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`INFORMATION oIscLosuRE STATEMENT
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`U.S. DEPARTMENT OF COMMERCE
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`LIST or REFERENCES CITED BY APPL|CANT(S)
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`Date Submitted to PTO: July 12, 2007
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`ATTY DOCKET No.
`2005_0232A
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`APPLICANT
`SW0“ 5/‘WA 93 at
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`March 28_ 2005
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`U.S. PATENT DOCUMENTS
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`‘
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`sERIAL NO.
`10/525.006
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`'9
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`4 name”
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`GROUP
`1609
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`FOREIGN PATENT DOCUMENTS
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`DATE CONSIDERED
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`09/19/2007
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`Notice of References Cited Examiner
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`Application/Control No.
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`10/525906
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`App|icant(s)/Patent Under
`Reexamination
`SAWA ET AL.
`
`Timothy P. Thomas
`U.S. PATENT DOCUMENTS
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`Art Unit
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`1614
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`Page 1 of 1
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`US-6,319,513
`11-2001
`Dobrozsi. Douglas Joseph
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`c'ass'fi°at'°n
`A61K 31/00
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`FOREIGN PATENT DOCUMENTS
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`Date
`MM-YYYY
`03-2001
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`Country
`PCT/US -
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`Gamache, et al.
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`Document Number
`Country Code—Number-Kind Code
`n wo 01/15677 A2
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`I
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`NON-PATENT DOCUMENTS
`Include as applicable: Author, Title Date, Publisher, Edition or Volume, Pertinent Pages)
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`9/19/2007
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`Nolan, et al.; “The topical anti-inflammatory and analgesic properties of bromfenic in rodents:; Agents and Actions; 1988 Aug;
`25(1-2):77-85, abstract
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`I ISTAPharmaceuticals;“NewDrugApplications: Xibrom",http://www.drugs.com/nda/xibrom_040525.html.accessedonline
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`‘A copy of this reference is not being furnished with this Office action. (See MPEP § 707.05(a).)
`Dates in MM-YYYY format are publication dates. Classifications may be US or foreign.
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`Notice of References Cited
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`Part of Paper No. 20070919
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`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
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`(19) World Intellectual Property Organization
`International Bureau
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`8 March 2001 (08.03.2001) llllllIlllllllllllllll||l|I||||||||ll|l||||||||||||Il||||l||||l|||llllllllllllll
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`W0 01/15677 A2
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`(51) International Patent Classification’:
`31/498. A6lP 27/16
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`A61K 31/00.
`
`(21) International Application Number:
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`PC1‘/USOOl22764
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`(22) International Filing Date: 18 August 2000 (18.08.2000)
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`(25) Filing Language:
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`(26) Publication Language:
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`English
`
`English
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`Donnybrook Drive, Burleson, TX 76028 (US). SHARIF.
`Najam, A. [US/US]; 7 Couttney Court. Arlington, TX
`76015 (US).
`
`(74) Agents: YEAGER, Sally, S. el al.; Alcon Research. Ltd.,
`R & D Counsel. Mail Code Q-148, 6201 South Freeway.
`Fort Worth, TX 76134 (US).
`
`(81) Designated States (national): AU. BR. CA. CN, JP, MX,
`PL. TR. US, ZA.
`
`(30) Priority Data:
`09/387,358
`
`31 August 1999 (31.08.1999)
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`US
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`(84) Designated States (regional): European patent (AT, BE,
`CH, CY. DE, DK, ES, FI, FR, GB, GR. IE, IT. LU, MC,
`NL, PT. SE).
`
`(71) Applicant (for all designated States except US): ALCON
`LABORATORIES, INC. [US/US]: 6201 South Freeway,
`Mail Code Q-148. Fort Worth. TX 76134 (US).
`
`(72) Inventors; and
`GAMACI-IE,
`(for US only):
`(75) Inventors/Applicants
`Daniel, A. [US/US]; 5610 Hunterwood Lane, Arling-
`ton, TX 76017 (US). YANNI, John, M. [US/US]; 2821
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`Published:
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`Without international search report and to be republished
`upon receipt ofthat report.
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`For two-letter codes and other abbreviations, refer to the ”Guid-
`ance Notes on Codes and’/tbbrevian'onx” appearing at the begin-
`ning ofeach regular issue ofthe PCT Gazette.
