Ulllted States Patent [19]
`Ulllted States Patent
`[19]
`Kennedy
`Kennedy
`
`[54] PHARMACEUTICAL COMPOSITIONS
`[54] PHARMACEUTICAL COMPOSITIONS
`CONTAINING ALKYLARYL POLYETHER
`CONTAINING ALKYLARYL POLYETHER
`ALCOHOL POLYMER
`ALCOHOL POLYMER
`
`[75] Inventor: Thomas P. Kennedy, Richmond, Va.
`[75]
`Inventor: Thomas P. Kennedy, Richmond, Va.
`
`[ * ] Notice:
`[*] Notice:
`
`[731 Assignee? Charlmite'Mecklenburg Hospital
`[73] A55ignee3 Ch3rl0“e'MeCklenb“rg Hospital
`Auth0nty> Charlotte> N~C~
`A“th0rity> Char10tte> N0
`This patent issued on a Continued prOS_
`This patent issued on a continued pros-
`ecution application filed under 37 CFR
`ecution application ?led under 37 CFR
`1.53(d), and is subject to the twenty year
`1.53(d), and is subject to the tWenty year
`patent
`term provisions of 35 U.S.C.
`patent term provisions of 35 U.S.C.
`154(a)(2).
`154(a)(2).
`
`[21] Appl' No’: 09/210’032
`[21] Appl' NO‘: 09/210’032
`[22]
`Filed;
`Dec, 11, 1998
`[22]
`Ffled;
`[)ec_ 11, 1993
`
`Related U.S. Application Data
`Related US. Application Data
`
`[60] Division of application No. 08/638,893, Apr. 25, 1996, Pat.
`[60] Division of application No. 08/638,893, Apr. 25, 1996, Pat.
`No. 5,849,263, which is a continuation-in-part of application
`No. 5,849,263, which is a continuation—in—part of application
`No. 08/299,316, Aug. 31, 1994, Pat. No. 5,512,270, which
`NO. 08/299,316, Aug. 31, 1994, Pat. NO. 5,512,270, which
`is a continuation—in—part of application No. 08/039,732, Mar.
`is a continuation-in-part of application No. 08/039,732, Mar.
`30, 1993, abandoned.
`30, 1993, abandoned.
`
`[51]
`Int. Cl.7 ........................... A61K 9/12; A61K 31/765
`[51] Int. Cl. ......................... .. A61K 9/12, A61K 31/765
`
`7
`
`.
`
`[52] U.S. Cl.
`.............................................................. .. 424/45
`[52] US. Cl. .............................................................. .. 424/45
`[58] Field of Search .................................. .. 424/45, 78.05,
`[58] Field of Search .................................. .. 424/45, 78.05,
`424/78.06’ 78.08’ 7837; 514/179’ 885’
`424N806, 7808, 7837; 514/179, 885,
`887
`
`887
`
`[56]
`[56]
`
`References Cited
`References Cited
`
`US. PATENT DOCUMENTS
`U~S~ PATENT DOCUMENTS
`2,454,541
`11/1948 Bock et al.
`.
`2,454,541 11/1948 Bock 6181..
`3,272,700
`9/1966 Shupe .................................... .. 514/535
`3,272,700
`9/1966 Shupe .................................... .. 514/535
`3,553,230
`5/1972 saw 6] a1.
`.
`3,663,230
`5/1972 Sato 6181..
`
`(List continued on next page.)
`(List continued on neXt page.)
`FOREIGN PATENT DOCUMENTS
`FOREIGN PATENT DOCUMENTS
`0571670 12/1993 European Pat. Off.
`.
`0571670 12/1993 European Pat. Off. .
`0780127 6/1997 European Pat. Off. .
`0780127
`6/1997 European Pat. Off.
`.
`WO9422425
`10/1994 WIPO .
`WO9422425 10/1994 WIPO .
`WO9511669
`5/1995 WIPO .
`WO9511669 5/1995 WIPO .
`WO9630028 10/1996 WIPO .
`WO9630028 10/1996 WIPO .
`
`US006165445A
`US006165445A
`[11] Patent Number:
`[11] Patent Number:
`[45] Date of Patent:
`[45] Date of Patent:
`
`6,165,445
`6,165,445
`*Dec. 26, 2000
`*Dec. 26, 2000
`
`OTHER PUBLICATIONS
`OTHER PUBLICATIONS
`
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`Harold N. Glassman, Hemolytic Activity Of Some Nonionic
`Surface—Active Agents, Science, vol. III, Jun. 23, 1950, pp.
`Sf —At' A tS'
`1111] .231950 .
