US 20090226,500A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2009/0226500 A1 AVelar et al. (43) Pub. Date: Sep. 10, 2009 (54) SUTURES AND ANTI-SCARRINGAGENTS Related U.S. Application Data (75) Inventors: Rui Avelar, Vancouver (CA); (60) Provisional application No. 60/763.945, filed on Jan. Arpita Maiti, Vancouver (CA); 31, 2006. Philip M. Toleikis, Vancouver (CA); Johanne Diane Cashman, Publication Classification Vancouver (CA); David M. (51) Int. Cl. Gravett, Mountain View, CA (US) A6IF 2/04 (2006.01) Correspondence Address: A63L/35 (2006.01) SEED INTELLECTUAL PROPERTY LAW A 6LX 3/553 (2006.01) GROUP PLLC A63/496 (2006.01) 701 FIFTHAVENUE, SUITE 5400 A63L/464 (2006.01) SEATTLE, WA 98104-7092 (US) A 6LX 3L/395 (2006.01) A6II 3/426 (2006.01) (73) Assignee: Angiotech Pharmaceuticals, Inc. (52) U.S. Cl. .................... 424/423: 514/649; 514/211.08: Vancouver (CA) 514/254.07: 514/399; 514/183: 514/370 (21) Appl. No.: 12/162,572 (57) ABSTRACT (22) PCT Filed: Jan. 31, 2007 Sutures are used in combination with anti-scarring agents to (86). PCT No.: PCT/US07/02714 inhibit fibrosis between the sutures and the host tissues into which the Sutures are inserted. Compositions and methods are S371 (c)(1), described for use in reducing excessive scarring, Surgical (2), (4) Date: May 6, 2009 adhesion, and other disorders. Patent Application Publication Sep. 10, 2009 Sheet 1 of 29 US 2009/0226500 A1 Patent Application Publication Sep. 10, 2009 Sheet 2 of 29 US 2009/0226,500 A1 ºs||eoL-AHLKquoqonpoudp-JNLWu018=ºolZ802-14Ke8 Patent Application Publication Sep. 10, 2009 Sheet 3 of 29 US 2009/0226,500 A1 s LIOC Patent Application Publication Sep. 10, 2009 Sheet 4 of 29 US 2009/0226500 A1 g 9 S Y s s O D. C. war 809 club 9. Patent Application Publication Sep. 10, 2009 Sheet 5 of 29 US 2009/0226500 A1 s E S O 9 was a E s C. Y s del 9 Patent Application Publication Sep. 10, 2009 Sheet 6 of 29 US 2009/0226,500 A1 s to 9, Patent Application Publication Sep. 10, 2009 Sheet 7 of 29 US 2009/0226,500 A1 ' s' t E;E. .." Eigi E s E.3. E.S. E. ESSES SEE seesaaSS eye says 8 E s Patent Application Publication Sep. 10, 2009 Sheet 8 of 29 US 2009/0226,500 A1 al 3.ive s E8 f s Patent Application Publication Sep. 10, 2009 Sheet 9 of 29 US 2009/0226,500 A1 E. E. 5 ., E A eme ve ed R a SS ses e. SS int 3 S 'g a e) ifas as to gi32 (S is on as ae E. A. S. Patent Application Publication Sep. 10, 2009 Sheet 10 of 29 US 2009/0226,500 A1 Patent Application Publication Sep. 10, 2009 Sheet 11 of 29 US 2009/0226,500 A1 i. e. Cld - is 5 apie AP-1 FIG. 10B Patent Application Publication Sep. 10, 2009 Sheet 12 of 29 US 2009/0226500A1 (-01 x udo) 4AHby YO Patent Application Publication Sep. 10, 2009 Sheet 13 of 29 US 2009/0226,500 A1 SIROMELYSIN GAPDH FIG 10D Patent Application Publication Sep. 10, 2009 Sheet 14 of 29 US 2009/0226,500 A1 ly 290 18 SL-1 (ng/ml) .0 20 20 20 20, 20 Drug () 0 0 10 10- 0-5 10 FIG. 1 1A Patent Application Publication Sep. 10, 2009 Sheet 15 of 29 US 2009/0226,500 A1 2-Methyl-2,4-Pentanediol (Hexylene Glycol) collagenase GAPDH IL-1 (ng/ml) 0, 20 20, 20. 