`
`1111111111111111111111111111111111111111111111111111111111111
`US008633162B2
`
`c12) United States Patent
`Acheampong et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 8,633,162 B2
`*Jan.21,2014
`
`(54) METHODS OF PROVIDING THERAPEUTIC
`EFFECTS USING CYCLOSPORIN
`COMPONENTS
`
`(71) Applicant: Allergan, Inc., Irvine, CA (US)
`
`(72)
`
`Inventors: Andrew Acheampong, Irvine, CA (US);
`Diane D. Tang-Liu, Las Vegas, NV
`(US); James N. Chang, Newport Beach,
`CA (US); David F. Power, Hubert, NC
`(US)
`
`(73) Assignee: Allergan, Inc., Irvine, CA (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`
`(21) Appl. No.: 13/967,179
`
`(22) Filed:
`
`Aug. 14, 2013
`
`(65)
`
`Prior Publication Data
`
`US 2013/0338083 Al
`
`Dec. 19, 2013
`
`Related U.S. Application Data
`
`(63) Continuation of application No. 13/961,818, filed on
`Aug. 7, 2013, which is a continuation of application
`No. 11/897,177, filed on Aug. 28, 2007, which is a
`continuation of application No. 10/927,857, filed on
`Aug. 27, 2004, now abandoned.
`
`(60) Provisional application No. 60/503,137, filed on Sep.
`15, 2003.
`
`(51)
`
`(2006.01)
`
`Int. Cl.
`A61K 38113
`(52) U.S. Cl.
`USPC ......................................................... 514/20.5
`(58) Field of Classification Search
`None
`See application file for complete search history.
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3,278,447 A
`4,388,229 A
`4,388,307 A
`4,614,736 A
`4,649,047 A
`4,764,503 A
`4,814,323 A
`4,839,342 A
`4,970,076 A
`4,990,337 A
`4,996,193 A
`5,047,396 A
`5,051,402 A
`5,053,000 A
`5,286,730 A
`5,286,731 A
`5,294,604 A
`
`10/1966 McNicholas
`6/1983 Fu
`6/1983 Cavanak
`9/1986 Delevallee et a!.
`3/1987 Kaswan
`8/1988 Wenger
`3/1989 Andrieu et a!.
`6/1989 Kaswan
`1111990 Horrobin
`2/1991 Kurihara et a!.
`2/1991 Hewitt eta!.
`9/1991 Orban eta!.
`9/1991 Kurihara et a!.
`10/1991 Booth eta!.
`2/1994 Caufield et a!.
`2/1994 Caufield et a!.
`3/1994 Nussenblatt et a!.
`
`5,296,158 A
`5,342,625 A
`5,368,854 A
`5,411,952 A
`5,424,078 A
`5,474,919 A
`5,474,979 A
`5,504,068 A
`5,540,931 A
`5,543,393 A
`5,589,455 A
`5,591,971 A
`5,614,491 A
`5,639,724 A
`5,652,212 A
`5,719,123 A
`5,739,105 A
`5,753,166 A
`5,766,629 A
`5,798,333 A
`5,807,820 A
`5,827,822 A
`5,827,862 A
`5,834,017 A
`5,843,452 A
`5,843,891 A
`5,858,401 A
`5,866,159 A
`5,891,846 A
`
`3/1994 MacGilp et a!.
`8/1994 Hauer eta!.
`1111994 Rennick
`5/1995 Kaswan
`6/1995 Dziabo
`12/1995 Chartrain et a!.
`12/1995 Ding eta!.
`4/1996 Komiya et al.
`7/1996 Hewitt eta!.
`8/1996 Kimet al.
`12/1996 Woo
`111997 Shahar eta!.
`3/1997 Walch eta!.
`6/1997 Cavanak
`7/1997 Cavanak et a!.
`2/1998 Morley eta!.
`4/1998 Kimet al.
`5/1998 Dalton eta!.
`6/1998 Cho eta!.
`8/1998 Sherman
`9/1998 Elias eta!.
`10/1998 Floch'h eta!.
`10/1998 Yamamura
`1111998 Cho eta!.
`12/1998 Wiedmann et a!.
`12/1998 Sherman
`111999 Bhalani et a!.
`2/1999 Hauer eta!.
`4/1999 Ishida eta!.
`(Continued)
`
`FOREIGN PATENT DOCUMENTS
`
`DE
`EP
`
`9/1999
`19810655
`2/1992
`0471293
`(Continued)
`
`OTHER PUBLICATIONS
`
`Abdulrazik, M. eta!, Ocular Delivery of Cyclosporin A II. Effect of
`Submicron Emulsion's Surface Charge on Ocular Distribution of
`Topical CyclosporinA, S.T.P. Pharma Sciences, Dec. 2001,427-432,
`11(6).
`Acheampong, Andrew eta!, Cyclosporine Distribution into the Con(cid:173)
`junctiva, Cornea, Lacrimal Gland and Systemic Blood Following
`Topical Dosing of Cyclosporine to Rabbit, Dog and Human eyes,
`1996, 179.
