(12) United States Patent
`Williams et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,638,981 B2
`Oct. 28, 2003
`
`US006638981B2
`
`(54) TOPICAL COMPOSITIONS AND METHODS
`FOR TREATING PAIN
`
`6,191,131 B1
`6,191,165 B1
`
`2/2001 He et a1. .................. .. 514/246
`2/2001 Ognyanov et a1. .
`514/523
`
`6,197,830 B1
`
`3/2001 Frome . . . . . . . . .
`
`. . . . . . . .. 514/654
`
`(75) Inventors: Robert 0. Williams, Austin, TX (US);
`Feng Zhang’ Ausnn’ TX (Us)
`
`~
`
`g1
`6,225,324 B1
`
`,
`
`,
`
`15x79? 9: ai- ---- -
`5/2001 Poss et a1. ................ .. 514/316
`
`am is e a .
`
`......... ..
`
`(73> Assam EPiCePt Corporation, Englewood
`
`_
`(*) Notlcel
`
`Chffs> NJ (Us)
`_
`_
`_
`_
`sublectto any dlsclalmer?heterm Ofthls
`patent is eXtended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`2:33:13; 51
`
`215881 $23313255T;.111111175153238?
`
`6/2001 Upadhyay et a1. ........ .. 514/321
`6,245,781 B1
`6/2001 Cai et a1. .................. .. 514/249
`6,251,903 B1
`6/2001 Weber et a1.
`....... .. 514/634
`6,251,948 B1
`7/2001 Kelly et a1. ..
`514/217.05
`6,255,302 B1
`5/2002 Frome . . . . .
`. . . . .. 514/647
`6,387,957 B1
`6,461,600 B1 * 10/2002 Ford ..................... .. 424/78.02
`
`(21) Appl. No.: 09/931,293
`(22) Filed:
`Aug. 17, 2001
`
`(65)
`
`Prior Publication Data
`
`US 2003/0082214 A1 May 1, 2003
`
`(51) Int. cl.7 ............................................ .. A61K 31/135
`
`(52) US. Cl. ..................... .. 514/656; 514/646; 514/887;
`514/817; 514/938; 424/448
`(58) Field of Search ........................ .. 424/401; 514/938,
`514/646, 656, 817
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`4,615,699 A 10/1986 Gale et a1. ................ .. 604/897
`4,751,087 A
`6/1988
`424/449
`4,755,535 A
`7/1988 Minaskanian et a1. .... .. 514/947
`4,801,586 A
`1/1989 Minaskanian et a1_ ____ __ 514/212
`4,808,414 A
`2/1989 Peck et a1. ................ .. 424/449
`4,920,101 A
`4/1990 Minaskanian et a1. ...... .. 514/24
`4,989,607 A
`2/1991 Keusch et aL ____________ __ 128/640
`5,635,204 A
`6/1997 Gevirtz et a1_ _
`424/449
`5,646,151 A
`7/1997 Kruse et a1.
`514/255
`2
`$232? :6 :11:
`546/276_4
`5,688,955 A 11/1997 Kruse et a1_
`5,708,168 A
`1/1998 Keana et a1. ............. .. 540/520
`2
`gruff; it 2112
`""""
`5,763,445 A
`6/1998 Kruse et a1_ ______________ __ 514/255
`5,783,700 A
`7/1998 Nichols et a1. ........... .. 546/162
`2
`£25303‘:
`514/647
`5,817,699 A 10/1998 Flores et a1. .... ..
`. 514/226.2
`5,834,465 A 11/1998 Olney ..... ..
`414/327
`5,849,762 A 12/1998 Farrar et a1.
`5,863,916 A
`1/1999 Cai et a1. .................. .. 514/249
`5,869,521 A
`2/1999 Farrar et a1. .............. .. 514/422
`5,888,494 A
`3/1999 Farrar et a1.
`424/78.05
`
`5,914,403 A 5,922,340 A
`
`6/1999 NiChOlS 618.1. 7/1999 Berde et a1.
`
`..... .. 546/162 424/426
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`W0
`W0
`
`W0
`W0
`W0
`W0
`W0
`W0
`W0
`
`0 107 376 A1
`0 577 394 A1
`WO 93/10163
`WO 94/13643
`
`W0 94/ 13644
`WO 94/13661
`WO 94/13676
`WO 94/13677
`WO 95/16679
`WO 95/18124
`WO 95/23798
`
`5/1984
`1/1994
`5/1993
`6/1994
`
`6/199‘‘
`6/1994
`@1994
`6/1994
`6/1995
`6/1995
`9/1995
`
`OTHER PUBLICATIONS
`
`Skin Care and Cosmetic Ingredients Dictionary, p. 243
`(1994)_*
`
`“Handbook of Pharmaceutical Excipients,” Edited byArthur
`H. Kibbe, Ph.D., Am. Pharm. Assoc, 3:292—294, 2000.
