabalin. In some embodiments, the GABA analog
is muscimol. In some embodiments, the GABA analogue is baclofen.
Baclofen is an analogue of GABA that binds to and activates the
GABA.sub.B receptor. Muscimol is also an analogue of GABA. In some
embodiments, muscimol agonizes the GABA.sub.A receptor.
Neurotransmitter Reuptake Inhibitors
[0155] Contemplated for use with the compositions disclosed herein
are agents that ameliorate otic disorders, including vestibular
disorders and/or tinnitus, through local modulation of central
nervous system (CNS) activity. Accordingly, some embodiments
incorporate the use of agents that inhibit the reuptake of
neurotransmitters in the CNS. Neurotransmitter reuptake inhibitors
inhibit the reuptake of neurotransmitters into presynaptic cells of
the CNS. This increases the concentration of neurotransmitter
available to stimulate post-synaptic cells of the CNS.
[0156] In some embodiments, the neurotransmitter reuptake
inhibitors are tricyclic antidepressants. Tricyclic antidepressants
work by inhibiting the re-uptake of the neurotransmitters
norepinephrine and serotonin by pre-synaptic cells. This increases
the level of serotonin and/or norepinephrine available to bind to
the postsynaptic receptor. In some embodiments, the tricyclic
antidepressant is amitriptyline, nortriptyline, or trimipramine. In
some embodiments, the tricyclic antidepressant is amitriptyline. In
some embodiments, the tricyclic antidepressant is nortriptyline. In
some embodiments, the tricyclic antidepressant is trimipramine.
[0157] In some embodiments, the neurotransmitter reuptake inhibitor
is a selective serotonin reuptake inhibitor. By inhibiting the
reuptake of serotonin into the presynaptic cells, SSRIs increase
the extracellular level of serotonin. This increases the level of
serotonin available to bind to the postsynaptic receptor. SSRIs are
hypothesized to stimulate new neural growth within the inner ear.
In some embodiments, the selective serotonin reuptake inhibitor is
fluoxetine, paroxetine, or sertraline. In some embodiments, the
selective serotonin reuptake inhibitor is fluoxetine. In some
embodiments, the selective serotonin reuptake inhibitor is
paroxetine. In some embodiments, the selective serotonin reuptake
inhibitor is sertraline.
Anticholinergics
[0158] Contemplated for use with the compositions disclosed herein
are agents that ameliorate otic disorders, including vestibular
disorders and/or tinnitus, through local modulation of central
nervous system (CNS) activity. Accordingly, some embodiments
incorporate the use of agents that inhibit the release of the
neurotransmitter acetylcholine in the CNS. Anticholinergic agents
are substances that block acetylcholine in the central and the
peripheral nervous system. They treat balance disorders by
suppressing conduction in vestibular cerebellar pathways, thus
increasing motion tolerance.
[0159] In some embodiments, the anticholinergic is glycopyrrolate,
homatropine, scopolamine or atropine. In some embodiments, the
anticholinergic is glycopyrrolate. In some embodiments, the
anticholinergic is homatropine. In some embodiments, the
anticholinergic is scopolamine. In some embodiments, the
anticholinergic is atropine.
Local Anesthetics
[0160] Contemplated for use with the compositions disclosed herein
are agents that ameliorate otic disorders, including vestibular
disorders and/or tinnitus, through local modulation of central
nervous system (CNS) activity. Accordingly, some embodiments
incorporate the use of agents that decrease the rate of the
depolarization and repolarization of neurons by, for example,
blocking the Na.sup.+ channels in cell membranes.
[0161] In some embodiments, the CNS modulator is a local
anesthetic. In some embodiments, the local anesthetic is selected
from the group consisting of: benzocaine, carticaine, cinchocaine,
cyclomethycaine, lidocaine, prilocaine, propxycaine, proparacaine,
tetracaine, tocainide, and trimecaine. In some embodiments, the
local anesthetic is lidocaine. In some embodiments, the local
anesthetic is tocainide.
Sodium Channel Blockers
[0162] Contemplated for use with the compositions disclosed herein
are agents that ameliorate otic disorders, including vestibular
disorders and/or tinnitus, through local modulation of central
nervous system (CNS) activity. Accordingly, some embodiments
incorporate the use of agents that block or antagonize Na+
channels. Sodium channels are channels formed in the plasma
membrane of neurons (amongst other cells) by integral membrane
proteins. These channels conduct Na.sup.+ through a cell's plasma
membrane. In neurons, the flow of Na.sup.+ is partly responsible
for creating and propagating action potentials in the neurons.
[0163] In some embodiments, the sodium channel blocker is
carbamazepine, oxcarbazepine, phenytein, valproic acid, or sodium
valproate. In some embodiments, the sodium channel blocker is
carbamazepine. In some embodiments, the sodium channel blocker is
oxcarbazepine. In some embodiments, the sodium channel blocker is
phenytein. In some embodiments, the sodium channel blocker is
valproic acid. In some embodiments, the sodium channel blocker is
sodium valproate.
Calcium Channel Blockers
[0164] Contemplated for use with the compositions disclosed herein
are agents that ameliorate otic disorders, including vestibular
disorders and/or tinnitus, through local modulation of central
nervous system (CNS) activity. Accordingly, some embodiments
incorporate the use of agents that block or antagonize Ca+
channels. Calcium channels are channels formed in the plasma
membrane of neurons (amongst other cells) by integral membrane
proteins. These channels conduct Ca.sup.+ through a cell's plasma
membrane. In neurons, the flow of Ca.sup.2+ is partly responsible
for creating and propagating action potentials in neurons. It can
also be responsible for the release of certain
neurotransmitters.
[0165] In some embodiments, the calcium channel antagonist is
cinnarizine, flunarizine, or nimodipine. In some embodiments, the
calcium channel antagonist is cinnarizine. In some embodiments, the
calcium channel antagonist is flunarizine. In some embodiments, the
calcium channel antagonist is nimodipine.
Thyrotropin-Releasing Hormone
[0166] Contemplated for use with the compositions disclosed herein
are agents that ameliorate otic disorders, including vestibular
disorders and/or tinnitus, through local modulation of central
nervous system (CNS) activity. Accordingly, some embodiments
incorporate the use of agents that modulate neurotransmitters.
Thyrotropin-releasing hormone is a neurotransmitter that inhibits
glutamate-induced excitation of neurons. In some embodiments, the
CNS modulator is thyrotropin-releasing hormone.
[0167] In some embodiments, the compositions further comprise a CNS
modulator as an immediate release agent (i.e. an immediate release
CNS agent). In some embodiments, the immediate release CNS
modulator is the same agent as the controlled-release agent, a
different CNS modulator, an additional therapeutic agent, or a
combination thereof.
Concentration of Active Agent
[0168] In some embodiments, the concentration of a CNS modulating
agent in a pharmaceutical composition or device described herein is
about 1% by weight of the composition. In some embodiments, the
concentration of a CNS modulating agent in a pharmaceutical
composition or device described herein is about 2% by weight of the
composition. In some embodiments, the concentration of a CNS
modulating agent in a pharmaceutical composition or device
described herein is about 3% by weight of the composition. In some
embodiments, the concentration of a CNS modulating agent in a
pharmaceutical composition or device described herein is about 4%
by weight of the composition. In some embodiments, the
concentration of a CNS modulating agent in a pharmaceutical
composition or device described herein is about 5% by weight of the
composition. In some embodiments, the concentration of a CNS
modulating agent in a pharmaceutical composition or device
described herein is about 10% by weight of the composition. In some
embodiments, the concentration of a CNS modulating agent in a
pharmaceutical composition or device described herein is about 15%
by weight of the composition. In some embodiments, the
concentration of a CNS modulating agent in a pharmaceutical
composition or device described herein is about 20% by weight of
the composition. In some embodiments, the concentration of a CNS
modulating agent in a pharmaceutical composition or device
described herein is about 25% by weight of the composition. In some
embodiments, the concentration of a CNS modulating agent in a
pharmaceutical composition or device described herein is about 30%
by weight of the composition. In some embodiments, the
concentration of a CNS modulating agent in a pharmaceutical
composition or device described herein is about 40% by weight of
the composition. In some embodiments, the concentration of a CNS
modulating agent in a pharmaceutical composition or device
described herein is about 50% by weight of the composition. In some
embodiments, the concentration of a CNS modulating agent in a
pharmaceutical composition or device described herein is about 60%
by weight of the composition. In some embodiments, the
concentration of a CNS modulating agent in a pharmaceutical
composition or device described herein is about 70% by weight of
the composition. In some embodiments, the concentration of a CNS
modulating agent in a pharmaceutical composition or device
described herein is about 80% by weight of the composition. In some
embodiments, the concentration of a CNS modulating agent in a
pharmaceutical composition or device described herein is about 90%
by weight of the composition.
[0169] In some embodiments, the compositions 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
composition.
Combination Therapy
[0170] In some embodiments, the compositions disclosed herein
further comprise an additional therapeutic agent. In some
embodiments, the additional therapeutic agent is an acidifying
agent, an anesthetic, an analgesic, an antibiotic, antiemetic, an
antifungal, an anti-microbial agent, an antipsychotic (especially
those in the phenothiazine class), an antiseptic, an antiviral, an
astringent, a chemotherapeutic agent, a collagen, a corticosteroid,
a diuretic, a keratolytic agent, a nitric oxide synthase inhibitor,
or combinations thereof.
Acidifying Agents
[0171] Acidifying agents are optionally used in combination with
the compositions disclosed herein. Acidifying agents lower the pH
level of the vestibular environment making it unfavorable to most
microbial growth. Acidifying agents include, but are not limited
to, acetic acid.
Anti-Emetic Agents
[0172] Anti-Emetic agents are optionally used in combination with
the compositions disclosed herein. Anti-emetic agents include
promethazine, prochlorperazine, trimethobenzamide, and
triethylperazine. Other anti-emetic agents include 5HT3 antagonists
such as dolasetron, granisetron, ondansetron, tropisetron, and
palonosetron; and neuroleptics such as droperidol. Further
anti-emetic agents include antihistamines, such as meclizine;
phenothiazines such as perphenazine, and thiethyl perazine;
dopamine antagonists, including domperidone, properidol,
haloperidol, chlorpromazine, promethazine, prochlorperazine,
metoclopramide and combinations thereof; cannabinoids, including
dronabinol, nabilone, sativex, and combinations thereof;
anticholinergics, including scopolamine; and steroids, including
dexamethasone; trimethobenzamine, emetrol, propofol, muscimol, and
combinations thereof.
Antimicrobial Agents
[0173] Antimicrobial agents are also contemplated as useful with
the compositions disclosed herein. Antimicrobial agents include
agents that act to inhibit or eradicate microbes, including
bacteria, fungi or parasites. Specific antimicrobial agents may be
used to combat specific microbes. Accordingly, a skilled
practitioner would know that antimicrobial agent would be relevant
or useful depending on the microbe identified, or the symptoms
displayed. Antimicrobial agents include antibiotics, antiviral
agents, antifungal agents, and antiparasitic agents.
[0174] Antibiotics include, but are not limited to, amikacin,
gentamicin, kanamycin, neomycin, netilmicin, streptomycin,
tobramycin, paromomycin, geldanmycin, herbimycin, loracarbef,
ertapenem, doripenem, imipenem, cilastatin, meropenem, cefadroxil,
cefazolin, cefalotin, cefalexin, cefaclor, cefamandole, cefoxitin,
defprozil, cefuroxime, cefixime, cefdinir, cefditoren,
cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten,
ceftizoxime, ceftriaxone, cefepime, ceftobiprole, teicoplanin,
vancomycin, azithromycin, clarithromycin, dirithromycin,
erythromycin, roxithromycin, troleandomycin, telithromycin,
spectinomycin, aztreonam, amoxicillin, ampicillin, azlocillin,
carbenicillin, cloxacillin, dicloxacillin, flucloxacillin,
mezlocillin, meticillin, nafcillin, oxacillin, penicillin,
piperacillin, ticarcillan, bacitracin, colistin, polymyxin B,
ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin,
moxifloxacin, norfloxacin, ofloxacin, trovfloxacin, mafenide,
prontosil, sulfacetamide, sulfamethizole, sulfanimilimde,
sulfsalazine, sulfsioxazole, trimethoprim, demeclocycline,
doxycycline, minocycline, oxtetracycline, tetracycline,
arsphenamine, chloramphenicol, clindamycin, lincomycin, ethambutol,
fosfomycin, fusidic acid, furazolidone, isoniazid, linezolid,
metronidazole, mupirocin, nitrofurantoin, platensimycin,
pyrazinamide, quinuspristin/dalfopristin, rifampin, tinidazole, and
combinations thereof.
[0175] Antiviral agents include, but are not limited to, acyclovir,
famciclovir and valacyclovir. Other antiviral agents include
abacavir, aciclovir, adfovir, amantadine, amprenavir, arbidol.,
atazanavir, artipla, brivudine, cidofovir, combivir, edoxudine,
efavirenz, emtricitabine, enfuvirtide, entecavir, fomvirsen,
fosamprenavir, foscarnet, fosfonet, ganciclovir, gardasil,
ibacitabine, imunovir, idoxuridine, imiquimod, indinavir, inosine,
integrase inhibitors, interferons, including interferon type III,
interferon type II, interferon type I, lamivudine, lopinavir,
loviride, MK-0518, maraviroc, moroxydine, nelfinavir, nevirapine,
nexavir, nucleoside analogues, oseltamivir, penciclovir, peramivir,
pleconaril, podophyllotoxin, protease inhibitors, reverse
transcriptase inhibitors, ribavirin, rimantadine, ritonavir,
saquinavir, stavudine, tenofovir, tenofovir disoproxil, tipranavir,
trifluridine, trizivir, tromantadine, truvada, valganciclovir,
vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir,
zidovudine, and combinations thereof.
[0176] Antifungal agents include, but are not limited to,
amrolfine, utenafine, naftifine, terbinafine, flucytosine,
fluconazole, itraconazole, ketoconazole, posaconazole,
ravuconazole, voriconazole, clotrimazole, econazole, miconazole,
oxiconazole, sulconazole, terconazole, tioconazole, nikkomycin Z,
caspofungin, micafungin, anidulafungin, amphotericin B, liposomal
nystastin, pimaricin, griseofulvin, ciclopirox olamine, haloprogin,
tolnaftate, undecylenate, and combinations thereof. Antiparasitic
agents may include amitraz, amoscanate, avermectin, carbadox,
diethylcarbamizine, dimetridazole, diminazene, ivermectin,
macrofilaricide, malathion, mitaban, oxamniquine, permethrin,
praziquantel, prantel pamoate, selamectin, sodium stibogluconate,
thiabendazole, and combinations thereof.
Anti-Septic Agents
[0177] Anti-septic agents are also contemplated as useful with the
compositions disclosed herein. Anti-septic agents include, but are
not limited to, acetic acid, boric acid, gentian violet, hydrogen
peroxide, carbamide peroxide, chlorhexidine, saline, mercurochrome,
povidone iodine, polyhyroxine iodine, cresylate and aluminum
acetate, and mixtures thereof.
Astringents
[0178] Astringents are also contemplated as useful with the
compositions disclosed herein. Astringents include, but are not
limited to, isopropyl alcohol, ethanol and propylene glycol.
Corticosteroids
[0179] Corticosteroids are also contemplated as useful with the
compositions disclosed herein. Corticosteroids include, but are not
limited to, hydrocortisone, prednisone, fluprednisolone,
dexamethasone, betamethasone, betamethasone valerate,
methylprednisolone, fluocinolone acetonide, flurandrenolone
acetonide, fluorometholone, cortisone, prednisolone, alclometasone,
amcinonide, betamethasone, clobetasol, clocortolone, desonide,
desoximetasone, diflorasone, fluocinonide, flurandrenolide,
fluticasone, halcinonide, halobetasol, mometasone, flumethasone,
prednicarbate and triamcinolone, and mixtures thereof.
Platelet Activating Factor Antagonists
[0180] Platelet activating factor antagonists are also contemplated
for use in combination with the CNS modulating compositions
disclosed herein. Platelet activating factor antagonists include,
by way of example only, kadsurenone, phomactin G, ginsenosides,
apafant
(4-(2-chlorophenyl)-9-methyl-2[3(4-morpholinyl)-3-propanol-1-yl[6H-thieno-
[3.2-f[[1.2.4]triazolo]4,3-1]]1.4]diazepine), A-85783, BN-52063,
BN-52021, BN-50730 (tetrahedra-4,7,8,10 methyl-1 (chloro-1
phenyl)-6 (methoxy-4 phenyl-carbamoyl)-9 pyrido [4',3'-4,5] thieno
[3,2-f] triazolo-1,2,4 [4,3-a] diazepine-1,4), BN 50739, SM-12502,
RP-55778, Ro 24-4736, SR27417A, CV-6209, WEB 2086, WEB 2170,
14-deoxyandrographolide, CL 184005, CV-3988, TCV-309, PMS-601,
TCV-309 and combinations thereof.
[0181] Presented below (Table 1) are examples of active agents
contemplated for use with the compositions and devices disclosed
herein. In some embodiments, one or more active agents disclosed in
Table 1 are used in a composition or device described herein.
TABLE-US-00001 TABLE 1 Auris Condition Therapeutic Agent Benign
Paroxysmal Diphenhydramine Positional Vertigo Benign Paroxysmal
Lorazepam Positional Vertigo Benign Paroxysmal Meclizine Positional
Vertigo Benign Paroxysmal Oldansetron Positional Vertigo Hearing
Loss Estrogen AIED Etanercept (Enbrel) AIED GW3333 AIED Copaxone
Hearing Loss Estrogen and progesterone (E + P) Hearing Loss Folic
acid Hearing Loss Lactated Ringer's with 0.03% Ofloxacin Hearing
Loss Methotrexate Hearing Loss N-acetyl cysteine Meniere's Disease
Betahistine Meniere's Disease Sildenafil Meniere's Disease
Tacrolimus Middle Ear Effusion Pneumonococcal vaccine Otitis
Externa Diclofenac sodium; dexotc Otitis Externa, Acute
AL-15469A/AL-38905 Otitis Media Amoxicillin/clavulanate Otitis
Media Dornase alfa Otitis Media Echinacea purpurea Otitis Media
Faropenem medoxomil Otitis Media Levofloxacin Otitis Media PNCRM9
Otitis Media Pneumococcal vaccine Otitis Media Telithromycin Otitis
Media Zmax Otitis Media with Lansoprazole Effusion Otitis Media,
Acute AL-15469A; AL-38905 Otitis Media, Acute Amoxicillin Otitis
Media, Acute Amoxicillin-clavulanate Otitis Media, Acute
Azithromycin Otitis Media, Acute Azithromycin SR Otitis Media,
Acute Cefdinir Otitis Media, Acute Hyland's earache drops Otitis
Media, Acute Montelukast Otitis Media, Acute Pneumonococcal vaccine
Otitis Media, Acute AL-15469A/AL38905 with Typanostomy Tubes Otitis
Media, Chronic Sulfamethoxazole- trimethoprim Otitis Media,
Azithromycin Suppurative Otitis Media, Telithromycin Suppurative
Otosclerosis Acetylcysteine Ototoxicity Aspirin Tinnitus
Acamprosate Tinnitus Gabapentin Tinnitus Modafinil Tinnitus
Neramexane Tinnitus Neramexane mesylate Tinnitus Piribedil Tinnitus
Vardenafil Tinnitus Vestipitant + Paroxetine Tinnitus Vestiplitant
Tinnitus Zinc sulfate
[0182] In some embodiments, the additional therapeutic agent is an
immediate release agent. In some embodiments, the additional
therapeutic agent is a controlled-release agent.
General Methods of Sterilization
[0183] Provided herein are otic compositions that ameliorate or
lessen otic disorders described herein. Further provided herein, in
some embodiments, 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.
[0184] 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 contemplated for use with the
compositions and devices disclosed herein. Available methods for
the inactivation of microorganisms include, but are not limited to,
the application of extreme heat, lethal chemicals, or gamma
radiation. Disclosed herein, in some embodiments, are processes for
the preparation of an otic therapeutic composition comprising
subjecting the composition 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.
[0185] Sterilization by Heat
[0186] 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.
[0187] Dry heat sterilization is a method that 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
compositions is also sterilized by autoclave. In some embodiments,
the compositions described herein comprise micronized
pharmaceutical 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.
[0188] Chemical Sterilization
[0189] 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.
[0190] Radiation Sterilization
[0191] 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
compositions described herein are also optionally sterilized using
beta irradiation.
[0192] Filtration
[0193] 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 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.71 cm.sup.2) of unusually small microorganisms, such as
Brevundimonas diminuta (ATCC 19146).
[0194] Pharmaceutical compositions are optionally sterilized by
passing through membrane filters. Compositions 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.
[0195] In some embodiments, the methods disclosed herein comprise
sterilizing the composition (or components thereof) by means of
filtration sterilization. In another embodiment the
auris-acceptable otic therapeutic agent composition comprises a
particle wherein the particle composition is suitable for
filtration sterilization. In a further embodiment said particle
composition 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 composition comprises a particle
composition wherein the sterility of the particle is ensured by
sterile filtration of the precursor component solutions. In another
embodiment the auris-acceptable composition comprises a particle
composition wherein the sterility of the particle composition 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.
[0196] In another embodiment is a process for the preparation of an
auris-acceptable particle composition comprising: filtering the
aqueous solution containing the particle composition at low
temperature through a sterilization filter; lyophilizing the
sterile solution; and reconstituting the particle composition with
sterile water prior to administration. In some embodiments, a
composition described herein is manufactured as a suspension in a
single vial composition containing the micronized active
pharmaceutical ingredient. A single vial composition is prepared by
aseptically mixing a sterile poloxamer solution with sterile
micronized active ingredient (e.g., PD98059) and transferring the
composition to sterile pharmaceutical containers. In some
embodiments, a single vial containing a composition described
herein as a suspension is resuspended before dispensing and/or
administration.
[0197] In specific embodiments, filtration and/or filling
procedures are carried out at about 5.degree. C. below the gel
temperature (T.sub.gel) of a composition described herein and with
viscosity below a theoretical value of 100 cP to allow for
filtration in a reasonable time using a peristaltic pump.
[0198] In another embodiment the auris-acceptable otic therapeutic
agent composition comprises a nanoparticle composition wherein the
nanoparticle composition is suitable for filtration sterilization.
In a further embodiment the nanoparticle composition 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 composition comprises a microsphere composition
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 composition comprises a
thermoreversible gel composition wherein the sterility of the gel
composition 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 composition 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
composition with sterile water prior to administration.