`
`
`G3: 52:2 cU:m o'11 U:
`§2E E30EU)-1U) E’:5 § ‘UE
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`(57) Abstract: Compositions and methods for treating otic pain am disclosed. In particular. the invention discloses compositions
`and methods of using 5-I-lT,3,.D agonists for the prevention or alleviation of otic pain.
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`001/15677A2|l||||Illlllllllllllllllllllllllll||||||||||l||lllll||||l|||||||||l|l|||l|||llll
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`Use of 5-HT,,,,,,, Agonists to Treat Otic Pain
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`The present
`
`invention relates to the pharmaceutical
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`treatment of otic pain.
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`ln
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`particular. the present invention relates to the topical use of 5-l-lT,,3,,D receptor agonists and
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`partial agonists for the prevention or alleviation of pain in the ear.
`
`’
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`I0
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`Background of the Invention
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`Pain is a perceived nociceptive response to local stimuli in the body. The perception
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`of pain at the level of the central nervous system requires the transmission of painful stimuli
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`by peripheral sensory nerve fibers. Upon stimulation of tissue (i.e., thermal, mechanical or
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`chemical), electro-chemical signals are transmitted from the sensory nerve endings to the
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`spinal column, and hence to the brain where pain is perceived.
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`The ear is highly innervated with sensory afferents capable of transmitting various
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`painful stimuli to the central nervous system. The ear is comprised of outer, middle and inner
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`ear portions andotic pain may arise in any of these portions of the ear. Pain conditions
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`involving the ear, therefore, can arise in numerous instances, such as: foreign body stimulus,
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`inflammation, edema, otic congestion, otic pressure, infection, accidental
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`trauma, surgical
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`15
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`20
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`procedures and post—surgical recovery.
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`The outer or “extemal”i ear is comprised of the pinna and external ear canal (“EAC”).
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`The EAC is a tubular, slightly curved structure extending from the pinna to the tympanic
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`25
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`membrane or “ear drum.”
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`Sound travels through the EAC and causes the tympanic
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`membrane to vibrate. Various disorders can arise in the outer ear eliciting pain to the host.
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`For example. otitis extema is an acute, painful
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`inflammatory condition of the EAC that
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`affects all age groups of humansand accounts for roughly half of the ear pain pathologies
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`known to exist. During the summer months, cases of otitis extema tend to increase due to
`3
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`what is known as “swimmer’s ear.’
`
`Swimmer’s ear generally arises from the seepage of
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`water into the EAC during swimming and the onset of infection and pain. Other outer ear
`
`5
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`disorders causing pain to the host include insertion of foreign objects in the car, cerumen
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`impaction, long-term use of hearing aids, and dermatological disorders, including psoriasis,
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`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 car.
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`It has a
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`to
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`volume of about two milliliters and is connected to the back of the throat via the eustachian
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`tube. The middle ear contains the malleus, icus and stapes, which are tiny bones that translate
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`the movement of the tympanic membrane to the inner ear. Various conditions of the middle
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`car can cause pain to the host. For example, otitis media, which can be acute (“AOM”) or
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`associated with effusion (“OMB”),
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`is an inflammatory condition of the middle car which
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`15
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`generally affects children more often than adults (Karver, Otitis Media, Primgy Care,
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`Volume 25, No. 3, pages 619-632 (1998). The etiology of otitis media is fairly broad and can
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`be caused by various inflammatory events including infection and allergy. Effusion, which
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`can be sterile or contain infectious material, may also result from otitis media. The fluid
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`consists of various inflammatory cells (white blood cells), mediators of allergy and
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`20
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`inflammation and cellular debris.
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`The inner ear comprises the sensory organs of the auditory and vestibular systems.
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`It
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`consists of two major compartments, known as the bony and membranous labyrinths. These
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`chambers are highly organized and sensitive tissues and provide both auditory perception and
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`PCT/US00/22.764
`\A/ariouslpathologies may arise in the inner ear, creating distortion of
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`hearing, loss of balance and pain.
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`Since otic pain is often associated with infection and resultant congestion and
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`pressure,
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`the primary therapeutic approach to treating otic pain is the administration of
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`5
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`. antiobiotics, both systemically and topically.
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`Various other therapies‘ have been attempted for the alleviation of otic pain. Topical
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`steroids (e.g., hydrocortisone) and systemic non-steroidal anti-inflammatory drugs (NSAIDS),
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`such as aspirin and ibuprofen, have been used typically in conjunction with anti-infectives to
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`treat ‘otic pain.