`_
`_
`_
`_
`_
`J. SaWynok et al., “Peripheral Antmoclceptlve Actlonof
`Amitriptyline in the Rat Formalin Test: Involvement of
`Adenosine,” Pain, 80:45—55, 1999.
`J. SaWynok et al., “Peripheral Antinociceptive Actions of
`Desipramine and FluoXetine in an In?ammatory and Neu
`ropathic Pain Test in the Rat,” Pain, 821149458, 1999
`“Cardinal Manifestations and Presentations of Diseases,”
`Harrlson’s Principles of Internal Medicine, Edited by A.
`Fauci @I 211-, 14115358, 1998
`C. Stein et al., “Peripheral Morphine Analgesia”, Pain,
`711119—121> 1997~
`
`(List continued on next page.)
`
`Primary Examiner—]yothsna Venkat
`Attorney)
`Or Firm_Pennie & Edmonds,
`
`5,948,389 A
`
`9/1999 Stein . . . . . . . . .
`
`. . . .. 424/45
`
`(57)
`
`ABSTRACT
`
`. 514/327
`5,962,477 A 10/1999 Mak ........ ..
`5,981,513 A 11/1999 Kruse et a1. ................ .. 514/91
`5,985,586 A 11/1999 Daggett et a1. .......... .. 435/7.21
`514/255
`6,004,964 A 12/ 1999 Farrar et a1
`
`Topical Compositions and methods for treating pain- The
`invention provides oil-in-Water emulsions comprising an
`antidepressant; an NMDA-receptor antagonists; a lipophilic
`
`A
`
`Flores etal. . . . . . . . . . . . . . . ..
`
`Component; Water; and a surfactant' The Compositions
`
`,
`
`,
`
`io§§nqulit ‘lit ‘11' """" "
`2
`9/2000 Carlson et a1.
`.... .. 514/90
`6,117,855 A
`6,133,282 A 10/2000 Horvath et a1. ........... .. 514/292
`6,172,097 B
`1/2001 Cordi et a1. .............. .. 514/396
`B
`6,174,192
`1/2001 Watanabe et a1. ......... .. 439/377
`
`0]ima e a . ............ ..
`
`-
`
`-
`
`induce a local-anesthetic effect When topically administered
`to Intact 5km therfg'by .treatmg or preventmg pm’ for
`example’ neuropathlc Pam
`
`-
`
`-
`
`-
`
`9 Claims, N0 Drawings
`
`

`
`US 6,638,981 B2
`Page 2
`
`OTHER PUBLICATIONS
`
`T. Ghosh et al., Transdermal and Topical Drug Delivery
`Systems, “Types of Dermal Drug Delivery,” Interpharm
`Press, Inc., p. 7, 1997.
`T. Ghosh et al., Transdermal and Topical Drug Delivery
`Systems, “Transdermal and Dermal Therapeutic Systems,”
`Interpharm Press, Inc., pp. 87—93, 1997.
`T. Ghosh et al., Transdermal and Topical Drug Delivery
`Systems, “Transdermal and Dermal Therapeutic Systems:
`Current Status,” Interpharm Press, Inc., p. 33—112, 1997.
`Goodman & Gilman’s The Pharmacological Basis of Thera
`peutics, Edited by J. Hardman et al., “Chapter 23 Opioid
`Analgesics and Antagonists,” 9:521—525, 1996.
`Goodman & Gilman’s The Pharmacological Basis of Thera
`peutics, Edited by J. Hardman et al., “Chapter 23 Opioid
`Analgesics and Antagonists,” 9:529, 1996.
`Gennaro, Remington: The Science and Practice of Phar
`macy, “Coarse Dispersions,” 19(1):289, 1995.
`Wolfe et al., “Massive DeXtromethorphan Ingestion and
`Abuse,” Am J. Emerg Med. P, 13:174—176, 1995.
`Jia—He Li et al., “Potent, Orally Active, Competitive
`N—Methyl—D—aspartate (NMDA) Receptor Antagonists Are
`Substractes for a Neutral Amino Acid Update System in
`Chinese Hamster Overy Cells,” J. Med. Chem.,
`38:1955—1965, 1995.
`Olney et al., “NDMA Antagonists as Neurotherapeutic
`Drugs, Psychotogens, NeurotoXins, and Research Tools for
`Studying
`Schizophrenia,”
`Neuropsychopharmacology,
`13(4):335—345, 1995.
