Use of 5-HT]B/iD Agonists to Treat Otic Pain
The present invention relates to the pharmaceutical treatment of otic pain. In
particular, the present invention relates to the topical use of 5-HT1B/1D receptor agonists and
partial agonists for the prevention or alleviation of pain in the ear.
Background of the Invention
Pain is a perceived nociceptive response to local stimuli in the body. The perception
of pain at the level of the central nervous system requires the transmission of painful stimuli
by peripheral sensory nerve fibers. Upon stimulation of tissue (i.e., thermal, mechanical or
chemical), electro-chemical signals are transmitted from the sensory nerve endings to the
spinal column, and hence to the brain where pain is perceived.
The ear is highly innervated with sensory afferents capable of transmitting various
painful stimuli to the central nervous system. The ear is comprised of outer, middle and inner ear portions and otic pain may arise in any of these portions of the ear. Pain conditions
involving the ear, therefore, can arise in numerous instances, such as: foreign body stimulus,
inflammation, edema, otic congestion, otic pressure, infection, accidental trauma, surgical
procedures and post-surgical recovery.
The outer or "external" ear is comprised of the pinna and external ear canal ("EAC").
The EAC is a tubular, slightly curved structure extending from the pinna to the tympanic
membrane or "ear drum." Sound travels through the EAC and causes the tympanic
membrane to vibrate. Various disorders can arise in the outer ear eliciting pain to the host.
For example, otitis externa is an acute, painful inflammatory condition of the EAC that
affects all age groups of humans and accounts for roughly half of the ear pain pathologies
known to exist. During the summer months, cases of otitis externa tend to increase due to
what is known as "swimmer's ear." Swimmer's ear generally arises from the seepage of
water into the EAC during swimming and the onset of infection and pain. Other outer ear
disorders causing pain to the host include insertion of foreign objects in the ear, cerumen
impaction, long-term use of hearing aids, and dermatological disorders, including psoriasis,
eczema and seborrhea.
The middle ear is an air-filled cavity between the outer and inner ears. The middle ear
is separated from the outer ear by the tympanic membrane and abuts the inner ear. It has a
volume of about two milliliters and is connected to the back of the throat via the eustachian
tube. The middle ear contains the malleus, icus and stapes, which are tiny bones that translate
the movement of the tympanic membrane to the inner ear. Various conditions of the middle
ear can cause pain to the host. For example, otitis media, which can be acute ("AOM") or
associated with effusion ("OME"), is an inflammatory condition of the middle ear which
generally affects children more often than adults (Karver, Otitis Media, Primary Care,
Volume 25, No. 3, pages 619-632 (1998). The etiology of otitis media is fairly broad and can
be caused by various inflammatory events including infection and allergy. Effusion, which
can be sterile or contain infectious material, may also result from otitis media. The fluid
consists of various inflammatory cells (white blood cells), mediators of allergy and
inflammation and cellular debris.
The inner ear comprises the sensory organs of the auditory and vestibular systems. It
consists of two major compartments, known as the bony and membranous labyrinths. These
chambers are highly organized and sensitive tissues and provide both auditory perception and
balance to the animal. Various pathologies may arise in the inner ear. creating distortion of
hearing, loss of balance and pain.
Since otic pain is often associated with infection and resultant congestion and
pressure, the primary therapeutic approach to treating otic pain is the administration of
antiobiotics, both systemically and topically.
Various other therapies have been attempted for the alleviation of otic pain. Topical
steroids (e.g., hydrocortisone) and systemic non-steroidal anti-inflammatory drugs (NSAIDs),
such as aspirin and ibuprofen, have been used typically in conjunction with anti-infectives to
treat otic pain. Local anesthetics are another class of compounds which relieve pain by directly
inhibiting nerve cellular function. A drawback of local anesthetic therapy is the short
duration of action of such drugs. Another problem with the use of local anesthetics is that
their mechanism of action, non-specific membrane stabilization, can have the undesired
coincident effect of also inhibiting biological functions of cells, such as fibroblasts and
surrounding neural cells. Therefore, even though pain sensation can be abated with local
anesthetic treatment, healing and normal function of the tissue may be significantly
compromised. There is a need, therefore, to discover agents which potently and specifically
inhibit the transmission of painful stimuli by sensory afferents. following local otic
application. Opiates are a class of compounds with well documented clinical analgesic efficacy.