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`10
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`Local anesthetics are another class of compounds which relieve pain by directly
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`inhibiting nerve cellular function. A drawback of local anesthetic therapy is the short
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`duration of action of such drugs. Another problem with the use of local anesthetics is that
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`their mechanism of action, non-specific membrane stabilization, can have the undesired
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`coincident effect of also inhibiting biological functions of cells, such as fibroblasts and
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`15
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`surrounding neural cells. Therefore, even though pain sensation can be abated with local
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`anesthetic treatment, healing and normal
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`function of the tissue may be significantly
`
`compromised. There is a need, therefore, to discover agents which potently and specifically
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`‘inhibit
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`the transmission of painful stimuli by sensory afferents,
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`following local otic .
`
`application.
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`20
`
`Opiates are a class of compounds with well documented clinical analgesic efficacy.
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`Opiates can be administered in a number of ways. For example, opiates can be administered
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`systematically, by intravenous injection or oral dosage, or
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`locally, by subcutaneous,
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`intramuscular or topical application. Systemic administration of opiates, however, has been
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`associated with several problems including dose escalation (tolerance), addiction. respiratory
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`depression and constipation.
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`Other agents have also been suggested for use in treating pain. Such agents include
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`tricyclic antidepressants suchas imipramine and desipramine, alpha-2 adrenergic agonists,
`
`5
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`serotonin uptake blockers, such as prozac, and other analgesics such as paracetamol. as
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`described in United States Patent No. 5,270,050 (Coquelet et al.). Some of these therapies,
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`however, have been associated with side-effects such as dryness of mouth, drowsiness,
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`constipation, and low potencies and efficacies.
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`A class of agents which potently and specifically inhibit the transmission of painful
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`10
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`stimuli by sensory afferents without local anesthetic activity following local otic application
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`has yet to be described.
`
`Serotonin, or 5-hydroxytryptamine (“5-HT”), is an endogenous peripheraland central
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`neurotransmitter. Activation of serotonin receptors elicits the transduction of specific
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`intracellular signals which lead to various physiological responses, depending on the receptor
`
`15
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`sub-type activated and the tissue stimulated. Certain classes of molecules have been
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`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
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`antagonists in an effort to modulate cellular activity, and hence, effect various therapies to the
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`afflicted tissues.
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`20
`
`A number of different sub-types_of 5-HT receptors have been discovered, based on
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`differential agonist/antagonist sensitivities, second messenger coupling and protein structures.
`
`Such sub—types include, for example, 5-HTm, 5-HT,D, 5-HT“, and 5-HT“ (Hoyer et al., VII.
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`International Union of Pharmacology Classification of Receptors for 5-Hydroxytryptamine
`
`(Serotonin), Pharmacological Reviews, volume 46, No. 2, Pages 157-170_ (1994)). While all
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`-4-
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`serotonin receptors bind serotonin, different ‘sub-types of serotonin receptors, which
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`demonstrate a selective sensitivity to different agonists and antagonists, exist in various
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`tissues and species. As noted by I-loyer et al. (1994), there are significant differences in the
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`types of serotonin receptors evident among various species.
`
`For example,
`
`the 5-HT”,
`
`5
`
`_ receptor exists in rodents, while the homolog of this receptor, the pharrnacologically defined
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`5-HT”, receptor, exists in canine, pig and human species (Adham et al., The Rat 5-
`
`Hydroxytryptamine1B Receptor
`
`Is
`
`the Species Homologue of
`
`the Human
`
`5-
`
`Hydroxytryptamine1D/3 Receptor, Molecular Pharmacology, volume .41, pages 1-7 (1992)
`
`and Hoyer et al.,
`
`IV/II.
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`International Union ofPharmacologr Classification of Receptors for
`
`10
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`5-Hydroxytryptamine (Serotonin), Pharmacological Reviews, volume 46, no. 2, pages 157-
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`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 emesisiin
`
`cancer chemotherapy patients is disclosed in U.S. Patent No. 5,446,050 (Rosen); the use of
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`15
`
`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 inthese
`
`- publications has it been disclosed toiuse 5-HT”, or 5-HT”, agonists for the treatment of otic
`
`pain.
`
`20
`
`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-HT”, and/or 5-
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`-5-
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`HT,B agonists for the treatment of otic pain. The present
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`invention is also directed to
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`compositions
`
`comprising combinations of 5-HT“) and/or HT”,
`
`agonists
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`and other
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`pharmaceutical agents (i.e., anti-microbial agents, anti-inflammatory agents or anti-allergy
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`agents) and methods of use.