`6:523:59 C We gen S’ clence’ V0
`’ un
`’
`’ pp
`688_689
`
`Oliver H. LoWry, Nira J. Rosebaugh, A Lewis Farr and Rose
`Oliver H. Lowry, Nira J. Rosebaugh, A Lewis Farr and Rose
`J. Randall, Protein Measurement With The Folin Phenol
`J. Randall, Protein Measurement With The Folin Phenol
`R
`t]
`lOB'l ' lCh '[
`1.1931951
`Reagent, Journal Of Biological Chemistry, vol. 193, 1951,
`pgagzglz7osuma f 10 oglca
`emls ry’ V0
`’
`’
`pp. 265 275'
`'
`'
`M. V. Pimm and R.W. Baldwin, Influence Of ICRF 159 and
`M. V. Pimm and R.W. Baldwin, In?uence Of ICRF 159 and
`Triton WR 1339 On Metastases Of ARat Epithelioma, The
`Triton WR 1339 On Metastases Of ARat Epithelioma, The
`British Journal Of Cancer, vol. 31, No. 1, Jan. 1975, pp.
`British Journal Of Cancer, vol. 31, No. 1, Jan. 1975, pp.
`62-67.
`62—67.
`Kunihisa Hashimoto, Senji Miura and Chigashi Suzuki,
`Kunihisa Hashimoto, Senji Miura and Chigashi Suzuki,
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`Antimetastatic Effect Of Triton WR 1339, a Nonionic Deter-
`gent, On Rat Ascites Tumors, The Tohoku Journal Of
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`Experimental Medicine, vol. 128, No. 3, Jul. 1979, pp.
`Experimental Medicine, vol. 128, No. 3, Jul. 1979, pp.
`259-265.
`259—265.
`
`t
`d
`t-
`L- t
`d
`.
`L.
`( 15‘ °°““““" 0“ “ext Page)
`( 15 Con “1116 on “ex Page)
`
`Primary Examiner—Robert H. Harrison
`Primary Examiner—Robert H. Harrison
`Attorney) Agent) or Firm_A1St0n & Bird LLP
`Attorney) Agent) Or Firm ilston & Bird LLP
`
`.
`
`.
`
`.
`
`ABSTRACT
`[57]
`ABSTRACT
`[57]
`.t.
`1
`1 h
`t.
`.d d
`.
`Th
`There is provided novel pharmaceutical compositions con-
`~ere 1s prov1 e nove p armaceu ica composi lOIlS con
`taming tyloXapol as the active ingredient. These formula
`taining tyloxapol as the active ingredient. These formula-
`tions comprise tyloxapol at concentrations above 0.125%,
`tions comprise tyloXapol at concentrations above 0.125%,
`preferably from about 0.25% to about 5.0%. In addition, the
`preferably from about 0.25% to about 5.0%. In .a[1d1I10I1, the
`invention encompasses pharmaceutical compositions having
`invention encompasses pharmaceutical compositions having
`reduced hypertonicity Which compositions comprise tyloX
`reduced hypertonicity which compositions comprise tyloX-
`apol in pharmaceutically acceptable solutions Without sig
`apol in pharmaceutically acceptable solutions without sig-
`ni?cant concentrations of hypertonic agents or other active
`¥11fiCaH}C0HC€Htfat10HS Of hYP§Tt0U1C ag€HtS.0r. Other aCt1V€
`ingredients NaHCO3, or active phospholipids, such as
`ingredients NaHCO3, or active phospholipids, such as
`DPPC. The less hypertonic formulations allow one to derive
`DPPC. The less hypertonic formulations alloW one to derive
`all the benefits of the active ingredient tyloxapol, such as its
`all the bene?ts of the active ingredient tyloXapol, such as its
`reduced toxicity and enhanced half-life, while avoiding or
`reduced toxicity and enhanced half-life, While avoiding or
`reducing side effects, such as bronchospasms, associated
`reducing side effects, such as bronchospasms, associated
`with the various hypertonic agents or other active ingredient
`With the various hypertonic agents or other active ingredient
`agents
`agents.
`'
`
`9 Claims, 8 Drawing Sheets
`9 Claims, 8 Drawing Sheets
`
`l
`.5O
`IOO ]
`LO
`910 e
`
`8.0 -
`
`5 7.0 -
`:>
`8 6o _
`$0 '
`g? 5.0
`i i 4.0 -
`‘j
`__1 5:)
`
`><
`
`
`
`SALLCYLATEPRODUCTpM/mlx|02
`
`\
`
`05‘E3888£35'325I1III1IJ1
`
`_
`
`3.0
`
`2.0 *
`
`l.O -
`
`O
`
`T
`
`II
`
`2,5 DIHYDROXYBENZOIC ACID
`D 2,5 DIHYDROXYBENZOIC ACID
`Q 2,3 DIHYDROXBENZOIC ACID
`E 2,3 DIHYUR’OXBENZOIC ACID
`
`
`
`&\\X\\\\\\N
`
`§E
`mI”Ern
`
`TYLOXAPOLTYLOXAPOLTYLOXAPOL
`TYLOXAPOLTYLOXAPOL
`|.Omg/ml
`l0.0mg/ml
`0.|mg/ml
`|.Omg/ ml IQOmg/ ml
`
`Petitioner |nnoPharma EX 1092
`|PR2015—OO902
`
`|PR2015-00903
`
`Page 1
`
`

`
`6,165,445
`Page 2
`
`US. PATENT DOCUMENTS
`
`8/1977 Beyler et al. .