Opiates can be administered in a number of ways. For example, opiates can be administered
systematically, by intravenous injection or oral dosage, or locally, by subcutaneous,
intramuscular or topical application. Systemic administration of opiates, however, has been
associated with several prob ems inc u ng ose esca at on (tolerance), addiction, respiratory
depression and constipation.
Other agents have also been suggested for use in treating pain. Such agents include
tricyclic antidepressants such as imipramine and desipramine, alpha-2 adrenergic agonists,
serotonin uptake blockers, such as prozac, and other analgesics such as paracetamol, as
described in United States Patent No. 5,270,050 (Coquelet et al.). Some of these therapies,
however, have been associated with side-effects such as dryness of mouth, drowsiness,
constipation, and low potencies and efficacies.
A class of agents which potently and specifically inhibit the transmission of painful
stimuli by sensory afferents without local anesthetic activity following local otic application
has yet to be described.
Serotonin, or 5-hydroxytryptamine ("5-HT"), is an endogenous peripheral and central
neurotransmitter. Activation of serotonin receptors elicits the transduction of specific
intracellular signals which lead to various physiological responses, depending on the receptor
sub-type activated and the tissue stimulated. Certain classes of molecules have been
discovered which bind to 5-HT receptors and either elicit 5-HT agonist or antagonist
responses. Researchers have pursued the use of various 5-HT receptor agonists and
antagonists in an effort to modulate cellular activity, and hence, effect various therapies to the
afflicted tissues.
A number of different sub-types of 5-HT receptors have been discovered, based on
differential agonist/antagonist sensitivities, second messenger coupling and protein structures.
Such sub-types include, for example, 5-HT1B, 5-HT1D, 5-HT1A and 5-HT2A (Hoyer et al., VII.
International Union of Pharmacology Classification of Receptors for 5-Hydroxytryptamine
(Serotonin), Pharmacological Reviews, volume 46, No. 2, Pages 157-170 (1994)). While all
serotonin receptors bind serotonin, different sub-types of serotonin receptors, which
demonstrate a selective sensitivity to different agonists and antagonists, exist in various
tissues and species. As noted by Hoyer et al. (1994), there are significant differences in the
types of serotonin receptors evident among various species. For example, the 5-HT1B
receptor exists in rodents, while the homolog of this receptor, the pharmacologically defined
5-HT,D receptor, exists in canine, pig and human species (Adham et al., The Rat 5-
HydroxytryptaminelB Receptor Is the Species Homologue of the Human 5-
HydroxytryptaminelDβ Receptor, Molecular Pharmacology, volume 41, pages 1-7 (1992)
and Hoyer et al., VII International Union of Pharmacology Classification of Receptors for
5-Hydroxytryptamine (Serotonin), Pharmacological Reviews, volume 46, no. 2, pages 157- 170 (1994)).
Numerous therapeutic approaches involving the manipulation of various serotonin
receptors have been attempted. For example, the use of 5-HT, antagonists to treat emesis in
cancer chemotherapy patients is disclosed in U.S. Patent No. 5,446,050 (Rosen); the use of
certain 5-HT, agonists to treat a myriad of ailments is disclosed in U.S. Patent No. 5,409,941
(Nowakowski); and the use of 5-HT2 antagonists to treat CNS disorders such as anxiety have
been disclosed in U.S. Patent No. 5,393,761 (Perregaard et al.). However, nowhere in these
publications has it been disclosed to use 5-HTIB or 5-HT1D agonists for the treatment of otic
pain.
Summary of the Invention
The present invention is directed to compositions and methods of treating otic pain.