`
`5
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`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
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`inhibition of pain is receptor-specific, as contrasted with non—specific therapy, such as local
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`anesthetic treatment. This specific activity may reduce greatly the number of closings per
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`day, and also reduce the drawbacks of short duration of action and inhibition of wound
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`I0
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`healing which are associated with local anesthetics. Additionally, serotonin receptor binding
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`agents ‘acting locally within otic tissue avoiduthe problems of tolerance, addiction and
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`constipation associated with the chronic, systemic administration of opiates.
`
`Detailed Description of the Invention
`
`15
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`The present invention is directed to the use of 5-HT”, and/or 5-HT”, receptor agonists
`
`for the prevention or alleviation of otic pain. The 5-HT”, (“ID”) receptor is found in human
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`tissue such as cerebral arteries and parts of the brain, such as the basal ganglia, raphe and the
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`cerebral cortex (Hoyer et al., (1994)). The 5-HT”, (“IB”) receptor, thus far, has been found
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`20
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`in the" CNS and peripheral nerves of other species such as rat, mouse and hamster. However,
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`the 1B receptor has been shown to possess similar homology, and thus similar sensitivity, as
`
`the 1D receptor (Hoyer et al., (1994)). It has now been found that 1B receptor agonists will
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`activate 1D receptors‘.
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`It is believed that the 5~HT,B and/or 5-HT”, receptors are present in
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`otic tissue.
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`The compounds of the present invention are 1D agonists, 1B agonists or 1B/1D
`
`agonists. As used herein, a “1B agonist” refers to a compound which activates a 1B receptor,
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`a “ID agonist” refers to a compound which activates a 1D receptor, and a “lB/ 1D agonist"
`
`refers to a compound which activates either a 1B or a 1D receptor.
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`5
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`Preferred lB/ 1D agonists of the present invention are: 7-trifluoromethyl-4(4-methyl-
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`1-piperazinyl)-pyrrolo[1,2-a]quinoxaline maleate (CGS-12066A); Anpirtoline; RU—24969; 5-
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`carboxamidotryptamine (5-CT); 5-methoxy-n,n,dimethyl-tryptamine; 1H-Indole~5-
`
`methanesulfonamide, 3-[2-(dimethylamino)ethyl]-N-methy1- ,butanedioate (Sumatriptan
`
`(GR4317SC)); Methanesu1fonamide,N-[4-[[5-[3-(2—aminoethyl)-I H-indol-5 -yl]-1,2,4-
`oxadiazol- 3-yl]methyl]phenyl] (L-694247); Metergoline; LY165l63 (PAPP); BMS-180048;
`
`10
`
`PNU-142633; 1H-2-Benzopyran-6-carboxamide, 3,4~dihydro-1-[2-[4-(4-methoxyphenyl)-1-
`
`piperazinyl]ethyl]-N-methyl-, (S) -, (PNU-109291); 5(R)-(methylamino)-2,4,5,6-tetrahydro-
`
`1H-imidazo[4,5, I -ij]-quinolin-2- onemaleate (PNUV-95666); N—[4-methoxy-3-(4-methyl-1 -
`
`piperazinyl)phenyl[-4-(2-pheny1ethyl)-1-piperazinecarboxaminde (F-14258); F-12640, which
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`15
`
`is a 4-a.ryl-I-(tryptamine—5-0-carboxymethyl)-piperazide; ALX-0646; 1H-Carbazole-6-
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`carboxamide, 2,3,4,9-tetrahydro-3—(methy1amino)—, (R) (frovatriptan); 11-I-Indole, 3-((1-
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`methyl-2—pyrrolidinyl)methyI)-5-(2-(phenylsulfonyl)ethyl)-(R) (eletriptan); Pyrrolidine, 1-
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`(((3-(2-(dimethylarnino)ethyl)-1H-indol-5—y1)methy1)sulfonvl) (almotriptan); lH-Indole-3-
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`ethanamie,N,N-dirnethyl-5-(1 H-1 ,2,4-triazol-1 -ylmethyl)-,monobenzoate (rizatriptan
`
`20
`
`benzoate); 1H-Indole-5-ethanesulfonamide, N-methyl-3-(1-methyl-4-piperidinyl)
`
`(naratriptan); 2-Oxazolidinone, 4-((3-(2-(dimethylamino)ethyl)-1H-indol-5-y1)methyl)-, (S)
`
`(zolmitriptan); Glycinarnide, N-[[[3-(2-aminoethyl)-1I-I-indol-5-yl]oxy]acetyl]-L-tyrosyl- (IS-
`
`159); 1'-Methy1-5-[2'-methyl-4'—(5-methyl— I ,2,4—oxadiazol-3—y1)-biphenyl-4-ylcarbonyl]-
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`2,3,6,7-tetrahydro-SH-spiro[furo[2,3-f]indole-3,4’-piperidine] (SB-224289); L-782097; 3-[3-
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`-7-
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`[4-(5,6-Dimethoxypyrimidin-4-yl)piperazin-l-yl]propyI]-N-methyl-1H-indol- 5-
`
`ylmethylsulfonamide (VS-395); (R)-N-methyl-[3-(l-methyl-2-pyrro1idinyl)—1H-indol-5-
`
`yl]methanesulphonamide (CP-122288); 3-[3-[4-(5-methoxy-4-pyrimidinyl)~l-piperazinyl]-
`
`propyl]-N-methyl-1H-indole-5- 5-methanesulfonamide (avitriptan); Piperazine, 1-(2,3-
`
`'5 .