`Acheampong, Andrew eta!, Cyclosporine Distribution Into the Con(cid:173)
`junctiva, Cornea, Lacrimal Gland, and Systemic Blood Following
`Topical Dosing of Cyclosporine to Rabbit, Dog, and Human Eyes,
`Adv. Exp. Med. Bioi., 1998, 1001-1004,438.
`Acheampong, Andrew eta!, Distribution of Cyclosporin A in Ocular
`Tissues After Topical Administration to Albino Rabbits and Beagle
`Dogs, Current Eye Research, 1999,91-103, 18(2).
`
`(Continued)
`
`Primary Examiner- Marcela M Cordero Garcia
`(74) Attorney, Agent, or Firm- Laura L. Wine; Joel
`German
`
`ABSTRACT
`(57)
`Methods of treating an eye of a human or animal include
`administering to an eye of a human or animal a composition
`in the form of an emulsion including water, a hydrophobic
`component and a cyclosporin component in a therapeutically
`effective amount ofless than 0.1% by weight of the compo(cid:173)
`sition. The weight ratio of the cyclosporin component to the
`hydrophobic component is less than 0.8.
`
`24 Claims, No Drawings
`
`APOTEX 1001, pg. 1
`
`
`
`US 8,633,162 B2
`Page 2
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5,916,589 A
`5,929,030 A
`5,951,971 A
`5,962,014 A
`5,962,017 A
`5,962,019 A
`5,977,066 A
`5,981,479 A
`5,981,607 A
`5,998,365 A
`6,004,566 A
`6,007,840 A
`6,008,191 A
`6,008,192 A
`6,022,852 A
`6,024,978 A
`6,046,163 A
`6,057,289 A
`6,159,933 A
`6,197,335 B1
`6,254,860 B1
`6,254,885 B1
`6,267,985 B1
`6,284,268 B1
`6,294,192 B1
`6,306,825 B1
`6,323,204 B1
`6,346,511 B1
`6,350,442 B2
`6,413,547 B1
`6,420,355 B2
`6,468,968 B2
`6,475,519 B1
`6,486,124 B2
`6,544,953 B2
`6,555,526 B2
`6,562,873 B2
`6,569,463 B2
`6,582,718 B2
`6,656,460 B2
`6,872,705 B2
`6,984,628 B2 *
`7,202,209 B2
`7,276,476 B2
`7,288,520 B2
`7,297,679 B2
`7,501,393 B2
`8,211,855 B2
`8,288,348 B2
`200110003589 A1
`200110014665 A1
`200110036449 A1
`2002/0012680 A1
`2002/0013272 A1
`2002/0016290 A1
`2002/0016292 A1
`2002/0025927 A1
`2002/0045601 A1
`2002/0107183 A1
`2002/0119190 A1
`2002/0165134 A1
`2003/0021816 A1
`2003/0044452 A1
`2003/0055028 A1
`2003/0059470 A1
`2003/0060402 A1
`2003/0087813 A1
`2003/0104992 A1
`2003/0108626 A1
`2003/0109425 A1
`2003/0109426 A1
`2003/0133984 A1
`2003/0143250 A1
`2003/0147954 A1
`2003/0166517 A1
`
`6/1999 Hauer eta!.
`7/1999 Hamiedet a!.
`9/1999 Kawashima et a!.
`10/1999 Hauer eta!.
`10/1999 Hauer eta!.
`10/1999 Cho eta!.
`1111999 Cavanak
`1111999 Ko eta!.
`1111999 Ding eta!.
`12/1999 Sherman
`12/1999 Friedman eta!.
`12/1999 Hauer eta!.
`12/1999 Singh
`12/1999 AI-Razzak et a!.
`212000 Klokkers et a!.
`212000 Hauer eta!.
`4/2000 Stuchlik et al.
`5/2000 Mulye
`12/2000 Sherman
`3/2001 Sherman
`7/2001 Garst
`7/2001 Cho eta!.
`7/2001 Chen eta!.
`9/2001 Mishra eta!.
`9/2001 Patel eta!.
`10/2001 Cavanak
`1112001 Burke
`212002 Singh eta!.
`212002 Garst
`7/2002 Bennett et a!.
`7/2002 Richter et al.
`10/2002 Cavanak et al.
`1112002 Meinzer et al.
`1112002 Olbrich eta!.
`4/2003 Tsuzuki et a!.
`4/2003 Matsuo
`5/2003 Olejnik et al.
`5/2003 Patel eta!.
`6/2003 Kawashima
`12/2003 Benita et al.
`3/2005 Lyons
`112006 Bakhit eta!.
`4/2007 Chang
`10/2007 Chang et al.
`10/2007 Chang et al.
`1112007 Chang
`3/2009 Tien et al.
`7/2012 Chang et al.
`10/2012 Chang et al.
`6/2001 Neuer eta!.
`8/2001 Fischer et al.