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`5/1989 Clements ................................ .. 514/78
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`7/1990 Ammann .
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`5/1992 Clements .
`5,110,806
`7/1992 Lichtenberger .
`5,134,129
`9/1992 Liversidge et al. .
`5,145,684
`5,259,963 11/1993 Wiedemann .
`5,362,758 11/1994 Ahmed .................................. .. 514/777
`5,399,363
`3/1995 Liversidge et al. .
`5,474,760 12/1995 Ghio et al. .
`5,512,270
`4/1996 Ghio et al. .
`5,576,311 11/1996 Guy .
`5,747,001
`5/1998 Wiedmann et al. .
`5,770,585
`6/1998 Kaufman et al. .
`5,830,436 11/1998 Ghio et al. .............................. .. 424/45
`5,840,277 11/1998 Ghio et al. .
`424/45
`5,849,263 12/1998 Kennedy
`.... .. 424/45
`6,024,940
`2/2000 Ghio et al. .
`424/45
`6,037,328
`3/2000 Hu et al. ................................. .. 514/23
`
`OTHER PUBLICATIONS
`
`Robert A. Floyd, Julia J. Watson and Peter K. Wong,
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`Robert A. Floyd, Julia J. Watson and Peter K. Wong, Use Of
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`2, 1986, pp. 13—18.
`M.F. McCarty, An Antithrombotic Role For Nutritional
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`Eiko Kondo and Koomi Kanai, Triton WR—1339 As A
`Biological—Response Modi?er In Mycobacterial Infection,
`Japan Journal Medical Science Biology, vol. 39, 1986, pp.
`35—47.
`Sadis Matalon, Bruce A. Holm and Robert H. Notter,
`Mitigation Of Pulmonary Hyperoxic Injury By Administra
`tion Of Exogenous Surfactant, American Physiological
`Society, 1987, pp. 756—761.
`Robert A. GreenWald, Determination Of HOC1 Production
`By Micloperoxidase, CRC Handbook Of Methods For Oxy
`gen Radical Research, 1987, p. 300.
`W.H. Tooley, J .A. Clements, K. Muramatsu, C.L. BroWn and
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`Rabbits Treated With ASynthetic Surfactant,Am Rev Respir
`Dis, Sep. 1987, pp. 651—656.
`Robert H. Notter, Biophysical Behavior Of Lung Surfactant:
`Implications For Respiratory Physiology And Pathophysi
`ology, Seminars In Perinatology, vol. 12, No. 3, Jul. 1988,
`pp. 180—212.
`R. Randall Baker, Bruce A. Hom, Peter C. Panus and Sadis
`Matalon, Development Of O2 Tolerance In Rabbits With No
`Increase In Antioxidant Enzymes, American Physiological
`Society, 1989, pp. 1679—1684.
`
`Barry HalliWell and John M.C. Gutteridge, Role Of Free
`Radicals And Catalytic Metal Ions In Human Disease: An
`OvervieW, Methods In Enzymology, vol. 186, 1990, pp.
`1—83.
`Michael I. Lethem, Stuart L. James and Christopher Marri
`ott, The Role Of Mucous Glycoproteins In The Rheologic
`Properties Of Cystic Fibrosis Sputum, Am Rev Respir Dis,
`1990, pp. 1053—1058.
`H. Wiseman, M. Cannon, H.R. Arnstein and DJ. BarloW,
`The Structural Mimicry Of Membrane Sterols By Tamox
`ifen: Evidence From Cholesterol Coef?cients And Molecu
`lar—Modelling For Its Action As A Membrane Anti—Oxidant
`And An Anti—Cancer Agent, Biochim—Biophys—Acta., Mar.
`20, 1992, pp. 197—202.
`AndreW J. Ghio, Thomas P. Kennedy, A. Richard Whorton,
`Alvin L. Crumbliss, Gary E. Hatch and John R. Hoidal, Role
`Of Surface Complexed Iron In Oxidant Generation And
`Lung In?ammation Induced By Silicates,American Journal
`Of Physiology, Lung Cellular And Molecular Physiology 7,
`vol. 263, Jun. 29, 1992, pp. L511—L518.
`H. Wiseman, C. Smith, B. HalliWell, M. Cannon, H.R.
`Arnstein and MS. Lennard, Droloxifene (3—Hydroxytamox
`ifen) Has Membrane Antioxidant Ability: Potential Rel
`evance To Its Mechanism Of Therapeutic Actions In Breast
`Cancer, Cancer—Lett., Sep. 14, 1992, pp. 61—68.
`Hong—Suk Kim, Soon—Kyu Chung and Jin Jung, Reevalu
`ation Of The Effect Of Triton X—100 On The Assay Of
`Superoxide Radical By The NitrobluetertaZolium Reduction
`Method, Hanguk Nonghwahak Hoechi (J. Korean Agric.
`Chem. Soc.), 1993, pp. 364—369.