More specifically, the present invention provides compositions containing 5-HTID and/or 5-
HTIB agonists for the treatment of otic pain. The present invention is also directed to
compositions comprising combinations of 5-HT1D and/or HT1B agonists and other
pharmaceutical agents (i.e., anti-microbial agents, anti-inflammatory agents or anti-allergy
agents) and methods of use.
The methods of the present invention involve the topical otic or intranasal application
of the compositions of the present invention. One advantage of this therapy is that the
inhibition of pain is receptor-specific, as contrasted with non-specific therapy, such as local
anesthetic treatment. This specific activity may reduce greatly the number of dosings per
day, and also reduce the drawbacks of short duration of action and inhibition of wound
healing which are associated with local anesthetics. Additionally, serotonin receptor binding
agents acting locally within otic tissue avoid the problems of tolerance, addiction and
constipation associated with the chronic, systemic administration of opiates.
Detailed Description of the Invention
The present invention is directed to the use of 5-HT1D and/or 5-HT1B receptor agonists
for the prevention or alleviation of otic pain. The 5-HT,D ("ID") receptor is found in human
tissue such as cerebral arteries and parts of the brain, such as the basal ganglia, raphe and the
cerebral cortex (Hoyer et al., (1994)). The 5-HT1B ("IB") receptor, thus far, has been found
in the CNS and peripheral nerves of other species such as rat, mouse and hamster. However,
the IB receptor has been shown to possess similar homology, and thus similar sensitivity, as
the ID receptor (Hoyer et al., (1994)). It has now been found that IB receptor agonists will
activate ID receptors. It is believed that the 5-HT1B and/or 5-HT1D receptors are present in
otic tissue.
The compounds of the present invention are ID agonists, IB agonists or IB/ID
agonists. As used herein, a "IB agonist" refers to a compound which activates a IB receptor,
a "ID agonist" refers to a compound which activates a ID receptor, and a "IB/ID agonist"
refers to a compound which activates either a 1 B or a 1 D receptor.
Preferred IB/ ID agonists of the present invention are: 7-trifluoromethyl-4(4-methyl-
l-piperazinyl)-pyrrolo[l,2-a]quinoxaline maleate (CGS-12066A); Anpirtoline; RU-24969; 5-
carboxamidotryptamine (5-CT); 5-methoxy-n,n,dimethyl-tryptamine; lH-Indole-5-
methanesulfonamide, 3-[2-(dimethylamino)ethyl]-N-methyl- ,butanedioate (Sumatriptan
(GR43175C)); Methanesulfonamide,N-[4-[[5-[3-(2-aminoethyl)-lH-indol-5-yl]- 1,2,4-
oxadiazol- 3-yl]methyl]phenyl] (L-694247); Metergoline; LY165163 (PAPP); BMS-180048; PNU- 142633 ; 1 H-2-Benzopyran-6-carboxamide, 3 ,4-dihydro- 1 - [2- [4-(4-methoxypheny 1)- 1 -
piperazinyl]ethyl]-N-methyl-, (S) -, (PNU- 109291); 5(R)-(methylamino)-2,4,5,6-tetrahydro-
lH-imidazo[4,5,l-ij]-quinolin-2- onemaleate (PNU-95666); N-[4-methoxy-3-(4-methyl-l-
piperazinyl)phenyl[-4-(2-phenylethyl)-l-piperazinecarboxaminde (F- 14258); F- 12640, which
is a 4-aryl-l-(tryptamine-5-0-carboxymethyl)-piperazide; ALX-0646; 1 H-Carbazole-6-
carboxamide, 2,3,4,9-tetrahydro-3-(methylamino)-, (R) (frovatriptan); lH-Indole, 3-((l-
methyl-2-pyrrolidinyl)methyl)-5-(2-(phenylsulfonyl)ethyl)-(R) (eletriptan); Pyrrolidine, 1-
(((3-(2-(dimethylamino)ethyl)-lH-indol-5-yl)methyl)sulfonyl) (almotriptan); lH-Indole-3-