`1112001 Garst
`112002 Patel eta!.
`112002 Cavanak et al.
`212002 Floc 'h et al.
`212002 Richter et al.
`212002 Olbrich eta!.
`4/2002 Kawashima
`8/2002 Petszulat et a!.
`8/2002 Meinzer et al.
`1112002 Richter et al.
`112003 Kang eta!.
`3/2003 Ueno
`3/2003 Stergiopoulos et a!.
`3/2003 Muller
`3/2003 Cavanak et al.
`5/2003 Or eta!.
`6/2003 Or eta!.
`6/2003 Benita et al.
`6/2003 Or eta!.
`6/2003 Or eta!.
`7/2003 Ambuhl eta!.
`7/2003 Hauer eta!.
`8/2003 Yang eta!.
`9/2003 Fricker et a!.
`
`2005/0014691 A1
`2005/0059583 A1
`2007/0015691 A1
`2007/0027072 A1
`2007/0087962 A1
`2007/0149447 A1
`2007/0299004 A1
`2008/0039378 A1
`2008/0070834 A1
`2008/0146497 A1
`2008/0207495 A1
`2009/0131307 A1
`2010/0279951 A1
`201110009339 A1
`201110294744 A1
`2012/0270805 A1
`2013/0059796 A1
`
`1/2005 Bakhit eta!.
`3/2005 Acheampong
`1/2007 Chang
`2/2007 Tien eta!.
`4/2007 Tien eta!.
`6/2007 Chang eta!.
`12/2007 Acheampong eta!.
`2/2008 Graham et al.
`3/2008 Chang eta!.
`6/2008 Graham et al.
`8/2008 Graham et al.
`5/2009 Tien eta!.
`1112010 Morgan eta!.
`112011 Schiffman
`12/2011 Morgan eta!.
`10/2012 Chang eta!.
`3/2013 Chang eta!.
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`wo
`
`0547229
`0760237
`95-31211
`00-00179
`01-32142
`01-41671
`02-09667
`02-49603
`03-030834
`03-053405
`
`111993
`3/1997
`1111995
`1/2000
`5/2001
`6/2001
`212002
`6/2002
`4/2003
`7/2003
`
`OTHER PUBLICATIONS
`Akpek, Esen Karamursel et a!, A Randomized Trial of Topical
`0.05%
`in Topical
`Steroid-Resistant Atopic
`Cyclosporin
`Keratoconjunctivitis, Ophthalmology, 2004, 476-482, 111.
`Angelov, 0. et a!, Preclinical Safety Studies of Cyclosporine
`Ophthalmic Emulsion, Adv Exp Med Bioi, 1998,991-995,438.
`Angelov, 0. et a!, Safety Assessment of Cyclosporine Ophthalmic
`Emulsion in Rabbits and Dogs, XIth Congress of the European Soci(cid:173)
`ety of Ophthalmology, 1997, 25-28, 1-5, Soc. Ophthalmol Eur., Hu.
`Ardizzone Sandro et a!, A Practical Guide to the Management of
`Distal Ulceratve Colitis, Drugs, 1998, 519-542, 55(4).
`Banic, Marko et a!, Effect of Cyclosporine in a Murine Model of
`Experimental Colitis, Digestve Diseases and Sciences, Jun. 2002,
`1362-1368, 47(6).
`Bonini, S. et al, Vernal Keratoconjunctivitis, Eye, 2004,345-351, 18.
`Brewster, Marcus et al, Enhanced Delivery of Ganciclovir to the
`Brain Though the Use of Redox Targeting, Antimicrobial Agents and
`Chemotherapy, Apr. 1994, 817-823, 38(4).
`Brewster, Marcus eta!, Intravenous and Oral Pharrnacokinetic Evalu(cid:173)
`ation of a 2-Hydroxypropyl-f:l-cyclodextrin-Based Formulation of
`Carbamazepine in the Dog: Comparison with Commercially Avail(cid:173)
`able Tablets and Suspensions, Journal of Pharmaceutical Sciences,
`Mar. 1997, 335-339, 86(3).
`Brewster, Marcus eta!, Preparation, Characterization, and Anesthetic
`Properties of 2-Hydroxypropyl-f:l-cyclodextrin Complexes of
`Pregnanolone and Pregnenolone in Rat and Mouse, Journal of Phar(cid:173)
`maceutical Sciences, Oct. 1995, 1154-1159, 84(10).
`Brinkmeier, Thomas eta!, Pyodermatitis-Pyostomatitis Vegetans: A
`Clinical Course of Two Decades with Response to Cyclosporine and
`Low-Dose Prednisolone, Acta Derm Venereol, 2001, 134-136, 81.
`Castillo, Jose M. Benitez Del eta!, Influence ofTopical Cyclosporine
`A and Dissolvent on Corneal Epithelium Permeability of Fluores(cid:173)
`cein, Documenta Ophthalmologica, 1995,49-55, 91.