`Correspondence from Carolann W. Hootan, Department Of
`Health & Human Services, regarding Alevaire, dated May
`27, 1994, including brochure of Alevaire® dated Nov. 1965.
`André Cantin and Donald E. Woods, Protection By Antibi
`otics Against Myeloperxiodase—Dependent Cytotoxicity To
`Lung Epithelial Cells In Vitro, J. Clin. Invest., vol. 91, Jan.
`1993, pp. 38—45.
`OkeZie I. Aruoma, Deoxyribose Assay For Detecting
`Hydroxyl Radicals, Methods In Enzymology, vol. 233, 1994,
`pp. 57—82.
`AndreW J. Ghio, Philip J. Fracica, Stephen L. Young and
`Claude A. Piantadosi, Synthetic Surfactant Scavenges Oxi
`dants And Protects Against Hyperoxic Lung Injury, Journal
`OfApplied Physiology, vol. 77, 1994, pp. 1217—1223.
`Carol A. Vasconcellos, Phillip G. Allen, Mary Ellen Wohl,
`Jeffrey M. DraZen, Paul A. J anmey and Thomas P. Stoesel,
`Reduction In Viscosity Of Cystic Fibrosis Sputum In Vitro
`By Gelsolin, Science, vol. 263, Feb. 16, 1994, pp. 969—971.
`Henry J. Fuchs, M.D., Drucy S. BoroWitZ, M.D., David H.
`Christiansen, Dr. P.H., EdWard M. Morris, Pharm.D., Martha
`L. Nash, R.N., Boonie W. Ramsey, M.D., Beryl J. Rosen
`stein, M.D., Arnold I. Smith, MD. and Mary Ellen Wohl,
`M.D., Effect Of AerosoliZed Recombinant Human DNase
`On Exacerbations Of Respiratory Symptoms And On Pul
`monary Function In Patients With Cystic Fibrosis, The New
`England Journal OfMedicine, vol. 331, No. 10, Sep. 1994,
`pp. 637—642.
`Bonnie W. Ramsey, M.D., Henry L. Dorrin, M.D., Jay D.
`Eisenberg, M.D., Ronald L. Gibson, M.D., Ph.D., Evan R.
`HarWood, M.D., Richard M. KravitZ, M.D., Daniel V. Scrid
`loW, M.D., Robert W. Wilmott, M.D., Susan J. Astley, Ph.D.,
`Mary Ann McBurne, M.S., Kim WentZ, M.D., MPH, and
`Arnold I. Smith, M.D., Ef?cacy Of AerosoliZed Tobramycin
`In Patients With Cystic Fibrosis, The New England Journal
`OfMedicine, vol. 328, No. 24, pp. 1740—1746.
`
`Page 2
`
`

`
`6,165,445
`Page 3
`
`1 995,
`Stof?iste”,
`“PharmaZeutische
`Abdata
`Pharma—Daten—Service, Eschborn/Taunus
`XP00203775
`“TyloXapol”—pp. 87—88.
`Internal Search Report Application No. PCT/US 97/ 06862.
`Rossi, Die Moderne Behandlung Der Mucoviscidose (Zys
`tische Pankreas?brose), Deutsche Med. Wochenschr, vol.
`95, No. 42, pp. 2133—2135, (1970).
`Rudnik, Behandlungsergebnisse Von MucovisZidosekran
`ken Kindern In Einem Sanatorium, Z. Erkrank. Atm. Org.,
`vol. 139, No. 2—3, pp. 117—120, (1974).
`Thomassen, Regulation Of Human Alveolar Macrophage
`In?ammatory Cytokines By TyloXapol: A Component Of
`The Synthetic Surfactant EXosurf, Clin. Immonol. Immuno
`pathol., vol. 77, No. 2, pp. 201—205, (Nov. 1995).
`
`Dr. J .W. Cornforth, Dr. P. D’Arcy Hart, R.J.W. Rees and J .A.
`Stock, Antituberculous effect Of Certain Surface—Active
`PolyoXyethylene Ethers In Mice, Nature, vol. 168, Jul. 28,
`1951, pp. 150—153.
`Maurice L. Tainter, M.D., Frederick C. Nachod, Ph.D. and
`Joseph G. Bird, M.D., Alevaire As A Mucolytic Agent, The
`New England Journal OfMea'icine, vol. 253, Nov. 3, 1995,
`pp. 764—767.
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`An Aerosol Detergent In Chronic Bronchitis, The Lancet,
`Mar. 23, 1957, pp. 611—613.
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`parative Study Of Alevaire And A NeW Mucolytic Agent,
`Acumist In Postoperative Patients, The Eye, Ear; Nose and
`Throat Monthly, vol. 49, Jul. 1970, pp. 321—324.
`
`Page 3
`
`

`
`U.S. Patent
`
`Dec. 26,2000
`
`Sheet 1 0f8
`
`6,165,445
`
`nlv. 9 8 7 6 5 4 3 2 l
`N9 x E52“.
`
`
`
`580% 536.3%
`
`7 q _ _ _ _ _ A _ _
`
`o o. o. o. o. o. o. 0. o. o. o
`
`_ /////////////////////mm
`
`I/////////////Wm.