`Yoneda et al., “Differential Pro?les of Binding of a Radio
`labeled Agonist and Antagonist at a Glycine Recognition
`Domain on the N—Methyl—D—Aspartate Receptor Ionophore
`Complex in Rat Brain,” J. Neurochem. 62(1):102—112,
`1994.
`Bigge, “Structural Requirements for the Development of
`Potent N—Methyl—D—Aspartic Acid (NMDA) Receptor
`Antagonists,” Biochem. Pharmacol. P, 45(8):1547—1561,
`1993.
`T. Ghosh et al., “Methods of Enhancement of Transdermal
`Drug Delivery: Part IIA, Chemical Permeation Enhancers,”
`Pharm. Tech., 17:62—90, 1993.
`T. Ghosh et al., “Methods of Enhancement of Transdermal
`Drug Delivery: Part IIB, Chemical Permeation Enhancers,”
`Pharm. Tech., 17:68—76, 1993.
`P. Leeson, “Glycine—Site N—Methyl—D—Aspartate Receptor
`Antagonists,” Drug Design for Neuroscience, pp. 338—381,
`1993.
`Wong et al., “Nor?uoXetine Enantiomers as Inhibitors of
`Serotonin Uptake in Rat Brain,” Neuropsychoopharmacol
`ogy, 8(4):337—344, 1993.
`Albers et al., “Tolerability of Oral DeXtromethorphan in
`Patients With a History of Brain Ischemia,” Clinical Neur
`pharmacology, 15(6):509—514, 1992.
`Faden et al., “Pharmacological Strategies in CNS Trauma,”
`TiPS, 13:29—35, 1992.
`
`Steinberg et al., “DeXtromethorphan Alters Cerebral Blood
`FloW and Protects Against Cerebral Injury FolloWing Focal
`Ischemia,” Neuroscience Letters, 133:225—228, 1991.
`Meldrum et al., “EXcitatory Amino Acid NeurotoXicity and
`Neurodegenerative Disease,” TiPS, 11:379—387, 1990.
`Willetts et al., “The Behavioral Pharmacology of NMDA
`Receptor Antagonists,” TiPS, 11:423—428, 1990.
`“Percutaneous Absorption,” edited by R. Bronaugh et al.,
`2”’ Ed., Contents, 1989.
`Mayer et al., “Sites of Antagonist Action on N—Methyl—
`D—Aspartic Acid Receptors Studied Using Fluctuation
`Analysis and a Rapid Perfusion Technique,” Journal of
`Neurophysiology, 60(2):645—663, 1988.
`Thurkauf et al., “Synthesis, Absolute Con?guration, and
`Molecular Modeling Study of EtoXadrol, a Potent Phencyc
`lidine—Like Agonist,” J. Med. Chem., 31:2257—2263, 1988.
`G. Eccleston, “Emulsions,” Encyclopedia of Pharmaceutical
`Technology, edited by J. SWarbrick et al., 5:137—189, 1988.
`J. Dohner, “Development of Processes and Equipment for
`Rate—Controlled Transdermal Therapeutic Systems,” Trans
`dermal Controlled Systemic Medications, edited by Y.
`Chien, pp 349—364,1987.
`H. Wolff et al., “Development of Processes and Technology
`for Adhesive—Type Transdermal Therapeutic Systems,”
`Transdermal Controlled Systemic Medications, edited by Y.
`Chien, pp 365—378, 1987.
`D. Bova et al., “Product Development and Technology
`Transfer for Transdermal Therapeutic Systems,” Transder
`mal Controlled Systemic Medications, edited by Y. Chien,
`pp 379-396, 1987.
`A. Jacobson et al., “Enantiomeric and Diastereomeric
`DioXadrols: Behavioral, Biochemical and Chemical Deter
`mination of the Con?guration Necessary for Phencyclidine—
`Like Properties,” J. Pharmacol. Exp. T her P,
`243(1):110—117, 1987.
`M. RogaWski, “Therapeutic Potential of EXcitatory Amino
`Acid Antagonists: Channel Blockers and 2,3—benZodiaZ
`epines,” TiPS, 14:325—331, 1993.
`GrimWood et al., “Characterization of the Binding of [3H]
`L—689,560, An Antagonist for the Glycine Site on the
`N—Methyl—D—Aspartate Receptor, to Rat Brain Mem
`branes,” Molecular Pharmacology, 41:923—930, 1992.
`Skolnick et al., “Monoaminergic Involvement in the Phar
`macological Actions of Buspirone,” Br J. Pharmac,
`86:637—644, 1985.
`Wong et al., “A NeW Inhibitor of Norepinephrine Uptake
`Devoid of Affinity for Receptors in Rat Brain,” J. Pharm.