`Cheeks, Lisa eta!, Influence ofVehicle and Anterior Chamber Protein
`Concentration on Cyclosporine Penetration Through the Isolated
`Rabbit Cornea, Current Eye Research, 1992, 641-649, 11(7).
`Database WPI Week 200044, Derwent Pub. Ltd., London, GB; An
`2000-492678 & JP2000/143542, 2000, 2 Pages.
`Ding, Shulin et al, Cyclosporine Ophthalmic 0/W emulsion: Formu(cid:173)
`lation and Emulsion Characterization, Pharm Res, 1997, 1 page, 14
`(11).
`Donnenfeld, Eric D., The Economics ofUsing Restasis, Ophthalmol(cid:173)
`ogy Management, Oct. 2003, 3 pages, US.
`Drosos, A. A. et a!, Efficacy and Safety of Cyclosporine-A Therapy
`for Primary Sjogren's Syndrome, Ter. Arkh., 1998, 77-80, 60(4).
`
`514/20.8
`
`APOTEX 1001, pg. 2
`
`
`
`US 8,633,162 B2
`Page 3
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`Drosos, A.A. et a!, Cyclosporin A Therapy in Patients with Primary
`Sjogren's Syndrome: Results at One Year, Scand J Rheumatology,
`1986, 246-249, 61.
`Eisen, Drore et al, Topical Cyclosporine for Oral Mucosal Disorders,
`J AmAcad Dermatol, Dec. 1990, 1259-1264, 23.
`Epstein, Joel eta!, Topical Cyclosporine in a Bioadhesive for Treat(cid:173)
`ment of Oral Lichenoid Musco sal Reactions, Oral Surg Oral Med
`Oral Pathol Oral, 1996, 532-536, 82.
`Erdmann, S. et a!, Pemphigus Vulgaris Der Mund- Und
`Kehlkopfschleirnhaut Pemphigus Vulgaris of the Oral Mucosa and
`the Larynx, H+G Zeitschrift Fuer Hautkrankheiten, 1997, 283-286,
`72(4).
`FDA Concludes Restasis (Cyclosporine) Not Effective for Dry Eye
`(Jun. 18, 1999). Accessed online at http://www.dryeyeinfo.org/
`Restasis_Cyclosporine.htm on Aug. 14, 2009. 1 Page.
`Gaeta, G.M. eta!, Cyclosporin Bioadhesive Gel in the Topical Treat(cid:173)
`ment of Erosive Oral Lichen Planus, International Journal of
`Immunopathology and Pharmacology, 1994, 125-132, 7(2).
`Gipson, Ilene et a!, Character of Ocular Surface Mucins and Their
`Alteration in Dry Eye Disease, The Ocular Surface, Apr. 2004, 131-
`148, 2(2).
`Gremse, David et a!, Ulcerative Colitis in Children, Pediatr Drugs,
`2002, 807-815, 4(12).
`Gunduz, Kaan et a!, Topical Cyclosporin Treatment of
`Keratoconjunctivitis Sicca in Secondary Sjogren's Syndrome, Acta
`Ophthalmologica, 1994, 438-442, 72.
`http:/ /web.archive.org/web/200 1 030625323/http:/ /www. surfactant.
`co.kr/surfactants/pegester.html, 2001, 6 Pages, retrieved on Jul. 5,
`2008.
`Hunter, P.A. eta!, Cyclosporin A Applied Topically to the Recipient
`Eye Inhibits Corneal Graft Rejection, Clin Exp Immunol, 1981,
`173-177, 45.
`Jumaa, Muhannad eta!, Physicochemical Properties and Hemolytic
`Effect of Different Lipid Emulsion Formulations Using a Mixture of
`Emulsifiers, Pharmaceutica Acta Helvetiae, 1999, 293-301, 73.
`Kanai, A. et a!, The Effect on the Cornea of Alpha Cyclodextrin
`Vehicle for Eye Drops, Transplantation Proceedings, Feb. 1989,
`3150-3152, vol. 21.
`Kanpolat, Ayfer et a!, Penetration of Cyclosporin A into the Rabbit
`Cornea and Aqueous Humor after Topical Drop and Collagen Shield
`Administration, Cornea/External Disease, Apr. 1994, 119-122,
`20(2).
`Kaur, Rabinder et al, Solid Dispersions of Drugs in Polyocyethylene
`40 Stearate: Dissolution Rates and Physico-Chemical Interactions,
`Journal of Pharmacy and Pharmacology, Dec. 1979, 48P.
`Kuwano, Mitsuaki et a!, Cyclosporine A Formulation Affects Its
`Ocular Distribution in Rabbits, Pharmaceutical Research, Jan. 2002,
`108-111' 19( 1 ).
`Lambert Technologies Corp. Material Safety Data Sheet for
`LUMULSE™ POE-40 MS KP, last revision Aug. 22, 2003. 3 pages.
`Leibovitz, Z. et al., Our Experience In Processing Maize (Corn)
`Germ Oil, Journal of the American Oil Chemists Society, Feb. 1983,
`395-399, 80 (2), us.