`
`W W _
`___ Zééw.
`
`m + mm
`
`FIG. I.
`
`Page 4
`
`

`
`U.S. Patent
`
`Dec. 26,2000
`
`Sheet 2 of8
`
`6,165,445
`
` _.|
`
`.
`3
`§l‘0
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`
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`LUNG WEIGHT RATIOS (WET/DRY)
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`
`«.5
`L1.
`
`Page 5
`
`Page 5
`
`

`
`U.S. Patent
`
`Dec. 26,2000
`
`Sheet 3 0f8
`
`6,165,445
`
`|0.0 —
`
`9.0 -
`
`8.0 —
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`
`NORMAL TYLOXAPOL TYLOXAPOL
`SAUNE
`AND CETYL
`ALCOHOL
`
`FIG. 4.
`
`Page 6
`
`

`
`U.S. Patent
`
`Dec. 26,2000
`
`Sheet 4 0f8
`
`6,165,445
`
`2/
`goiso-
`%
`“gO.25—
`T % T
`EOZO-
`/____ 7 % 7/
`25015-
`322;: y % % %
`
`?gé-iéfALlNE
`
`TYL?|zl(g?|€tATlg£g| N E
`
`TYLOXAPQL
`
`E50T
`
`IO 0
`
`
`
`\\\\\\\\\\\\\\\\ \.
`
`/ T %
`
`SALINE/
`SALINE
`FIG. 5B.
`
`HOCl/
`SALINE/
`SALINE
`TYLOXAPOL
`INSTILLATIONS
`
`
`
`\\\\\\ '.
`
`HOCI/
`TYLOXAPOL
`
`Page 7
`
`

`
`U.S. Patent
`
`Dec. 26,2000
`
`Sheet 5 0f8
`
`6,165,445
`
`1'“ “On
`I lL-1B
`lL-1B+Tyloxapol
`' H202
`_‘|H202+TyIoxa_-po|
`Competition
`
`>
`1
`l
`-L
`
`Page 8
`
`

`
`U.S. Patent
`
`Dec. 26,2000
`
`Sheet 6 0f8
`
`6,165,445
`
`0.00\
`
`PERCETW MAXIMAL RELEASE OF lL-8
`
`Page 9
`
`

`
`U.S. Patent
`
`Dec. 26,2000
`
`Sheet 7 of8
`
`6,165,445
`
`
`mmwmmmwmmmmoA.mmwmmmwmwmmoam8-
`
`..._z._.<h._m_.__8BG.FF
`
`
`
`W
`
`l.OOO
`
`Page 10
`
`
`
`

`
`U.S. Patent
`
`Dec. 26,2000
`
`Sheet 8 0f8
`
`6,165,445
`
`0%
`
`L000
`
`2%
`
`V/
`
`0. I00
`QOlO
`TYLOXAPOL (mg/ ml)
`
`FIG. 8E.
`
`OOOI
`
`Page 11
`
`

`
`1
`PHARMACEUTICAL COMPOSITIONS
`CONTAINING ALKYLARYL POLYETHER
`ALCOHOL POLYMER
`
`6,165,445
`
`CROSS-REFERENCE TO RELATED
`APPLICATIONS
`
`This application is a divisional of US. patent application
`Ser. No. 08/638,893 ?led Apr. 25, 1996, now US. Pat. No.
`5,849,263 Which is a Continuation-in-Part of US. applica
`tion Ser. No. 08/299,316, ?led Aug. 31, 1994 now US. Pat.
`No. 5,512,270 and noW alloWed; Which is a Continuation
`in-Part of US. application Ser. No. 08/039,732, ?led Mar.
`30, 1993, noW abandoned.
`
`BACKGROUND OF THE INVENTION
`
`1. Field of the Invention
`The present invention relates to pharmaceutical compo
`sitions containing a alkylaryl polyether alcohol polymer.
`More speci?cally, the present invention relates to pharma
`ceutical compositions containing alkylaryl polyether alcohol
`polymer tyloxapol and to methods for treating respiratory
`in?ammation With the pharmaceutical compositions.
`2. The Prior Art
`Discussion Of Oxidant-Mediated Injury
`Oxygen is life-giving to aerobic plants and animals Who
`depend on it for energy metabolism. It can also be lethal to
`those same organisms When it is altered from its stable
`dioxygen (O2) state to any one of three partially reduced
`species: a) the one electron reduced form superoxide anion
`(02-); b) the tWo electron reduced form hydrogen peroxide
`(H202); or the deadly three electron reduced form the
`hydroxyl radical
`In biologic systems 02' and H202
`are metabolic byproducts of a host of enZymes (oxygenases)
`that use oxygen as a cofactor. H2O2 is also produced from
`O; by the enZymatic action of superoxide dismutases.