[0199] In certain embodiments, the active ingredients are dissolved
in a suitable vehicle (e.g. a buffer) and sterilized separately
(e.g. by heat treatment, filtration, gamma radiation). 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
compositions) 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 composition. In
some instances, the final aseptic mixing is performed just prior to
administration of a composition described herein.
[0200] In some instances, conventionally used methods of
sterilization (e.g., heat treatment (e.g., in an autoclave), gamma
irradiation, filtration) lead to irreversible degradation of
polymeric components (e.g., thermosetting, gelling or mucoadhesive
polymer components) and/or the active agent in the composition. In
some instances, sterilization of an auris composition by filtration
through membranes (e.g., 0.2 .mu.M membranes) is not possible if
the composition comprises thixotropic polymers that gel during the
process of filtration.
[0201] Accordingly, provided herein are methods for sterilization
of auris compositions 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
compositions. In some embodiments, the choice of an appropriate
gelling agent and/or thermosetting polymer allows for sterilization
of compositions 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 composition allows for high temperature
sterilization of compositions 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 compositions 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.
[0202] Microorganisms
[0203] 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 sterility
levels are based on applicable standards that define
therapeutically acceptable otic compositions, including but not
limited to United States Pharmacopeia Chapters <1111> et seq.
For example, acceptable sterility levels include about 10 colony
forming units (cfu) per gram of composition, about 50 cfu per gram
of composition, about 100 cfu per gram of composition, about 500
cfu per gram of composition or about 1000 cfu per gram of
composition. In some embodiments, acceptable sterility levels for
compositions 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 sterility levels 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.
[0204] Sterility of the auris-acceptable otic therapeutic agent
composition 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 that 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.
[0205] 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.
[0206] In certain embodiments, any controlled-release composition
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 composition. In certain embodiments,
the otic compositions described herein are formulated to be
isotonic with the endolymph and/or the perilymph.
[0207] Endotoxins
[0208] 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 that 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 sterility 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 composition has less than about 5 EU/kg of body
weight of a subject. In other embodiments, the auris-acceptable
otic therapeutic agent composition has less than about 4 EU/kg of
body weight of a subject. In additional embodiments, the
auris-acceptable otic therapeutic agent composition has less than
about 3 EU/kg of body weight of a subject. In additional
embodiments, the auris-acceptable otic therapeutic agent
composition has less than about 2 EU/kg of body weight of a
subject.
[0209] In some embodiments, the auris-acceptable otic therapeutic
agent composition or device has less than about 5 EU/kg of
composition. In other embodiments, the auris-acceptable otic
therapeutic agent composition has less than about 4 EU/kg of
composition. In additional embodiments, the auris-acceptable otic
therapeutic agent composition has less than about 3 EU/kg of
composition. In some embodiments, the auris-acceptable otic
therapeutic agent composition has less than about 5 EU/kg Product.
In other embodiments, the auris-acceptable otic therapeutic agent
composition has less than about 1 EU/kg Product. In additional
embodiments, the auris-acceptable otic therapeutic agent
composition has less than about 0.2 EU/kg Product. In some
embodiments, the auris-acceptable otic therapeutic agent
composition has less than about 5 EU/g of unit or Product. In other
embodiments, the auris-acceptable otic therapeutic agent
composition has less than about 4 EU/g of unit or Product. In
additional embodiments, the auris-acceptable otic therapeutic agent
composition has less than about 3 EU/g of unit or Product. In some
embodiments, the auris-acceptable otic therapeutic agent
composition has less than about 5 EU/mg of unit or Product. In
other embodiments, the auris-acceptable otic therapeutic agent
composition has less than about 4 EU/mg of unit or Product. In
additional embodiments, the auris-acceptable otic therapeutic agent
composition 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 composition. In certain
embodiments, otic compositions described herein contain from about
2 to about 5 EU/mL of composition, from about 3 to about 5 EU/mL of
composition, or from about 4 to about 5 EU/mL of composition.
[0210] In certain embodiments, otic compositions or devices
described herein contain lower endotoxin levels (e.g. <0.5 EU/mL
of composition) when compared to conventionally acceptable
endotoxin levels (e.g., 0.5 EU/mL of composition). In some
embodiments, the auris-acceptable otic therapeutic agent
composition or device has less than about 0.5 EU/mL of composition.
In other embodiments, the auris-acceptable otic therapeutic agent
composition has less than about 0.4 EU/mL of composition. In
additional embodiments, the auris-acceptable otic therapeutic agent
composition has less than about 0.2 EU/mL of composition.
[0211] 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 composition is subject to
depyrogenation. In a further embodiment, the process for the
manufacture of the auris-acceptable otic therapeutic agent
composition comprises testing the composition for pyrogenicity. In
certain embodiments, the compositions described herein are
substantially free of pyrogens.
[0212] pH and Practical Osmolarity
[0213] As used herein, "practical osmolarity/osmolality" or
"deliverable osmolarity/osmolality" means the osmolarity/osmolality
of a composition 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 described herein is measured by any 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 described herein is measured
by vapor pressure osmometry (e.g., vapor pressure depression
method) that allows for determination of the osmolarity of a
composition at higher temperatures. In some instances, vapor
pressure depression method allows for determination of the
osmolarity of a composition comprising a gelling agent (e.g., a
thermoreversible polymer) at a higher temperature wherein the
gelling agent is in the form of a gel. The practical osmolality of
an otic composition described 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, the compositions 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 250 mOsm/L to about 320
mOsm/L, or about 280 mOsm/L to about 320 mOsm/L.
[0214] 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 any composition described herein. In
some embodiments, the compositions described herein have 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.
[0215] 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 composition described herein is formulated to provide an
ionic balance that is compatible with inner ear fluids (e.g.,
endolymph and/or perilymph).
[0216] 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.
[0217] 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.
[0218] In some embodiments, useful compositions 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.
[0219] In one embodiment, when one or more buffers are utilized in
the compositions of the present disclosure, they are combined
(e.g., with a pharmaceutically acceptable vehicle) and are present
in the final composition (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 compositions are an amount such that the pH of
the gel composition does not interfere with the body's natural
buffering system.
[0220] In one embodiment, diluents are also used to stabilize
compounds because they can provide a more stable environment. Salts
dissolved in buffered solutions (that also can provide pH control
or maintenance) are utilized as diluents in the art, including, but
not limited to a phosphate buffered saline solution.
[0221] In some embodiments, any gel composition 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 composition without degradation of the
pharmaceutical 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 composition in the 7-8 range during the process
of sterilization (e.g., high temperature autoclaving).
[0222] In specific embodiments, any gel composition described
herein has a pH that allows for terminal sterilization (e.g., by
heat treatment and/or autoclaving) of a gel composition without
degradation of the pharmaceutical 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
composition in the 7-8 range at elevated temperatures. Any
appropriate buffer is used depending on the otic agent used in the
composition. 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. P407, CMC) as described
herein.
[0223] In some embodiments, a composition 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 compositions described herein. In specific
embodiments a composition 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.
[0224] In some embodiments, the compositions have a pH as described
herein, and include a thickening agent (e.g., a viscosity enhancing
agent) such as, by way of non-limiting example, a cellulose based
thickening agent described herein. In some instances, the addition
of a secondary polymer (e.g., a thickening agent) and a pH of
composition as described herein, allows for sterilization of a
composition described herein without any substantial degradation of
the otic agent and/or the polymer components in the otic
composition. In some embodiments, the ratio of a thermoreversible
poloxamer to a thickening agent in a composition that has a pH as
described herein, is about 40:1, about 35:1, about 30:1, about
25:1, about 20:1, about 15:1 about 10:1, or about 5:1. For example,
in certain embodiments, a sustained and/or extended release
composition described herein comprises a combination of poloxamer
407 (pluronic F127) and carboxymethylcellulose (CMC) in a ratio of
about 40:1, about 35:1, about 30:1, about 25:1, about 20:1, about
15:1, about 10:1 or about 5:1.
[0225] In some embodiments, the amount of thermoreversible polymer
in any composition described herein is about 10%, about 15%, about
20%, about 25%, about 30%, about 35% or about 40% of the total
weight of the composition. In some embodiments, the amount of
thermoreversible polymer in any composition described herein is
about 10%, about 11%, about 12%, about 13%, about 14%, about 15%,
about 16%, about 17%, about 18%, about 19%, about 20%, about 21%,
about 22%, about 23%, about 24% or about 25% of the total weight of
the composition. In some embodiments, the amount of
thermoreversible polymer (e.g., pluronic F127) in any composition
described herein is about 7.5% of the total weight of the
composition. In some embodiments, the amount of thermoreversible
polymer (e.g., pluronic F127) in any composition described herein
is about 10% of the total weight of the composition. In some
embodiments, the amount of thermoreversible polymer (e.g., pluronic
F127) in any composition described herein is about 11% of the total
weight of the composition. In some embodiments, the amount of
thermoreversible polymer (e.g., pluronic F127) in any composition
described herein is about 12% of the total weight of the
composition. In some embodiments, the amount of thermoreversible
polymer (e.g., pluronic F127) in any composition described herein
is about 13% of the total weight of the composition. In some
embodiments, the amount of thermoreversible polymer (e.g., pluronic
F127) in any composition described herein is about 14% of the total
weight of the composition. In some embodiments, the amount of
thermoreversible polymer (e.g., pluronic F127) in any composition
described herein is about 15% of the total weight of the
composition. In some embodiments, the amount of thermoreversible
polymer (e.g., pluronic F127) in any composition described herein
is about 16% of the total weight of the composition. In some
embodiments, the amount of thermoreversible polymer (e.g., pluronic
F127) in any composition described herein is about 17% of the total
weight of the composition. In some embodiments, the amount of
thermoreversible polymer (e.g., pluronic F127) in any composition
described herein is about 18% of the total weight of the
composition. In some embodiments, the amount of thermoreversible
polymer (e.g., pluronic F127) in any composition described herein
is about 19% of the total weight of the composition. In some
embodiments, the amount of thermoreversible polymer (e.g., pluronic
F127) in any composition described herein is about 20% of the total
weight of the composition. In some embodiments, the amount of
thermoreversible polymer (e.g., pluronic F127) in any composition
described herein is about 21% of the total weight of the
composition. In some embodiments, the amount of thermoreversible
polymer (e.g., pluronic F127) in any composition described herein
is about 23% of the total weight of the composition. In some
embodiments, the amount of thermoreversible polymer (e.g., pluronic
F127) in any composition described herein is about 25% of the total
weight of the composition.
[0226] In some embodiments, the amount of thickening agent (e.g., a
gelling agent) in any composition described herein is about 1%,
about 5%, about 10%, or about 15% of the total weight of the
composition. In some embodiments, the amount of thickening agent
(e.g., a gelling agent) in any composition described herein is
about 0.5%, about 1%, about 1.5%, about 2%, about 2.5%, about 3%,
about 3.5%, about 4%, about 4.5%, or about 5% of the total weight
of the composition.
[0227] In some embodiments, the pharmaceutical compositions
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 compositions
described herein are stable with respect to pH over a period of at
least about 1 week. Also described herein are compositions that are
stable with respect to pH over a period of at least about 1
month.
[0228] Tonicity Agents
[0229] 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 compositions described herein in an amount as to
provide a practical osmolality of an otic composition 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 compositions 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.
[0230] In some embodiments, the deliverable osmolarity of any
composition 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
(osmolality of about 250 to about 320 mOsm/kg H.sub.2O); and
preferably about 270 to about 320 mOsm/L (osmolality of about 270
to about 320 mOsm/kg H.sub.2O). In specific embodiments, the
deliverable osmolarity/osmolality of the compositions (i.e., the
osmolarity/osmolality of the composition 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 that renders the compositions
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 composition 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 composition is a reliable measure and
is measured by any suitable method (e.g., freezing point depression
method, vapor depression method). In some instances, the
compositions 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.
[0231] In some embodiments, any composition described herein is
isotonic with the perilymph and/or endolymph. Isotonic compositions
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.
[0232] 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.
[0233] In some embodiments, the compositions 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 compositions 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 composition.
In some embodiments, the compositions 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 composition. In some
embodiments, the compositions 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.g/mL, between about 1 .mu.s 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
composition.
Particle Size
[0234] Size reduction is used to increase surface area and/or
modulate composition 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 composition described herein. In some embodiments,
any composition described herein is multiparticulate (i.e.,
comprises a plurality of particle sizes (e.g., micronized
particles, nano-sized particles, non-sized particles, colloidal
particles)). In some embodiments, any composition 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 a CNS modulating agent allows for
extended and/or sustained release of the CNS modulating agent from
any composition described herein compared to a composition
comprising non-multiparticulate (e.g., non-micronized) CNS
modulating agent. In some instances, compositions containing
multiparticulate (e.g. micronized) CNS modulating agent are ejected
from a 1 mL syringe adapted with a 27 G needle without any plugging
or clogging.
[0235] In some instances, any particle in any composition 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, compositions described herein
comprise crystalline particles and/or isotropic particles. In some
embodiments, compositions described herein comprise amorphous
particles and/or anisotropic particles. In some embodiments,
compositions described herein comprise therapeutic agent particles
wherein the therapeutic agent is a neutral molecule, a free acid, a
free base, or a salt, or a prodrug of a therapeutic agent, or any
combination thereof.
[0236] In some embodiments, a composition described herein
comprises one or more CNS modulating agents wherein the CNS
modulating agent comprises nanoparticulates. In some embodiments, a
composition described herein comprises CNS modulating agent beads
(e.g., tacrolimus beads) that are optionally coated with
controlled-release excipients. In some embodiments, a composition
described herein comprises a CNS modulating agent that is
granulated and/or reduced in size and coated with
controlled-release excipients; the granulated coated CNS modulating
agent particulates are then optionally micronized and/or formulated
in any of the compositions described herein.
[0237] In some instances, a combination of a CNS modulating agent
as a neutral molecule, a free acid, a free base and a salt of the
CNS modulating agent is used to prepare pulsed release otic agent
compositions using the procedures described herein. In some
compositions, a combination of a micronized CNS modulating agent
(and/or salt or prodrug thereof) and coated particles (e.g.,
nanoparticles, liposomes, microspheres) is used to prepare pulsed
release otic agent compositions using any procedure described
herein. Alternatively, a pulsed release profile is achieved by
solubilizing up to 20% of the delivered dose of the CNS modulating
agent (e.g., micronized CNS modulating agent, a neutral molecule,
free base, free acid or salt or prodrug thereof; multiparticulate
CNS modulating agent, a neutral molecule, a 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 compositions using any
procedure described herein.
[0238] In specific embodiments, any auris-compatible composition
described herein comprises one or more micronized pharmaceutical
agents (e.g., CNS modulating 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 a CNS
modulating 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 a CNS
modulating agent as a micronized powder.
[0239] The multiparticulates and/or micronized CNS modulating
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 CNS modulating 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.
Pharmaceutical Compositions
[0240] Provided herein are pharmaceutical compositions or devices
that include at least one CNS modulating agent 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 preserving, stabilizing, wetting or emulsifying
agents, solution promoters, salts for regulating the osmotic
pressure, and/or buffers. In other embodiments, the pharmaceutical
compositions also contain other therapeutic substances.
[0241] Some pharmaceutical excipients, diluents or carriers are
potentially ototoxic. For example, benzalkonium chloride, a common
preservative, is ototoxic and therefore potentially harmful if
introduced into the vestibular or cochlear structures. In
formulating a controlled-release CNS modulating composition, it is
advised to avoid or combine the appropriate excipients, diluents or
carriers to lessen or eliminate potential ototoxic components from
the composition, or to decrease the amount of such excipients,
diluents or carriers. Optionally, a controlled-release CNS
modulating composition includes otoprotective agents, such as
antioxidants, alpha lipoic acid, calcium, fosfomycin or iron
chelators, to counteract potential ototoxic effects that may arise
from the use of specific therapeutic agents or excipients, diluents
or carriers.
[0242] In some embodiments, the compositions or devices described
herein include a dye to help enhance the visualization of the gel
when applied. In some embodiments, dyes that are compatible with
the auris-acceptable compositions or devices described herein
include Evans blue (e.g., 0.5% of the total weight of an otic
composition), Methylene blue (e.g., 1% of the total weight of an
otic composition), Isosulfan blue (e.g., 1% of the total weight of
an otic composition), Trypan blue (e.g., 0.15% of the total weight
of an otic composition), and/or indocyanine green (e.g., 25
mg/vial). Other common dyes, e.g., FD&C red 40, FD&C red 3,
FD&C yellow 5, FD&C yellow 6, FD&C blue 1, FD&C
blue2, FD&C green 3, fluorescence dyes (e.g., Fluorescein
isothiocyanate, rhodamine, Alexa Fluors, DyLight Fluors) and/or
dyes that are visualizable in conjunction with non-invasive imaging
techniques such as MRI, CAT scans, PET scans or the like.
Gadolinium-based MRI dyes, iodine-base dyes, barium-based dyes or
the like are also contemplated for use with any otic composition
described herein. Other dyes that are compatible with any
composition or composition described herein are listed in the
Sigma-Aldrich catalog under dyes (that is included herein by
reference for such disclosure).
[0243] Any pharmaceutical composition or device described herein is
administered by locating the composition or device in contact with
the crista fenestrae cochlea, the round window, the tympanic
cavity, the tympanic membrane, the auris media or the auris
externa.
[0244] In one specific embodiment of the auris-acceptable
controlled-release CNS modulating agent pharmaceutical compositions
described herein, the CNS modulating agent is provided in a gel
matrix, also referred to herein as "auris acceptable gel
compositions," "auris interna-acceptable gel compositions," "auris
media-acceptable gel compositions," "auris externa-acceptable gel
compositions", "auris gel compositions" or variations thereof. All
of the components of the gel composition must be compatible with
the targeted auris structure. Further, the gel compositions provide
controlled-release of the CNS modulating agent to the desired site
within the targeted auris structure; in some embodiments, the gel
composition also has an immediate or rapid release component for
delivery of the CNS modulating agent to the desired target site. In
other embodiments, the gel composition has a sustained release
component for delivery of the CNS modulating agent. In some
embodiments, the gel composition comprises a multiparticulate
(e.g., micronized) CNS modulating agent. In some embodiments, the
auris gel compositions are biodegradable. In other embodiments, the
auris gel compositions include a mucoadhesive excipient to allow
adhesion to the external mucous layer of the round window membrane.
In yet other embodiments, the auris gel compositions include a
penetration enhancer excipient; in further embodiments, the auris
gel composition contains a viscosity enhancing agent sufficient to
provide a viscosity of between about 500 and 1,000,000 centipoise,
between about 750 and 1,000,000 centipoise; between about 1000 and
1,000,000 centipoise; between about 1000 and 400,000 centipoise;
between about 2000 and 100,000 centipoise; between about 3000 and
50,000 centipoise; between about 4000 and 25,000 centipoise;
between about 5000 and 20,000 centipoise; or between about 6000 and
15,000 centipoise. In some embodiments, the auris gel composition
contains a viscosity enhancing agent sufficient to provide a
viscosity of between about 50,0000 and 1,000,000 centipoise.
[0245] In other embodiments, the auris interna pharmaceutical
compositions described herein further provide an auris-acceptable
hydrogel; in yet other embodiments, the auris pharmaceutical
compositions provide an auris-acceptable microsphere or
microparticle; in still other embodiments, the auris pharmaceutical
compositions provide an auris-acceptable liposome. In some
embodiments, the auris pharmaceutical compositions provide an
auris-acceptable foam; in yet other embodiments, the auris
pharmaceutical compositions provide an auris-acceptable paint; in
still further embodiments, the auris pharmaceutical compositions
provide an auris-acceptable in situ forming spongy material. In
some embodiments, the auris pharmaceutical compositions provide an
auris-acceptable solvent release gel. In some embodiments, the
auris pharmaceutical compositions provide an actinic radiation
curable gel. Further embodiments include a thermoreversible gel in
the auris pharmaceutical composition, such that upon preparation of
the gel at room temperature or below, the composition is a fluid,
but upon application of the gel into or near the auris interna
and/or auris media target site, including the tympanic cavity,
round window membrane or the crista fenestrae cochleae, the
auris-pharmaceutical composition stiffens or hardens into a
gel-like substance.
[0246] In further or alternative embodiments, the auris gel
compositions are capable of being administered on or near the round
window membrane via intratympanic injection. In other embodiments,
the auris gel compositions are administered on or near the round
window or the crista fenestrae cochleae through entry via a
post-auricular incision and surgical manipulation into or near the
round window or the crista fenestrae cochleae area. Alternatively,
the auris gel composition is applied via syringe and needle,
wherein the needle is inserted through the tympanic membrane and
guided to the area of the round window or crista fenestrae
cochleae. The auris gel compositions are then deposited on or near
the round window or crista fenestrae cochleae for localized
treatment. In other embodiments, the auris gel compositions are
applied via microcatheters implanted into the patient, and in yet
further embodiments the compositions are administered via a pump
device onto or near the round window membrane. In still further
embodiments, the auris gel compositions are applied at or near the
round window membrane via a microinjection device. In yet other
embodiments, the auris gel compositions are applied in the tympanic
cavity. In some embodiments, the auris gel compositions are applied
on the tympanic membrane. In still other embodiments, the auris gel
compositions are applied onto or in the auditory canal.
[0247] In further specific embodiments, any pharmaceutical
composition or device described herein comprises a multiparticulate
CNS modulating agent in a liquid matrix (e.g., a liquid composition
for intratympanic injection, or otic drops). In certain
embodiments, any pharmaceutical composition described herein
comprises a multiparticulate CNS modulating agent in a solid
matrix.
Controlled-Release Compositions
[0248] In general, controlled-release drug compositions 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
composition 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.
[0249] Accordingly, one aspect of the embodiments disclosed herein
is to provide a controlled-release CNS modulating auris-acceptable
composition or. The controlled-release aspect of the compositions
and/or compositions and/or devices disclosed herein is imparted
through a variety of agents, including but not limited to
excipients, agents or materials that are acceptable for use in the
auris interna or other otic structure. By way of example only, such
excipients, agents or materials include an auris-acceptable
polymer, an auris-acceptable viscosity enhancing agent, an
auris-acceptable gel, an auris-acceptable paint, an
auris-acceptable foam, an auris-acceptable xerogel, an
auris-acceptable microsphere or microparticle, an auris-acceptable
hydrogel, an auris-acceptable in situ forming spongy material, an
auris-acceptable actinic radiation curable gel, an auris-acceptable
solvent release gel, an auris-acceptable liposome, an
auris-acceptable nanocapsule or nanosphere, an auris-acceptable
thermoreversible gel, or combinations thereof.