`Exp. Therap., 222(1):61—65, 1982.
`Kinemuchi et al., “Substrate Selectivity of Type A and Type
`B Monoamine OXidase in Rat Brain,” J. Neurochem.,
`35(1):109—115, 1980.
`W. Grif?n, “Classi?cationof Surface—Active Agents by
`HLB,” J. Soc. Cosmet. Chem., 311—326, 1949.
`
`* cited by examiner
`
`Page 2
`
`

`
`US 6,638,981 B2
`
`1
`TOPICAL COMPOSITIONS AND METHODS
`FOR TREATING PAIN
`
`I. FIELD OF THE INVENTION
`
`The present invention relates to methods for treating or
`preventing pain via topical formulations that induce a local
`anesthetic effect When applied to intact skin. The composi
`tions comprise an antidepressant and a N-methyl-D
`aspartate-receptor antagonist.
`
`II. BACKGROUND OF THE INVENTION
`
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`
`Pain results from the noxious stimulation of nerve end
`ings. Nociceptive pain is caused by noxious stimulation of
`nociceptors (e.g., a needle stick or skin pinch), Which then
`transmit impulses over intact neural pathWays to the spinal
`neurons and then to the brain. Neuropathic pain is caused by
`damage to neural structures, such as damage to peripheral
`nerve endings or nociceptors, Which become extremely
`sensitive to stimulation and can generate impulses in the
`absence of stimulation (e.g., herpes Zoster pain after the rash
`has healed). Peripheral nerve damage can lead to pathologi
`cal states Where there is a reduction in pain threshold (i.e.,
`allodynia), an increased response to noxious stimuli
`(hyperalgesia), or an increased response duration (persistent
`pain). GOODMAN & GILMAN’S THE PHARMACO
`LOGICAL BASIS OF THERAPEUTICS 529 (Joel G. Hard
`man et al. eds., 9th ed. 1996); HARRISON’S PRINCIPLES
`OF INTERNAL MEDICINE 53—58 (Anthony S. Fauci et al.
`eds., 14th ed. 1998).
`In contrast to pain treatment With systemic agents, pain
`can be treated locally by topically administering a local
`anesthetic directly to the painful area to block the nocicep
`tive mechanistic pathWay. Local anesthetics prevent the
`generation and conduction of nociceptive nerve impulses.
`Thus, for example, a local anesthetic can be injected intra
`dermally (non-systemic injection Within the skin) or topi
`cally applied at the pain area. Advantages of topical local
`anesthetic administration over systemic administration of
`pain relievers include decrease or preclusion of side effects,
`improved patient compliance, and reversible action (i.e., the
`action can be reversed by removing the anesthetic from the
`application site). TRAN SDERMALAN D TOPICAL DRUG
`DELIVERY SYSTEMS 33—112 (Tapash K. Ghosh et al.
`eds., 1997).
`Avariety of drug classes have local-anesthetic properties
`and can be administered in topical formulations. Traditional
`local anesthetics or sodium-channel blockers, such as
`lidocaine prevent the generation and conduction of nerve
`impulses by decreasing or preventing the large transient
`increase in the permeability of excitable membranes to Na+.
`Other agents With local-anesthetic properties include
`analgesics, such as non-steroidal anti-in?ammatories
`(“NSAIDs”), see, for example, TRANSDERMAL AND
`TOPICAL DRUG DELIVERY SYSTEMS 87—93 (Tapash
`K. Ghosh et al. eds., 1997) and opioids, such as morphine.
`See e.g., US. Pat. No. 5,948,389 (issued Sept. 7, 1999);
`Christoph Stein & Alexander Yassouridis 71 Pain 119
`(1997).
`N-methyl-D-aspartate (“NMDA”) receptor antagonists,
`such as ketamine have local-aesthetic properties and topical
`administration is as an effective neuropathic pain treatment.
`See, for example, US. Pat. No. 5,817,699 (issued Oct. 6,
`1998). In another example, topical administration of anti
`depressant medications, such as amitriptyline, has been
`reported effective for neuropathic pain treatment. See, for
`
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`45
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`50
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`55
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`60
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`65
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`2
`example, US. Pat. No. 6,211,171 (issued Apr. 3, 2001); J.
`SaWynok et al., 82 PAIN 149 (1999). In addition, topical
`administration of a combination of a tricyclic antidepressant
`and an NMDA-receptor antagonist is reported to have
`excellent local-anesthetic properties When topically applied
`and is useful for treatment of neuropathic pain, US. Pat. No.
`6,197,830 (issued Mar. 6, 2001).