`HoWever, 'OH is generally produced only When O2“ and
`H202 interact With transitional ions of metals such as iron
`and copper in dangerous cyclical redox reactions:
`
`The above reactions are termed the superoxide-driven
`Fenton reaction common in biological systems. The Fenton
`reaction can also be initiated by other reducing substances
`such as ascorbate in the presence of ferric iron and H202.
`While '02- and H202 are each toxic for biological
`systems, 'OH (and its alternate hypothesiZed form the ferryl
`intermediate FeO2+) is a highly reactive species that can
`oxidiZe unsaturated membrane lipids, damage cellular pro
`teins and cause mutagenic strand breaks in DNA. To prevent
`injury from partially reduced O2 species under normal
`conditions, cells have evolved an elaborate system of anti
`oxidant enZymes (superoxide dismutase, catalase, glu
`tathione peroxidase) and antioxidant molecules (glutathione,
`alpha-tocopherol, beta carotene). HoWever, When produc
`tion of partially reduced O2 species exceeds the capacity of
`cellular antioxidant defenses to contain them, oxidant injury
`occurs.
`AgroWing number of mammalian disease entities are noW
`thought to be related to overproduction of partially reduced
`O2 species, including the reperfusion injury syndromes
`myocardial infarction and stroke, adult respiratory distress
`syndrome, oxygen toxicity of the lung, lung injury from
`asbestos, Parkinson’s disease, thermal and solar burns of the
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`skin, and injury to the gastrointestinal tract from nonsteroi
`dal anti-in?ammatory agents (see Table IV, page 60, Halli
`Well B and Gutteridge J M C. Methods in Enzymology
`(1990) 186:1—85). Treatment of these conditions is increas
`ingly directed either toWard strategies that prevent enZy
`matic production of partially reduced O2 species and to the
`introduction of exogenous antioxidant compounds that
`restore oxidant-antioxidant balance in biologic and chemical
`systems. More recently, as Will be outlined beloW, treatment
`of in?ammation in many of these conditions has been
`directed toWard interrupting activation of the transcription
`factors mediating the genetic expression of pro
`in?ammatory cytokines important in the pathogenesis of
`these conditions.
`Discussion Of Transcription Factors And Cytokines
`Transcription factors are cellular proteins that bind to
`regulatory sequences of genes and increase or decrease the
`rate of gene transcription. By affecting the rate of gene
`transcription, transcription factors play a critical role in
`regulation of cell function during health and disease. Among
`the most important transcription factors in disease are those
`that regulate expression of the genes for pro-in?ammatory
`cytokines. These cytokines are secreted cellular proteins that
`dramatically affect the behavior of other cells. As examples,
`the cytokine TNF-ot causes Weight loss in patients With
`tumors or chronic infections, produces cellular death and is
`thought to be an important mediator of septic shock. The
`cytokine IL-1[3 mediates fever, and shares many of the
`properties of TNF. The cytokine IL-8 (and its close relatives
`such as RANTES) is a potent chemotactic signal aiding in
`the recruitment of in?ammatory cells such as neutrophils.
`GM-CSF signals the bone marroW to produce more in?am
`matory cells, activates those cells once produced and length
`ens their survival. These cytokines play important roles in
`mediating the pathogenesis of such in?ammatory diseases as
`cystic ?brosis, chronic bronchitis, asthma and viral
`infections, among many others (T. L. Bon?eld, et al.
`“In?ammatory cytokines in cystic ?brosis lungs”. American
`Journal ofRespiratory and Critical Care Medicine (1996) In
`Press; N. G. McElvaney, et al. “Modulation of airWay
`in?ammation in cystic ?brosis. In vivo suppression of
`interleukin-8 levels on the respiratory epithelial surface by
`aerosoliZation of recombinant secretory leukoprotease
`inhibitor”. Journal of Clinical Investigation (1992)
`90:1296—1301; K. D. Pfeffer, et al. “Expression and regu
`lation of tumor necrosis factor in macrophages from cystic
`?brosis patients”. American Journal of Respiratory, Cell
`and Molecular Biology (1993) 9:511—519; G. Williams and
`B. P. Giroir. “Regulation of cytokine gene expression:
`Tumor necrosis factor, interleukin-1, and the emerging biol
`ogy of cytokine receptors”. New Horizons (1995)
`3:276—287; C. A. Dinarello. “Role of interleukin-1 and
`tumor necrosis factor in systemic responses to infection and
`in?ammation”. In In?ammation: Basic Principles and C lini
`cal Correlates, second edition. J. I Gallin, I. M. Goldstein,
`and R. Snyderman, editors. Raven Press, Ltd., NeW York
`(1992) p. 211—232; W. C. Greene. “The interleukins”. In
`In?ammation: Basic Principles and Clinical Correlates,
`second edition. J. I. Gallin, I. M. Goldstein, and R.
`Snyderman, editors. Raven Press, Ltd., NeW York (1992) p.
`233—245; M. Baggiolini, et al. “Interleukin-8 and related
`chemotactic cytokines”. In In?ammation: Basic Principles
`and Clinical Correlates, second edition. J. I. Gallin, I. M.