ethanamie,N,N-dimethyl-5-( 1 H- 1 ,2,4-triazol- 1 -ylmethyl)-,monobenzoate (rizatriptan
benzoate); lH-Indole-5-ethanesulfonamide, N-methyl-3-(l-methyl-4-piperidinyl)
(naratriptan); 2-Oxazolidinone, 4-((3-(2-(dimethylamino)ethyl)-lH-indol-5-yl)methyl)-, (S)
(zolmitriptan); Glycinamide, N-[[[3-(2-aminoethyl)-lH-indol-5-yl]oxy]acetyl]-L-tyrosyl- (IS-
159); l'-Methyl-5-[2'-methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)-biphenyl-4-ylcarbonyl]- 2,3,6,7-tetrahydro-5H-spiro[furo[2,3-f]indole-3,4'-piperidine] (SB-224289); L-782097; 3-[3-
[4-(5,6-Dimethoxypyrimidin-4-yl)piperazin-l-yl]propyl]-N-methyl-lH-indol- 5-
ylmethylsulfonamide (VS-395); (R)-N-methyl-[3-(l-methyl-2-pyrrolidinyl)-lH-indol-5-
yljmethanesulphonamide (CP-122288); 3-[3-[4-(5-methoxy-4-pyrimidinyl)-l-piperazinyl]- propyl]-N-methyl-l H-indole-5- 5-methanesulfonamide (avitriptan); Piperazine, l-(2,3-
dihydro- 1 ,4-benzodioxin-5-yl) (eltoprazine); N-[3-(2-dimethylamino)ethoxy-4-
methoxyphenyl]-2'-methyl-4'-(5-methyl-l,2,4-oxadiazol-3-yl)-(l ,r-biphenyl)-4-carboxamide (SB-216641); and 3-[4-(3-chlorophenyl) piperazin-l-yl]-l,l-diphenyl-2-propanol) (BRL-
15572).
Other classes of IB/ ID agonists have been suggested or are known in the art and may
be useful in the present invention. For example, U.S. Patent Nos. 5,504,104 (Glennon) and
5,252,749 (Badorc et al.) disclose tryptamine analogs and thienocyclopentanone oxime
ethers, respectively, and WIPO Patent Publication No. WO 95/14004 (Halazy et al.) discloses
azylpiperazines, for use as IB/ID agonists; the foregoing patents and publication are
incorporated herein by reference to the extent they disclose IB, ID or IB/ ID agonists and
methods of preparation or attainment. The IB/ ID agonists of the present invention are
available from commercial sources or may be synthesized by methods known to those skilled
in the art.
The IB/ ID agonists of the present invention may also be elucidated by employing
standard methods known in the art. For example, the IB/ ID compounds may be ascertained
by using radioligand binding assays to determine drug affinities at the 5HT1B/D receptor such
as those described in Hoyer, et al., Characterization of the 5HTjβ recognition sites in rat
brain: binding studies with (-/-[^^IJcyanopindolol, Eur. J. Pharmacol., volume 1 18, pages
1-12 (1985). The IB/ID compounds may also be determined using a number of functional in
vitro assays. Common assays include methods involving the inhibition of forskolin-induced
adenylyl cyclase activity in (1) cells that naturally express the 5HT,B/D receptor (e.g.. in
Chinese hamster ovary cells as described in Giles, et al., Characterization of a 5HT1B
receptor in CHO cells: functional responses in the absence of radioligand binding, Br. J.
Pharmacol., volume 1 17, pages 1 1 19-1 126 (1996)), and (2) in host cells genetically
engineered to express recombinant human or animal 5HT,B/D receptors (e.g., Price, et al., SB-
216641 and BRL-15572 compounds to pharmacologically discriminate h5HT[β and
h5HT]f) receptors, Naunyn-Schmiedeburg's Arch. Pharmacol, volume 356, pages 312-320
(1997)). In addition, intercellular Ca2+-mobilization assays have also been employed to
determine the efficacy of IB/ID compounds for agonist activity at the 5HT1B/D receptor
(Dickenson and Hill, Coupling of an endogenous 5 HI B-like receptor to increases in
intracellular calcium through a pertussis toxin-sensitive mechanism in CHO-K1 cells, Br. J.
