USOO8748402B2 (12) United States Patent (10) Patent No.: US 8,748,402 B2 Abelson et al. (45) Date of Patent: *Jun. 10, 2014 (54) OPHTHALMIC FORMULATIONS AND USES 6,117,907 A 9, 2000 Sher THEREOF 6.432,934 B1 8, 2002 Gilbard 6,465,506 B2 10/2002 Abelson et al. 6,482,799 B1 1 1/2002 Tusé et al. (75) Inventors: Mark Abelson, Andover, MA (US); 6,599,891 B2 7/2003 North et al. Kirk McMullin, Villa Park, CA (US); 6,624, 193 B1 9/2003 Naka et al. Angel Padilla, Aliso Viejo, CA (US) 6,646,001 B2 11/2003 Hellberg et al. 6,699,493 B2 3/2004 Wong (73) Assignee: Bausch & Lomb Pharma Holdings 2004/0072809 A1 4/2004 Demopulos et al. Corp.,s Rochester,s NY (US) 2.93. A 3: ShayarkarSO et al. 2007,0254.841 A1 11/2007 Ousler et al. (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 FOREIGN PATENT DOCUMENTS U.S.C. 154(b) by 59 days. This patent is Subject to a terminal dis WO WO O2/49614 6, 2002 claimer. OTHER PUBLICATIONS (21) Appl. No.: 13/369,452 Tsubotaetal (Progress in Retinal and Eye Research vol. 17. No.4, pp. 565 to 596, 1998).* 1-1. International Search Report and Written Opinion issued by the World (22) Filed: Feb. 9, 2012 Intellectual Property Office, dated Dec. 20, 2006. (65) Prior Publication Data station Ety, rt Patentability issued by the World Intellectual Property Office, dated Oct. 30, 2007. US 2012/O195972 A1 Aug. 2, 2012 WWW.Ou.edureSearchWNN Built electronbmZals 3. uters.html.A PEast from http:// O O The Roberts Lab Group, SB (Sodium Borate) Buffer, 20x, printed Related U.S. Application Data from http://mmadisplay.usc.edu/lab? protocols/perfsb-Sodium (63) Continuation-in-part of application No. 1 1/146,652, borate-buffer-20x on May 22, 2010. filed on Jun. 7, 2005, now Pat. No. 8,372,814. www.teknova.com, 10x Borate Saline Buffer, printed from http:// www.teknova.com/product-p/b0230.htm May 22, 2010. (60) Provisional application No. 60/675,179, filed on Apr. Tananuvatet al. Controlled Study of the Use of Autologous Serum in 26, 2005, provisional application No. 60/577.567, Dry Eye Patients, Cornea vol. 20, No. 8 (2001), pp. 802-806. filed on Jun. 7, 2004. Engel et al. “Effectiveness of Specific Antibiotic/Steroid Combina tions for Therapy of Experimental Pseudomonas aerugionos (51) Int. Cl. Keratitis' Current Eye Research, vol. 4. No. 3 (1995) pp. 229-234. AOIN 43/04 (2006.01) Van Haeringen, "Clinical Biochemistry of Tears' Survey of A6 IK3I/70 (2006.01) Ophthamology, vol. 26, No. 2 (1991), pp. 84-96. (52) st (2006.01) * cited by examiner CPC ........................................ A61K 9/48 (2013.01) Primary Examiner — Benjamin Packard USPC ............................................. 514/40: 514/178 (74) Attorney, Agent, or Firm — Thompson Hine LLP (58) Field of Classification Search CPC ........................................................ A61 K9/48 (57) ABSTRACT USPC .................................................... 514/40, 178 See application file for complete search history Provided by the present invention are compositions or formu lations Suitable for application to a patient’s eyes which ulti (56) References Cited lizes a topical ophthalmically-acceptable formulation com prising a therapeutically-effective amount of an U.S. PATENT DOCUMENTS ophthalmically-active antimicrobial agent, and an ophthalmi cally-active anti-inflammatory or steroidal agent in combina 4,134,403 A 1/1979 Johnson et al. tion with physiologic levels of serum electrolytes in an oph 4,315,024 A 2f1982 Abelson 4,981,871 A 1/1991 Abelson thalmic formulation for the treatment of changes in the 5,290,781 A 3/1994 Espino et al. normal eye condition. The invention also includes methods of 5,340,572 A 8, 1994 Patel et al. treating patients having an ophthalmic disease, injury or 5,403,598 A 4/1995 Becket al. disorder, utilizing the compositions or formulations. Also 5,407,669 A 4/1995 Lindstrom et al. provided are kits comprising the compositions or formula 5,475,034 A 12/1995 Yanni et al. 5,624,893 A 4, 1997 Yanni tions and a means of applying the compositions or formula 5,767,105 A 6/1998 Peyman tion to the patient’s eyes. 5,811,446 A 9, 1998 Thomas 5,929, 111 A 7, 1999 Conrow et al. 32 Claims, No Drawings US 8,748,402 B2 1. 