`
`dihydro-1,4—benzodioxin-5-yl) (eltoprazine); N—[3-(2-dimethylamino)ethoxy~4-
`
`methoxyphenyl]-2'-methyl-4'-(5-methy1-1,2,4-oxadiazol-3-yl)-(1 ,1'-biphenyl)-4-carboxamide
`
`‘(SB-216641); and 3—[4-(3—chlorophenyl) piperazin-1-yl]—1,1—diphenyl-2-propanol) (BRL-
`
`15572).
`
`Other classes of 1B/1D agonists have been suggested or are known in the art and may
`
`to
`
`be usefiil 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. W0 95/ 14004 (Halazy et al.) discloses
`
`azylpiperazines, for use as 1B/l D agonists; the foregoing patents and publication are
`
`incorporated herein by reference to the extent they disclose 1B, 1D or 1B/1D agonists and
`
`I5 ' methods of preparation or attainment. The 1B/1 D agonists of the present invention are
`
`available from commercial sources or may be synthesized by methods known to those skilled
`
`in the art.
`
`The 1B/1D agonists of the present invention may also be elucidated by employing
`
`standard methods known in the art. For example, the 1B/ID compounds may be ascertained
`
`20
`
`by using radioligand binding assays to determine drug affinities at the 5HT,B,D receptor such_
`
`as those described in Hoyer, et al., Characterization of the 5HT13 recognition sites in rat
`
`brain.‘ binding studies with (-)-[125I]cyanopindoloI, Eur. J. Pharmacol., volume 118, pages
`
`1-12 (1985). The 1B/lD compounds may also be determined using a number of functional in
`
`vilro assays. Common assays include methods involving the inhibition of forskolin-induced
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`-3-
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`adenylyl cyclase activity in (1) cells that naturally express the 5HT,3,D receptor (e.g.,
`
`in
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`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.
`
`Pharmacol._. volume 117. pages 1119-1126 (1996)), and (2)
`
`in host cells genetically
`
`5
`
`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]B and
`
`h5HT1]_) receptors, Naunyn-Schmiedeburg’s Arch. Pharrnacol., volume 356, pages 312-320
`
`(1997)).
`
`In addition,
`
`intercellular Caz‘-mobilization assays have also been employed to
`
`determine the efficacy of 1B/1D compounds for agonist activity at the 5HT,,,,D receptor
`
`10
`
`(Dickenson and Hill, Coupling of an endogenous 5HTIB-like receptor to increases in
`
`intracellular calcium through a pertussis toxin-sensitive mechanism in CHO-K1 cells, Br. J .
`
`Pharmaco1., volume 116, pages 2889-2896 (1995)). Assays involving the functional activity
`
`in vivo at the 5HT,B,D receptor are also useful for the determination 1B/1D compounds. For
`
`example, Matsubara et al. describe a method to elucidate 1B/1D compounds using the
`
`IS
`
`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
`
`5HTj3 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 1B/ 1D agonists of the present invention will be contained in topical or intranasal
`
`20
`
`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 1B/1D agonist and dosing regimen.