`But even though topical local-anesthetic administration to
`intact skin is routinely used to treat minor indications, it has
`not found signi?cant use for treating more severe nocicep
`tive and neuropathic pain because it is dif?cult to get
`signi?cant concentrations through the skin barrier. Because
`of the skin’s drug-permeation resistance, as little as about 1
`percent and usually no more than about 15 percent of a drug
`in a topical formulation is bioavailable (TRANSDERMAL
`AND TOPICAL DRUG DELIVERY SYSTEMS 7 (Tapash
`K. Ghosh et al. eds., 1997)). Another problem With topical
`administration of pain relievers is stability of the composi
`tion. Local-anesthetics emulsion compositions are inher
`ently unstable, and phase separation can occur during ship
`ment and storage. Furthermore, many topical local
`anesthetic compositions suffer from oxidative instability.
`Lecithin compositions are routinely used as bases for topical
`local-aesthetic compositions, but are highly oxidatively
`unstable (AM. PHARM. ASSOC, HANDBOOK OF
`PHARMACEUTICAL EXCIPIENTS 292—294, 292 (Arthur
`H. Kibbe ed., 3rd ed. 2000)). For example, US. Pat. No.
`6,197,830 (issued Mar. 6, 2001) describes a lecithin-based
`composition for topically administering a combination of an
`NMDA-receptor antagonist and a tricyclic antidepressant
`and US. Pat. No. 5,817,699 (issued Oct. 6, 1998) and US.
`Pat. No. 6,017,961 (issued Jan. 25, 2000) describe topical
`administration of ketamine in pluronic lecithin organogel.
`In sum, topical local-anesthetic administration has advan
`tages over systemic administration of pain relievers.
`Unfortunately, topical local-anesthetic compositions suffer
`from instability and poor skin-penetration properties, Which
`limit their use to less severe pain. What are needed are stable
`topical local-anesthetic compositions With good skin
`penetration properties. Particularly, stable, skin-penetrating
`compositions comprising a combination of an antidepressant
`and an NMDA-receptor antagonists are needed.
`Citation or identi?cation of any reference in the Back
`ground section of this application is not an admission that
`such reference is prior art to the present invention.
`
`III. SUMMARY OF THE INVENTION
`The invention provides methods and topical compositions
`for treating or preventing pain. The compositions of the
`invention can be topically administered to intact skin to
`provide a local-anesthetic effect thereby treating or prevent
`ing pain, for example, neuropathic pain. In one embodiment,
`the invention provides stable, skin penetrating compositions
`for topical administration comprising a combination of an
`antidepressant and an NMDA-receptor antagonist.
`In a second embodiment, the invention provides an emul
`sion comprising:
`(a) an antidepressant or a pharmaceutically acceptable salt
`thereof;
`(b) an NMDA-receptor antagonists or a pharmaceutically
`acceptable salt thereof;
`(c) a lipophilic component;
`(d) Water; and
`(e) a surfactant, Wherein the emulsion is an oil-in-Water
`emulsion.
`
`Page 3
`
`

`
`US 6,638,981 B2
`
`3
`Preferably, the mean oil-droplet siZe is Within the range of
`about 0.01 microns to about 100 microns, more preferably,
`Within the range of about 0.1 microns to about 10 microns.
`In another embodiment, the invention relates to a patch
`comprising:
`(a) an antidepressant or a pharmaceutically acceptable salt
`thereof;
`(b) an NMDA receptor antagonists or a pharmaceutically
`acceptable salt thereof;
`(c) a lipophilic component;
`(d) Water; and
`(e) a surfactant, Wherein the emulsion is an oil in Water
`emulsion.
`In still another embodiment, the invention provides a
`method of treating or preventing pain in a mammal com
`prising topically administering to the skin of a mammal in
`need thereof an emulsion comprising:
`(a) a therapeutically effective amount of an antidepressant
`or a pharmaceutically acceptable salt thereof;
`(b) a therapeutically effective amount of an NMDA
`receptor antagonists or a pharmaceutically acceptable
`salt thereof;
`(c) a lipophilic component;
`(d) Water; and
`(e) a surfactant,
`Wherein the emulsion is an oil-in-Water emulsion.
`In still another embodiment, the invention relates to a
`method of inducing local anesthesia in a mammal compris
`ing topically administering to the skin of a mammal in need
`thereof an emulsion comprising:
`(a) a therapeutically effective amount of an antidepressant
`or a pharmaceutically acceptable salt thereof;
`(b) a therapeutically effective amount of an NMDA
`receptor antagonists or a pharmaceutically acceptable
`salt thereof,
`(c) a lipophilic component;
`(d) Water; and
`(e) a surfactant,
`Wherein the emulsion is an oil-in-Water emulsion.