`Lixin, Xie eta!, Effect ofCyclosporine A Delivery System in Corneal
`Transplantation, Chinese Medical Journal, 2002, 110-113, 115 (1),
`us.
`Lopatin, D.E., Chemical Compositions and Functions of Saliva, Aug.
`24, 2001, 31 Pages.
`Lyons, R.T. eta!, Influence of Three Emulsion Formulation Param(cid:173)
`eters on the Ocular Bioavailability of Cyclosporine A in Albino
`Rabbits, AmAssoc Pharm Sci, 2000, 1 Page, 2(4).
`Pedersen, Anne Marie et a!, Primary Sjogren's Syndrome: Oral
`Aspects on Pathogenesis, Diagnostic Criteria, Clinical Features and
`Approaches for Therapy, Expert Opin Pharma, 2001, 1415-1436,
`2(9).
`Phillips, Thomas et a!, Cyclosporine Has a Direct Effect on the
`Differentiation of a Mucin-Secreting Cell Line, Journal of Cellular
`Physiology, 2000, 400-408, 184.
`
`Present, D.H. et a!, Cyclosporine and Other Immunosuppressive
`Agents: Current and Future Role in the Treatment of Inflammatory
`Bowel Disease, American Journal of Gastroenterology, 1993, 627-
`630, 88(5).
`Restasis® Product Information Sheet, Allergan, Inc., 2009, 5 Pages.
`Restasis® Increasing Tear Production, Retrieved on Aug. 14, 2009,
`http:/ /www.restasisprofessional.com/ _clinical/clinical_increasing.
`htm 3 pages.
`Robinson, N.A. et a!, Desquamative Gingivitis: A Sign of
`Mucocutaneous Disorders-a Review, Australian Dental Journal,
`2003, 205-211, 48(4).
`Rudinger, J., Characteristics of the Amino Acids as Components of a
`Peptide Hormone Sequence, Peptide Hormones, 1976, 1-7.
`Sail, Kenneth et a!, Two Multicenter, Randomized Studies of the
`Efficacy and Safety ofCyclosporine Ophthalmic Emulsion in Mod(cid:173)
`erate to Severe Dry Eye Disease, Ophthalmology, 2000, 631-639,
`107.
`Sandborn, William eta!, A Placebo-Controlled Trial of Cyclosporine
`Enemas for Mildly to Moderately Active Left-Sided Ulcerative
`Colitis, Gastroenterology, 1994, 1429-1435, 106.
`Sandborn, William eta!, Cyclosporine Enemas for Treatment-Resis(cid:173)
`tant, Mildly to Moderately Active, Left-Sided Ulcerative Colitis,
`American Journal of Gastroenterology, 1993, 640-645, 88(5).
`Schwab, Matthias eta!, Pharmacokinetic Considerations in the Treat(cid:173)
`ment of Inflammatory Bowel Disease, Clin Pharm, 2001,723-751,
`60(10).
`Secchi, Antonio eta!, Topical Use ofCyclosporine in the Treatment
`ofVernal Keratoconjunctivitis, American Journal of Ophthalmology,
`Dec. 1990, 641-645, 110.
`Small, Dave et a!, The Ocular Pharmacokinetics of Cyclosporine in
`Albino Rabbits and Beagle Dogs, Ocular Drug Delivery and Metabo(cid:173)
`lism, 1999, 54.
`Small, David et a!, Blood Concentrations of Cyclosporin A During
`Long-Term Treatment With Cyclosporin A ophthalmic Emulsions in
`Patients with Moderate to Severe Dry Eye Disease, Journal of Ocular
`Pharmacology and Therapeutics, 2002, 411-418, 18( 5).
`Smilek, Dawn eta!, A Single Amino Acid Change in a Myelin Basic
`Protein Peptide Confers the Capacity to Prevent Rather Than Induce
`Experimental Autoimmune Encephalomyelitis, Proc. Nat!. Acad.
`Sci., Nov. 1991, 9633-9637, 88.
`Stephenson, Michelle, The Latest Uses ofRestasis, Review of Oph(cid:173)
`thalmology, Dec. 30, 2005, 7 Pages, US.
`Stevenson, Dara et a!, Efficacy and Safety of Cyclosporin A
`ophthalmic Emulsion in the Treatment of Moderate-to-Severe Dry
`Eye Disease, Ophthalmology, 2000, 967-974, 107.
`Tesavibul, N. eta!, Topical Cyclosporine A (CsA) for Ocular Surface
`Abnormalities in Graft Versus Host Disease Patients, Invest
`Ophthalmol Vis Sci, Feb. 1996, S1026, 37(3).
`The Online Medical Dictionary, Derivative, Analog, Analogue,
`Xerostomia, accessed Jul. 7, 2005 and Jul. 13, 2005, 6 Pages.