Auris-Acceptable Gels
[0250] 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.
[0251] 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.
[0252] In one embodiment the enhanced viscosity auris-acceptable
composition described herein is not a liquid at room temperature.
In certain embodiments, the enhanced viscosity composition 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 composition
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 composition described herein is about
35.degree. C., or about 40.degree. C. In one embodiment,
administration of any composition described herein at about body
temperature reduces or inhibits vertigo associated with
intratympanic administration of otic compositions. 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 .about.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.
[0253] 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 compositions 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.
[0254] 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##
[0255] 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.
[0256] 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.
[0257] 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 that 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.
[0258] 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.
[0259] 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 CNS modulating agent and various additives such as
buffers, salts, and preservatives are subsequently added and
dissolved. In some instances the CNS modulating 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 that is incorporated herein
by reference for such disclosure).
[0260] In one embodiment are auris-acceptable pharmaceutical gel
compositions that do not require the use of an added viscosity
enhancing agent. Such gel compositions incorporate at least one
pharmaceutically acceptable buffer. In one aspect is a gel
composition comprising a CNS modulating agent and a
pharmaceutically acceptable buffer. In another embodiment, the
pharmaceutically acceptable excipient or carrier is a gelling
agent.
[0261] In other embodiments, useful CNS modulating agent
auris-acceptable pharmaceutical compositions 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 compositions of the present disclosure,
they are combined, e.g., with a pharmaceutically acceptable vehicle
and are present in the final composition, 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 compositions is an amount such that the
pH of the gel composition does not interfere with the natural
buffering system of the auris media or auris interna, or does not
interfere with the natural pH of the endolymph or perilymph:
depending on where in the cochlea the CNS modulating agent
composition is targeted. In some embodiments, from about 10 .mu.M
to about 200 mM concentration of a buffer is present in the gel
composition. 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.
[0262] 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.
[0263] Also described herein are controlled-release compositions or
devices comprising a CNS modulating agent and a viscosity enhancing
agent. Suitable viscosity-enhancing agents include by way of
example only, gelling agents and suspending agents. In one
embodiment, the enhanced viscosity composition does not include a
buffer. In other embodiments, the enhanced viscosity composition
includes a pharmaceutically acceptable buffer. Sodium chloride or
other tonicity agents are optionally used to adjust tonicity, if
necessary.
[0264] By way of example only, the auris-acceptable viscosity agent
include hydroxypropyl methylcellulose, hydroxyethyl cellulose,
polyvinylpyrrolidone, carboxymethyl cellulose, polyvinyl alcohol,
sodium chondroitin sulfate, sodium hyaluronate. Other viscosity
enhancing agents compatible with the targeted auris structure
include, but are not limited to, acacia (gum arabic), agar,
aluminum magnesium silicate, sodium alginate, sodium stearate,
bladderwrack, bentonite, carbomer, carrageenan, Carbopol, xanthan,
cellulose, microcrystalline cellulose (MCC), ceratonia, chitin,
carboxymethylated chitosan, chondrus, dextrose, furcellaran,
gelatin, Ghatti gum, guar gum, hectorite, lactose, sucrose,
maltodextrin, mannitol, sorbitol, honey, maize starch, wheat
starch, rice starch, potato starch, gelatin, sterculia gum, xanthum
gum, gum tragacanth, ethyl cellulose, ethylhydroxyethyl cellulose,
ethylmethyl cellulose, methyl cellulose, hydroxyethyl cellulose,
hydroxyethylmethyl cellulose, hydroxypropyl cellulose,
poly(hydroxyethyl methacrylate), oxypolygelatin, pectin,
polygeline, povidone, propylene carbonate, methyl vinyl
ether/maleic anhydride copolymer (PVM/MA), poly(methoxyethyl
methacrylate), poly(methoxyethoxyethyl methacrylate), hydroxypropyl
cellulose, hydroxypropylmethyl-cellulose (HPMC), sodium
carboxymethyl-cellulose (CMC), silicon dioxide,
polyvinylpyrrolidone (PVP: povidone), Splenda.RTM. (dextrose,
maltodextrin and sucralose) or combinations thereof. In specific
embodiments, the viscosity-enhancing excipient is a combination of
MCC and CMC. In another embodiment, the viscosity-enhancing agent
is a combination of carboxymethylated chitosan, or chitin, and
alginate. The combination of chitin and alginate with the CNS
modulating agents disclosed herein acts as a controlled-release
composition, restricting the diffusion of the CNS modulating agents
from the composition. Moreover, the combination of
carboxymethylated chitosan and alginate is optionally used to
assist in increasing the permeability of the CNS modulating agents
through the round window membrane.
[0265] In some embodiments, is an enhanced viscosity composition,
comprising from about 0.1 mM and about 100 mM of a CNS modulating
agent, a pharmaceutically acceptable viscosity agent, and water for
injection, the concentration of the viscosity agent in the water
being sufficient to provide a enhanced viscosity composition with a
final viscosity 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. In
other embodiments, when an even more viscous medium is desired, the
biocompatible gel comprises at least about 35%, at least about 45%,
at least about 55%, at least about 65%, at least about 70%, at
least about 75%, or even at least about 80% or so by weight of the
CNS modulating agent. In highly concentrated samples, the
biocompatible enhanced viscosity composition comprises at least
about 25%, at least about 35%, at least about 45%, at least about
55%, at least about 65%, at least about 75%, at least about 85%, at
least about 90% or at least about 95% or more by weight of the CNS
modulating agent.
[0266] In some embodiments, the viscosity of the gel compositions
presented herein are measured by any means described. For example,
in some embodiments, an LVDV-II+CP Cone Plate Viscometer and a Cone
Spindle CPE-40 is used to calculate the viscosity of the gel
composition described herein. In other embodiments, a Brookfield
(spindle and cup) viscometer is used to calculate the viscosity of
the gel composition 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).
[0267] In one embodiment, the pharmaceutically acceptable enhanced
viscosity auris-acceptable composition comprises at least one CNS
modulating agent and at least one gelling agent. Suitable gelling
agents for use in preparation of the gel composition include, but
are not limited to, celluloses, cellulose derivatives, cellulose
ethers (e.g., carboxymethylcellulose, ethylcellulose,
hydroxyethylcellulose, hydroxymethylcellulose,
hydroxypropylmethylcellulose, hydroxypropylcellulose,
methylcellulose), guar gum, xanthan gum, locust bean gum, alginates
(e.g., alginic acid), silicates, starch, tragacanth, carboxyvinyl
polymers, carrageenan, paraffin, petrolatum and any combinations or
mixtures thereof. In some other embodiments,
hydroxypropylmethylcellulose (Methocel.RTM.) is utilized as the
gelling agent. In certain embodiments, the viscosity enhancing
agents described herein are also utilized as the gelling agent for
the gel compositions presented herein.
[0268] In some embodiments, the otic therapeutic agents disclosed
herein are dispensed as an auris-acceptable paint. As used herein,
paints (also known as film formers) are solutions comprised of a
solvent, a monomer or polymer, an active agent, and optionally one
or more pharmaceutically-acceptable excipients. After application
to a tissue, the solvent evaporates leaving behind a thin coating
comprised of the monomers or polymers, and the active agent. The
coating protects active agents and maintains them in an immobilized
state at the site of application. This decreases the amount of
active agent that may be lost and correspondingly increases the
amount delivered to the subject. By way of non-limiting example,
paints include collodions (e.g. Flexible Collodion, USP), and
solutions comprising saccharide siloxane copolymers and a
cross-linking agent. Collodions are ethyl ether/ethanol solutions
containing pyroxylin (a nitrocellulose). After application, the
ethyl ether/ethanol solution evaporates leaving behind a thin film
of pyroxylin. In solutions comprising saccharide siloxane
copolymers, the saccharide siloxane copolymers form the coating
after evaporation of the solvent initiates the cross-linking of the
saccharide siloxane copolymers. For additional disclosures
regarding paints, see Remington: The Science and Practice of
Pharmacy that is hereby incorporated with respect to this subject
matter. The paints contemplated for use herein, are flexible such
that they do not interfere with the propagation of pressure waves
through the ear. Further, the paints may be applied as a liquid
(i.e. solution, suspension, or emulsion), a semisolid (i.e. a gel,
foam, paste, or jelly) or an aerosol.
[0269] In some embodiments, the otic therapeutic agents disclosed
herein are dispensed as a controlled-release foam. Examples of
suitable foamable carriers for use in the compositions disclosed
herein include, but are not limited to, alginate and derivatives
thereof, carboxymethylcellulose and derivatives thereof, collagen,
polysaccharides, including, for example, dextran, dextran
derivatives, pectin, starch, modified starches such as starches
having additional carboxyl and/or carboxamide groups and/or having
hydrophilic side-chains, cellulose and derivatives thereof, agar
and derivatives thereof, such as agar stabilized with
polyacrylamide, polyethylene oxides, glycol methacrylates, gelatin,
gums such as xanthum, guar, karaya, gellan, arabic, tragacanth and
locust bean gum, or combinations thereof. Also suitable are the
salts of the aforementioned carriers, for example, sodium alginate.
The composition optionally further comprises a foaming agent, which
promotes the formation of the foam, including a surfactant or
external propellant. Examples of suitable foaming agents include
cetrimide, lecithin, soaps, silicones and the like. Commercially
available surfactants such as Tween.RTM. are also suitable.
[0270] In some embodiments, other gel compositions are useful
depending upon the particular CNS modulating agent, other
pharmaceutical agent or excipients/additives used, and as such are
considered to fall within the scope of the present disclosure. For
example, other commercially-available glycerin-based gels,
glycerin-derived compounds, conjugated, or crosslinked gels,
matrices, hydrogels, and polymers, as well as gelatins and their
derivatives, alginates, and alginate-based gels, and even various
native and synthetic hydrogel and hydrogel-derived compounds are
all expected to be useful in the CNS modulating agent compositions
described herein. In some embodiments, auris-acceptable gels
include, but are not limited to, alginate hydrogels SAF.RTM.-Gel
(ConvaTec, Princeton, N.J.), Duoderm.RTM. Hydroactive Gel
(ConvaTec), Nu-gel.RTM.(Johnson & Johnson Medical, Arlington,
Tex.); Carrasyn.RTM.(V) Acemannan Hydrogel (Carrington
Laboratories, Inc., Irving, Tex.); glycerin gels Elta.RTM. Hydrogel
(Swiss-American Products, Inc., Dallas, Tex.) and K-Y.RTM. Sterile
(Johnson & Johnson). In further embodiments, biodegradable
biocompatible gels also represent compounds present in
auris-acceptable compositions disclosed and described herein.
[0271] In some compositions developed for administration to a
mammal, and for compositions formulated for human administration,
the auris-acceptable gel comprises substantially all of the weight
of the composition. In other embodiments, the auris-acceptable gel
comprises as much as about 98% or about 99% of the composition by
weight. This is desirous when a substantially non-fluid, or
substantially viscous composition is needed. In a further
embodiment, when slightly less viscous, or slightly more fluid
auris-acceptable pharmaceutical gel compositions are desired, the
biocompatible gel portion of the composition comprises at least
about 50% by weight, at least about 60% by weight, at least about
70% by weight, or even at least about 80% or 90% by weight of the
compound. All intermediate integers within these ranges are
contemplated to fall within the scope of this disclosure, and in
some alternative embodiments, even more fluid (and consequently
less viscous) auris-acceptable gel compositions are formulated,
such as for example, those in that the gel or matrix component of
the mixture comprises not more than about 50% by weight, not more
than about 40% by weight, not more than about 30% by weight, or
even those than comprise not more than about 15% or about 20% by
weight of the composition.
[0272] Auris-Acceptable Suspending Agents
[0273] In one embodiment, at least one CNS modulating agent is
included in a pharmaceutically acceptable enhanced viscosity
composition wherein the composition further comprises at least one
suspending agent, wherein the suspending agent assists in imparting
controlled-release characteristics to the composition. In some
embodiments, suspending agents also serve to increase the viscosity
of the auris-acceptable CNS modulating compositions and
compositions.
[0274] Suspending agents include, by way of example only, compounds
such as polyvinylpyrrolidone, e.g., polyvinylpyrrolidone K12,
polyvinylpyrrolidone K17, polyvinylpyrrolidone K25, or
polyvinylpyrrolidone K30, vinyl pyrrolidone/vinyl acetate copolymer
(S630), sodium carboxymethylcellulose, methylcellulose,
hydroxypropylmethylcellulose (hypromellose), hydroxymethylcellulose
acetate stearate, polysorbate-80, hydroxyethyl cellulose, sodium
alginate, gums, such as, e.g., gum tragacanth and gum acacia, guar
gum, xanthans, including xanthan gum, sugars, cellulosics, such as,
e.g., sodium carboxymethylcellulose, methylcellulose, sodium
carboxymethylcellulose, hydroxypropylmethylcellulose,
hydroxyethylcellulose, polysorbate-80, sodium alginate,
polyethoxylated sorbitan monolaurate, polyethoxylated sorbitan
monolaurate, povidone and the like. In some embodiments, useful
aqueous suspensions also contain one or more polymers as suspending
agents. Useful polymers include water-soluble polymers such as
cellulosic polymers, e.g., hydroxypropyl methylcellulose, and
water-insoluble polymers such as cross-linked carboxyl-containing
polymers.
[0275] In one embodiment, the present disclosure provides
auris-acceptable gel compositions comprising a therapeutically
effective amount of a CNS modulating agent in a hydroxyethyl
cellulose gel. Hydroxyethyl cellulose (HEC) is obtained as a dry
powder that is reconstituted in water or an aqueous buffer solution
to give the desired viscosity (generally about 200 cps to about
30,000 cps, corresponding to about 0.2 to about 10% HEC). In one
embodiment the concentration of HEC is between about 1% and about
15%, about 1% and about 2%, or about 1.5% to about 2%.
[0276] In other embodiments, the auris-acceptable compositions,
including gel compositions and viscosity-enhanced compositions,
further include excipients, other medicinal or pharmaceutical
agents, carriers, adjuvants, such as preserving, stabilizing,
wetting or emulsifying agents, solution promoters, salts,
solubilizers, an antifoaming agent, an antioxidant, a dispersing
agent, a wetting agent, a surfactant, and combinations thereof.
[0277] Auris-Acceptable Actinic Radiation Curable Gel
[0278] In other embodiments, the gel is an actinic radiation
curable gel, such that following administration to or near the
targeted auris structure, use of actinic radiation (or light,
including UV light, visible light, or infrared light) the desired
gel properties are formed. By way of example only, fiber optics are
used to provide the actinic radiation so as to form the desired gel
properties. In some embodiments, the fiber optics and the gel
administration device form a single unit. In other embodiments, the
fiber optics and the gel administration device are provided
separately.
[0279] Auris-Acceptable Solvent Release Gel
[0280] In some embodiments, the gel is a solvent release gel such
that the desired gel properties are formed after administration to
or near the targeted auris structure, which is, as the solvent in
the injected gel composition diffuses out the gel, a gel having the
desired gel properties is formed. For example, a composition that
comprises sucrose acetate isobutyrate, a pharmaceutically
acceptable solvent, one or more additives, and the CNS modulating
agent is administered at or near the round window membrane:
diffusion of the solvent out of the injected composition provides a
depot having the desired gel properties. For example, use of a
water soluble solvent provides a high viscosity depot when the
solvent diffuses rapidly out of the injected composition. On the
other hand, use of a hydrophobic solvent (e.g., benzyl benzoate)
provides a less viscous depot. One example of an auris-acceptable
solvent release gel composition is the SABER.TM. Delivery System
marketed by DURECT Corporation.
[0281] Auris-Acceptable In Situ Forming Spongy Material
[0282] Also contemplated within the scope of the embodiments is the
use of a spongy material, formed in situ in the auris interna or
auris media. In some embodiments, the spongy material is formed
from hyaluronic acid or its derivatives. The spongy material is
impregnated with a desired CNS modulating agent and placed within
the auris media so as to provide controlled-release of the CNS
modulating agent within the auris media, or in contact with the
round window membrane so as to provide controlled-release of the
CNS modulating agent into the auris interna. In some embodiments,
the spongy material is biodegradable.
[0283] Round Window Membrane Mucoadhesives
[0284] Also contemplated within the scope of the embodiments is the
addition of a round window membrane mucoadhesive with the CNS
modulating agent compositions and compositions and devices
disclosed herein. The term `mucoadhesion` is used for materials
that bind to the mucin layer of a biological membrane, such as the
external membrane of the 3-layered round window membrane. To serve
as round window membrane mucoadhesive polymers, the polymers
possess some general physiochemical features such as predominantly
anionic hydrophilicity with numerous hydrogen bond forming groups,
suitable surface property for wetting mucus/mucosal tissue surfaces
or sufficient flexibility to penetrate the mucus network.
[0285] Round window membrane mucoadhesive agents that are used with
the auris-acceptable compositions include, but are not limited to,
at least one soluble polyvinylpyrrolidone polymer (PVP); a
water-swellable, but water-insoluble, fibrous, cross-linked
carboxy-functional polymer; a crosslinked poly(acrylic acid) (e.g.
Carbopol.RTM. 947P); a carbomer homopolymer; a carbomer copolymer;
a hydrophilic polysaccharide gum, maltodextrin, a cross-linked
alignate gum gel, a water-dispersible polycarboxylated vinyl
polymer, at least two particulate components selected from the
group consisting of titanium dioxide, silicon dioxide, and clay, or
a mixture thereof. The round window membrane mucoadhesive agent is
optionally used in combination with an auris-acceptable viscosity
increasing excipient, or used alone to increase the interaction of
the composition with the mucosal layer target otic component. In
one non-limiting example, the mucoadhesive agent is maltodextrin
and/or an alginate gum. When used, the round window membrane
mucoadhesive character imparted to the composition is at a level
that is sufficient to deliver an effective amount of the CNS
modulating agent composition to, for example, the mucosal layer of
round window membrane or the crista fenestrae cochleae in an amount
that coats the mucosal membrane, and thereafter deliver the
composition to the affected areas, including by way of example
only, the vestibular and/or cochlear structures of the auris
interna. When used, the mucoadhesive characteristics of the
compositions provided herein are determined, and using this
information (along with the other teachings provided herein), the
appropriate amounts are determined. One method for determining
sufficient mucoadhesiveness includes monitoring changes in the
interaction of the composition with a mucosal layer, including but
not limited to measuring changes in residence or retention time of
the composition in the absence and presence of the mucoadhesive
excipient.
[0286] Mucoadhesive agents have been described, for example, in
U.S. Pat. Nos. 6,638,521, 6,562,363, 6,509,028, 6,348,502,
6,319,513, 6,306,789, 5,814,330, and 4,900,552, each of that is
hereby incorporated by reference for such disclosure.
[0287] In another non-limiting example, a mucoadhesive agent is,
for example, at least two particulate components selected from
titanium dioxide, silicon dioxide, and clay, wherein the
composition is not further diluted with any liquid prior to
administration and the level of silicon dioxide, if present, is
from about 3% to about 15%, by weight of the composition. Silicon
dioxide, if present, includes fumed silicon dioxide, precipitated
silicon dioxide, coacervated silicon dioxide, gel silicon dioxide,
and mixtures thereof. Clay, if present, includes kaolin minerals,
serpentine minerals, smectites, illite or a mixture thereof. For
example, clay includes laponite, bentonite, hectorite, saponite,
montmorillonites or a mixture thereof.
[0288] In one non-limiting example, the round window membrane
mucoadhesive agent is maltodextrin. Maltodextrin is a carbohydrate
produced by the hydrolysis of starch that is optionally derived
from corn, potato, wheat or other plant products. Maltodextrin is
optionally used either alone or in combination with other round
window membrane mucoadhesive agents to impart mucoadhesive
characteristics on the compositions disclosed herein. In one
embodiment, a combination of maltodextrin and a carbopol polymer
are used to increase the round window membrane mucoadhesive
characteristics of the compositions or devices disclosed
herein.
[0289] In another embodiment, the round window membrane
mucoadhesive agent is an alkyl-glycoside and/or a saccharide alkyl
ester. As used herein, an "alkyl-glycoside" means a compound
comprising any hydrophilic saccharide (e.g. sucrose, maltose, or
glucose) linked to a hydrophobic alkyl. In some embodiments, the
round window membrane mucoadhesive agent is an alkyl-glycoside
wherein the alkyl-glycoside comprises a sugar linked to a
hydrophobic alkyl (e.g., an alkyl comprising about 6 to about 25
carbon atoms) by an amide linkage, an amine linkage, a carbamate
linkage, an ether linkage, a thioether linkage, an ester linkage, a
thioester linkage, a glycosidic linkage, a thioglycosidic linkage,
and/or a ureide linkage. In some embodiments, the round window
membrane mucoadhesive agent is a hexyl-, heptyl-, octyl-, nonyl-,
decyl-, undecyl-, dodecyl-, tridecyl-, tetradecyl, pentadecyl-,
hexadecyl-, heptadecyl-, and octadecyl .alpha.- or
.beta.-D-maltoside; hexyl-, heptyl-, octyl-, nonyl-, decyl-,
undecyl-, dodecyl-, tridecyl-, tetradecyl, pentadecyl-, hexadecyl-,
heptadecyl-, and octadecyl .alpha.- or .beta.-D-glucoside; hexyl-,
heptyl-, octyl-, nonyl-, decyl-, undecyl-, dodecyl-, tridecyl-,
tetradecyl, pentadecyl-, hexadecyl-, heptadecyl-, and octadecyl
.alpha.- or .beta.-D-sucroside; hexyl-, heptyl-, octyl-, dodecyl-,
tridecyl-, and tetradecyl-.beta.-D-thiomaltoside; heptyl- or
octyl-1-thio-.alpha.- or .beta.-D-glucopyranoside; alkyl
thiosucroses; alkyl maltotriosides; long chain aliphatic carbonic
acid amides of sucrose .beta.-amino-alkyl ethers; derivatives of
palatinose or isomaltamine linked by an amide linkage to an alkyl
chain and derivatives of isomaltamine linked by urea to an alkyl
chain; long chain aliphatic carbonic acid ureides of sucrose
.beta.-amino-alkyl ethers and long chain aliphatic carbonic acid
amides of sucrose .beta.-amino-alkyl ethers. In some embodiments,
the round window membrane mucoadhesive agent is an alkyl-glycoside
wherein the alkyl glycoside is maltose, sucrose, glucose, or a
combination thereof linked by a glycosidic linkage to an alkyl
chain of 9-16 carbon atoms (e.g., nonyl-, decyl-, dodecyl- and
tetradecyl sucroside; nonyl-, decyl-, dodecyl- and tetradecyl
glucoside; and nonyl-, decyl-, dodecyl- and tetradecyl maltoside).