`
`The 1B/1D compounds will be contained in compositions of the present invention in
`
`concentrations effective to prevent or ameliorate otic pain. As used herein,
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`the term
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`“pharmaceutically. effective amount” refers to that amount of one or more 1B/1D agonists
`
`which prevents or alleviates otic pain. Generally, the dosage of 1B/1D agonists utilized for any
`
`of the uses described herein will be from about one to two drops of a 0.01 to 3% weight/voltune
`
`(“% w/v”) composition, or corresponding amount for aerosol ‘application, administered one to
`
`5‘
`
`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 1B/1D agonists and a
`pharmaceutically acceptable vehicle for these agonist(s). Various types of vehicles may be
`
`IQ
`
`used. The vehicles will generally be aqueous in nature. Aclueous solutions or suspensions are
`
`generally preferred, based on case 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
`
`I5
`
`incorporated into other types of compositions, such as aerosols (intranasal or
`
`intraotic),
`
`suspensions, viscous or semi-viscousigels or other types of solid or-semi-solid compositions.
`
`Suspensions may be preferred for 1B/1D 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
`
`20
`
`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
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`containing compositions. Examples of anti-microbial agents include, but are not limited to.
`
`chloremphenicol, ofloxacin, norfloxacin, lomefloxacin, ciprofloxacin, natamycin, neomycin,
`
`polymyxin B, gentarnycin, tobramycin, bacitracin, gramicidin, erythromycin, moxifloxacin,
`oxazolidinones,
`trovafloxacin, grepafloxacin,
`sulfacetamidc,
`tetracycline,
`sulfisoxazole,
`
`5
`
`diolamine.
`
`trifluorothymidine, acyclovir,‘ gancyclovir, vaniomycin or other antibiotic,
`
`antiviral and antifungal agents known to those skilled in the art. The 1B/ ID agonist/anti-
`
`microbial agent combination compositions will contain one or more 1B/1D 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
`
`10
`
`amountiof one or more anti-microbial agents” or “an amount effective to prevent, treat or
`
`ameliorate A-otic
`
`infection."
`
`In general, however,
`
`the
`
`lB/lD 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
`
`15
`
`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 closed concurrently or
`
`sequentially with anti-allergy agent containing compositions. Examples of anti-allergy agents
`
`include, but are not
`
`limited to, mizolastine, mapinastine,
`
`levocabastine, pheniramine,
`
`20
`
`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,
`
`diphenhydrarnine,
`
`brompheniramine,
`
`chlorpheniramine,
`
`clemastine,
`
`pyrilamine, cromolyn, nedocromil, lodoxamide. or other anti-allergy agents known to those
`
`skilled in the art. The 1B/ lD agonist/anti-allergy agent combinationgcompositions will contain
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`-1]-
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`one or more 1B/l D 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
`
`5
`
`general. however,
`
`the 1B/lD 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
`
`I0
`
`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-13749], ABT-
`
`299, apafant, bepafant, minopafant, E-6123, BN-50727, nupafant and modipafant; PDE IV
`
`inhibitors, ‘such as ariflo, torbafylline, roliprarn, filaminast, piclamilast, cipamfylline, CG-
`
`15
`
`1088, V-11294A, CT-2820, PD-168787, CP-293121, DWP-205297, CP-220629, SH-636,
`
`BAY-19-8004,land 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,
`
`20
`
`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 1B/ID agonist/anti-inflammatory agent
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`combination compositions will contain one or more 1B/l D 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 morelanti-inflammatory agents” or “an amount effective to prevent,
`5
`
`5
`
`treat or ameliorate otic inflammatory reactions or responses.’
`
`In general, however, the 1B/1D
`
`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 V of the present
`
`invention may also include various other
`
`I0
`
`ingredients, such as buffers, preservatives, co-solvents and viscosity building agents.
`
`An appropriate bufier 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
`
`I5
`
`preservatives include:
`
`benzalkonium chloride,
`
`thimerosal, chlorobutanol, methyl paraben,
`
`propyl paraben, phenylethyl alcohol, edetate disodium, sorbic acid, polyquatemium-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
`
`20
`
`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—l03 (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 0.0] to 2% w/v.
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`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 fonnulations, 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,
`
`5
`
`hydroxyethyl cellulose. carboxymethyl, 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.
`
`10
`
`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 noninvasiveotic 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 lB/lD
`
`15
`
`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 lB/lD agonists can be
`
`individually dosed, or in combination with other pharmaceutical agents known in the art.
`
`The compositions of the present
`
`invention are filrther illustrated by the following
`
`20
`
`formulation examples 1-4. The ingredient “1B/ lD agonist” denotes a compound of the present
`
`invention.
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`The following is an example of an otic/ nasal solution:
`
`Example 1
`
`Ingredient
`
`Amount (°/o w/v)
`
`7-t