`Tibell, A. eta!., CyclosporinA In Fat Emulsion Carriers: Experimen(cid:173)
`tal Studies on Pharmacokinetics and Tissue Distribution, Pharmacol(cid:173)
`ogy & Toxicology, 1995, 115-121, 76, US.
`Tsubota, Kazuo et a!, Use of Topical Cyclosporin A in a Primary
`Sjogren's Syndrome Mouse Model, Invest Ophthalmol Vis Sci, Aug.
`1998, 1551-1559, 39(9).
`Van Der Reijden, Willy et a!, Treatment of Oral Dryness Related
`Complaints (Xerostomia) in Sjogren's Syndrome, Ann Rheum Dis,
`1999, 465-473, 58.
`Winter, T.A. et al, Cyclosporin A Retention Enemas in Refractory
`Distal Ulcerative Colitis and 'Pouchitis', Scand J Gastroenterol,
`1993, 701-704, 28.
`Pending U.S. Appl. No. 13/967,189, filed Aug. 14, 2013.
`Pending U.S. Appl. No. 13/961,818, filed Aug. 7, 2013.
`Pending U.S. Appl. No. 13/961,828, filed Aug. 7, 2013.
`Pending U.S. Appl. No. 13/961,835, filed Aug. 7, 2013.
`Pending U.S. Appl. No. 13/961,808, filed Aug. 7, 2013.
`Pending U.S. Appl. No. 13/967,163, filed Aug. 14, 2013.
`Pending U.S. Appl. No. 13/967,168, filed Aug. 14, 2013.
`U.S. Re-Examination Application: 90/009,944 Filed on Aug. 27,
`2011.
`* cited by examiner
`
`APOTEX 1001, pg. 3
`
`
`
`US 8,633,162 B2
`
`1
`METHODS OF PROVIDING THERAPEUTIC
`EFFECTS USING CYCLOSPORIN
`COMPONENTS
`
`RELATED APPLICATION
`
`2
`weight of cyclosporin A. With cyclosporin A concentrations
`less than 0.2%, the amount of castor oil employed has been
`reduced since one of the functions of the castor oil is to
`solubilize the cyclosporin A. Thus, if reduced amounts of
`cyclosporin are employed, reduced amounts of castor oil are
`needed to provide effective solubilization of cyclosporin A.
`There continues to be a need for providing enhanced meth(cid:173)
`ods of treating ophthalmic or ocular conditions with
`cyclosporin-containing emulsions.
`
`SUMMARY OF THE INVENTION
`
`This application is a continuation of copending U.S. appli(cid:173)
`cation Ser. No. 13/961,818 filed Aug. 7, 2013, which is a
`continuation of copending U.S. application Ser. No. 11/897,
`177, filed Aug. 28, 2007, which is a continuation of U.S. 10
`application Ser. No. 10/927,857, filed Aug. 27, 2004, now
`abandoned, which claimed the benefit of U.S. Provisional
`Application No. 60/503,137 filed Sep. 15, 2003, which are
`incorporated in their entirety herein by reference.
`
`BACKGROUND OF THE INVENTION
`
`The present invention relates to methods of providing
`desired therapeutic effects to humans or animals using com(cid:173)
`positions including cyclosporin components. More particu(cid:173)
`larly, the invention relates to methods including administer(cid:173)
`ing to an eye of a human or animal a therapeutically effective
`amount of a cyclosporin component to provide a desired
`therapeutic effect, preferably a desired ophthalmic or ocular
`therapeutic effect.
`The use of cyclosporin-A and cyclosporinA derivatives to
`treat ophthalmic conditions has been the subject of various
`patents, for example Ding eta! U.S. Pat. No. 5,474,979; Garst
`U.S. Pat. No. 6,254,860; and Garst U.S. Pat. No. 6,350,442,
`this disclosure of each of which is incorporated in its entirely
`herein by reference. In addition, cyclosporinA compositions
`used in treating ophthalmic conditions is the subject of a
`number of publications. Such publications include, for
`example, "Blood concentrations of cyclosporin a during
`long-term treatment with cyclosporin a ophthalmic emul(cid:173)
`sions in patients with moderate to severe dry eye disease,"
`Small etai,JOcul Pharmacal Ther, 2002 October, 18(5):411-
`8; "Distribution of cyclosporin A in ocular tissues after topi(cid:173)
`cal administration to albino rabbits and beagle dogs,"
`Acheampong eta!, Curr Eye Res, 1999 February, 18(2):91-
`103b; "Cyclosporine distribution into the conjunctiva, cor(cid:173)
`nea, lacrimal gland, and systemic blood following topical
`dosing of cyclosporine to rabbit, dog, and human eyes,"
`Acheampong eta!, Adv Exp Med Biol, 1998, 438:1001-4;
`"Preclinical safety studies of cyclosporine ophthalmic emul(cid:173)
`sion," Angelov eta!, Adv Exp Med Biol, 1998, 438:991-5;
`"Cyclosporin & Emulsion & Eye," Stevenson eta!, Ophthal(cid:173)
`mology, 2000 May, 107(5):967-74; and "Two multicenter,
`randomized studies of the efficacy and safety of cyclosporine
`ophthalmic emulsion in moderate to severe dry eye disease.