Pharmacol., volume 1 16, pages 2889-2896 (1995)). Assays involving the functional activity
in vivo at the 5HT,B/D receptor are also useful for the determination IB/ID compounds. For
example, Matsubara et al. describe a method to elucidate IB/ ID compounds using the
electrically-induced neurogenic plasma extravasation from the brain dura matter by
stimulation of the trigeminal ganglion (Matsubara, et al., CP-93,129, a potent and selective
5HTjβ receptor agonist blocks neurogenic plasma extravasation within rat but not in guinea
pig dura matter, Br. J. Pharmacol, volume 104, pages 3-4 (1991)).
The IB/ ID agonists of the present invention will be contained in topical or intranasal
compositions, in accordance with formulation techniques known to those skilled in the art.
The compounds may be included in solutions, suspensions, aerosols and other dosage forms
adapted for the particular IB/ID agonist and dosing regimen.
The IB/ ID compounds will be contained in compositions of the present invention in
concentrations effective to prevent or ameliorate otic pain. As used herein, the term
"pharmaceutically effective amount" refers to that amount of one or more IB/ID agonists
which prevents or alleviates otic pain. Generally, the dosage of IB/ ID agonists utilized for any
of the uses described herein will be from about one to two drops of a 0.01 to 3% weight/volume
("% w/v") composition, or corresponding amount for aerosol application, administered one to
four times per day.
The present invention is particularly directed to the provision of compositions adapted
for topical treatment of otic tissues. The compositions may also be adapted for administration
intranasally for treatment of otic tissues, such as nasal drops or an aerosol composition. The
otic compositions of the present invention will include one or more IB/ ID agonists and a
pharmaceutically acceptable vehicle for these agonist(s). Various types of vehicles may be
used. The vehicles will generally be aqueous in nature. Aqueous solutions or suspensions are
generally preferred, based on ease of formulation, as well as a patient's ability to easily
administer such compositions by means of instilling one to two drops of the solutions in the
affected ears. However, the compounds of the present invention may also be readily
incorporated into other types of compositions, such as aerosols (intranasal or intraotic),
suspensions, viscous or semi-viscous gels or other types of solid or semi-solid compositions.
Suspensions may be preferred for IB/ ID agonists which are relatively insoluble in water.
As stated above, the compositions of the present invention may also contain additional
pharmaceutically active agents or may be dosed concurrently with other pharmaceutical
compositions.
In particular, when treating a mammal for the prevention, treatment or amelioration of
otic infection, the compositions of the present invention may also contain one or more
antibiotic, antiviral and/or antifungal agents (hereinafter collectively referred to as "anti¬
microbial agents") or may be dosed concurrently or sequentially with anti-microbial agent
containing compositions. Examples of anti-microbial agents include, but are not limited to.
chloremphenicol, ofloxacin, norfloxacin, lomefloxacin, ciprofloxacin, natamycin, neomycin,
polymyxin B, gentamycin, tobramycin, bacitracin, gramicidin, erythromycin, moxifloxacin,
oxazolidinones, trovafloxacin, grepafloxacin, sulfacetamide, tetracycline, sulfisoxazole,
diolamine, trifluorothymidine, acyclovir, gancyclovir, vaniomycin or other antibiotic,
antiviral and antifungal agents known to those skilled in the art. The IB/ID agonist/anti¬
microbial agent combination compositions will contain one or more IB/ ID agonists, as stated
above, and one or more anti-microbial agents in an amount effective to prevent, treat or
ameliorate otic infection. As used herein, such an amount is referred to as "an effective
amount of one or more anti-microbial agents" or "an amount effective to prevent, treat or
ameliorate otic infection." In general, however, the IB/ID agonist/anti-microbial
combination compositions of the present invention will typically contain one or more
antibiotics in an amount of about 0.05 to 3.0 % w/v.