`Goldstein, and R. Snyderman, editors. Raven Press, Ltd.,
`NeW York (1992) p. 247—263; D. W. Golde and G. C.
`BaldWin. “Myeloid groWth factors”. In In?ammation: Basic
`Principles and Clinical Correlates, second edition. J. I.
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`Page 12
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`6,165,445
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`Gallin, I. M. Goldstein, and R. Snyderman, editors. Raven
`Press, Ltd., NeW York (1992) p. 291—301; R. J. HorWitZ and
`W. W. Busse. “In?ammation and asthma”. Clinics in Chest
`Medicine (1995) 16:583—602).
`These cytokines share regulation of their expression by
`the transcription factor Nuclear Factor kappa-B (NF-KB), a
`particularly important transcription factor mediating in?am
`matory events (U. Siebenlist, G. GranZuso and R. BroWn.
`“Structure, regulation and function of NF-KB”. Annual
`Review of Cell Biology (1994) 10:405—455). NF-KB is also
`an important transcriptional regulator chemokines such as
`RANTES (U. Siebenlist, G. GranZuso and R. BroWn.
`“Structure, regulation and function of NF-KB”. Annual
`Review of Cell Biology (1994) 10:405—455) and of inducible
`nitric oxide synthase (iNOS) (P. J. Nelson, et al. “Genomic
`organisation and transcriptional regulation of the RANTES
`chemokine gene”. Journal of Immunology (1993)
`151:2601—2612), the enZyme producing nitric oxide (NO), a
`critical oxidant chemical produced as part of the pathogen
`esis of septic shock. NF-KB is present in the cytoplasm in an
`inactive form complexed to an inhibitory protein IKB. A
`number of events, yet to be completely characterized, cause
`IKB to dissociate from NF-KB in the cytoplasm. Free NF-KB
`then localiZes to the nucleus, Where it binds to a speci?c KB
`recognition site in the promoter region of target genes,
`prompting their expression. NF-KB is activated by a number
`of stimuli, including cytokines themselves, and by
`lipopolysaccharide (LPS) (U. Siebenlist, G. GranZuso and R.
`BroWn. “Structure, regulation and function of NF-KB”.
`AnnualReview of Cell Biology (1994) 10:405—455). NF-KB
`is also activated by oxidants such as hydrogen peroxide (M.
`Meyer, R. Schreck, and P. A. Baeverie. “H202 and antioxi
`dants have opposite effects on the activation of NF-KB and
`AP-1 in intact cells: AP-1 as secondary antioxidant response
`factor”. EMBO Journal (1993) 12:2005—2015), suggesting
`that it may be an oxidant-stress responsive transcription
`factor. Conversely, some of the most potent inhibitors of
`NF-KB activation are compounds Which can also act as
`antioxidants. A feW, but not most, antioxidants prevent
`activation of NF-KB by LPS, prevent increases in corre
`sponding messenger RNAs for in?ammatory cytokines and
`decrease levels of TNF and IL-1 in the circulation folloWing
`LPS injection
`M. Eugui, et al. “Some antioxidants
`inhibit, in a coordinate fashion, the production of tumor
`necrosis factor 0t, IL-1[3 and IL-6 by human peripheral blood
`mononuclear cells”. International Journal of Immunology
`(1993) 6:409—422; R. Schreck, et al. “Dithiocarbamates as
`potent inhibitors of nuclear factor KB activation in intact
`cells”. Journal of Experimental Medicine (1992)
`175:1181—1194). HoWever, the feW antioxidants knoWn to
`inhibit NF-KB activation share no common structural simi
`larity distinguishing them from those antioxidants that fail to
`prevent activation of NF-KB (see Eugui, above), preventing
`one skilled in the art from predicting Which antioxidant
`compounds Will and Which Will not favorably reduce NF-KB
`activation as a strategy of ameliorating in?ammatory events
`in disease.
`Another class of compounds knoWn to inhibit NF-KB
`activation are anti-in?ammatory corticosteroids. Corticos
`teroids act by combining in the cytoplasm With an intracel
`lular protein called the Glucocorticoid Receptor (GR).
`Previously, the anti-in?ammatory action of corticosteroids
`Was thought to occur exclusively as a result of passage of the
`GR-steroid complex to the nucleus, Where the complex
`attaches to and in?uences regulatory gene regions called
`Glucocorticoid Responsive Elements (GREs). HoWever,
`recently it has been shoWn that a major mechanism of
`
`4
`anti-in?ammatory glucocorticoid activity is inhibition of
`NF-KB (I. M. Adcock, et al. “Effects of glucocorticoids on
`transcription factor activation in human peripheral blood
`mononuclear cells”. American Journal ofPhysiology (1995)
`268(Cell Physiology 37):C331—C338). The GR-steroid com
`plex prevents activation of NF-KB by directly interacting
`With free NF-KB in the cytoplasm, preventing NF-KB from
`translocating to the nucleus (A. Ray and K. E. Prefontaine.