In some embodiments, the round window membrane mucoadhesive agent
is an alkyl-glycoside wherein the alkyl glycoside is
dodecylmaltoside, tridecylmaltoside, and tetradecylmaltoside.
[0290] In some embodiments, the round window membrane mucoadhesive
agent is an alkyl-glycoside wherein the alkyl-glycoside is a
disaccharide with at least one glucose. In some embodiments, the
auris acceptable penetration enhancer is a surfactant comprising
.alpha.-D-glucopyranosyl-.beta.-glycopyranoside,
n-Dodecyl-4-O-.alpha.-D-glucopyranosyl-.beta.-glycopyranoside,
and/or
n-tetradecyl-4-O-.alpha.-D-glucopyranosyl-.beta.-glycopyranoside.
In some embodiments, the round window membrane mucoadhesive agent
is an alkyl-glycoside wherein the alkyl-glycoside has a critical
miscelle concentration (CMC) of less than about 1 mM in pure water
or in aqueous solutions. In some embodiments, the round window
membrane mucoadhesive agent is an alkyl-glycoside wherein an oxygen
atom within the alkyl-glycoside is substituted with a sulfur atom.
In some embodiments, the round window membrane mucoadhesive agent
is an alkyl-glycoside wherein the alkylglycoside is the .beta.
anomer. In some embodiments, the round window membrane mucoadhesive
agent is an alkyl-glycoside wherein the alkylglycoside comprises
90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.5%, or
99.9% of the .beta. anomer.
[0291] Auris-Acceptable Controlled-Release Particles
[0292] CNS modulating agents and/or other pharmaceutical agents
disclosed herein are optionally incorporated within
controlled-release particles, lipid complexes, liposomes,
nanoparticles, microparticles, microspheres, coacervates,
nanocapsules or other agents that enhance or facilitate the
localized delivery of the CNS modulating agent. In some
embodiments, a single enhanced viscosity composition is used, in
that at least one CNS modulating agent is present, while in other
embodiments, a pharmaceutical composition that comprises a mixture
of two or more distinct enhanced viscosity compositions is used, in
that at least one CNS modulating agent is present. In some
embodiments, combinations of sols, gels and/or biocompatible
matrices is also employed to provide desirable characteristics of
the controlled-release CNS modulating compositions or compositions.
In certain embodiments, the controlled-release CNS modulating
compositions or compositions are cross-linked by one or more agents
to alter or improve the properties of the composition.
[0293] Examples of microspheres relevant to the pharmaceutical
compositions disclosed herein include: Luzzi, L. A., J. Pharm. Psy.
59:1367 (1970); U.S. Pat. No. 4,530,840; Lewis, D. H.,
"Controlled-release of Bioactive Agents from Lactides/Glycolide
Polymers" in Biodegradable Polymers as Drug Delivery Systems,
Chasin, M. and Langer, R., eds., Marcel Decker (1990); U.S. Pat.
No. 4,675,189; Beck et al., "Poly(lactic acid) and Poly(lactic
acid-co-glycolic acid) Contraceptive Delivery Systems," in Long
Acting Steroid Contraception, Mishell, D. R., ed., Raven Press
(1983); U.S. Pat. No. 4,758,435; U.S. Pat. No. 3,773,919; U.S. Pat.
No. 4,474,572. Examples of protein therapeutics formulated as
microspheres include: U.S. Pat. No. 6,458,387; U.S. Pat. No.
6,268,053; U.S. Pat. No. 6,090,925; U.S. Pat. No. 5,981,719; and
U.S. Pat. No. 5,578,709, and are herein incorporated by reference
for such disclosure.
[0294] Microspheres usually have a spherical shape, although
irregularly-shaped microparticles are possible. Microspheres may
vary in size, ranging from submicron to 1000 micron diameters.
Microspheres suitable for use with the auris-acceptable
compositions disclosed herein are submicron to 250 micron diameter
microspheres, allowing administration by injection with a standard
gauge needle. The auris-acceptable microspheres are prepared by any
method that produces microspheres in a size range acceptable for
use in an injectable composition. Injection is optionally
accomplished with standard gauge needles used for administering
liquid compositions.
[0295] Suitable examples of polymeric matrix materials for use in
the auris-acceptable controlled-release particles herein include
poly(glycolic acid), poly-d,l-lactic acid, poly-1-lactic acid,
copolymers of the foregoing, poly(aliphatic carboxylic acids),
copolyoxalates, polycaprolactone, polydioxonene,
poly(orthocarbonates), poly(acetals), poly(lactic
acid-caprolactone), polyorthoesters, poly(glycolic
acid-caprolactone), polydioxonene, polyanhydrides,
polyphosphazines, and natural polymers including albumin, casein,
and some waxes, such as, glycerol mono- and distearate, and the
like. Various commercially available poly (lactide-co-glycolide)
materials (PLGA) are optionally used in the method disclosed
herein. For example, poly (d,l-lactic-co-glycolic acid) is
commercially available from Boehringer-Ingelheim as RESOMER RG 503
H. This product has a mole percent composition of 50% lactide and
50% glycolide. These copolymers are available in a wide range of
molecular weights and ratios of lactic acid to glycolic acid. One
embodiment includes the use of the polymer
poly(d,l-lactide-co-glycolide). The molar ratio of lactide to
glycolide in such a copolymer includes the range of from about 95:5
to about 50:50.
[0296] The molecular weight of the polymeric matrix material is of
some importance. The molecular weight should be high enough so that
it forms satisfactory polymer coatings, i.e., the polymer should be
a good film former. Usually, a satisfactory molecular weight is in
the range of 5,000 to 500,000 Daltons. The molecular weight of a
polymer is also important from the point of view that molecular
weight influences the biodegradation rate of the polymer. For a
diffusional mechanism of drug release, the polymer should remain
intact until all of the drug is released from the microparticles
and then degrade. The drug is also released from the microparticles
as the polymeric excipient bioerodes. By an appropriate selection
of polymeric materials a microsphere composition is made such that
the resulting microspheres exhibit both diffusional release and
biodegradation release properties. This is useful in affording
multiphasic release patterns.
[0297] A variety of methods are known by that compounds are
encapsulated in microspheres. In these methods, the CNS modulating
agent is generally dispersed or emulsified, using stirrers,
agitators, or other dynamic mixing techniques, in a solvent
containing a wall-forming material. Solvent is then removed from
the microspheres, and thereafter the microsphere product is
obtained.
[0298] In one embodiment, controlled-release CNS modulating
compositions are made through the incorporation of the CNS
modulating agents and/or other pharmaceutical agents into
ethylene-vinyl acetate copolymer matrices. (See U.S. Pat. No.
6,083,534, incorporated herein for such disclosure). In another
embodiment, CNS modulating agents are incorporated into poly
(lactic-glycolic acid) or poly-L-lactic acid microspheres. Id. In
yet another embodiment, the CNS modulating agents are encapsulated
into alginate microspheres. (See U.S. Pat. No. 6,036,978,
incorporated herein for such disclosure). Biocompatible
methacrylate-based polymers to encapsulate the CNS modulating
compounds or compositions are optionally used in the compositions
and methods disclosed herein. A wide range of methacrylate-based
polymer systems are commercially available, such as the EUDRAGIT
polymers marketed by Evonik. One useful aspect of methacrylate
polymers is that the properties of the composition are varied by
incorporating various co-polymers. For example, poly(acrylic
acid-co-methylmethacrylate) microparticles exhibit enhanced
mucoadhesion properties as the carboxylic acid groups in the
poly(acrylic acid) form hydrogen bonds with mucin (Park et al,
Pharm. Res. (1987) 4(6):457-464). Variation of the ratio between
acrylic acid and methylmethacrylate monomers serves to modulate the
properties of the co-polymer. Methacrylate-based microparticles
have also been used in protein therapeutic compositions (Naha et
al, Journal of Microencapsulation 4 Feb. 2008 (online
publication)). In one embodiment, the enhanced viscosity
auris-acceptable compositions described herein comprises CNS
modulating microspheres wherein the microspheres are formed from a
methacrylate polymer or copolymer. In an additional embodiment, the
enhanced viscosity composition described herein comprises CNS
modulating microspheres wherein the microspheres are mucoadhesive.
Other controlled-release systems, including incorporation or
deposit of polymeric materials or matrices onto solid or hollow
spheres containing CNS modulating agents, are also explicitly
contemplated within the embodiments disclosed herein. The types of
controlled-release systems available without significantly losing
activity of the CNS modulating agent are determined using the
teachings, examples, and principles disclosed herein
[0299] An example of a conventional microencapsulation process for
pharmaceutical preparations is shown in U.S. Pat. No. 3,737,337,
incorporated herein by reference for such disclosure. The CNS
modulating substances to be encapsulated or embedded are dissolved
or dispersed in the organic solution of the polymer (phase A),
using conventional mixers, including (in the preparation of
dispersion) vibrators and high-speed stirrers, etc. The dispersion
of phase (A), containing the core material in solution or in
suspension, is carried out in the aqueous phase (B), again using
conventional mixers, such as high-speed mixers, vibration mixers,
or even spray nozzles, in that case the particle size of the
microspheres will be determined not only by the concentration of
phase (A), but also by the emulsate or microsphere size. With
conventional techniques for the microencapsulation of a CNS
modulating agents, the microspheres form when the solvent
containing an active agent and a polymer is emulsified or dispersed
in an immiscible solution by stirring, agitating, vibrating, or
some other dynamic mixing technique, often for a relatively long
period of time.
[0300] Methods for the construction of microspheres are also
described in U.S. Pat. No. 4,389,330, and U.S. Pat. No. 4,530,840,
incorporated herein by reference for such disclosure. The desired
CNS modulating agent is dissolved or dispersed in an appropriate
solvent. To the agent-containing medium is added the polymeric
matrix material in an amount relative to the active ingredient that
gives a product of the desired loading of active agent. Optionally,
all of the ingredients of the CNS modulating microsphere product
can be blended in the solvent medium together. Suitable solvents
for the agent and the polymeric matrix material include organic
solvents such as acetone, halogenated hydrocarbons such as
chloroform, methylene chloride and the like, aromatic hydrocarbon
compounds, halogenated aromatic hydrocarbon compounds, cyclic
ethers, alcohols, ethyl acetate and the like.
[0301] The mixture of ingredients in the solvent is emulsified in a
continuous-phase processing medium; the continuous-phase medium
being such that a dispersion of microdroplets containing the
indicated ingredients is formed in the continuous-phase medium.
Naturally, the continuous-phase processing medium and the organic
solvent must be immiscible, and includes water although nonaqueous
media such as xylene and toluene and synthetic oils and natural
oils are optionally used. Optionally, a surfactant is added to the
continuous-phase processing medium to prevent the microparticles
from agglomerating and to control the size of the solvent
microdroplets in the emulsion. A preferred surfactant-dispersing
medium combination is a 1 to 10 wt. % poly (vinyl alcohol) in water
mixture. The dispersion is formed by mechanical agitation of the
mixed materials. An emulsion is optionally formed by adding small
drops of the active agent-wall forming material solution to the
continuous phase processing medium. The temperature during the
formation of the emulsion is not especially critical but influences
the size and quality of the microspheres and the solubility of the
drug in the continuous phase. It is desirable to have as little of
the agent in the continuous phase as possible. Moreover, depending
on the solvent and continuous-phase processing medium employed, the
temperature must not be too low or the solvent and processing
medium will solidify or the processing medium will become too
viscous for practical purposes, or too high that the processing
medium will evaporate, or that the liquid processing medium will
not be maintained. Moreover, the temperature of the medium cannot
be so high that the stability of the particular agent being
incorporated in the microspheres is adversely affected.
Accordingly, the dispersion process is conducted at any temperature
that maintains stable operating conditions, which preferred
temperature being about 15.degree. C. to 60.degree. C., depending
upon the drug and excipient selected.
[0302] The dispersion that is formed is a stable emulsion and from
this dispersion the organic solvent immiscible fluid is optionally
partially removed in the first step of the solvent removal process.
The solvent is removed by techniques such as heating, the
application of a reduced pressure or a combination of both. The
temperature employed to evaporate solvent from the microdroplets is
not critical, but should not be that high that it degrades the CNS
modulating agent employed in the preparation of a given
microparticle, nor should it be so high as to evaporate solvent at
such a rapid rate to cause defects in the wall forming material.
Generally, from 5 to 75%, of the solvent is removed in the first
solvent removal step.
[0303] After the first stage, the dispersed microparticles in the
solvent immiscible fluid medium are isolated from the fluid medium
by any convenient means of separation. Thus, for example, the fluid
is decanted from the microsphere or the microsphere suspension is
filtered. Still other, various combinations of separation
techniques are used if desired.
[0304] Following the isolation of the microspheres from the
continuous-phase processing medium, the remainder of the solvent in
the microspheres is removed by extraction. In this step, the
microspheres are suspended in the same continuous-phase processing
medium used in step one, with or without surfactant, or in another
liquid. The extraction medium removes the solvent from the
microspheres and yet does not dissolve the microspheres. During the
extraction, the extraction medium with dissolved solvent is
optionally removed and replaced with fresh extraction medium. This
is best done on a continual basis. The rate of extraction medium
replenishment of a given process is a variable that is determined
at the time the process is performed and, therefore, no precise
limits for the rate must be predetermined. After the majority of
the solvent has been removed from the microspheres, the
microspheres are dried by exposure to air or by other conventional
drying techniques such as vacuum drying, drying over a desiccant,
or the like. This process is very efficient in encapsulating the
CNS modulating agent since core loadings of up to 80 wt. %,
preferably up to 60 wt. % are obtained.
[0305] Alternatively, controlled-release microspheres containing a
CNS modulating agent is prepared through the use of static mixers.
Static or motionless mixers consist of a conduit or tube in that is
received a number of static mixing agents. Static mixers provide
homogeneous mixing in a relatively short length of conduit, and in
a relatively short period of time. With static mixers, the fluid
moves through the mixer, rather than some part of the mixer, such
as a blade, moving through the fluid.
[0306] A static mixer is optionally used to create an emulsion.
When using a static mixer to form an emulsion, several factors
determine emulsion particle size, including the density and
viscosity of the various solutions or phases to be mixed, volume
ratio of the phases, interfacial tension between the phases, static
mixer parameters (conduit diameter; length of mixing element;
number of mixing elements), and linear velocity through the static
mixer. Temperature is a variable because it affects density,
viscosity, and interfacial tension. The controlling variables are
linear velocity, sheer rate, and pressure drop per unit length of
static mixer.
[0307] In order to create microspheres containing a CNS modulating
agent using a static mixer process, an organic phase and an aqueous
phase are combined. The organic and aqueous phases are largely or
substantially immiscible, with the aqueous phase constituting the
continuous phase of the emulsion. The organic phase includes a CNS
modulating agent as well as a wall-forming polymer or polymeric
matrix material. The organic phase is prepared by dissolving a CNS
modulating agent in an organic or other suitable solvent, or by
forming a dispersion or an emulsion containing the CNS modulating
agent. The organic phase and the aqueous phase are pumped so that
the two phases flow simultaneously through a static mixer, thereby
forming an emulsion that comprises microspheres containing the CNS
modulating agent encapsulated in the polymeric matrix material. The
organic and aqueous phases are pumped through the static mixer into
a large volume of quench liquid to extract or remove the organic
solvent. Organic solvent is optionally removed from the
microspheres while they are washing or being stirred in the quench
liquid. After the microspheres are washed in a quench liquid, they
are isolated, as through a sieve, and dried.
[0308] In one embodiment, microspheres are prepared using a static
mixer. The process is not limited to the solvent extraction
technique discussed above, but is used with other encapsulation
techniques. For example, the process is optionally used with a
phase separation encapsulation technique. To do so, an organic
phase is prepared that comprises a CNS modulating agent suspended
or dispersed in a polymer solution. The non-solvent second phase is
free from solvents for the polymer and active agent. A preferred
non-solvent second phase is silicone oil. The organic phase and the
non-solvent phase are pumped through a static mixer into a
non-solvent quench liquid, such as heptane. The semi-solid
particles are quenched for complete hardening and washing. The
process of microencapsulation includes spray drying, solvent
evaporation, a combination of evaporation and extraction, and melt
extrusion.
[0309] In another embodiment, the microencapsulation process
involves the use of a static mixer with a single solvent. This
process is described in detail in U.S. application Ser. No.
08/338,805, herein incorporated by reference for such disclosure.
An alternative process involves the use of a static mixer with
co-solvents. In this process, biodegradable microspheres comprising
a biodegradable polymeric binder and a CNS modulating agent are
prepared, which comprises a blend of at least two substantially
non-toxic solvents, free of halogenated hydrocarbons to dissolve
both the agent and the polymer. The solvent blend containing the
dissolved agent and polymer is dispersed in an aqueous solution to
form droplets. The resulting emulsion is then added to an aqueous
extraction medium preferably containing at least one of the
solvents of the blend, whereby the rate of extraction of each
solvent is controlled, whereupon the biodegradable microspheres
containing the pharmaceutically active agent are formed. This
process has the advantage that less extraction medium is required
because the solubility of one solvent in water is substantially
independent of the other and solvent selection is increased,
especially with solvents that are particularly difficult to
extract.
[0310] Nanoparticles are also contemplated for use with the CNS
modulating agents disclosed herein. Nanoparticles are material
structures of about 100 nm or less in size. One use of
nanoparticles in pharmaceutical compositions is the formation of
suspensions as the interaction of the particle surface with solvent
is strong enough to overcome differences in density. Nanoparticle
suspensions are sterilized as the nanoparticles are small enough to
be subjected to sterilizing filtration (see, e.g., U.S. Pat. No.
6,139,870, herein incorporated by reference for such disclosure).
Nanoparticles comprise at least one hydrophobic, water-insoluble
and water-indispersible polymer or copolymer emulsified in a
solution or aqueous dispersion of surfactants, phospholipids or
fatty acids. The CNS modulating agent is optionally introduced with
the polymer or the copolymer into the nanoparticles.
[0311] Lipid nanocapsules as controlled-release structures, as well
for penetrating the round window membrane and reaching auris
interna and/or auris media targets, is also contemplated herein.
Lipid nanocapsules are optionally formed by emulsifying capric and
caprylic acid triglycerides (Labrafac WL 1349; avg. mw 512),
soybean lecithin (LIPOID.RTM. S75-3; 69% phosphatidylcholine and
other phospholipids), surfactant (for example, Solutol HS15), a
mixture of polyethylene glycol 660 hydroxystearate and free
polyethylene glycol 660; NaCl and water. The mixture is stirred at
room temperature to obtain an oil emulsion in water. After
progressive heating at a rate of 4.degree. C./min under magnetic
stirring, a short interval of transparency should occur close to
70.degree. C., and the inverted phase (water droplets in oil)
obtained at 85.degree. C. Three cycles of cooling and heating is
then applied between 85.degree. C. and 60.degree. C. at the rate of
4.degree. C./min, and a fast dilution in cold water at a
temperature close to 0.degree. C. to produce a suspension of
nanocapsules. To encapsulate the CNS modulating agents, the agent
is optionally added just prior to the dilution with cold water.
[0312] CNS modulating agents are also inserted into the lipid
nanocapsules by incubation for 90 minutes with an aqueous micellar
solution of the auris active agent. The suspension is then vortexed
every 15 minutes, and then quenched in an ice bath for 1
minute.
[0313] Suitable auris-acceptable surfactants are, by way of
example, cholic acid or taurocholic acid salts. Taurocholic acid,
the conjugate formed from cholic acid and taurine, is a fully
metabolizable sulfonic acid surfactant. An analog of taurocholic
acid, tauroursodeoxycholic acid (TUDCA), is a naturally occurring
bile acid and is a conjugate of taurine and ursodeoxycholic acid
(UDCA). Other naturally occurring anionic (e.g., galactocerebroside
sulfate), neutral (e.g., lactosylceramide) or zwitterionic
surfactants (e.g., sphingomyelin, phosphatidyl choline, palmitoyl
carnitine) are optionally used to prepare nanoparticles.
[0314] The auris-acceptable phospholipids are chosen, by way of
example, from natural, synthetic or semi-synthetic phospholipids;
lecithins (phosphatidylcholine) such as, for example, purified egg
or soya lecithins (lecithin E100, lecithin E80 and phospholipons,
for example phospholipon 90), phosphatidylethanolamine,
phosphatidylserine, phosphatidylinositol, phosphatidylglycerol,
dipalmitoylphosphatidylcholine,
dipalmitoylglycerophosphatidylcholine,
dimyristoylphosphatidylcholine, di stearoylphosphatidylcholine and
phosphatidic acid or mixtures thereof are used more
particularly.
[0315] Fatty acids for use with the auris-acceptable compositions
are chosen from, by way of example, lauric acid, mysristic acid,
palmitic acid, stearic acid, isostearic acid, arachidic acid,
behenic acid, oleic acid, myristoleic acid, palmitoleic acid,
linoleic acid, alpha-linoleic acid, arachidonic acid,
eicosapentaenoic acid, erucic acid, docosahexaenoic acid, and the
like.
[0316] Suitable auris-acceptable surfactants are selected from
known organic and inorganic pharmaceutical excipients. Such
excipients include various polymers, low molecular weight
oligomers, natural products, and surfactants. Preferred surface
modifiers include nonionic and ionic surfactants. Two or more
surface modifiers are used in combination.