`The present invention may be understood more fully by
`reference to the folloWing ?gures, detailed description and
`illustrative examples, Which are intended to exemplify non
`limiting embodiments of the invention.
`
`IV. DEFINITIONS
`
`As used herein, the phrase “composition of the invention”
`refers to an oil-in-Water emulsion having a mean droplet siZe
`Within the range of 0.01 microns to 100 microns comprising:
`(1) a therapeutically effective amount of an
`antidepressant, a pharmaceutically acceptable salts
`thereof, a complex thereof (e.g., hydrates, solvates, and
`clathrates), a prodrug thereof, or any stereoisomeric
`forms or mixtures of stereoisomeric forms thereof (e.g.,
`geometrical isomers, enantiomers, diastereomers,
`racemates, or mixtures thereof);
`(2) a therapeutically effective amount of an NMDA
`receptor antagonists, a pharmaceutically acceptable
`salts thereof, a complex thereof (e.g., hydrates,
`solvates, and clathrates), a prodrug thereof, or any
`stereoisomeric forms or mixtures of stereoisomeric
`forms thereof (e.g., geometrical isomers, enantiomers,
`diastereomers, racemates, or mixtures thereof);
`(3) a lipophilic component;
`
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`(4) Water; and
`(5) a surfactant.
`As used herein, a “therapeutically effective amount” of an
`antidepressant or an NMDA-receptor antagonist means the
`amount of the antidepressant or the NMDA-receptor antago
`nist required in a composition of the invention to induce a
`local-anesthetic effect sufficient to treat or ameliorate pain in
`a mammal.
`As used herein, the term mammal means any mammal, for
`example, but not limited to humans; pets, such as dogs and
`cats; farm mammals, such as horses, coWs, pigs, and sheep;
`and laboratory animals, such as monkeys, guinea pigs, rats,
`and mice. Preferably, a “mammal” is a human.
`As used herein, the term “intradermal administration”
`means administration of a pharmaceutical to the skin of a
`mammal, preferably a human, to deliver the pharmaceutical
`to the local tissue under and around the site of administra
`tion. Preferably, intradermal administration is effected With
`out absorption of the pharmaceutical into the mammal’s
`blood stream. The purpose of intradermal administration is
`to elicit a local affect in contrast to transdermal administra
`tion Where the objective is to transfer the pharmaceutical
`through the skin and into the blood stream for a systemic
`effect.
`As used herein, the term “topical administration” or
`“topical delivery” means intradermal administration of a
`pharmaceutical by administration of the pharmaceutical or a
`composition comprising the pharmaceutical to intact skin.
`For example, by rubbing a composition of the invention onto
`an area of intact skin or by placing an intradermal patch
`comprising a composition of the invention onto an area of
`intact skin.
`The term “topical composition” means a pharmaceutical
`composition designed for topical administration and con
`taining a pharmaceutical.
`As used herein, the phrase “intradermally-acceptable”
`means any pharmaceutical, excipient or other component of
`a topical formulation that is safe or approved for intradermal
`or topical administration in mammals.
`The phrase “pharmaceutically acceptable salt(s),” as used
`herein includes, but is not limited to, salts of acidic or basic
`groups that may be present in the compounds of the inven
`tion. Compounds of the invention that are basic in nature are
`capable of forming a Wide variety of salts With various
`inorganic and organic acids. The acids that may be used to
`prepare pharmaceutically acceptable salts of such basic
`compounds are those that form salts comprising pharmaco
`logically acceptable anions including, but not limited to,
`acetate, benZenesulfonate, benZoate, bicarbonate, bitartrate,
`bromide, calcium edetate, camsylate, carbonate, chloride,
`bromide, iodide, citrate, dihydrochloride, edetate, edisylate,
`estolate, esylate, fumarate, gluceptate, gluconate, glutamate,
`glycollylarsanilate, hexylresorcinate, hydrabamine,
`hydroxynaphthoate, isethionate, lactate, lactobionate,
`malate, maleate, mandelate, mesylate, methylsulfate,
`muscate, napsylate, nitrate, panthothenate, phosphate/
`diphosphate, polygalacturonate, salicylate, stearate,
`succinate, sulfate, tannate, tartrate, teoclate, triethiodide, and
`pamoate (i.e., 1,1‘-methylene-bis-(2-hydroxy-3
`naphthoate)). Compounds of the invention that include an
`amino moiety also can form pharmaceutically acceptable
`salts With various amino acids, in addition to the acids
`mentioned above. Compounds of the invention that are
`acidic in nature are capable of forming base salts With
`various pharmacologically acceptable cations. Examples of
`such salts include alkali metal or alkaline earth metal salts
`and, particularly, calcium, magnesium, sodium, lithium,
`Zinc, potassium, and iron salts.