When treating a mammal for the prevention, treatment or amelioration of otic allergic
reactions and responses, the compositions of the present invention may also contain one or
more anti-allergy agents, histamine H, receptor antagonists or anti-histaminic agents
(hereinafter collectively referred to as "anti-allergy agents"), or may be dosed concurrently or
sequentially with anti-allergy agent containing compositions. Examples of anti-allergy agents
include, but are not limited to, mizolastine, mapinastine, levocabastine, pheniramine,
antazoline, ketotifen, azelastine, doxepine analogs, such as those described in U.S. Patent
Nos. 4,871,865 (Lever et al.) and 4,923,892 (Lever et al), cetirizine, loratadine,
fenoxifenadine, diphenhydramine, brompheniramine, chlorpheniramine, clemastine,
pyrilamine, cromolyn, nedocromil, lodoxamide, or other anti-allergy agents known to those
skilled in the art. The IB/ID agonist/anti-allergy agent combination compositions will contain
one or more IB/ ID agonists, as stated above, and one or more anti-allergy agents in an amount
effective to prevent, treat or ameliorate otic allergic reactions and responses. As used herein,
such an amount is referred to as "an effective amount of one or more anti-allergy agents" or "an
amount effective to prevent, treat or ameliorate otic allergic reactions or responses." In
general however, the IB/ID agonist/anti-allergy agent combination compositions of the
present invention will typically contain one or more anti-allergy agents in an amount of about
0.001 to 1.0 % w/v.
When treating a mammal for the prevention, treatment or amelioration of otic
inflammatory reactions and responses, the compositions of the present invention may also
contain one or more anti-inflammatory agents or may be dosed concurrently or sequentially
with anti-inflammatory agent containing compositions. Examples of anti-inflammatory
agents include, but are not limited to, PAF antagonists, such as SR-27417, A- 137491, ABT-
299, apafant, bepafant, minopafant, E-6123, BN-50727, nupafant and modipafant; PDE IV
inhibitors, such as ariflo, torbafylline, rolipram, filaminast, piclamilast, cipamfylline, CG- 1088, V-11294A, CT-2820, PD-168787, CP-293121, DWP-205297, CP-220629, SH-636,
BAY- 19-8004, and roflumilast; cyclooxygenase type I and II inhibitors, such as nepafenac,
amfenac, diclofenac, flurbiprofen, indomethacin, naproxen, ketorolac, ibuprofen, bromfenac,
ketoprofen, meclofenamate, piroxicam, sulindac, suprofen, mefanamic acid, diflusinal,
oxaprozin, tolmetin, fenoprofen, benoxaprofen, nabumetome, etodolac, phenylbutazone,
aspirin, oxyphenbutazone, NCX-4016, HCT-1026, NCX-284, NCX-456, tenoxicam and
carprofen; cyclooxygenase type II selective inhibitors, such as NS-398, vioxx, celecoxib, P54,
etodolac, darbufelone mesylate, L-804600 and S-33516; and inhibitors of cytokine
production, such as inhibitors of the NFkB transcription factor; or other anti -inflammatory
agents known to those skilled in the art. The IB/ ID agonist/anti-inflammatory agent
combination compositions will contain one or more IB/ID agonists, as stated above, and one or
more anti-inflammatory agents in an amount effective to prevent, treat or ameliorate otic
inflammatory reactions and responses. As used herein, such an amount is referred to as "an
effective amount of one or more anti-inflammatory agents" or "an amount effective to prevent,
treat or ameliorate otic inflammatory reactions or responses." In general, however, the IB/ID
agonist/anti-inflammatory agent combination compositions of the present invention will
typically contain one or more anti-inflammatory agents in an amount of about 0.01 to 1.0 %
w/v.
The otic compositions of the present invention may also include various other
ingredients, such as buffers, preservatives, co-solvents and viscosity building agents.
An appropriate buffer system (e.g., sodium phosphate, sodium acetate or sodium borate)
may be added to prevent pH drift under storage conditions.