`CsA Phase 3 Study Group," Sail eta!, Ophthalmology, 2000
`April, 107 ( 4 ): 631-9. Each of these publications is incorpo(cid:173)
`rated m its entirety herein by reference. In addition,
`cyclosporin A-containing oil-in-water emulsions have been
`clinically tested, under conditions of confidentiality, since the
`mid 1990's in order to obtain U.S. Food and Drug Adminis(cid:173)
`tration (FDA) regulatory approval.
`Examples of useful cyclosporin A-containing emulsions
`are setoutinDingetal U.S. Pat. No. 5,474,979. Example 1 of
`this patent shows a series of emulsions in which the ratio of 60
`cyclosporin A to castor oil in each of these compositions was
`0.08 or greater, except for Composition B, which included
`0.2% by weight cyclosporinA and 5% by weight castor oil.
`The Ding et a! patent placed no significance in Composition
`B relative to Compositions A, C and D of Example 1.
`Over time, it has become apparent that cyclosporinA emul(cid:173)
`sions for ophthalmic use preferably have less than 0.2% by
`
`65
`
`New methods of treating a human or animal using
`cyclosporin component-containing emulsions have been dis-
`15 covered. Such methods provide substantial overall efficacy in
`providing desired therapeutic effects. In addition, other
`important benefits are obtained employing the present meth(cid:173)
`ods. For example, patient safety is enhanced. In particular, the
`present methods provide for reduced risks of side effects
`20 and/or drug interactions. Prescribing physicians advanta(cid:173)
`geously have increased flexibility in prescribing such meth(cid:173)
`ods and the compositions useful in such methods, for
`example, because of the reduced risks of harmful side effects
`and/or drug interactions. The present methods can be easily
`25 practiced.
`In short, the present methods provide substantial and
`acceptable overall efficacy, together with other advantages,
`such as increased safety and/or flexibility.
`In one aspect of the present invention, the present methods
`30 comprise administering to an eye of a human or animal a
`composition in the form of an emulsion comprising water, a
`hydrophobic component and a cyclosporin component in a
`therapeutically effective amount ofless than 0.1% by weight
`of the composition. The weight ratio of the cyclosporin com-
`35 ponent to the hydrophobic component is less than 0.08.
`It has been found that the relatively increased amounts of
`hydrophobic component together with relatively reduced, yet
`therapeutically effective, amounts of cyclosporin component
`provide substantial and advantageous benefits. For example,
`40 the overall efficacy of the present compositions, for example
`in treating dry eye disease, is substantially equal to an iden(cid:173)
`tical composition in which the cyclosporin component is
`present in an amount ofO.l% by weight. Further, a relatively
`high concentration of hydrophobic component is believed to
`45 provide for a more quick or rapid breaking down or resolving
`of the emulsion in the eye, which reduces vision distortion
`which may be caused by the presence of the emulsion in the
`eye and/ or facilitates the therapeutic effectiveness of the com(cid:173)
`position. Additionally, and importantly, using reduced
`50 amounts of the active cyclosporin component mitigates
`against undesirable side effects and/or potential drug interac(cid:173)
`tions.
`In short, the present invention provides at least one advan(cid:173)
`tageous benefit, and preferably a plurality of advantageous
`55 benefits.
`The present methods are useful in treating any suitable
`condition which is therapeutically sensitive to or treatable
`with cyclosporin components. Such conditions preferably are
`ophthalmic or ocular conditions, that is relating to or having
`to do with one or more parts of an eye of a human or animal.
`Included among such conditions are, without limitation, dry
`eye syndrome, phacoanaphylactic endophthalmitis, uveitis,
`vernal conjunctivitis, atopic kerapoconjunctivitis, corneal
`graft rejection and the like conditions. The present invention
`is particularly effective in treating dry eye syndrome.
`Employing reduced concentrations of cyclosporin compo(cid:173)
`nent, as in the present invention, is advantageously effective
`
`APOTEX 1001, pg. 4
`
`
`
`US 8,633,162 B2
`
`20
`
`DETAILED DESCRIPTION
`
`3
`4
`positions. For example, components which are effective as
`to provide the blood of the human or animal under treatment
`with reduced concentrations of cyclosporin component, pref(cid:173)
`both emulsifiers and surfactants may be employed, and/or
`erably with substantially no detectable concentration of the
`components which are effective as both polyelectrolyte com(cid:173)
`cyclosporin component. The cyclosporin component concen(cid:173)
`ponents and viscosity
`inducing components may be
`tration of blood can be advantageously measured using a
`employed. The specific composition chosen for use in the
`validated liquid chromatography/mass spectrometry-mass
`present invention advantageously is selected taking into
`spectrometry (VLC/MS-MS) analytical method, such as
`account various factors present in the specific application at
`described elsewhere herein.