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`US 6,638,981 B2
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`5
`As used herein, the term “solvate” means a compound of
`the invention or a salt thereof, that further includes a
`stoichiometric or non-stoichiometric amount of a solvent
`bound by non-covalent intermolecular forces. Preferred sol
`vents are volatile, non-toxic, and/or acceptable for topical
`administration to humans.
`As used herein, the term “hydrate” means a compound of
`the invention or a salt thereof, that further includes a
`stoichiometric or non-stoichiometric amount of Water bound
`by non-covalent intermolecular forces.
`The term “clathrate” means a compound of the invention
`or a salt thereof in the form of a crystal lattice that contains
`spaces (e.g., channels) that have a guest molecule (e.g., a
`solvent or Water) trapped Within.
`The term “prodrug” refers to a compound that, following
`administration in a mammal, converts, via a
`biotransformation, into an antidepressant or an NMDA
`receptor antagonist in vivo. Prodrugs can be synthesiZed
`using Well-knoWn methods, such as those described by 1
`BURGER’S MEDICINAL CHEMISTRY AND DRUG
`20
`DISCOVERY, 172—178, 949—982 (Manfred E. Wolff ed.,
`5th ed. 1995).
`As used herein, an “emulsion” means a dispersed system
`containing at lease tWo immiscible phases (a lipophilic
`phase and a hydrophilic or aqueous phase), Wherein one
`immiscible phase is dispersed Within the other in the form of
`droplets. Emulsions are thermodynamically unstable as a
`result of excess free energy associated With the surface of the
`droplet. A stable emulsion must contain at least three
`components, i.e., a dispersion medium, a dispersed phase,
`and an emulsifying agent. As used herein, a “oil-in-Water
`type emulsion” is a stable emulsion in Which the aqueous
`phase is the dispersion medium and the lipophilic compo
`nent is the dispersed phase. Several tests are available to
`determine Whether an emulsion is an oil-in-Water type
`emulsion or a Water-in-oil type emulsion: for example, the
`dilution test, the conductivity test, and the dye solubility test,
`Which tests are described in 1 REMINGTON: THE SCI
`ENCE AND PRACTICE OF PHARMACY 282—291
`(Alfonso R. Gennaro ed., 19th ed. 1995), hereby expressly
`incorporated herein by reference.
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`V. DETAILED DESCRIPTION OF THE
`INVENTION
`The compositions of the invention comprise an antide
`pressant and an NMDA-receptor antagonist in a colloidal
`dispersion (emulsion). The colloidal dispersion comprises
`an aqueous phase, a lipophilic phase, and a surfactant
`system, Wherein the lipophilic phase is dispersed Within the
`aqueous phase (oil-in-Water emulsion) and the mean-droplet
`siZe is Within the range of about 0.01 microns to about 100
`microns, preferably about 0.1 microns to 10 about microns.
`In a preferred embodiment, the compositions of the inven
`tion further comprise a stiffening agent and a hydrophobic
`surfactant. When topically administered to a mammal, the
`compositions of the invention can deliver a combination of
`an antidepressant and an NMDA-receptor antagonist
`through intact skin at a high ?ux rate to induce local
`anesthesia and thereby treat, ameliorate, or prevent neuro
`pathic pain. Furthermore, the compositions of the invention
`are stable both physically (resists coalescing of droplets and
`OstWald ripening) and chemically stable (e.g., resist
`oxidation) and impart a soothing feeling When administered.
`A. Pain Indications
`The compositions and methods of the invention can be
`used to treat or prevent any indication resulting from nox
`ious stimulation of peripheral nociceptors. The compositions
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`6
`and methods of the invention are effective to induce local
`anesthesia and to treat neuropathic pain. As used herein the
`term “neuropathic pain” refers to neuropathic-pain
`syndromes, that is, pain due to lesions or dysfunction in the
`nervous system. The compositions and methods of the
`invention can be used to treat or prevent pain related to or
`induced by the folloWing diseases, trauma, or conditions:
`general neuropathic conditions, such as peripheral
`neuropathy, phantom pain, re?ex-sympathetic dystrophy,
`causalgia, syringomyelia, and painful scar; speci?c neural
`gias at any location of the body; back pain; diabetic neur
`opathy; alcoholic neuropathy; metabolic neuropathy;
`in?ammatory neuropathy; chemotherapy-induced
`neuropathy, herpetic neuralgias; traumatic odontalgia; endo
`dontic odontalgia; thoracic-outlet syndrome; cervical,
`thoracic, or lumbar radiculopathies With nerve compression;
`cancer With nerve invasion; traumatic-avulsion injuries;
`mastectomy, thoracotomy pain; spinal-cord-injury; stroke;
`abdominal-cutaneous nerve entrapments; tumors of neural
`tissues; arachnoiditis; stump pain; ?bromyalgia; regional
`sprains or strains; myofascial pain; psoriatic arthropathy;
`polyarteritis nodosa; osteomyelitis; bums involving nerve
`damage; AIDS-related pain syndromes; connective tissue
`disorders, such as systemic lupus erythematosis, systemic
`sclerosis, polymyositis, and dermatomyositis; and in?am
`matory conditions, such as acute in?ammation (e.g. trauma,
`surgery and infection) or chronic in?ammation (e.g., arthri
`tis and gout).