[0317] Representative examples of auris-acceptable surfactants
include cetyl pyridinium chloride, gelatin, casein, lecithin
(phosphatides), dextran, glycerol, gum acacia, cholesterol,
tragacanth, stearic acid, calcium stearate, glycerol monostearate,
cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters,
polyoxyethylene alkyl ethers, polyoxyethylene castor oil
derivatives, polyoxyethylene sorbitan fatty acid esters; dodecyl
trimethyl ammonium bromide, polyoxyethylenestearates, colloidal
silicon dioxide, phosphates, sodium dodecyl sulfate,
carboxymethylcellulose calcium, hydroxypropyl cellulose (HPC,
HPC-SL, and HPC-L), hydroxypropyl methylcellulose (HPMC),
carboxymethylcellulose sodium, methylcellulose, hydroxyethyl
cellulose, hydroxypropylcellulose, hydroxypropylmethyl-cellulose
phthalate, noncrystalline cellulose, magnesium aluminum silicate,
triethanolamine, polyvinyl alcohol (PVA), polyvinylpyrrolidone
(PVP), 4-(1,1,3,3-tetaamethylbutyl)-phenol polymer with ethylene
oxide and formaldehyde (also known as tyloxapol, superione, and
triton), poloxamers, poloxamnines, a charged phospholipid such as
dimyristoyl phophatidyl glycerol, dioctylsulfosuccinate (DOSS);
Tetronic.RTM. 1508, dialkylesters of sodium sulfosuccinic acid,
Duponol P, Tritons X-200, Crodestas F-110,
p-isononylphenoxypoly-(glycidol), Crodestas SL-40 (Croda, Inc.);
and SA9OHCO, which is C.sub.18 H.sub.37 CH.sub.2
(CON(CH.sub.3)--CH.sub.2 (CHOH).sub.4 (CH.sub.2 OH).sub.2 (Eastman
Kodak Co.); decanoyl-N-methylglucamide; n-decyl
.beta.-D-glucopyranoside; n-decyl .beta.-D-maltopyranoside;
n-dodecyl .beta.-D-glucopyranoside; n-dodecyl .beta.-D-maltoside;
heptanoyl-N-methylglucamide; n-heptyl-.beta.-D-glucopyranoside;
n-heptyl .beta.-D-thioglucoside; n-hexyl .beta.-D-glucopyranoside;
nonanoyl-N-methylglucamide; n-noyl .beta.-D-glucopyranoside;
octanoyl-N-methylglucarmide; n-octyl-.beta.-D-glucopyranoside;
octyl .beta.-D-thioglucopyranoside; and the like. Most of these
surfactants are known pharmaceutical excipients and are described
in detail in the Handbook of Pharmaceutical Excipients, published
jointly by the American Pharmaceutical Association and The
Pharmaceutical Society of Great Britain (The Pharmaceutical Press,
1986), specifically incorporated by reference for such
disclosure.
[0318] The hydrophobic, water-insoluble and water-indispersible
polymer or copolymer may be chosen from biocompatible and
biodegradable polymers, for example lactic or glycolic acid
polymers and copolymers thereof, or polylactic/polyethylene (or
polypropylene) oxide copolymers, preferably with molecular weights
of between 1000 and 200,000, polyhydroxybutyric acid polymers,
polylactones of fatty acids containing at least 12 carbon atoms, or
polyanhydrides.
[0319] The nanoparticles may be obtained by coacervation, or the
technique of evaporation of solvent, from an aqueous dispersion or
solution of phospholipids and of an oleic acid salt into that is
added an immiscible organic phase comprising the active principle
and the hydrophobic, water-insoluble and water-indispersible
polymer or copolymer. The mixture is pre-emulsified and then
subjected to homogenization and evaporation of the organic solvent
to obtain an aqueous suspension of very small-sized
nanoparticles.
[0320] A variety of methods are optionally employed to fabricate
the CNS modulating nanoparticles that are within the scope of the
embodiments. These methods include vaporization methods, such as
free jet expansion, laser vaporization, spark erosion, electro
explosion and chemical vapor deposition; physical methods involving
mechanical attrition (e.g., "pearlmilling" technology, Elan
Nanosystems), super critical CO2 and interfacial deposition
following solvent displacement. In one embodiment, the solvent
displacement method is used. The size of nanoparticles produced by
this method is sensitive to the concentration of polymer in the
organic solvent; the rate of mixing; and to the surfactant employed
in the process. Continuous flow mixers provide the necessary
turbulence to ensure small particle size. One type of continuous
flow mixing device that is optionally used to prepare nanoparticles
has been described (Hansen et al J Phys Chem 92, 2189-96, 1988). In
other embodiments, ultrasonic devices, flow through homogenizers or
supercritical CO2 devices may be used to prepare nanoparticles.
[0321] If suitable nanoparticle homogeneity is not obtained on
direct synthesis, then size-exclusion chromatography is used to
produce highly uniform drug-containing particles that are freed of
other components involved in their fabrication. Size-exclusion
chromatography (SEC) techniques, such as gel-filtration
chromatography, is used to separate particle-bound CNS modulating
agent or other pharmaceutical compound from free CNS modulating
agent or other pharmaceutical compound, or to select a suitable
size range of CNS modulating-containing nanoparticles. Various SEC
media, such as Superdex 200, Superose 6, Sephacryl 1000 are
commercially available and are employed for the size-based
fractionation of such mixtures. Additionally, nanoparticles are
optionally purified by centrifugation, membrane filtration and by
use of other molecular sieving devices, crosslinked gels/materials
and membranes.
[0322] Auris-Acceptable Cyclodextrin and Other Stabilizing
Compositions
[0323] In a specific embodiment, the auris-acceptable compositions
alternatively comprises a cyclodextrin. Cyclodextrins are cyclic
oligosaccharides containing 6, 7, or 8 glucopyranose units,
referred to as .alpha.-cyclodextrin, .beta.-cyclodextrin, or
.gamma.-cyclodextrin respectively. Cyclodextrins have a hydrophilic
exterior, which enhances water-soluble, and a hydrophobic interior
that forms a cavity. In an aqueous environment, hydrophobic
portions of other molecules often enter the hydrophobic cavity of
cyclodextrin to form inclusion compounds. Additionally,
cyclodextrins are also capable of other types of nonbonding
interactions with molecules that are not inside the hydrophobic
cavity. Cyclodextrins have three free hydroxyl groups for each
glucopyranose unit, or 18 hydroxyl groups on .alpha.-cyclodextrin,
21 hydroxyl groups on .beta.-cyclodextrin, and 24 hydroxyl groups
on .gamma.-cyclodextrin. One or more of these hydroxyl groups can
be reacted with any of a number of reagents to form a large variety
of cyclodextrin derivatives, including hydroxypropyl ethers,
sulfonates, and sulfoalkylethers. Shown below is the structure of
.beta.-cyclodextrin and the hydroxypropyl-.beta.-cyclodextrin
(HP.beta.CD).
##STR00002##
R.dbd.H
[0324] .beta.-cyclodextrin R.dbd.CH.sub.2CH(OH)CH.sub.3
hydroxypropyl .beta.-cyclodextrin
[0325] In some embodiments, the use of cyclodextrins in the
pharmaceutical compositions described herein improves the
solubility of the drug. Inclusion compounds are involved in many
cases of enhanced solubility; however other interactions between
cyclodextrins and insoluble compounds also improves solubility.
Hydroxypropyl-.beta.-cyclodextrin (HP.beta.CD) is commercially
available as a pyrogen free product. It is a nonhygroscopic white
powder that readily dissolves in water. HP.beta.CD is thermally
stable and does not degrade at neutral pH. Thus, cyclodextrins
improve the solubility of a therapeutic agent in a composition or
composition. Accordingly, in some embodiments, cyclodextrins are
included to increase the solubility of the auris-acceptable CNS
modulating agents within the compositions described herein. In
other embodiments, cyclodextrins in addition serve as
controlled-release excipients within the compositions described
herein.
[0326] By way of example only, cyclodextrin derivatives for use
include .alpha.-cyclodextrin, .beta.-cyclodextrin,
.gamma.-cyclodextrin, hydroxyethyl .beta.-cyclodextrin,
hydroxypropyl .gamma.-cyclodextrin, sulfated .beta.-cyclodextrin,
sulfated .alpha.-cyclodextrin, sulfobutyl ether
.beta.-cyclodextrin.
[0327] The concentration of the cyclodextrin used in the
compositions and methods disclosed herein varies according to the
physiochemical properties, pharmacokinetic properties, side effect
or adverse events, composition considerations, or other factors
associated with the therapeutically active agent, or a salt or
prodrug thereof, or with the properties of other excipients in the
composition. Thus, in certain circumstances, the concentration or
amount of cyclodextrin used in accordance with the compositions and
methods disclosed herein will vary, depending on the need. When
used, the amount of cyclodextrins needed to increase solubility of
the CNS modulating agent and/or function as a controlled-release
excipient in any of the compositions described herein is selected
using the principles, examples, and teachings described herein.
[0328] Other stabilizers that are useful in the auris-acceptable
compositions disclosed herein include, for example, fatty acids,
fatty alcohols, alcohols, long chain fatty acid esters, long chain
ethers, hydrophilic derivatives of fatty acids, polyvinyl
pyrrolidones, polyvinyl ethers, polyvinyl alcohols, hydrocarbons,
hydrophobic polymers, moisture-absorbing polymers, and combinations
thereof. In some embodiments, amide analogues of stabilizers are
also used. In further embodiments, the chosen stabilizer changes
the hydrophobicity of the composition (e.g., oleic acid, waxes), or
improves the mixing of various components in the composition (e.g.,
ethanol), controls the moisture level in the formula (e.g., PVP or
polyvinyl pyrrolidone), controls the mobility of the phase
(substances with melting points higher than room temperature such
as long chain fatty acids, alcohols, esters, ethers, amides etc. or
mixtures thereof waxes), and/or improves the compatibility of the
formula with encapsulating materials (e.g., oleic acid or wax). In
another embodiment some of these stabilizers are used as
solvents/co-solvents (e.g., ethanol). In other embodiments,
stabilizers are present in sufficient amounts to inhibit the
degradation of the CNS modulating agent. Examples of such
stabilizing agents, include, but are not limited to: (a) about 0.5%
to about 2% w/v glycerol, (b) about 0.1% to about 1% w/v
methionine, (c) about 0.1% to about 2% w/v monothioglycerol, (d)
about 1 mM to about 10 mM EDTA, (e) about 0.01% to about 2% w/v
ascorbic acid, (f) 0.003% to about 0.02% w/v polysorbate 80, (g)
0.001% to about 0.05% w/v. polysorbate 20, (h) arginine, (i)
heparin, (j) dextran sulfate, (k) cyclodextrins, (1) pentosan
polysulfate and other heparinoids, (m) divalent cations such as
magnesium and zinc; or (n) combinations thereof.
[0329] Additional useful CNS modulating agent auris-acceptable
compositions include one or more anti-aggregation additives to
enhance stability of a CNS modulating agent compositions by
reducing the rate of protein aggregation. The anti-aggregation
additive selected depends upon the nature of the conditions to that
the CNS modulating agents, for example CNS modulating agent
antibodies are exposed. For example, certain compositions
undergoing agitation and thermal stress require a different
anti-aggregation additive than a composition undergoing
lyophilization and reconstitution. Useful anti-aggregation
additives include, by way of example only, urea, guanidinium
chloride, simple amino acids such as glycine or arginine, sugars,
polyalcohols, polysorbates, polymers such as polyethylene glycol
and dextrans, alkyl saccharides, such as alkyl glycoside, and
surfactants.
[0330] Other useful compositions optionally include one or more
auris-acceptable antioxidants to enhance chemical stability where
required. Suitable antioxidants include, by way of example only,
ascorbic acid, methionine, sodium thiosulfate and sodium
metabisulfite. In one embodiment, antioxidants are selected from
metal chelating agents, thiol containing compounds and other
general stabilizing agents.
[0331] Still other useful compositions include one or more
auris-acceptable surfactants to enhance physical stability or for
other purposes. Suitable nonionic surfactants include, but are not
limited to, polyoxyethylene fatty acid glycerides and vegetable
oils, e.g., polyoxyethylene (60) hydrogenated castor oil; and
polyoxyethylene alkylethers and alkylphenyl ethers, e.g., octoxynol
10, octoxynol 40.
[0332] In some embodiments, the auris-acceptable pharmaceutical
compositions described herein are stable with respect to compound
degradation 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 3 months, at
least about 4 months, at least about 5 months, or at least about 6
months. In other embodiments, the compositions described herein are
stable with respect to compound degradation over a period of at
least about 1 week. Also described herein are compositions that are
stable with respect to compound degradation over a period of at
least about 1 month.
[0333] In other embodiments, an additional surfactant
(co-surfactant) and/or buffering agent is combined with one or more
of the pharmaceutically acceptable vehicles previously described
herein so that the surfactant and/or buffering agent maintains the
product at an optimal pH for stability. Suitable co-surfactants
include, but are not limited to: a) natural and synthetic
lipophilic agents, e.g., phospholipids, cholesterol, and
cholesterol fatty acid esters and derivatives thereof; b) nonionic
surfactants, which include for example, polyoxyethylene fatty
alcohol esters, sorbitan fatty acid esters (Spans), polyoxyethylene
sorbitan fatty acid esters (e.g., polyoxyethylene (20) sorbitan
monooleate (Tween 80), polyoxyethylene (20) sorbitan monostearate
(Tween 60), polyoxyethylene (20) sorbitan monolaurate (Tween 20)
and other Tweens, sorbitan esters, glycerol esters, e.g., Myrj and
glycerol triacetate (triacetin), polyethylene glycols, cetyl
alcohol, cetostearyl alcohol, stearyl alcohol, polysorbate 80,
poloxamers, poloxamines, polyoxyethylene castor oil derivatives
(e.g., Cremophor.RTM. RH40, Cremphor A25, Cremphor A20,
Cremophor.RTM. EL) and other Cremophors, sulfosuccinates, alkyl
sulphates (SLS); PEG glyceryl fatty acid esters such as PEG-8
glyceryl caprylate/caprate (Labrasol), PEG-4 glyceryl
caprylate/caprate (Labrafac Hydro WL 1219), PEG-32 glyceryl laurate
(Gelucire 444/14), PEG-6 glyceryl mono oleate (Labrafil M 1944 CS),
PEG-6 glyceryl linoleate (Labrafil M 2125 CS); propylene glycol
mono- and di-fatty acid esters, such as propylene glycol laurate,
propylene glycol caprylate/caprate; Brij.RTM. 700,
ascorbyl-6-palmitate, stearylamine, sodium lauryl sulfate,
polyoxethyleneglycerol triiricinoleate, and any combinations or
mixtures thereof; c) anionic surfactants include, but are not
limited to, calcium carboxymethylcellulose, sodium
carboxymethylcellulose, sodium sulfosuccinate, dioctyl, sodium
alginate, alkyl polyoxyethylene sulfates, sodium lauryl sulfate,
triethanolamine stearate, potassium laurate, bile salts, and any
combinations or mixtures thereof; and d) cationic surfactants such
as cetyltrimethylammonium bromide, and
lauryldimethylbenzyl-ammonium chloride.
[0334] In a further embodiment, when one or more co-surfactants are
utilized in the auris-acceptable compositions of the present
disclosure, they are combined, e.g., with a pharmaceutically
acceptable vehicle and is present in the final composition, e.g.,
in an amount ranging from about 0.1% to about 20%, from about 0.5%
to about 10%.
[0335] In one embodiment, the surfactant has an HLB value of 0 to
20. In additional embodiments, the surfactant has an HLB value of 0
to 3, of 4 to 6, of 7 to 9, of 8 to 18, of 13 to 15, of 10 to
18.
[0336] In one embodiment, diluents are also used to stabilize the
CNS modulating agent or other pharmaceutical compounds because they
provide a more stable environment. Salts dissolved in buffered
solutions (that also can provide pH control or maintenance) are
utilized as diluents, including, but not limited to a phosphate
buffered saline solution. In other embodiments, the gel composition
is isotonic with the endolymph or the perilymph: depending on the
portion of the cochlea that the CNS modulating agent composition is
targeted. Isotonic compositions 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 and sodium chloride. In further embodiments, the tonicity
agents are present in an amount from about 100 mOsm/kg to about 500
mOsm/kg. In some embodiments, the tonicity agent is present in an
amount from about 200 mOsm/kg to about 400 mOsm/kg, from about 280
mOsm/kg to about 320 mOsm/kg. The amount of tonicity agents will
depend on the target structure of the pharmaceutical composition,
as described herein.
[0337] Useful tonicity compositions also include one or more salts
in an amount required to bring osmolality of the composition into
an acceptable range for the perilymph or the endolymph. 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.
[0338] In some embodiments, the auris-acceptable gel compositions
disclosed herein alternatively or additionally contains
preservatives to prevent microbial growth. Suitable
auris-acceptable preservatives for use in the enhanced viscosity
compositions described herein include, but are not limited to
benzoic acid, boric acid, p-hydroxybenzoates, alcohols, quarternary
compounds, stabilized chlorine dioxide, mercurials, such as merfen
and thiomersal, mixtures of the foregoing and the like.
[0339] In a further embodiment, the preservative is, by way of
example only, an antimicrobial agent, within the auris-acceptable
compositions presented herein. In one embodiment, the composition
includes a preservative such as by way of example only, methyl
paraben, sodium bisulfite, sodium thiosulfate, ascorbate,
chorobutanol, thimerosal, parabens, benzyl alcohol, phenylethanol
and others. In another embodiment, the methyl paraben is at a
concentration of about 0.05% to about 1.0%, about 0.1% to about
0.2%. In a further embodiment, the gel is prepared by mixing water,
methylparaben, hydroxyethylcellulose and sodium citrate. In a
further embodiment, the gel is prepared by mixing water,
methylparaben, hydroxyethylcellulose and sodium acetate. In a
further embodiment, the mixture is sterilized by autoclaving at
120.degree. C. for about 20 minutes, and tested for pH,
methylparaben concentration and viscosity before mixing with the
appropriate amount of the CNS modulating agent disclosed
herein.
[0340] Suitable auris-acceptable water soluble preservatives that
are employed in the drug delivery vehicle include sodium bisulfite,
sodium thiosulfate, ascorbate, chorobutanol, thimerosal, parabens,
benzyl alcohol, Butylated hydroxytoluene (BHT), phenylethanol and
others. These agents are present, generally, in amounts of about
0.001% to about 5% by weight and, preferably, in the amount of
about 0.01 to about 2% by weight. In some embodiments,
auris-compatible compositions described herein are free of
preservatives.
[0341] Round Window Membrane Penetration Enhancers
[0342] In another embodiment, the composition further comprises one
or more round window membrane penetration enhancers. Penetration
across the round window membrane is enhanced by the presence of
round window membrane penetration enhancers. Round window membrane
penetration enhancers are chemical entities that facilitate
transport of coadministered substances across the round window
membrane. Round window membrane penetration enhancers are grouped
according to chemical structure. Surfactants, both ionic and
non-ionic, such as sodium lauryl sulfate, sodium laurate,
polyoxyethylene-20-cetyl ether, laureth-9, sodium dodecylsulfate,
dioctyl sodium sulfosuccinate, polyoxyethylene-9-lauryl ether
(PLE), Tween.RTM. 80, nonylphenoxypolyethylene (NP-POE),
polysorbates and the like, function as round window membrane
penetration enhancers. Bile salts (such as sodium glycocholate,
sodium deoxycholate, sodium taurocholate, sodium
taurodihydrofusidate, sodium glycodihydrofusidate and the like),
fatty acids and derivatives (such as oleic acid, caprylic acid,
mono- and di-glycerides, lauric acids, acylcholines, caprylic
acids, acylcarnitines, sodium caprates and the like), chelating
agents (such as EDTA, citric acid, salicylates and the like),
sulfoxides (such as dimethyl sulfoxide (DMSO), decylmethyl
sulfoxide and the like), and alcohols (such as ethanol,
isopropanol, glycerol, propanediol and the like) also function as
round window membrane penetration enhancers.
[0343] In some embodiments, the auris acceptable penetration
enhancer is a surfactant comprising an alkyl-glycoside wherein the
alkyl glycoside is tetradecyl-.beta.-D-maltoside. In some
embodiments, the auris acceptable penetration enhancer is a
surfactant comprising an alkyl-glycoside wherein the alkyl
glycoside is dodecyl-maltoside. In certain instances, the
penetration enhancing agent is a hyaluronidase. In certain
instances, a hyaluronidase is a human or bovine hyaluronidase. In
some instances, a hyaluronidase is a human hyaluronidase (e.g.,
hyaluronidase found in human sperm, PH20 (Halozyme), Hyelenex.RTM.
(Baxter International, Inc.)). In some instances, a hyaluronidase
is a bovine hyaluronidase (e.g., bovine testicular hyaluronidase,
Amphadase.RTM. (Amphastar Pharmaceuticals), Hydase.RTM.
(PrimaPharm, Inc). In some instances, a hyaluronidase is an ovine
hyaluronidase, Vitrase.RTM. (ISTA Pharmaceuticals). In certain
instances, a hyaluronidase described herein is a recombinant
hyaluronidase. In some instances, a hyaluronidase described herein
is a humanized recombinant hyaluronidase. In some instances, a
hyaluronidase described herein is a pegylated hyaluronidase (e.g.,
PEGPH20 (Halozyme)). In addition, the peptide-like penetration
enhancers described in U.S. Pat. Nos. 7,151,191, 6,221,367 and
5,714,167, herein incorporated by references for such disclosure,
are contemplated as an additional embodiment. These penetration
enhancers are amino-acid and peptide derivatives and enable drug
absorption by passive transcellular diffusion without affecting the
integrity of membranes or intercellular tight junctions.
[0344] Round Window Membrane Permeable Liposomes
[0345] Liposomes or lipid particles may also be employed to
encapsulate the CNS modulating agent compositions or compositions.
Phospholipids that are gently dispersed in an aqueous medium form
multilayer vesicles with areas of entrapped aqueous media
separating the lipid layers. Sonication, or turbulent agitation, of
these multilayer vesicles results in the formation of single layer
vesicles, commonly referred to as liposomes, with sizes of about
10-1000 nm. These liposomes have many advantages as CNS modulating
agents or other pharmaceutical agent carriers. They are
biologically inert, biodegradable, non-toxic and non-antigenic.
Liposomes are formed in various sizes and with varying compositions
and surface properties. Additionally, they are able to entrap a
wide variety of agents and release the agent at the site of
liposome collapse.
[0346] Suitable phospholipids for use in auris-acceptable liposomes
here are, for example, phosphatidyl cholines, ethanolamines and
serines, sphingomyelins, cardiolipins, plasmalogens, phosphatidic
acids and cerebrosides, in particular those that are soluble
together with the CNS modulating agents herein in non-toxic,
pharmaceutically acceptable organic solvents. Preferred
phospholipids are, for example, phosphatidyl choline, phosphatidyl
ethanolmine, phosphatidyl serine, phosphatidyl inositol,
lysophosphatidyl choline, phosphatidyl glycerol and the like, and
mixtures thereof especially lecithin, e.g. soya lecithin. The
amount of phospholipid used in the present composition range from
about 10 to about 30%, preferably from about 15 to about 25% and in
particular is about 20%.