`“Physical association and functional antagonism betWeen
`the p65 subunit of transcription factor NF-KB and the
`glucocorticoid receptor”. Proceedings of the National Acad
`emy of Sciences, USA (1994) 91:752—756). HoWever, the
`GR-steroid complex accomplishes inhibition of NF-KB by
`mutual repression. By combining With free NF-KB in the
`cytoplasm, it too is kept from translocating to the nucleus to
`up-regulate other anti-in?ammatory events. Indeed, mutual
`repression is thought to explain in part the phenomenon of
`steroid resistance in severe asthmatics. IL-1, IL-6, TNF and
`other pro-in?ammatory cytokines secreted in the airWay
`during an asthma attack increase cellular activation of
`NF-KB, providing more NF-KB subunits to bind GR-steroid
`complexes, reducing the amount of GR-steroid complex
`available to translocate to the nucleus (P. J. Barnes, A. P.
`Greening and G. K. Crompton. “Glucocorticoid resistance in
`asthma”.American Journal ofRespiratory and Critical Care
`Medicine (1995) 152:S125—S142).
`Discussion Of Alkylaryl Polyether Alcohol Polymers,
`Including Tyloxapol
`Antioxidants are compounds that can be easily oxidiZed to
`stable chemical forms. They can protect chemical and bio
`logic systems by sacri?cing themselves to oxidation in
`preference to oxidation of critically important chemical and
`biological molecules. Not all oxidiZable compounds can
`perform antioxidant function. To successfully protect chemi
`cal and biologic systems from oxidants, the antioxidant must
`have a higher reactivity for the oxidant than the chemical or
`biologic molecule Which it seeks to protect. To protect the
`desired chemical and biologic system from oxidation, it is
`also necessary for the antioxidant to partition itself adjacent
`to the molecule to be protected. As an example, a molecule
`to be protected Within the lipid bilayer of plasma, endosomal
`or nuclear membranes might be best protected by an anti
`oxidant With, at least in part, a lipophilic structure, so that it
`is partitioned to or near the lipid portion of the membrane,
`adjacent to the molecule needing protection from oxidation.
`It has recently been shoWn that a previously knoWn class
`of drugs, the alkylaryl polyether alcohol polymers, are
`potent antioxidants useful in the treatment of mammalian
`diseases (US. Pat. No. 5,474,760 issued 1995 to Ghio,
`Kennedy and Piantadosi, assignors to Duke University, and
`US. Ser. No. 08/039/732). Alkylaryl polyether alcohol
`polymers are used commercially as surface active detergents
`and Wetting agents (US. Pat. No. 2,454,541, issued in 1948
`to Bock and Rainey, assignors to Rohm & Haas). The best
`knoWn of this class is tyloxapol, a polymer of 4-(1,1,3,3
`tetramethylbutyl)phenol With formaldehyde and oxirane.
`HoWever, other compounds in the class, sharing the prop
`erties of tyloxapol, are Well knoWn in the art (J. W.
`Cornforth, et al. “Antituberculous effect of certain surface
`active polyoxyethylene ethers in mice”. Nature (1951)
`168:150—153).
`On alkylaryl polyether alcohol polymer used previously
`in aerosol pharmacologic formulations is tyloxapol, or Tri
`ton WR-1339 (M. L. Tainter, et al. “Alevaire as a mucolytic
`agent”. New England Journal of Medicine (1955)
`253:764—767). A composition sold by Winthrop Laborato
`ries (a division of Sterling Drug, Inc.) and by Breon Labo
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`ratories (subsidiary of Sterling Drug, Inc.) under the trade
`mark ALEVAIRE®, containing 0.125% aqueous
`SUPERINONE® (brand of tyloxapol) in combination With
`2% sodium bicarbonate and 5% glycerin, had been marketed
`for about 30 years for treatment of mucous secretions in
`patients With diseases and disorders such as chronic
`bronchitis, croup, pertussis, and poliomyelitis. (See, for
`example, a product brochure entitled “ALEVAIRE® Deter
`gent Aerosol for Inhalation” (November, 1961) distributed
`by Breon Laboratories.).
`At the time the ALEVAIRE formulation neW drug appli
`cation (NDA) Was approved in the early 1950’s, the Federal
`Food, Drug, and Cosmetic Act (FDA Act) did not require
`FDA to consider ef?cacy in the drug approval process. In
`1962, the FDAAct Was amended to require FDA to consider
`ef?cacy, and to authoriZe the agency to remove from the
`market drugs With approved NDAs if substantial evidence
`Was lacking that the drug Was ineffective for its intended use.
`To comply With the latter legislative mandate, FDA estab
`lished the Drug Ef?cacy Study Implementation (DESI)
`revieW. ALEVAIRE Was considered in the DESI revieW, and
`Was found to be ineffective. In July of 1968, FDA noti?ed its
`sponsor, Sterling Drug. Sterling appealed the FDA’s ?nd
`ings (Sterling Drug, Inc., v. Weinberger; 503F.2d 675 (2d Cir.
`1974), 384 F. Supp. 675 (S.D.N.Y. 1974), and 509 F.2d 1236
`(2d