Otic products are typically packaged in multidose form. Preservatives are thus required
in multidose compositions to prevent microbial contamination during use. Suitable
preservatives include: benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben,
propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, polyquaternium-1, or other
agents known to those skilled in the art. Such preservatives are typically employed at a level of
from 0.001 to 1.0 % w/v.
Some of the compounds of the present invention may have limited solubility in water
and therefore may require a surfactant or other appropriate co-solvent in the composition. Such
co-solvents include: polyethoxylated castor oils, Polysorbate 20, 60 and 80; Pluronic® F-68, F-
84 and P-103 (BASF Corp., Parsippany NJ, USA); cyclodextrin; or other agents known to those
skilled in the art. Such co-solvents are typically employed at a level of from 0.01 to 2% w/v.
Viscosity greater than that of simple aqueous solutions may be desirable to increase otic
absorption of the active compound, to decrease variability in dispensing the formulations, to
decrease physical separation of components of a suspension or emulsion of formulation and/or
otherwise to improve the otic formulation. Such viscosity building agents include, for example,
polyvinyl alcohol, polyvinyl pyrrolidone, methyl cellulose, hydroxypropyl methylcellulose,
hydroxyethyl cellulose, carboxymefhyl cellulose, hydroxypropyl cellulose or other agents
known to those skilled in the art. Such agents are typically employed at a level of from 0.01 to
2% w/v.
The compositions may also be used for treating irritated tissues following otic surgery.
The compositions may be used for acute treatment of temporary conditions, or may be
administered chronically. The compositions may also be used prophylactically, especially prior to otic surgery or noninvasive otic procedures, or other types of surgery.
As stated above, the compounds and compositions of the invention will be used to
prevent or ameliorate otic pain associated with various stimuli. For example, the IB/ID
agonists and compositions of the present invention may be used in treating pain arising from
allergens, inflammation, trauma, congestion, infection, foreign body sensation and surgery, e.g.,
following cochlear implant surgery. With such treatment, the IB/ ID agonists can be
individually dosed, or in combination with other pharmaceutical agents known in the art.
The compositions of the present invention are further illustrated by the following
formulation examples 1-4. The ingredient "IB/ID agonist" denotes a compound of the present
invention.
Example 1
The following is an example of an otic/ nasal solution:
Ingredient Amount (% w/v)
7-trifluoromethyl-4(4-methyl- 1 -piperazinyl) 0.01-1.0
-pyrrolo[l ,2-a]quinoxaline maleate (CGS-12066A)
Phosphate Buffered Saline 1.0
Polysorbate 80 0.5
Purified water q.s. to 100%
Example 2
The following is an example of an otic/ nasal suspension:
Ingredient Amount (% w/v)
IB/ ID agonist 0.01-1.0
Monobasic sodium phosphate 0.05
Dibasic sodium phosphate 0.15
(anhydrous)
Sodium chloride 0.75
Disodium EDTA (Edetate disodium) 0.05
Cremophor EL 0.1
Benzalkonium chloride 0.01
HC1 and/or NaOH pH 7.3 - 7.4
Purified water q.s. to 100%
Example 3
The following is an example of an otic/ nasal suspension or solution:
Ingredient Amount (% w/v)
I B/ID agonist 0.01-1.0 Phosphate Buffered Saline 1.0 Hydroxypropyl-β-cyclodextrin 4.0 Purified water q.s. to 100%
Example 4
The following is an example of an otic/nasal suspension:
Ingredient Amount (% w/v)
IB/ID agonist 0.1-1.0
Moxifloxacin 0.3
Benzalkonium Chloride 0.01
Edetate Disodium, USP 0.01
Sodium Chloride, USP 0.3
Sodium Sulfate, USP 1.2
Tyloxapol, USP 0.05
Hydroxyethylcellulose 0.25
Sulfuric Acid and/or
Sodium Hydroxide, NF q.s.
Purified Water, USP q.s. to 100%