[0347] Lipophilic additives may be employed advantageously to
modify selectively the characteristics of the liposomes. Examples
of such additives include by way of example only, stearylamine,
phosphatidic acid, tocopherol, cholesterol, cholesterol
hemisuccinate and lanolin extracts. The amount of lipophilic
additive used range from 0.5 to 8%, preferably from 1.5 to 4% and
in particular is about 2%. Generally, the ratio of the amount of
lipophilic additive to the amount of phospholipid ranges from about
1:8 to about 1:12 and in particular is about 1:10. Said
phospholipid, lipophilic additive and the CNS modulating agent and
other pharmaceutical compounds are employed in conjunction with a
non-toxic, pharmaceutically acceptable organic solvent system that
dissolve said ingredients. Said solvent system not only must
dissolve the CNS modulating agent completely, but it also has to
allow the composition of stable single bilayered liposomes. The
solvent system comprises dimethylisosorbide and tetraglycol
(glycofurol, tetrahydrofurfuryl alcohol polyethylene glycol ether)
in an amount of about 8 to about 30%. In said solvent system, the
ratio of the amount of dimethylisosorbide to the amount of
tetraglycol range from about 2:1 to about 1:3, in particular from
about 1:1 to about 1:2.5 and preferably is about 1:2. The amount of
tetraglycol in the final composition thus vary from 5 to 20%, in
particular from 5 to 15% and preferably is approximately 10%. The
amount of dimethylisosorbide in the final composition thus range
from 3 to 10%, in particular from 3 to 7% and preferably is
approximately 5%.
[0348] The term "organic component" as used hereinafter refers to
mixtures comprising said phospholipid, lipophilic additives and
organic solvents. The CNS modulating agent may be dissolved in the
organic component, or other means to maintain full activity of the
agent. The amount of a CNS modulating agent in the final
composition may range from 0.1 to 5.0%. In addition, other
ingredients such as anti-oxidants may be added to the organic
component. Examples include tocopherol, butylated hydroxyanisole,
butylated hydroxytoluene, ascorbyl palmitate, ascorbyl oleate and
the like.
[0349] Liposomal compositions are alternatively prepared, for CNS
modulating agents or other pharmaceutical agents that are
moderately heat-resistant, by (a) heating the phospholipid and the
organic solvent system to about 60-80.degree. C. in a vessel,
dissolving the active ingredient, then adding any additional
formulating agents, and stirring the mixture until complete
dissolution is obtained; (b) heating the aqueous solution to
90-95.degree. C. in a second vessel and dissolving the
preservatives therein, allowing the mixture to cool and then adding
the remainder of the auxiliary formulating agents and the remainder
of the water, and stirring the mixture until complete dissolution
is obtained; thus preparing the aqueous component; (c) transferring
the organic phase directly into the aqueous component, while
homogenizing the combination with a high performance mixing
apparatus, for example, a high-shear mixer; and (d) adding a
viscosity enhancing agent to the resulting mixture while further
homogenizing. The aqueous component is optionally placed in a
suitable vessel that is equipped with a homogenizer and
homogenization is effected by creating turbulence during the
injection of the organic component. Any mixing means or homogenizer
that exerts high shear forces on the mixture may be employed.
Generally, a mixer capable of speeds from about 1,500 to 20,000
rpm, in particular from about 3,000 to about 6,000 rpm may be
employed. Suitable viscosity enhancing agents for use in process
step (d) are for example, xanthan gum, hydroxypropyl cellulose,
hydroxypropyl methylcellulose or mixtures thereof. The amount of
viscosity enhancing agent depends on the nature and the
concentration of the other ingredients and in general ranges from
about 0.5 to 2.0%, or approximately 1.5%. In order to prevent
degradation of the materials used during the preparation of the
liposomal composition, it is advantageous to purge all solutions
with an inert gas such as nitrogen or argon, and to conduct all
steps under an inert atmosphere. Liposomes prepared by the above
described method usually contain most of the active ingredient
bound in the lipid bilayer and separation of the liposomes from
unencapsulated material is not required.
[0350] In other embodiments, the auris-acceptable compositions,
including gel compositions and viscosity-enhanced compositions,
further include excipients, other medicinal or pharmaceutical
agents, carriers, adjuvants, such as preserving, stabilizing,
wetting or emulsifying agents, solution promoters, salts,
solubilizers, an antifoaming agent, an antioxidant, a dispersing
agent, a wetting agent, a surfactant, and combinations thereof.
[0351] Suitable carriers for use in an auris-acceptable composition
described herein include, but are not limited to, any
pharmaceutically acceptable solvent compatible with the targeted
auris structure's physiological environment. In other embodiments,
the base is a combination of a pharmaceutically acceptable
surfactant and solvent.
[0352] In some embodiments, other excipients include, sodium
stearyl fumarate, diethanolamine cetyl sulfate, isostearate,
polyethoxylated castor oil, nonoxyl 10, octoxynol 9, sodium lauryl
sulfate, sorbitan esters (sorbitan monolaurate, sorbitan
monooleate, sorbitan monopalmitate, sorbitan monostearate, sorbitan
sesquioleate, sorbitan trioleate, sorbitan tristearate, sorbitan
laurate, sorbitan oleate, sorbitan palmitate, sorbitan stearate,
sorbitan dioleate, sorbitan sesqui-isostearate, sorbitan
sesquistearate, sorbitan tri-isostearate), lecithin pharmaceutical
acceptable salts thereof and combinations or mixtures thereof
[0353] In other embodiments, the carrier is a polysorbate.
Polysorbates are nonionic surfactants of sorbitan esters.
Polysorbates useful in the present disclosure include, but are not
limited to polysorbate 20, polysorbate 40, polysorbate 60,
polysorbate 80 (Tween 80) and any combinations or mixtures thereof.
In further embodiments, polysorbate 80 is utilized as the
pharmaceutically acceptable carrier.
[0354] In one embodiment, water-soluble glycerin-based
auris-acceptable enhanced viscosity compositions utilized in the
preparation of pharmaceutical delivery vehicles comprise at least
one CNS modulating agent containing at least about 0.1% of the
water-soluble glycerin compound or more. In some embodiments, the
percentage of a CNS modulating agent is varied between about 1% and
about 95%, between about 5% and about 80%, between about 10% and
about 60% or more of the weight or volume of the total
pharmaceutical composition. In some embodiments, the amount of the
compound(s) in each therapeutically useful CNS modulating agent
composition is prepared in such a way that a suitable dosage will
be obtained in any given unit dose of the compound. Factors such as
solubility, bioavailability, biological half-life, route of
administration, product shelf life, as well as other
pharmacological considerations are contemplated herein.
[0355] If desired, the auris-acceptable pharmaceutical gels also
contain co-solvents, preservatives, cosolvents, ionic strength and
osmolality adjustors and other excipients in addition to buffering
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 7.4.+-.0.2
and preferably, 7.4. As such, the buffering agent is as much as 5%
on a weight basis of the total composition.
[0356] Cosolvents are used to enhance CNS modulating agent
solubility, however, some CNS modulating agents or other
pharmaceutical compounds are insoluble. These are often suspended
in the polymer vehicle with the aid of suitable suspending or
viscosity enhancing agents.
[0357] Moreover, some pharmaceutical excipients, diluents or
carriers are potentially ototoxic. For example, benzalkonium
chloride, a common preservative, is ototoxic and therefore
potentially harmful if introduced into the vestibular or cochlear
structures. In formulating a controlled-release CNS modulating
agent composition, it is advised to avoid or combine the
appropriate excipients, diluents or carriers to lessen or eliminate
potential ototoxic components from the composition, or to decrease
the amount of such excipients, diluents or carriers. Optionally, a
controlled-release CNS modulating agent composition includes
otoprotective agents, such as antioxidants, alpha lipoic acid,
calcium, fosfomycin or iron chelators, to counteract potential
ototoxic effects that may arise from the use of specific
therapeutic agents or excipients, diluents or carriers.
[0358] The following are examples of therapeutically acceptable
otic compositions:
TABLE-US-00002 Example Composition Example Characteristics Chitosan
glycerophosphate tunable degradation of matrix in vitro (CGP)
tunable TACE inhibitor release in vitro: e.g., ~50% of drug
released after 24 hrs biodegradable compatible with drug delivery
to the inner ear suitable for macromolecules and hydrophobic drugs
PEG-PLGA-PEG triblock tunable high stability: e.g., maintains
mechanical integrity >1 polymers month in vitro tunable fast
release of hydrophilic drugs: e.g., ~50% of drug released after 24
hrs, and remainder released over ~5 days tunable slow release of
hydrophobic drugs: e.g., ~80% released after 8 weeks biodegradable
subcutaneous injection of solution: e.g., gel forms within seconds
and is intact after 1 month PEO-PPO-PEO triblock Tunable sol-gel
transition temperature: e.g., decreases with copolymers (e.g.,
Pluronic increasing F127 concentration or Poloxameres) (e.g., F127)
Chitosan glycerophosphate CGP composition tolerates liposomes:
e.g., up to 15 uM/ml with drug-loaded liposomes liposomes.
liposomes tunably reduce drug release time (e.g., up to 2 weeks in
vitro). increase in liposome diameter optionally reduces drug
release kinetics (e.g., liposome size between 100 and 300 nm)
release parameters are controlled by changing composition of
liposomes
[0359] The compositions disclosed herein alternatively encompass an
otoprotectant agent in addition to the at least one active agent
and/or excipients, including but not limited to such agents as
antioxidants, alpha lipoic acid, calcium, fosfomycin or iron
chelators, to counteract potential ototoxic effects that may arise
from the use of specific therapeutic agents or excipients, diluents
or carriers.
Modes of Treatment
[0360] Dosing Methods and Schedules
[0361] 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
that high levels of drug are found in the serum and correspondingly
lower levels are found at the inner ear.
[0362] 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
compositions described herein are administered directly onto the
round window membrane via transtympanic injection. In another
embodiment, the CNS modulating agent auris-acceptable compositions
described herein are administered onto the round window membrane
via a non-transtympanic approach to the inner ear. In additional
embodiments, the composition 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.
[0363] 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 CNS modulating
agent compositions or compositions, 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 possibly of
needle clogging while maintaining an adequate needle gauge.
[0364] In another embodiment, the needle is a hypodermic needle
used for instant delivery of the gel composition. 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 CNS modulating
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 composition is stored
before use. In other embodiments, the syringe comprises a
cylindrical syringe body wherein the CNS modulating agent
pharmaceutically acceptable gel-based compositions as disclosed
herein is stored before use that 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 CNS modulating agent or other
pharmaceutical compounds contained therein.
[0365] 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 CNS modulating agent gel composition. 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 composition 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 a CNS modulating 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.
[0366] 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 that 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.
[0367] The compositions described herein, and modes of
administration thereof, are also applicable to methods of direct
instillation or perfusion of the inner ear compartments. Thus, the
compositions described herein are useful in surgical procedures
including, by way of non-limiting examples, cochleostomy,
labyrinthotomy, mastoidectomy, stapedectomy, endolymphatic
sacculotomy or the like.
[0368] The auris-acceptable compositions or compositions containing
the CNS modulating agent compound(s) described herein are
administered for prophylactic and/or therapeutic treatments. In
therapeutic applications, the CNS modulating agent compositions are
administered to a patient already suffering from a disorder
disclosed herein, 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.
[0369] In the case wherein the patient's condition does not
improve, upon the doctor's discretion the administration of the CNS
modulating agent compounds may be administered chronically, which
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.
[0370] In the case wherein the patient's status does improve, upon
the doctor's discretion the administration of the CNS modulating
agent compounds may be given continuously; alternatively, the dose
of drug being administered may be temporarily reduced or
temporarily suspended for a certain length of time (i.e., a "drug
holiday"). The length of the drug holiday varies between 2 days and
1 year, including by way of example only, 2 days, 3 days, 4 days, 5
days, 6 days, 7 days, 10 days, 12 days, 15 days, 20 days, 28 days,
35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days,
200 days, 250 days, 280 days, 300 days, 320 days, 350 days, and 365
days. The dose reduction during a drug holiday may be from
10%-100%, including by way of example only 10%, 15%, 20%, 25%, 30%,
35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%,
and 100%.
[0371] Once improvement of the patient's otic conditions has
occurred, a maintenance CNS modulating agent dose is administered
if necessary. Subsequently, the dosage or the frequency of
administration, or both, is optionally reduced, as a function of
the symptoms, to a level at that the improved disease, disorder or
condition is retained. In certain embodiments, patients require
intermittent treatment on a long-term basis upon any recurrence of
symptoms.
[0372] The amount of a CNS modulating 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 CNS modulating agent being administered, the
route of administration, the condition being treated, the target
area being treated, and the subject or host being treated. In
general, however, doses employed for adult human treatment will
typically be in the range of 0.02-50 mg per administration,
preferably 1-15 mg per administration. The desired dose is
presented in a single dose or as divided doses administered
simultaneously (or over a short period of time) or at appropriate
intervals.
[0373] In some embodiments, the initial administration is a
particular CNS modulating agent and the subsequent administration a
different composition or CNS modulating agent.
[0374] Implants of Exogenous Materials
[0375] In some embodiments, the pharmaceutical formulations,
compositions and devices described herein are used in combination
with (e.g., implantation, short-term use, long-term use, or removal
of) the implantation of an exogenous material (e.g., a medical
device or a plurality of cells (e.g., stem cells)). As used herein,
the term "exogenous material" includes auris-interna or auris-media
medical devices (e.g., hearing sparing devices, hearing improving
devices, short electrodes, micro-prostheses or piston-like
prostheses); needles; drug delivery devices, and cells (e.g., stem
cells). In some instances, the implants of exogenous materials are
used in conjunction with a patient experiencing hearing loss. In
some instances, the hearing loss is present at birth. In some
instances, the hearing loss is associated with conditions that
develop or progress after birth (e.g., Merniere's disease)
resulting in osteoneogenesis, nerve damage, obliteration of
cochlear structures, or combinations thereof
[0376] In some instances, the exogenous material is a plurality of
cells. In some instances, the exogenous material is a plurality of
stem cells.
[0377] In some instances, the exogenous material is an electronic
device. In some embodiments, the electronic device has an external
portion placed behind the ear, and a second portion that is
surgically placed under the skin that helps provide a sense of
sound to a person who is profoundly deaf or severely
hard-of-hearing. By way of example only, such medical device
implants bypass damaged portions of the ear and directly stimulate
the auditory nerve. In some instances cochlear implants are used in
single sided deafness. In some instances cochlear implants are used
for deafness in both ears.
[0378] In some embodiments, administration of an active agent
described herein in combination with the implantation of an
exogenous material (e.g., a medical device implant or a stem cell
transplant) delays or prevents damage of auris structures, e.g.,
irritation, cell death osteoneogeneis and/or further neuronal
degeneration, caused by installation of an external device and/or a
plurality cells (e.g., stem cells) in the ear. In some embodiments,
administration of a composition or device described herein in
combination with an implant allows for a more effective restoration
of hearing loss compared to an implant alone.
[0379] In some embodiments, administration of an active agent
described herein reduces damage to auris structures caused by
underlying conditions allowing for successful implantation. In some
embodiments, administration of an active agent described herein, in
conjunction surgery and/or with the implantation of an exogenous
material reduces or prevents negative side-effects (e.g., cell
death).
[0380] In some embodiments, administration of an active agent
described herein in conjunction with the implantation of an
exogenous material has a trophic effect (i.e., promotes healthy
growth of cells and 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 (e.g., stem cell)
transplant. In some of such embodiments, the compositions or
devices described herein are administered via direct cochlear
injection, through a chochleostomy or via deposition on the round
window
[0381] In some embodiments, administration of an active agent
described herein reduces inflammation and/or infections associated
with otic surgery, or implantation of an exogenous material (e.g.,
a medical device or a plurality of cells (e.g., stem cells)). In
some instances, perfusion of a surgical area with a formulation
described herein reduces or eliminates post-surgical and/or
post-implantation complications (e.g., inflammation, hair cell
damage, neuronal degeneration, osteoneogenesis or the like). In
some instances, perfusion of a surgical area with a formulation
described herein reduces post-surgery or post-implantation
recuperation time.
[0382] In one aspect, the formulations described herein, and modes
of administration thereof, are applicable to methods of direct
perfusion of the inner ear compartments. Thus, the formulations
described herein are useful in combination with surgical procedures
including, by way of non-limiting examples, cochleostomy,
labyrinthotomy, mastoidectomy, stapedectomy, stapedotomy,
endolymphatic sacculotomy or the like. In some embodiments, the
inner ear compartments are perfused with a formulation described
herein prior to otic surgery, during otic surgery, after otic
surgery, or a combination thereof. In some of such embodiments, the
formulations described herein are substantially free of extended
release components (e.g., gelling components such as
polyoxyethylene-polyoxypropylene copolymers). In some of such
embodiments, the formulations described herein contain less than 5%
of the extended release components (e.g., gelling components such
as polyoxyethylene-polyoxypropylene triblock copolymers) by weight
of the formulation. In some of such embodiments, the formulations
described herein contain less than 2% of the extended release
components (e.g., gelling components such as
polyoxyethylene-polyoxypropylene triblock copolymers) by weight of
the formulation. In some of such embodiments, the formulations
described herein contain less than 1% of the extended release
components (e.g., gelling components such as
polyoxyethylene-polyoxypropylene triblock copolymers) by weight of
the formulation. In some of such embodiments, a composition
described herein that is used for perfusion of a surgical area
contains substantially no gelling component.
Pharmacokinetics of Controlled-Release Compositions
[0383] In one embodiment, the compositions disclosed herein
additionally provides an immediate release of a CNS modulating
agent from the composition, or within 1 minute, or within 5
minutes, or within 10 minutes, or within 15 minutes, or within 30
minutes, or within 60 minutes or within 90 minutes. In other
embodiments, a therapeutically effective amount of at least one CNS
modulating agent is released from the composition immediately, or
within 1 minute, or within 5 minutes, or within 10 minutes, or
within 15 minutes, or within 30 minutes, or within 60 minutes or
within 90 minutes. In certain embodiments the composition comprises
an auris-pharmaceutically acceptable gel composition providing
immediate release of at least one CNS modulating agent. Additional
embodiments of the composition may also include an agent that
enhances the viscosity of the compositions included herein.
[0384] In other or further embodiments, the composition provides an
extended release composition of at least one CNS modulating agent.
In certain embodiments, diffusion of at least one CNS modulating
agent from the composition occurs for a time period exceeding 5
minutes, or 15 minutes, or 30 minutes, or 1 hour, or 4 hours, or 6
hours, or 12 hours, or 18 hours, or 1 day, or 2 days, or 3 days, or
4 days, or 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 CNS modulating agent is released
from the composition for a time period exceeding 5 minutes, or 15
minutes, or 30 minutes, or 1 hour, or 4 hours, or 6 hours, or 12
hours, or 18 hours, or 1 day, or 2 days, or 3 days, or 4 days, or 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.
[0385] In other embodiments, the composition provides both an
immediate release and an extended release composition of a CNS
modulating agent. In yet other embodiments, the composition
contains a 0.25:1 ratio, or a 0.5:1 ratio, or a 1:1 ratio, or a 1:2
ratio, or a 1:3, or a 1:4 ratio, or a 1:5 ratio, or a 1:7 ratio, or
a 1:10 ratio, oral: 15 ratio, or a 1:20 ratio of immediate release
and extended release compositions. In a further embodiment the
composition provides an immediate release of a first CNS modulating
agent and an extended release of a second CNS modulating agent or
other therapeutic agent. In yet other embodiments, the composition
provides an immediate release and extended release composition of
at least one CNS modulating agent, and at least one therapeutic
agent. In some embodiments, the composition provides a 0.25:1
ratio, or a 0.5:1 ratio, or a 1:1 ratio, or a 1:2 ratio, or a 1:3,
or a 1:4 ratio, or a 1:5 ratio, or a 1:7 ratio, or a 1:10 ratio, or
a 1:15 ratio, or a 1:20 ratio of immediate release and extended
release compositions of a first CNS modulating agent and second
therapeutic agent, respectively.
[0386] In a specific embodiment the composition provides a
therapeutically effective amount of at least one CNS modulating
agent at the site of disease with essentially no systemic exposure.
In an additional embodiment the composition provides a
therapeutically effective amount of at least one CNS modulating
agent at the site of disease with essentially no detectable
systemic exposure. In other embodiments, the composition provides a
therapeutically effective amount of at least one CNS modulating
agent at the site of disease with little or no detectable systemic
exposure.
[0387] The combination of immediate release, delayed release and/or
extended release CNS modulating agent compositions or compositions
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 CNS
modulating 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.
[0388] In certain embodiments, the pharmacokinetics of the CNS
modulating agent compositions described herein are determined by
injecting the composition on or near the round window membrane of a
test animal (including by way of example, a guinea pig or a
chinchilla). At a determined period of time (e.g., 6 hours, 12
hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, and 7 days
for testing the pharmacokinetics of a composition over a 1 week
period), the test animal is euthanized and a 5 mL sample of the
perilymph fluid is tested. The inner ear removed and tested for the
presence of the CNS modulating agent. As needed, the level of a CNS
modulating agent is measured in other organs. In addition, the
systemic level of the CNS modulating agent is measured by
withdrawing a blood sample from the test animal. In order to
determine whether the composition impedes hearing, the hearing of
the test animal is optionally tested.
[0389] Alternatively, an inner ear is provided (as removed from a
test animal) and the migration of the CNS modulating agent is
measured. As yet another alternative, an in vitro model of a round
window membrane is provided and the migration of the CNS modulating
agent is measured.
[0390] The release of an 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.
[0391] In some embodiments, a composition described herein is a
solution that is substantially free of gelling components and
comprises micronized otic agent. In some of such embodiments, the
composition provides intermediate release of an active agent from
about 2 day to about 4 days.
[0392] 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.
[0393] In some embodiments, a composition described herein
comprises a gelling agent (e.g., poloxamer 407) in combination with
micronized otic agent and provides extended sustained release. In
some embodiments, a composition described herein comprises (a)
about 14-17% of a gelling agent (e.g., poloxamer 407) and (b) a
micronized otic agent; 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 (a) about 16%
of a gelling agent (e.g., poloxamer 407) and (b) a micronized otic
agent; and provides extended sustained release over a period of
from about 3 weeks. In some embodiments, a composition described
herein comprises (a) about 18-21% of a gelling agent (e.g.,
poloxamer 407) and (b) a micronized otic agent; 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 (a) about 20% of a gelling agent (e.g., poloxamer 407)
and (b) a micronized otic agent; and provides extended sustained
release over a period of from about 6 weeks. In some embodiments,
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.
[0394] In specific embodiments, compositions comprising micronized
otic agents provide extended release over a longer period of time
compared to compositions comprising non-micronized otic agents. 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.