`B. Antidepressants
`The term “antidepressant” means any compound or com
`position knoWn or to be discovered that, When tested accord
`ing to standard in vivo or in vitro assays, displays receptor
`binding properties or other mechanistic properties
`associated With the clinically approved antidepressants or
`any compound or composition knoWn or to be discovered
`that has demonstrated clinical efficacy in treating depression
`in mammals including those compounds and compositions
`that have been approved for treating depression in humans.
`Classes of antidepressant agents include norepinephrine
`reuptake inhibitors (NRIs”), selective-serotonin-reuptake
`inhibitors (SSRIs), monoamine-oxidase inhibitors (MAOIs),
`serotonin-and-noradrenaline-reuptake inhibitors (“SNFIs);
`corticotropin-releasing factor (CRF) antagonists,
`ot-adrenoreceptor antagonists; NK1-receptor antagonists,
`5-HTlA-receptor agonist, antagonists, and partial agonists,
`atypical antidepressants, and other antidepressants.
`An antidepressant can contain one or more chiral centers
`and/or double bonds and, therefore, exist as stereoisomers,
`such as double-bond isomers (i.e., geometric isomers),
`enantiomers, or diastereomers. As used herein, the term
`“antidepressant” encompass all such enantiomers and
`stereoisomers, that is, both the stereomerically-pure form
`(e.g., geometrically pure, enantiomerically pure, or diaste
`reomerically pure) and enantiomeric and stereoisomeric
`mixtures, e.g., racemates. The term “antidepressant” further
`encompasses all pharmaceutically acceptable salts, all com
`plexes (e.g., hydrates, solvates, and clathrates), and all
`prodrugs of antidepressants.
`Notably, the methods of the invention involve topical
`administration, thus “antidepressants” unsuitable for sys
`temic administration in mammals, because of toxicity or
`otherWise, may still be suitable for topical administration in
`combination With an NMDA-receptor antagonist according
`to the compositions and methods of the invention. Antide
`pressants suitable for use in the invention can be identi?ed
`by testing antidepressant compounds for local-anesthetic
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`Page 5
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`US 6,638,981 B2
`
`7
`and peripheral antinociceptive properties according to stan
`dard pain models. See, for example, J. SaWynok et al., 82
`PAIN 149 (1999); J. SaWynok et al., 80 PAIN 45 (1999),
`both of Which citations are hereby expressly incorporated by
`reference herein.
`Preferably an antidepressant is a norepinephrine-reuptake
`inhibitor, more preferably, a tricyclic antidepressant, most
`preferably, amitriptyline, even more preferably amitriptyline
`hydrochloride.
`1. Norepinephrine-reuptake Inhibitors
`The term “antidepressant” as used herein includes com
`pounds that When administered systemically in a mammal,
`inhibit norepinephrine-reuptake (“norepinephrine-reuptake
`inhibitors”) or that When tested according to standard in vivo
`or in vitro assays, display receptor-binding properties or
`other mechanistic properties associated With
`norepinephrine-reuptake inhibitors. One of skill in the art
`can readily identify norepinephrine-reuptake inhibitors by in
`vivo and in vitro assays. For example, norepinephrine
`reuptake inhibitors can be identi?ed by adapting the in vitro
`test method described by Wong et al., 61 J. PHARM. EXP.
`THERAP. 222 (1982); P. Skolnick et al., 86 BR. J. PHAR
`MACOLOGY 637—644 (1985), hereby expressly incorpo
`rated herein by reference. Examples of norepinephrine
`reuptake inhibitors include, but are not limited to
`amitriptyline, desmethylamitriptyline, clomipramine,
`doxepin, imipramine, imipramine-oxide, trimipramine;
`adinaZolam, amiltriptylinoxide, amoxapine, desipramine,
`maprotiline, nortriptyline, protriptyline, amineptine,
`butri