2 OPHTHALMC FORMULATIONS AND USES 85 to about 150 mg/L, and bicarbonate in a concentration THEREOF from about 1281 to about 2013 mg/L. The antimicrobial agent, and anti-inflammatory or steroi CROSS-REFERENCES TO RELATED dal agent of the composition or formulation are used to treat APPLICATIONS or mitigate the injury, disease or disorder. One steroidal agent contemplated in the present invention is prednisolone This application is a continuation in part of co-pending whereas a contemplated antimicrobial is tobramycin. application Ser. No. 1 1/146,652, filed Jun. 7, 2005, which The invention also includes methods of treating patients claims priority from U.S. Provisional Patent Applications having an ophthalmic disease, injury or disorder, utilizing the 60/577.567 filed Jun. 7, 2004, and 60/675,179 filed Apr. 26, 10 compositions or formulations. Further, the compositions or 2005, each of which is expressly incorporated by reference formulations can be utilized to restore the normal condition of the eye when the normal condition has been disrupted or herein in its entirety. changed. Also provided are kits comprising the compositions BACKGROUND OF THE INVENTION or formulations and a means of applying the compositions or 15 formulation to the patient’s eyes. The present invention relates to ophthalmic formulations, kits and uses thereof, wherein the formulations utilize physi DESCRIPTION OF THE INVENTION ologic levels of serum electrolytes in conjunction with phar Without being bound by a particular theory, it appears that macologically effective doses of an antimicrobial agent, and the physiology of the injured or diseased eye more closely an anti-inflammatory or steroidal agent in a single formula resembles the physiology of serum due to the release of vessel tion for the treatment of ocular disorders, diseases or injuries. contents into the tear film and, as Such, the contents are Combinations or formulations containing an antimicrobial pathological to the condition of the eye. Therefore, the appli agent and an anti-inflammatory agent are available in the cation of an ophthalmic formulation that mimics the injured ophthalmic art. However, there are concerns and expressed 25 eye condition is a focus of the present invention, since the reservations in the ophthalmic community about the safety application of such a formulation does not shock the already and efficacy of Such prior art combinations. There continues overly-sensitized tissues and is able to gradually restore the to be a need for an effective and safe topical ophthalmic eye to a normal condition (i.e. non-inflamed and non-infected pharmaceutical composition of a steroid oranti-inflammatory state). Such an approach is counterintuitive to conventional agent and a broad spectrum antibiotic which, when adminis 30 therapies, since physicians presently would not use a formu tered to the eye will not inhibit the activity of the antibiotic, or lation that continues the pathologic condition within the eye. steroidal or anti-inflammatory components. Nevertheless, it is important to consider that the addition of a Many ophthalmic conditions result in an aberrant tear film formulation with electrolytes in “equilibrium' with the elec composition. The electrolyte balances and concentrations in trolytes in the “inflamed eye may provide several advantages tears can change as a result of a disruption in the normal eye 35 when used in conjunction with an antimicrobial and a steroi physiology. For example, when ocular tissue is inflamed, dal or anti-inflammatory agent. Such advantages could serum components leak from the vasculature into the tear include, but are not necessarily limited to, a formulation that film. Many of these ophthalmic conditions are typically is more comfortable to the patient which may result in better treated with antimicrobial and/or steroidal or anti-inflamma patient compliance and/or a formulation that promotes faster tory compounds. 40 healing. SUMMARY OF THE INVENTION Definitions The present invention comprises a formulation which “Ophthalmically-acceptable” means that the formulation, mimics the serum components of the injured eye (instead of 45 active agent, excipient or other material is compatible with the normal eye tear physiology) which when used in conjunc ocular tissue; that is, it does not cause significant or undue tion with an antimicrobial, and anti-inflammatory or steroidal detrimental effects when brought into contact with ocular agentina single formulation assistin restoring the injured eye tissue. In some instances, actives and/or excipients of the to its normal condition (i.e., non-inflamed and non-infected formulation may cause some discomfort or stinging in the state). 50 eye; however, those excipients are still considered ophthalmi The present invention utilizes physiologic levels of various cally-acceptable for the purposes of this application. In many serum electrolytes in an ophthalmic composition or formula instances, these irritating components are removed from the tion also containing an antimicrobial agent, and an anti-in formulations for comfort of the patient. For example, polyvi flammatory or steroidal agent for the treatment of various nyl alcohol (PVA) can be eliminated from the formulation ophthalmic injuries, diseases or disorders. Typically, the 55 ingredients. injury, disease or disorder results in an inflammatory response Antimicrobial compound includes those that effectively in and around the eye and/or causes leakage of the blood kill or mitigate the activity of a microbe.