US 20060135609A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0135609 A1 TOOne et al. (43) Pub. Date: Jun. 22, 2006 (54) OPHTHAMOLOGICAL DRUGS Related U.S. Application Data (75) Inventors: Eric J. Toone, Durham, NC (US); (60) Provisional application No. 60/620,320, filed on Oct. David L. Epstein, Bahama, NC (US); 21, 2004. Pratap Challa, Durham, NC (US); Philip W. Snyder, Cambridge, MA Publication Classification (US); Xin Chen, Chapel Hill, NC (US); Mitchell A. deLong, Raleigh, NC (US) (51) Int. Cl. A6II 3L/225 (2006.01) Correspondence Address: (52) U.S. Cl. .............................................................. 514/547 Michael Best & Friedrich LLP Suite 3300 (57) ABSTRACT 100 East Wisconsin Avenue The present invention relates generally to ophthamological drugs. More specifically, the inventon relates to a method of Milwaukee, WI 53202-4108 (US) modifying (derivatizing) ophthamological drugs so as to (73) Assignee: Duke University. Durham, NC increase their penetration through the cornea. The invention also relates to drugs modified (derivatized) in accordance (21) Appl. No.: 11/255,478 with the instant method and to the use of same in treating conditions associated with elevated intraocular pressure, (22) Filed: Oct. 21, 2005 particularly, glaucoma. 15.0 10.0 5. O -- OD (drug) -A-OS (control) Time (hours) Patent Application Publication Jun. 22, 2006 Sheet 1 of 10 US 2006/01 35609 A1 O O V O v ves O CN: Y O O ve O OO O O O Cs V O GN C eue Sequoy effueuo 96 Patent Application Publication Jun. 22, 2006 Sheet 2 of 10 US 2006/01 35609 A1 N v O GN O O V & C eue Sequoy efueuo % Patent Application Publication Jun. 22, 2006 Sheet 3 of 10 US 2006/01 35609 A1 ---NS.. D O S. O) E s C. C. O eue Sequoy efueuo % Patent Application Publication Jun. 22, 2006 Sheet 4 of 10 US 2006/01 35609 A1 ??? (6H uul) Ol Patent Application Publication Jun. 22, 2006 Sheet 5 of 10 US 2006/0135609 A1 SNst 9 d c o ? C u? O C O cy N N v r- O o C c o CO N N N N N N CN N N w wer ve v- ve- wo (6H uu) dOl Patent Application Publication Jun. 22, 2006 Sheet 6 of 10 US 2006/0135609 A1 5-O-Ribitol (2,3-dichloro-4-(thiophene-2-carbonyl)phenoxyacetate O C { Cl OH pH ory O N-N-N-t OH O OH 5 15 O 10 s 5 -5 s E E - -- 0 SS SS N- -10 Y-1 3. 3 -5 -15 -10 -20 -O-anolin -15 -O-anoin -O-tanolin + 10% ticrynafen -o-lanolin + 15% ticrynafen O 20 40 60 80 100 120 140 160 O 20 40 60 80 100 120 140 160 time (hours) time (hours) 10% 15% IOP reduction from baseline, IOP reduction from baseline, mmHg mmHg time control ticrynafen control ticrynafen ---------- - = 4 (n=4) (n 4) baseline 23.6 23.4 21.9 22.2 24 hrs 21.1 (-2.3) 20.6 (-2.8) 22.8 (+0.9) 23.2 (+1.0) 48 hrs 22.4 (-l.2) 21.0 (-2.4) 21.8 (-0.1) 21.0 (-1.2 72 hrs 20.3 (-3.3) 19.9 (-3.5) 20.3 (-1.6) 20.6 (-1.6) 6 days 22.2 (-1.4 22.0 (-1.6) 24.3 (-2.4 23.7 (+1.5) FIG. 6 Patent Application Publication Jun. 22, 2006 Sheet 8 of 10 US 2006/01 35609 A1 5-O-(90.1 lo, 15R)-15-2-Benzo[b]thiophen-2-yl)-16, 17, 18,19,20-pentanor 5,6,13,14-tetrahydro-9,11,15-trihydroxyprostanoylxylitol Cl D oH ÖH S Hd dH 23.0 22.5 0.004% 22.0 IOP reduction from untreated 21.5 control, mmHg 21.0 time (n= 4) 20.5 - W / I O y f -- TTDay 0 -0.3orror-r---------------- 20.0 Day 1 -0.8 Day 2 -1.3 19.5 k Day 3 -1.5 19.0 k Day 5 -0.7 18.5 Day 7 -1.5 -O-- untreated Day 10 -0.1 18.0 -O- + O.O.04% Day 11 -1.0 17.5 Day 12 -0.8 17.0 t Day 14 -0.1 0 2 4 6 10 12 14 Time (days) FIG. 8 Patent Application Publication Jun. 22, 2006 Sheet 9 of 10 US 2006/0135609 A1 l-O-((9o, Ilo, 15R)-15-(2-Benzo(blthiophen-2-yl)- 5 16, 17, 18,19,20-pentanor-5,6,13, 1 4-tetrahydro-9, -0-0.004% -0- 0.02% 11, 15-trihydroxyprostanoyl-11-hydroxy-3,6,9- trioxaundecane HO OH -20 0 20 40 60 80 100 120 time (hours) 0.004% OP 0.02% IOP Change IOP (Change from Baseline), Change IOP (Change from Baseline), from mmHg from mmHg Untreated Untreated Control, Control, mmHg -ms time untreated treated untreated treated (n=4) (n-4) (n=4) (n= 4) Day 1 morning 24.0+0.8 (0) 24.0+09 (0) 0. 