`hand, for example, the desired therapeutic effect to be
`In one embodiment, in the present methods the blood of the
`10 achieved, the desired properties of the compositions to be
`human or animal has concentrations of clyclosporin compo(cid:173)
`employed, the sensitivities of the human or animal to whom
`nent of0.1 ng/ml or less.
`the composition is to be administered, and the like factors.
`Any suitable cyclosporin component effective in the
`The presently useful compositions advantageously are
`present methods may be used.
`Cyclosporins are a group of nonpolar cyclic oligopeptides 15 ophthalmically acceptable. A composition, component or
`material is ophthalmically acceptable when it is compatible
`with known immunosuppressant activity. Cyclosporin A,
`with ocular tissue, that is, it does not cause significant or
`along with several other minor metabolites, cyclosporin B
`undue detrimental effects when brought into contact with
`through I, have been identified. In addition, a number of
`ocular tissues.
`synthetic analogs have been prepared.
`Such compositions have pH's within the physiological
`In general, commercially available cyclosporins may con(cid:173)
`range of about 6 to about 10, preferably in a range of about 7.0
`tain a mixture of several individual cyclosporins which all
`to about 8.0 and more preferably in a range of about 7.2 to
`share a cyclic peptide structure consisting of eleven amino
`about 7.6.
`acid residues with a total molecular weight of about 1 ,200, but
`The present methods preferably provide for an administer(cid:173)
`with different substituents or configurations of some of the 25
`ing step comprising topically administering the presently use(cid:173)
`amino acids.
`ful compositions to the eye or eyes of a human or animal.
`The term "cyclosporin component" as used herein is
`Each and every feature described herein, and each and
`intended to include any individual member of the cyclosporin
`every combination of two or more of such features, is
`group and derivatives thereof, as well as mixtures of two or 30
`included within the scope of the present invention provided
`more individual cyclosporins and derivatives thereof.
`that the features included in such a combination are not mutu-
`Particularly preferred cyclosporin components include,
`ally inconsistent.
`without limitation, cyclosporin A, derivatives of cyclosporin
`These and other aspects and advantages of the present
`A and the like and mixtures thereof. Cyclosporin A is an
`35 invention are apparent in the following detailed description,
`especially useful cyclosporin component.
`example and claims.
`Any suitable hydrophobic component may be employed in
`the present invention. Advantageously, the cyclosporin com(cid:173)
`ponent is solubilized in the hydrophobic component. The
`hydrophobic component may be considered as comprising a
`discontinuous phase in the presently useful cyclosporin com-
`ponent-containing emulsions.
`The hydrophobic component preferably is present in the
`emulsion compositions in an amount greater than about
`0.625% by weight. For example, the hydrophobic component
`may be present in an amount of up to about 1.0% by weight or
`about 1.5% by weight or more of the composition.
`Preferably, the hydrophobic component comprises one or
`more oily materials. Examples of useful oil materials include,
`without limitation, vegetable oils, animal oils, mineral oils,
`synthetic oils and the like and mixtures thereof. In a very
`useful embodiment, the hydrophobic component comprises
`one or more higher fatty acid glycerides. Excellent results are
`obtained when the hydrophobic component comprises castor
`oil.
`The presently useful compositions may include one or
`more other components in amounts effective to facilitate the
`usefulness and effectiveness of the compositions. Examples
`of such other components include, without limitation, emul(cid:173)
`sifier components, tonicity components, polyelectrolyte
`components, surfactant components, viscosity inducing com(cid:173)
`ponents, acids and/or bases to adjust the pH of the composi(cid:173)
`tion, buffer components, preservative components and the
`like. Components may be employed which are effective to
`perform two or more functions in the presently useful com-
`
`The present methods are effective for treating an eye of a
`human or animal. Such methods, in general, comprise admin(cid:173)
`istering, preferably topically administering, to an eye of a
`human or animal a cyclosporin component-containing emul(cid:173)
`sion. The emulsion contains water, for example U.S. pure
`water, a hydrophobic component and a cyclosporin compo-
`nent in a therapeutically effective amount ofless than 0.1% by
`weight of the emulsion. In addition, beneficial results have
`been found when the weight ratio of the cyclosporin campo-
`50 nent to the hydrophobic component is less than 0.08.
`As noted above, the present administering step preferably
`includes topically administering the emulsion to the eye of a
`patient of a human or animal. Such administering may
`involve a single use of the presently useful compositions, or
`55 repeated or periodic use of such compositions, for example,
`as required or desired to achieve the therapeutic effect to be
`obtained. The topical administration of the presently useful
`composition may involve providing the composition in the
`form of eye drops or similar form or other form so as to
`60 facilitate such topical administration.
`The present methods have been found to be very effective
`in providing the desired therapeutic effect or effects while, at
`the same time, substantially reducing, or even substantially
`eliminating, side effects which may result from the presence
`65 of the cyclosporin component in the blood of the human or
`animal being treated, and eye irritation which, in the pas