Kits/Articles of Manufacture
[0395] 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 CNS modulating
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 CNS modulating 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.
[0396] 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.
[0397] 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 composition and intended mode of administration and
treatment. A wide array of a CNS modulating agent compositions
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 a CNS modulating
agent to the inner ear.
[0398] 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
composition 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.
[0399] In certain embodiments, the pharmaceutical compositions are
presented in a pack or dispenser device that 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 Diazepam Composition
TABLE-US-00003 [0400] Quantity (mg/g of Ingredient composition)
Diazepam 25.0 methylparaben 2.5 Hypromellose 25.0 Poloxamer 407
450. TRIS HCl buffer (0.1M) 1997.5
[0401] Diazepam is supplied in 5 mg/ml pre-filled glass
syringes.
[0402] A 10-g batch of gel composition containing 1.0% of diazepam
is prepared by first suspending Poloxamer 407 (BASF Corp.) in TRIS
HCl buffer (0.1 M). The Poloxamer 407 and TRIS are mixed under
agitation overnight at 4.degree. C. to ensure complete dissolution
of the Poloxamer 407 in the TRIS. The hypromellose, methylparaben
and additional TRIS HCl buffer (0.1 M) is added. The composition is
stirred until dissolution is observed. Diazepam is added and the
composition is mixed until a homogenous gel is produced. The
mixture is maintained below room temperature until use.
Example 2
Preparation of a Mucoadhesive, Thermoreversible Gel Diazepam
Composition
TABLE-US-00004 [0403] Quantity (mg/g of Ingredient composition)
Diazepam 25.0 methylparaben 2.5 Hypromellose 25.0 Carbopol 934P 5.0
Poloxamer 407 450.0 TRIS HCl buffer (0.1M) 1992.5
[0404] A 10-g batch of mucoadhesive gel composition containing 1.0%
of diazepam is prepared by first suspending Poloxamer 407 (BASF
Corp.) and Carbopol 934P in TRIS HCl buffer (0.1 M). The Poloxamer
407, Carbopol 934P and TRIS are mixed under agitation overnight at
4.degree. C. to ensure complete dissolution of the Poloxamer 407
and Carbopol 934P in the TRIS. The hypromellose, methylparaben and
additional TRIS HCl buffer (0.1 M) is added. The composition is
stirred until dissolution is observed. Diazepam is added and the
composition is mixed until a homogenous gel is produced. The
mixture is maintained below room temperature until use.
Example 3
Preparation of a Hydrogel-Based Lidocaine Composition
TABLE-US-00005 [0405] Quantity (mg/g of Ingredient composition)
Lidocaine HCl 30.0 paraffin oil 600 trihydroxystearate 30.0 cetyl
dimethicon copolyol 90.0 water qs ad 1000 phosphate buffer pH 7.4
qs pH 7.4
[0406] The cream-type composition is first prepared by gently
mixing Lidocaine HCl with water. Then, the oil base is prepared by
mixing paraffin oil, trihydroxystearate and cetyl dimethicon
copolyol at temperatures up to 60.degree. C. The oil base is cooled
to room temperature and the Lidocaine HCl solution is added. The
two phases are mixed until a homogenous, monophasic hydrogel is
formed.
Example 4
Preparation of a Gel Gabapentin Composition
TABLE-US-00006 [0407] Quantity (mg/g of Ingredient composition)
Gabapentin 40.0 chitosan 20.0 Glycerophosphate disodium 80.0 water
840
[0408] A 5 ml solution of acetic acid is titrated to a pH of about
4.0. The chitosan is added to achieve a pH of about 5.5. The
gabapentin is then dissolved in the chitosan solution. This
solution is sterilized by filtration. A 5 ml aqueous solution of
glycerophosphate disodium is also prepared and sterilized. The two
solutions are mixed and within 2 h at 37.degree. C., the desired
gel is formed.
Example 5
Application of an Enhanced Viscosity Diazepam Composition onto the
Round Window Membrane
[0409] A composition according to Example 2 is prepared and loaded
into 5 ml siliconized glass syringes attached to a 15-gauge luer
lock disposable needle. Lidocaine is topically applied to the
tympanic membrane, and a small incision made to allow visualization
into the middle ear cavity. The needle tip is guided into place
over the round window membrane, and the CNS Modulating composition
applied directly onto the round-window membrane.
Example 6
Effect of pH on Degradation Products for Autoclaved 17% Poloxamer
407NF/2% Otic Agent in PBS Buffer
[0410] A stock solution of a 17% poloxamer 407/2% otic agent is
prepared by dissolving 351.4 mg of sodium chloride (Fisher
Scientific), 302.1 mg of sodium phosphate dibasic anhydrous (Fisher
Scientific), 122.1 mg of sodium phosphate monobasic anhydrous
(Fisher Scientific) and an appropriate amount of an otic agent with
79.3 g of sterile filtered DI water. The solution is cooled down in
a ice chilled water bath and then 17.05 g of poloxamer 407NF
(SPECTRUM CHEMICALS) is sprinkled into the cold solution while
mixing. The mixture is further mixed until the poloxamer is
completely dissolved. The pH for this solution is measured.
[0411] 17% poloxamer 407/2% otic agent in PBS pH of 5.3. Take an
aliquot (approximately 30 mL) of the above solution and adjust the
pH to 5.3 by the addition of 1 M HCl.
[0412] 17% poloxamer 407/2% otic agent in PBS pH of 8.0. Take an
aliquot (approximately 30 mL) of the above stock solution and
adjust the pH to 8.0 by the addition of 1 M NaOH.
[0413] A PBS buffer (pH 7.3) is prepared by dissolving 805.5 mg of
sodium chloride (Fisher Scientific), 606 mg of sodium phosphate
dibasic anhydrous (Fisher Scientific), 247 mg of sodium phosphate
monobasic anhydrous (Fisher Scientific), then QS to 200 g with
sterile filtered DI water.
[0414] A 2% solution of an otic agent in PBS pH 7.3 is prepared by
dissolving an appropriate amount of the otic agent in the PBS
buffer and QS to 10 g with PBS buffer.
[0415] One mL samples are individually placed in 3 mL screw cap
glass vials (with rubber lining) and closed tightly. The vials are
placed in a Market Forge-sterilmatic autoclave (settings, slow
liquids) and sterilized at 250.degree. F. for 15 minutes. After the
autoclave the samples are left to cool down to room temperature and
then placed in refrigerator. The samples are homogenized by mixing
the vials while cold.
[0416] Appearance (e.g., discoloration and/or precipitation) is
observed and recorded. HPLC analysis is performed using an Agilent
1200 equipped with a Luna C18(2) 3 .mu.m, 100 .ANG., 250.times.4.6
mm column) using a 30-80 acetonitrile gradient (1-10 min) of
(water-acetonitrile mixture containing 0.05% TFA), for a total run
of 15 minutes. Samples are diluted by taking 30 .mu.L of sample and
dissolved with 1.5 mL of a 1:1 acetonitrile water mixture. Purity
of the otic agent in the autoclaved samples is recorded.
[0417] In general the composition should not have any individual
impurity (e.g., degradation product of otic agent) of more than 2%
and more preferably not more than one percent. In addition, the
composition should not precipitate during storage or change in
color after manufacturing and storage.
[0418] Compositions comprising alprazolam, clonazepam, diazepam, or
micronized diazepam, prepared according to the procedure in Example
6, are tested using the above procedure to determine the effect of
pH on degradation during the autoclaving step.
Example 7
Effect of Autoclaving on the Release Profile and Viscosity of a 17%
Poloxamer 407NF/2% Otic Agent in PBS
[0419] An aliquot of the sample from example 6 (autoclaved and not
autoclaved) is evaluated for release profile and viscosity
measurement to evaluate the impact of heat sterilization on the
properties of the gel.
[0420] Dissolution is performed at 37.degree. C. in snapwells (6.5
mm diameter polycarbonate membrane with a pore size of 0.4 .mu.m).
0.2 mL of gel is placed into snapwell and left to harden, then 0.5
mL is placed into reservoir and shaken using a Labline orbit shaker
at 70 rpm. Samples are taken every hour (0.1 mL withdrawn and
replace with warm buffer). Samples are analyzed for poloxamer
concentration by UV at 624 nm using the cobalt thiocyanate method,
against an external calibration standard curve. In brief, 20 .mu.L
of the sample is mixed with 1980 .mu.L of a 15 mM cobalt
thiocyanate solution and absorbance measured at 625 nm, using a
Evolution 160 UV/Vis spectrophotometer (Thermo Scientific).
[0421] The released otic agent is fitted to the Korsmeyer-Peppas
equation
Q Q .alpha. = kt n + b ##EQU00001##
where Q is the amount of otic agent released at time t,
Q.sub..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 calculated by:
MDT = nk - 1 / n n + 1 ##EQU00002##
[0422] Viscosity measurements are performed using a Brookfield
viscometer RVDV-II+P with a CPE-51 spindle rotated at 0.08 rpm
(shear rate of 0.31 s.sup.-1), equipped with a water jacketed
temperature control unit (temperature ramped from 15-34.degree. C.
at 1.6.degree. C./min). Tgel is defined as the inflection point of
the curve where the increase in viscosity occurs due to the sol-gel
transition.
[0423] Compositions comprising alprazolam, clonazepam, diazepam, or
micronized diazepam prepared according to the procedure in Example
6, are tested using the procedure described above to determine
Tgel.
Example 8
Effect of Addition of a Secondary Polymer on the Degradation
Products and Viscosity of a Composition Containing 2% Otic Agent
and 17% Poloxamer 407NF after Heat Sterilization (Autoclaving)
[0424] Solution A.
[0425] A solution of pH 7.0 comprising sodium
carboxymethylcellulose (CMC) in PBS buffer is prepared by
dissolving 178.35 mg of sodium chloride (Fisher Scientific), 300.5
mg of sodium phosphate dibasic anhydrous (Fisher Scientific), 126.6
mg of sodium phosphate monobasic anhydrous (Fisher Scientific)
dissolved with 78.4 of sterile filtered DI water, then 1 g of
Blanose 7M65 CMC (Hercules, viscosity of 5450 cP @ 2%) is sprinkled
into the buffer solution and heated to aid dissolution, and the
solution is then cooled down.
[0426] A solution of pH 7.0 comprising 17% poloxamer 407NF/1%
CMC/2% otic agent in PBS buffer is made by cooling down 8.1 g of
solution A in a ice chilled water bath and then adding an
appropriate amount of an otic agent followed by mixing. 1.74 g of
poloxamer 407NF (Spectrum Chemicals) is sprinkled into the cold
solution while mixing. The mixture is further mixed until all the
poloxamer is completely dissolved.
[0427] Two mL of the above sample is placed in a 3 mL screw cap
glass vial (with rubber lining) and closed tightly. The vial is
placed in a Market Forge-sterilmatic autoclave (settings, slow
liquids) and sterilized at 250.degree. F. for 25 minutes. After
autoclaving the sample is left to cool down to room temperature and
then placed in refrigerator. The sample is homogenized by mixing
while the vials are cold.
[0428] Precipitation or discoloration are observed after
autoclaving. HPLC analysis is performed using an Agilent 1200
equipped with a Luna C18(2) 3 .mu.m, 100 .ANG., 250.times.4.6 mm
column) using a 30-80 acetonitrile gradient (1-10 min) of
(water-acetonitrile mixture containing 0.05% TFA), for a total run
of 15 minutes. Samples are diluted by taking 30 .mu.L of sample and
dissolving with 1.5 mL of a 1:1 acetonitrile water mixture. Purity
of the otic agent in the autoclaved samples is recorded.
[0429] Viscosity measurements are performed using a Brookfield
viscometer RVDV-II+P with a CPE-51 spindle rotated at 0.08 rpm
(shear rate of 0.31 s.sup.-1), equipped with a water jacketed
temperature control unit (temperature ramped from 15-34.degree. C.
at 1.6.degree. C./min). Tgel is defined as the inflection point of
the curve where the increase in viscosity occurs due to the sol-gel
transition.
[0430] Dissolution is performed at 37.degree. C. for the
non-autoclaved sample in snapwells (6.5 mm diameter polycarbonate
membrane with a pore size of 0.4 .mu.m), 0.2 mL of gel is placed
into snapwell and left to harden, then 0.5 mL is placed into
reservoir and shaken using a Labline orbit shaker at 70 rpm.
Samples are taken every hour (0.1 mL withdrawn and replaced with
warm buffer). Samples are analyzed for otic agent concentration by
UV at 245 nm, against an external calibration standard curve.
[0431] Compositions comprising alprazolam, clonazepam, diazepam, or
micronized diazepam are tested using the above procedure to
determine the effect addition of a secondary polymer on the
degradation products and viscosity of a composition containing 2%
otic agent and 17% poloxamer 407NF after heat sterilization
(autoclaving).
Example 9
Effect of Buffer Type on the Degradation Products for Compositions
Containing Poloxamer 407NF after Heat Sterilization
(Autoclaving)
[0432] A TRIS buffer is made by dissolving 377.8 mg of sodium
chloride (Fisher Scientific), and 602.9 mg of Tromethamine (Sigma
Chemical Co.) then QS to 100 g with sterile filtered DI water, pH
is adjusted to 7.4 with 1M HCl.
Stock Solution Containing 25% Poloxamer 407 Solution in TRIS
Buffer:
[0433] Weigh 45 g of TRIS buffer, chill in an ice chilled bath then
sprinkle into the buffer, while mixing, 15 g of poloxamer 407 NF
(Spectrum Chemicals). The mixture is further mixed until all the
poloxamer is completely dissolved.
[0434] A series of compositions is prepared with the above stock
solution. An appropriate amount of otic agent (or salt or prodrug
thereof) and/or otic agent as micronized/coated/liposomal particles
(or salt or prodrug thereof) is used for all experiments.
Stock Solution (pH 7.3) Containing 25% Poloxamer 407 Solution in
PBS Buffer:
[0435] PBS buffer is prepared by dissolving 704 mg of sodium
chloride (Fisher Scientific), 601.2 mg of sodium phosphate dibasic
anhydrous (Fisher Scientific), 242.7 mg of sodium phosphate
monobasic anhydrous (Fisher Scientific) with 140.4 g of sterile
filtered DI water. The solution is cooled down in an ice chilled
water bath and then 50 g of poloxamer 407NF (SPECTRUM CHEMICALS) is
sprinkled into the cold solution while mixing. The mixture is
further mixed until the poloxamer is completely dissolved.
[0436] A series of compositions is prepared with the above stock
solution. An appropriate amount of otic agent (or salt or prodrug
thereof) and/or otic agent as micronized/coated/liposomal particles
(or salt or prodrug thereof) is used for all experiments.
[0437] Tables 2 and 3 list samples prepared using the procedures
described above. An appropriate amount of otic agent is added to
each sample to provide a final concentration of 2% otic agent in
the sample.
TABLE-US-00007 TABLE 2 Preparation of samples containing TRIS
buffer 25% Stock TRIS Sample pH Solution (g) Buffer (g) 20% P407/2
otic agent/TRIS 7.45 8.01 1.82 18% P407/2 otic agent/TRIS 7.45 7.22
2.61 16% P407/2 otic agent/TRIS 7.45 6.47 3.42 18% P4072 otic
agent/TRIS 7.4 7.18 2.64 4% otic agent/TRIS 7.5 -- 9.7 2% otic
agent/TRIS 7.43 -- 5 1% otic agent/TRIS 7.35 -- 5 2% otic
agent/TRIS (suspension) 7.4 -- 4.9
TABLE-US-00008 TABLE 3 Preparation of samples containing PBS buffer
(pH of 7.3) 25% Stock Solution PBS Sample in PBS (g) Buffer (g) 20%
P407/2 otic agent/PBS 8.03 1.82 18% P407/2 otic agent/PBS 7.1 2.63
16% P407/2 otic agent/PBS 6.45 3.44 18% P407/2 otic agent/PBS --
2.63 2% otic agent/PBS -- 4.9
[0438] One mL samples are individually placed in 3 mL screw cap
glass vials (with rubber lining) and closed tightly. The vials are
placed in a Market Forge-sterilmatic autoclave (setting, slow
liquids) and sterilized at 250.degree. F. for 25 minutes. After the
autoclaving the samples are left to cool down to room temperature.
The vials are placed in the refrigerator and mixed while cold to
homogenize the samples.
[0439] HPLC analysis is performed using an Agilent 1200 equipped
with a Luna C18(2) 3 .mu.m, 100 .ANG., 250.times.4.6 mm column)
using a 30-80 acetonitrile gradient (1-10 min) of
(water-acetonitrile mixture containing 0.05% TFA), for a total run
of 15 minutes. Samples are diluted by taking 30 .mu.L of sample and
dissolving with 1.5 mL of a 1:1 acetonitrile water mixture. Purity
of the otic agent in the autoclaved samples is recorded. The
stability of compositions in TRIS and PBS buffers is compared.
[0440] Viscosity measurements are performed using a Brookfield
viscometer RVDV-II+P with a CPE-51 spindle rotated at 0.08 rpm
(shear rate of 0.31 s.sup.-1), equipped with a water jacketed
temperature control unit (temperature ramped from 15-34.degree. C.
at 1.6.degree. C./min). Tgel is defined as the inflection point of
the curve where the increase in viscosity occurs due to the sol-gel
transition. Only compositions that show no change after autoclaving
are analyzed.
[0441] Compositions comprising Compositions comprising alprazolam,
clonazepam, diazepam, or micronized diazepam are tested using the
above procedure to determine the effect addition of a secondary
polymer on the degradation products and viscosity of a composition
containing 2% otic agent and 17% poloxamer 407NF after heat
sterilization (autoclaving). Stability of compositions containing
micronized otic agent is compared to non-micronized otic agent
composition counterparts.
Example 10
Pulsed Release Otic Compositions
[0442] Diazepam is used to prepare a pulsed release otic agent
composition using the procedures described herein. A 17% poloxamer
solution is prepared by dissolving 351.4 mg of sodium chloride
(Fisher Scientific), 302.1 mg of sodium phosphate dibasic anhydrous
(Fisher Scientific), 122.1 mg of sodium phosphate monobasic
anhydrous (Fisher Scientific) and an appropriate amount of an otic
agent with 79.3 g of sterile filtered DI water. The solution is
cooled down in a ice chilled water bath and then 17.05 g of
poloxamer 407NF (SPECTRUM CHEMICALS) is sprinkled into the cold
solution while mixing. The mixture is further mixed until the
poloxamer is completely dissolved. The pH for this solution is
measured. 20% of the delivered dose of diazepam is solubilized in
the 17% poloxamer solution with the aid of beta-cyclodextrins. The
remaining 80% of the otic agent is then added to the mixture and
the final composition is prepared using any procedure described
herein.
[0443] Pulsed release compositions comprising Compositions
comprising alprazolam, clonazepam, diazepam, or micronized diazepam
prepared according to the procedures and examples described herein,
are tested using procedures described herein to determine pulse
release profiles.
Example 11
Preparation of a 17% Poloxamer 407/2% Otic Agent/78 Ppm Evans Blue
in PBS
[0444] A Stock solution of Evans Blue (5.9 mg/mL) in PBS buffer is
prepared by dissolving 5.9 mg of Evans Blue (Sigma Chemical Co)
with 1 mL of PBS buffer. PBS buffer is prepared by dissolving 704
mg of sodium chloride (Fisher Scientific), 601.2 mg of sodium
phosphate dibasic anhydrous (Fisher Scientific), 242.7 mg of sodium
phosphate monobasic anhydrous (Fisher Scientific) with 140.4 g of
sterile filtered DI water.
[0445] A Stock solution containing 25% Poloxamer 407 solution in
PBS buffer (as in Example 9) is used in this study. An appropriate
amount of an otic agent is added to the 25% Poloxamer 407 solution
stock solution to prepare compositions comprising 2% of an otic
agent (Table 4).
TABLE-US-00009 TABLE 4 Preparation of poloxamer 407 samples
containing Evans Blue 25% P407 in PBS Evans Blue Sample ID PBS (g)
Buffer (g) Solution (.mu.L) 17% P407/2 otic agent/EB 13.6 6 265 20%
P407/2 otic agent/EB 16.019 3.62 265 25% P407/2 otic agent/EB 19.63
-- 265
[0446] Compositions comprising alprazolam, clonazepam, diazepam, or
micronized diazepam are prepared according to the procedures in
Example 12 and are sterile filtered through 0.22 .mu.m PVDF syringe
filters (Millipore corporation), and autoclaved.
[0447] The above compositions are dosed to guinea pigs in the
middle ear by procedures described herein and the ability of
compositions to gel upon contact and the location of the gel is
identified after dosing and at 24 hours after dosing.
Example 12
Terminal Sterilization of Poloxamer 407 Compositions with and
without a Visualization Dye
[0448] 17% Poloxamer 407/2% Otic Agent/in Phosphate Buffer, pH
7.3:
[0449] Dissolve 709 mg of sodium chloride (Fisher Scientific), 742
mg of sodium phosphate dibasic dehydrate USP (Fisher Scientific),
251.1 mg of sodium phosphate monobasic monohydrate USP (Fisher
Scientific) and an appropriate amount of an otic agent with 158.1 g
of sterile filtered DI water. The solution is cooled down in an ice
chilled water bath and then 34.13 g of poloxamer 407NF (Spectrum
chemicals) is sprinkled into the cold solution while mixing. The
mixture is further mixed until the poloxamer is completely
dissolved.
[0450] 17% Poloxamer407/2% Otic Agent/59 Ppm Evans Blue in
Phosphate Buffer:
[0451] Take two mL of the 17% poloxamer407/2% otic agent/in
phosphate buffer solution and add 2 mL of a 5.9 mg/mL Evans blue
(Sigma-Aldrich chemical Co) solution in PBS buffer.
[0452] 25% Poloxamer407/2% Otic Agent/in Phosphate Buffer:
[0453] Dissolve 330.5 mg of sodium chloride (Fisher Scientific),
334.5 mg of sodium phosphate dibasic dehydrate USP (Fisher
Scientific), 125.9 mg of sodium phosphate monobasic monohydrate USP
(Fisher Scientific) and an appropriate amount of an otic agent with
70.5 g of sterile filtered DI water.
[0454] The solution is cooled down in an ice chilled water bath and
then 25.1 g of poloxamer 407NF (Spectrum chemicals) is sprinkled
into the cold solution while mixing. The mixture is further mixed
until the poloxamer is completely dissolved.