18.1t1.2 (0) 17.5tl.8 (0) -0.6 afternoon 25.1+0.5 (+1.1) 22.3+0.4 (-1.7) -2.8 17.3t 1.2 (-0.8) 14.5it1.3 (-3.0) -2.8 Day 2 morning 25.5-0.7 (+1.5) 23.3+0.6 (-0.7) -2.2 18.0t:0.9 (-0.1) 16.5+0.7 (-1.0) -1.5 afternoon 24.1+0.9 (+0.1). 22.4+0.7 (-1.6) -1.7 17.6+1.2 (-0.5) 15.2+1.3 (-2.3) -2.4 Day 3 morning 24.20.7 (+0.2). 22.8+0.8 (-1.2) -1.4 17.6+1.4 (-0.5) 15.8+1.0 (-17) -1.8 afternoon 25.1+0.7 (+1.1) 23.5+0.6 (-0.5) -1.6 17.6tl.2 (-0.5) 15.3tl.3 (-2.2) -2.3 Day 4 morning 24.0tl.2 (0) 22.0+0.9 (-2.0) -2.0 17.2+0.9 (-0.9) 15.8+10 (-1.7) -14 afternoon 23.2+0.4 (-0.8) 22.0+0.3 (-2.0) -1.2 19.8+1.1 (+1.7) 16.8+09 (-0.7) -3.0 Day 5 morning 23.3+0.6 (-0.7) 22.1+0.7 (-1.9) -12 18.5:1.1 (+0.4) 16.5-0.9 (-1,0) -2.0 afternoon. 24.9.7 (+0.9) 23.00.3 (-2.0) -19 17.8+0.8 (-0.3) 15.9+0.9 (-1.6) -19 FIG. 9 US 2006/01 35609 A1 Jun. 22, 2006 OPHTHAMOLOGICAL DRUGS resistance of the nerve tissue to damage, and the compliance of connective tissue surrounding and Supporting the optic CROSS-REFERENCE TO RELATED nerve. One agent, Memantine, is in phase III clinical trials APPLICATIONS (Allergan) as an agent that may prove to be neuroprotective. 0001. This application claims priority under 35 U.S.C. 0008. The topical application of ophthamological drugs S119(e) to U.S. Provisional Patent Application No. 60/620, for the treatment of glaucoma requires penetration of the 320 filed Oct. 21, 2004, the entire content of which is hereby drug through the cornea and into the anterior chamber, incorporated by reference. which contains aqueous humor, which then drains into the conventional outflow pathway (trabecular meshwork and TECHNICAL FIELD Schlemm's canal) and the uveal-scleral pathway (unconven 0002 The present invention relates, in general, to oph tional outflow pathway). Intraocular pressure is lowered by thamological drugs, and, in particular, to a method of drugs acting in the trabecular meshwork/Schlemm's canal modifying ophthamological drugs so as to increase their and the uveal-scleral pathway. Penetration of the drug penetration through the cornea into the anterior chamber. through the cornea requires a balance of hydrophobic and The invention further relates to such modified drugs and to hydrophilic characteristics. The drug must be sufficiently the use of same in treating diseases/disorders of the eye, soluble in non-polar media to diffuse into the cornea and Such as glaucoma and other conditions related to elevated sufficiently soluble in polar (aqueous) media to diffuse out of intraocular pressure. the cornea into the aqueous humor. BACKGROUND 0009. Many drugs potentially useful for the treatment of glaucoma are carboxylic acids (e.g., phenoxyacetic acids or 0003 Glaucoma is one of the three leading causes of cinnaminic acids). Carboxylic acids are typically delivered blindness in the United States and a leading cause of in buffered aqueous solution; near neutral pH, carboxylic blindness in the world. Over 2.2 million people in the United acids exist as the deprotonated carboxylate salt. Ionized States have glaucoma, and several million more are at risk carboxylate salts, while soluble in aqueous Solution, will not of developing the disease. As the population ages, the penetrate the cornea. Such drugs can be delivered as pro number of individuals with glaucoma will continue to grow drug esters. The use of pro-drug esters, which are cleaved since glaucoma affects the oldest individuals disproportion enzymatically (e.g., in the cornea) to regenerate the active ately. compound, can enhance penetration of drug through the 0004 Glaucoma is not just one disease, rather, it is a cornea into the anterior chamber. spectrum of conditions that share a final common pathway 0010 Unfortunately, many esters are too hydrophobic of acquired, progressive deterioration of the neuronal com (non-polar) to diffuse out of the relatively non-polar external ponents of the optic nerve.