[0455] 25% Poloxamer407/2% Otic Agent/59 Ppm Evans Blue in
Phosphate Buffer:
[0456] Take two mL of the 25% poloxamer407/2% otic agent/in
phosphate buffer solution and add 2 mL of a 5.9 mg/mL Evans blue
(Sigma-Aldrich chemical Co) solution in PBS buffer.
[0457] Place 2 mL of composition into a 2 mL glass vial (Wheaton
serum glass vial) and seal with 13 mm butyl str (kimble stoppers)
and crimp with a 13 mm aluminum seal. The vials are placed in a
Market Forge-sterilmatic autoclave (settings, slow liquids) and
sterilized at 250.degree. F. for 25 minutes. After the autoclaving
the samples are left to cool down to room temperature and then
placed in refrigeration. The vials are placed in the refrigerator
and mixed while cold to homogenize the samples. Sample
discoloration or precipitation after autoclaving is recorded.
[0458] HPLC analysis is performed using an Agilent 1200 equipped
with a Luna C18(2) 3 .mu.m, 100 .ANG., 250.times.4.6 mm column)
using a 30-95 methanol:acetate buffer pH 4 gradient (1-6 min), then
isocratic for 11 minutes, for a total run of 22 minutes. Samples
are diluted by taking 30 .mu.L of sample and dissolved with 0.97 mL
of water. The main peaks are recorded in the table below. Purity
before autoclaving is always greater than 99% using this
method.
[0459] Viscosity measurements are performed using a Brookfield
viscometer RVDV-II+P with a CPE-51 spindle rotated at 0.08 rpm
(shear rate of 0.31 s.sup.-1), equipped with a water jacketed
temperature control unit (temperature ramped from 15-34.degree. C.
at 1.6.degree. C./min). Tgel is defined as the inflection point of
the curve where the increase in viscosity occurs due to the sol-gel
transition.
[0460] Compositions comprising alprazolam, clonazepam, diazepam, or
micronized diazepam prepared according to the procedure in Example
11, are tested using the above procedures to determine stability of
the compositions.
Example 13
In Vitro Comparison of Release Profile
[0461] Dissolution is performed at 37.degree. C. in snapwells (6.5
mm diameter polycarbonate membrane with a pore size of 0.4 .mu.m),
0.2 mL of a gel composition described herein is placed into
snapwell and left to harden, then 0.5 mL buffer is placed into
reservoir and shaken using a Labline orbit shaker at 70 rpm.
Samples are taken every hour (0.1 mL withdrawn and replace with
warm buffer). Samples are analyzed for otic agent concentration by
UV at 245 nm against an external calibration standard curve.
Pluronic concentration is analyzed at 624 nm using the cobalt
thiocyanate method. Relative rank-order of mean dissolution time
(MDT) as a function of % P407 is determined. A linear relationship
between the compositions mean dissolution time (MDT) and the P407
concentration indicates that the otic agent is released due to the
erosion of the polymer gel (poloxamer) and not via diffusion. A
non-linear relationship indicates release of otic agent via a
combination of diffusion and/or polymer gel degradation.
[0462] Alternatively, samples are analyzed using the method
described by Li Xin-Yu paper [Acta Pharmaceutica Sinica 2008,
43(2):208-203] and Rank-order of mean dissolution time (MDT) as a
function of % P407 is determined.
[0463] Compositions comprising alprazolam, clonazepam, diazepam, or
micronized diazepam prepared according to the procedures described
herein, are tested using the above procedure to determine the
release profile of the otic agents.
Example 14
In Vitro Comparison of Gelation Temperature
[0464] The effect of Poloxamer 188 and an otic agent on the
gelation temperature and viscosity of Poloxamer 407 compositions is
evaluated with the purpose of manipulating the gelation
temperature.
[0465] A 25% Poloxamer 407 stock solution in PBS buffer (as in
Example 9) and a PBS solution (as in Example 11) are used.
Poloxamer 188NF from BASF is used. An appropriate amount of otic
agent is added to the solutions described in Table 5 to provide a
2% composition of the otic agent.
TABLE-US-00010 TABLE 5 Preparation of samples containing poloxamer
407/poloxamer 188 25% P407 Stock Poloxamer 188 PBS Sample Solution
(g) (mg) Buffer (g) 16% P407/10% P188 3.207 501 1.3036 17% P407/10%
P188 3.4089 500 1.1056 18% P407/10% P188 3.6156 502 0.9072 19%
P407/10% P188 3.8183 500 0.7050 20% P407/10% P188 4.008 501 0.5032
20% P407/5% P188 4.01 256 0.770
[0466] Mean dissolution time, viscosity and gel temperature of the
above compositions are measured using procedures described
herein.
[0467] An equation is fitted to the data obtained and can be
utilized to estimate the gelation temperature of F127/F68 mixtures
(for 17-20% F127 and 0-10% F68).
T.sub.gel=-1.8(% F127)+1.3(% F68)+53
[0468] An equation is fitted to the data obtained and can be
utilized to estimate the Mean Dissolution Time (hr) based on the
gelation temperature of F127/F68 mixtures (for 17-25% F127 and
0-10% F68), using results obtained in example 13 and 15.
MDT=-0.2(T.sub.gel)8
[0469] Compositions comprising alprazolam, clonazepam, diazepam, or
micronized diazepam are prepared by addition of an appropriate
amount of otic agents to the solutions described in Table 5. The
gel temperature of the compositions is determined using the
procedure described above.
Example 15
Determination of Temperature Range for Sterile Filtration
[0470] The viscosity at low temperatures is measured to help guide
the temperature range at that the sterile filtration needs to occur
to reduce the possibility of clogging.
[0471] Viscosity measurements are performed using a Brookfield
viscometer RVDV-II+P with a CPE-40 spindle rotated at 1, 5 and 10
rpm (shear rate of 7.5, 37.5 and 75 s.sup.-1), equipped with a
water jacketed temperature control unit (temperature ramped from
10-25.degree. C. at 1.6.degree. C./min).
[0472] The Tgel of a 17% Pluronic P407 is determined as a function
of increasing concentration of otic agent. The increase in Tgel for
a 17% pluronic composition is estimated by:
.DELTA.T.sub.gel=0.93[% otic agent]
[0473] Compositions comprising alprazolam, clonazepam, diazepam, or
micronized diazepam prepared according to procedures described
herein, are tested using the above procedure to determine the
temperature range for sterile filtration. The effect of addition of
increased amounts of otic agent on the Tgel, and the apparent
viscosity of the compositions is recorded.
Example 16
Determination of Manufacturing Conditions
TABLE-US-00011 [0474] TABLE 6 Viscosity of potential compositions
at manufacturing/filtration conditions. Apparent Viscosity.sup.a
(cP) Temperature @ Sample 5.degree. C. below Tgel 20.degree. C. 100
cP Placebo 52 cP @ 17.degree. C. 120 cP .sup. 19.degree. C. 17%
P407/2% otic agent 90 cP @ 18.degree. C. 147 cP 18.5.degree. C. 17%
P407/6% otic agent 142 cP @ 22.degree. C. 105 cP 19.7.degree. C.
.sup.aViscosity measured at a shear rate of 37.5 s.sup.-1
[0475] An 8 liter batch of a 17% P407 placebo is manufactured to
evaluate the manufacturing/filtration conditions. The placebo is
manufactured by placing 6.4 liters of DI water in a 3 gallon SS
pressure vessel, and left to cool down in the refrigerator
overnight. The following morning the tank was taken out (water
temperature 5.degree. C., RT 18.degree. C.) and 48 g of sodium
chloride, 29.6 g of sodium phosphate dibasic dehydrate and 10 g of
sodium phosphate monobasic monohydrate is added and dissolved with
an overhead mixer (IKA RW20 @ 1720 rpm). Half hour later, once the
buffer is dissolved (solution temperature 8.degree. C., RT
18.degree. C.), 1.36 kg of poloxamer 407 NF (spectrum chemicals) is
slowly sprinkled into the buffer solution in a 15 minute interval
(solution temperature 12.degree. C., RT 18.degree. C.), then speed
is increased to 2430 rpm. After an additional one hour mixing,
mixing speed is reduced to 1062 rpm (complete dissolution).
[0476] The temperature of the room is maintained below 25.degree.
C. to retain the temperature of the solution at below 19.degree. C.
The temperature of the solution is maintained at below 19.degree.
C. up to 3 hours of the initiation of the manufacturing, without
the need to chill/cool the container.
[0477] Three different Sartoscale (Sartorius Stedim) filters with a
surface area of 17.3 cm.sup.2 are evaluated at 20 psi and
14.degree. C. of solution [0478] 1) Sartopore 2, 0.2 .mu.m
5445307HS-FF (PES), flow rate of 16 mL/min [0479] 2) Sartobran P,
0.2 .mu.m 5235307HS-FF (cellulose ester), flow rate of 12 mL/min
[0480] 3) Sartopore 2 XLI, 0.2 .mu.m 5445307IS-FF (PES), flow rate
of 15 mL/min
[0481] Sartopore 2 filter 5441307H4-SS is used, filtration is
carried out at the solution temperature using a 0.45, 0.2 .mu.m
Sartopore 2 150 sterile capsule (Sartorius Stedim) with a surface
area of 0.015 m.sup.2 at a pressure of 16 psi. Flow rate is
measured at approximately 100 mL/min at 16 psi, with no change in
flow rate while the temperature is maintained in the 6.5-14.degree.
C. range. Decreasing pressure and increasing temperature of the
solution causes a decrease in flow rate due to an increase in the
viscosity of the solution. Discoloration of the solution is
monitored during the process.
TABLE-US-00012 TABLE 7 Predicted filtration time for a 17%
poloxamer 407 placebo at a solution temperature range of
6.5-14.degree. C. using Sartopore 2, 0.2 .mu.m filters at a
pressure of 16 psi of pressure. Estimated flow rate Time to filter
8 L Filter Size (m.sup.2) (mL/min) (estimated) Sartopore 2, size 4
0.015 100 mL/min 80 min Sartopore 2, size 7 0.05 330 mL/min 24 min
Sartopore 2, size 8 0.1 670 mL/min 12 min
[0482] Viscosity, Tgel and UV/Vis absorption is check before
filtration evaluation. Pluronic UV/Vis spectra are obtained by a
Evolution 160 UV/Vis (Thermo Scientific). A peak in the range of
250-300 nm is attributed to BHT stabilizer present in the raw
material (poloxamer). Table 8 lists physicochemical properties of
the above solutions before and after filtration.
TABLE-US-00013 TABLE 8 Physicochemical properties of 17% poloxamer
407 placebo solution before and after filtration Viscosity.sup.a @
Absorbance @ Sample Tgel (.degree. C.) 19.degree. C. (cP) 274 nm
Before filtration 22 100 0.3181 After filtration 22 100 0.3081
.sup.aViscosity measured at a shear rate of 37.5 s.sup.-1
[0483] The above process is applicable for manufacture of 17% P407
compositions, and includes temperature analysis of the room
conditions. Preferably, a maximum temperature of 19.degree. C.
reduces cost of cooling the container during manufacturing. In some
instances, a jacketed container is used to further control the
temperature of the solution to ease manufacturing concerns.
Example 17
In Vitro Release of Otic Agent from an Autoclaved Micronized
Sample
[0484] 17% poloxamer 407/1.5% otic agent in TRIS buffer: 250.8 mg
of sodium chloride (Fisher Scientific), and 302.4 mg of
Tromethamine (Sigma Chemical Co.) is dissolved in 39.3 g of sterile
filtered DI water, pH is adjusted to 7.4 with 1M HCl. 4.9 g of the
above solution is used and an appropriate amount of micronized otic
agent is suspended and dispersed well. 2 mL of the composition is
transferred into a 2 mL glass vial (Wheaton serum glass vial) and
sealed with 13 mm butyl styrene (kimble stoppers) and crimped with
a 13 mm aluminum seal. The vial is placed in a Market
Forge-sterilmatic autoclave (settings, slow liquids) and sterilized
at 250.degree. F. for 25 minutes. After the autoclaving the sample
is left to cool down to room temperature. The vial is placed in the
refrigerator and mixed while cold to homogenize the sample. Sample
discoloration or precipitation after autoclaving is recorded.
[0485] Dissolution is performed at 37.degree. C. in snapwells (6.5
mm diameter polycarbonate membrane with a pore size of 0.4 .mu.m),
0.2 mL of gel is placed into snapwell and left to harden, then 0.5
mL PBS buffer is placed into reservoir and shaken using a Labline
orbit shaker at 70 rpm. Samples are taken every hour [0.1 mL
withdrawn and replaced with warm PBS buffer containing 2% PEG-40
hydrogenated castor oil (BASF) to enhance otic agent solubility].
Samples are analyzed for otic agent concentration by UV at 245 nm
against an external calibration standard curve. The release rate is
compared to other compositions disclosed herein. MDT time is
calculated for each sample.
[0486] Solubilization of otic agent in the 17% poloxamer system is
evaluated by measuring the concentration of the otic agent in the
supernatant after centrifuging samples at 15,000 rpm for 10 minutes
using an eppendorf centrifuge 5424. Otic agent concentration in the
supernatant is measured by UV at 245 nm against an external
calibration standard curve.
[0487] Compositions comprising alprazolam, clonazepam, diazepam, or
micronized diazepam prepared according to the procedures described
herein, are tested using the above procedures to determine release
rate of the otic agent from each composition.
Example 18
Release Rate or MDT and Viscosity of Composition Containing Sodium
Carboxymethyl Cellulose
[0488] 17% Poloxamer 407/2% Otic Agent/1% CMC (Hercules Blanose
7M):
[0489] A sodium carboxymethylcellulose (CMC) solution (pH 7.0) in
PBS buffer is prepared by dissolving 205.6 mg of sodium chloride
(Fisher Scientific), 372.1 mg of sodium phosphate dibasic dihydrate
(Fisher Scientific), 106.2 mg of sodium phosphate monobasic
monohydrate (Fisher Scientific) in 78.1 g of sterile filtered DI
water. 1 g of Blanose 7M CMC (Hercules, viscosity of 533 cP @ 2%)
is sprinkled into the buffer solution and heated to ease solution,
solution is then cooled down and 17.08 g poloxamer 407NF (Spectrum
Chemicals) is sprinkled into the cold solution while mixing. A
composition comprising 17% poloxamer 407NF/1% CMC/2% otic agent in
PBS buffer is made adding/dissolving an appropriate amount of otic
agent to 9.8 g of the above solution, and mixing until all the otic
agent is completely dissolved.
[0490] 17% Poloxamer 407/2% Otic Agent/0.5% CMC (Blanose 7M65):
[0491] A sodium carboxymethylcellulose (CMC) solution (pH 7.2) in
PBS buffer is prepared by dissolving 257 mg of sodium chloride
(Fisher Scientific), 375 mg of sodium phosphate dibasic dihydrate
(Fisher Scientific), 108 mg of sodium phosphate monobasic
monohydrate (Fisher Scientific) in 78.7 g of sterile filtered DI
water. 0.502 g of Blanose 7M65 CMC (Hercules, viscosity of 5450 cP
@ 2%) is sprinkled into the buffer solution and heated to ease
solution, solution is then cooled down and 17.06 g poloxamer 407NF
(Spectrum Chemicals) is sprinkled into the cold solution while
mixing. A 17% poloxamer 407NF/1% CMC/2% otic agent solution in PBS
buffer is made adding/dissolving an appropriate amount of otic
agent to 9.8 g of the above solution, and mixing until the otic
agent is completely dissolved.
[0492] 17% Poloxamer 407/2% Otic Agent/0.5% CMC (Blanose 7H9):
[0493] A sodium carboxymethylcellulose (CMC) solution (pH 7.3) in
PBS buffer is prepared by dissolving 256.5 mg of sodium chloride
(Fisher Scientific), 374 mg of sodium phosphate dibasic dihydrate
(Fisher Scientific), 107 mg of sodium phosphate monobasic
monohydrate (Fisher Scientific) in 78.6 g of sterile filtered DI
water, then 0.502 g of Blanose 7H9 CMC (Hercules, viscosity of 5600
cP @ 1%) is sprinkled to the buffer solution and heated to ease
solution, solution is then cooled down and 17.03 g poloxamer 407NF
(Spectrum Chemicals) is sprinkled into the cold solution while
mixing. A 17% poloxamer 407NF/1% CMC/2% otic agent solution in PBS
buffer is made adding/dissolving an appropriate amount of otic
agent to 9.8 of the above solution, and mixing until the otic agent
is completely dissolved.
[0494] Viscosity measurements are performed using a Brookfield
viscometer RVDV-II+P with a CPE-40 spindle rotated at 0.08 rpm
(shear rate of 0.6 s.sup.-1), equipped with a water jacketed
temperature control unit (temperature ramped from 10-34.degree. C.
at 1.6.degree. C./min). Tgel is defined as the inflection point of
the curve where the increase in viscosity occurs due to the sol-gel
transition.
[0495] Dissolution is performed at 37.degree. C. in snapwells (6.5
mm diameter polycarbonate membrane with a pore size of 0.4 .mu.m).
0.2 mL of gel is placed into snapwell and left to harden, then 0.5
mL PBS buffer is placed into reservoir and shaken using a Labline
orbit shaker at 70 rpm. Samples are taken every hour, 0.1 mL
withdrawn and replaced with warm PBS buffer. Samples are analyzed
for otic agent concentration by UV at 245 nm against an external
calibration standard curve. MDT time is calculated for each of the
above compositions.
[0496] Compositions comprising alprazolam, clonazepam, diazepam, or
micronized diazepam prepared according to procedures described
above, are tested using the above procedures to determine
relationship between release rate and/or mean dissolution time and
viscosity of composition containing sodium carboxymethyl cellulose.
Any correlation between the mean dissolution time (MDT) and the
apparent viscosity (measured at 2.degree. C. below the gelation
temperature) is recorded.
Example 19
Application of an Enhanced Viscosity CNS Modulating Agent
Composition onto the Round Window Membrane
[0497] A composition according to Example 2 is prepared and loaded
into 5 ml siliconized glass syringes attached to a 15-gauge luer
lock disposable needle. Lidocaine is topically applied to the
tympanic membrane, and a small incision made to allow visualization
into the middle ear cavity. The needle tip is guided into place
over the round window membrane, and the composition applied
directly onto the round-window membrane.
Example 20
In Vivo Testing of Intratympanic Injection of a CNS Modulating
Composition in a Guinea Pig
[0498] A cohort of 21 guinea pigs (Charles River, females weighing
200-300 g) is intratympanically injected with 50 .mu.L of different
P407-DSP compositions described herein, containing 0 to 6% of an
otic agent. The gel elimination time course for each composition is
determined. A faster gel elimination time course of a composition
indicates lower mean dissolution time (MDT). Thus the injection
volume and the concentration of an CNS modulating agent in a
composition are tested to determine optimal parameters for
preclinical and clinical studies.
Example 22
In Vivo Extended Release Kinetics
[0499] A cohort of 21 guinea pigs (Charles River, females weighing
200-300 g) is intratympanically injected with 50 .mu.L 17% Pluronic
F-127 composition buffered at 280 mOsm/kg and containing 1.5% to
4.5% of a CNS modulating agent by weight of the composition.
Animals are dosed on day 1. The release profile for the
compositions is determined based on analysis of the perilymph.
Example 23
Evaluation of Diazepam in an Endolymphatic Hydrops Animal Model
Induction of Endolymphatic Hydrops
[0500] Female albino National Institutes of Health-Swiss mice
(Harlan Sprague-Dawley, Inc., Indianapolis, Inc.) weighing 20 to 24
g are used. Artificial endolymph is injected into the cochlear
duct.
Treatment
[0501] The endolymphatic mice and control mice are sorted into two
groups (n=10 in each group). The CNS modulating composition of
Example 5 containing diazepam is applied to the round window
membrane of one group of animals. Control composition containing no
diazepam is applied to the second group. The CNS modulating and
control compositions are reapplied three days after the initial
application. The animals are sacrificed after the seventh day of
treatment.
Electrophysiologic Testing
[0502] The hearing threshold for the auditory brainstem response
threshold (ABR) to click stimuli for each ear of each animal is
initially measured and 1 week after the experimental procedure. The
animals are placed in a single-walled acoustic booth (Industrial
Acoustics Co, Bronx, N.Y., USA) on a heating pad. Subdermal
electrodes (Astro-Med, Inc. Grass Instrument Division, West
Warwick, R.I., USA) were inserted at the vertex (active electrode),
the mastoid (reference), and the hind leg (ground). Click stimuli
(0.1 millisecond) are computer generated and delivered to a Beyer
DT 48, 200 Ohm speaker fitted with an ear speculum for placement in
the external auditory meatus. The recorded ABR is amplified and
digitized by a battery-operated preamplifier and input to a
Tucker-Davis Technologies ABR recording system that provides
computer control of the stimulus, recording, and averaging
functions (Tucker Davis Technology, Gainesville, Fla., USA).
Successively decreasing amplitude stimuli are presented in 5-dB
steps to the animal, and the recorded stimulus-locked activity is
averaged (n=512) and displayed. Threshold is defined as the
stimulus level between the record with no visibly detectable
response and a clearly identifiable response.
Example 24
Clinical Trial of Diazepam as a Treatment for Tinnitus
Dosage
[0503] The dosage of diazepam is 10 ng delivered in 10 .mu.L of a
thermoreversible gel. Release of diazepam is controlled-release and
occurs over thirty (30) days.
Administration
[0504] The diazepam compositions are administered by intra-tympanic
injection once every thirty days for 3 months.
Inclusion Criteria
[0505] Male and female subjects between the 18 and 64 years of
age.
[0506] Subjects experiencing subjective tinnitus.
[0507] Duration of tinnitus is greater than 3 months.
[0508] No treatment of tinnitus within 4 weeks.
Study Design
[0509] Subjects are divided into three treatment groups. The first
group is the safety sample. The second group is the intent-to-treat
(ITT) sample. The third group is the valid for efficacy (VfE)
group.
[0510] For each group, one half of subjects to be given diazepam
and the remainder to be given placebo.
Statistical Methods
[0511] The primary efficacy analysis is based on the total score of
the Tinnitus Questionnaire in the ITT sample. The statistical
analysis is based on an analysis of covariance (ANCOVA) with
baseline as covariant and the last observation carried forward
value as dependent variable. Factor is "treatment." The homogeneity
of regression slopes is tested. The analysis is repeated for the
VfE sample.
[0512] Audiometric measurements (mode, frequency, loudness of the
tinnitus, pure tone audiogram, speech audiogram) as well as quality
of life are also analyzed via the aforementioned model. The
appropriateness of the model is not tested. P values are
exploratory and are not adjusted for multiplicity.
[0513] 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