20 Drug (M) O. O. 107 10 10 16-4 FIG 11B Patent Application Publication Sep. 10, 2009 Sheet 16 of 29 US 2009/0226,500 A1 Deuterium Oxide 99.9eforn2D Cologenase . :: :-. Patent Application Publication Sep. 10, 2009 Sheet 17 of 29 US 2009/0226,500 A1 Glycine Ethyi Esfer Collagenase . r. isa ist ... " . p . ."s . b Geon his f IL-1 (ng/ml) 0, 20 20 20 20, 20 Drug (M) 0 0 107 10-6 10-5 10 FIG. 1 1D Patent Application Publication Sep. 10, 2009 Sheet 18 of 29 US 2009/0226,500 A1 (succinimidylsuccinole)Ethylene Glycol Bis Collagenase M t frag s . s e. rus s . A A. s i;P. ... v. i; is see : GAPDH o IL-1 (ng/ml). D 20 2020. 20.20 Drug (M) 0 0 10-7 10-6 10-5 10-4 FIG. 11E Patent Application Publication Sep. 10, 2009 Sheet 19 of 29 US 2009/0226,500 A1 Tubercidin l-k (ng/ml), 9, 20 20 20 20 20 Drug (M). O: 0 10-7 10-6 10-5 10 FIG 11 F Patent Application Publication Sep. 10, 2009 Sheet 20 of 29 US 2009/0226,500 A1 Aluminum Fluoride Patent Application Publication Sep. 10, 2009 Sheet 21 of 29 US 2009/0226,500 A1 Epothilone B Collegenase up s GAPDH L-1 (ng/ml) O 20 20 20 Drug (M) 0 0 109 10-7 FIG. 11H Patent Application Publication Sep. 10, 2009 Sheet 22 of 29 US 2009/0226500A1 s g r w . unopells Patent Application Publication Sep. 10, 2009 Sheet 23 of 29 US 2009/0226500 A1 5 S s E 9. () s Locu% Patent Application Publication Sep. 10, 2009 Sheet 24 of 29 US 2009/0226,500 A1 E s E Vs s t s s Ocul Patent Application Publication Sep. 10, 2009 Sheet 25 of 29 US 2009/0226,500 A1 3 E S c o ser 5 s O3 , Patent Application Publication Sep. 10, 2009 Sheet 26 of 29 US 2009/0226,500 A1 or 9. Patent Application Publication Sep. 10, 2009 Sheet 27 of 29 US 2009/0226,500 A1 s O. Patent Application Publication Sep. 10, 2009 Sheet 28 of 29 US 2009/0226,500 A1 o O ar () f Ol - E u) S s edun Na3 Patent Application Publication Sep. 10, 2009 Sheet 29 of 29 US 2009/0226,500 A1 TGF-8 level in Rat Tissues 6 O O O SOOO . 4OOO to implant 3OOO . Shan 2000 1 OOO . O -- -T, a - --fil Shoticer Hip Abdorner Site FIG. 19 US 2009/0226500 A1 Sep. 10, 2009 SUTURES AND ANTI-SCARRINGAGENTS related complications include chronic back or pelvic pain, intestinal obstruction, urethral obstruction and Voiding dys BACKGROUND OF THE INVENTION function. Relieving the post-Surgical complications caused by adhesions generally requires another Surgery. However, 0001 1. Field of the Invention the Subsequent Surgery is further complicated by adhesions 0002 The present invention relates generally to pharma formed as a result of the previous Surgery. In addition, the ceutical agents and compositions for administration in asso second Surgery is likely to result in further adhesions and a ciation with sutures. More specifically, the present invention continuing cycle of additional Surgical complications relates to compositions and methods for preparing Sutures 0007 Adhesions generally begin to form within the first that inhibits a fibrotic response between the sutures and the several days after Surgery Generally, adhesion formation is an tissue in contact with the Suture material. inflammatory reaction in which factors are released, increas 0003 2. Description of the Related Art ing vascular permeability and resulting in fibrinogen influx 0004 Surgical adhesions are abnormal, fibrous bands of and fibrin deposition. This deposition forms a matrix that scar tissue that can form inside the body as a result of the bridges the abutting tissues. Fibroblasts accumulate, attach to healing process that follows any open or minimally invasive the matrix, deposit collagen and induce angiogenesis. If this Surgical procedure including abdominal, gynecologic, car cascade of events can be prevented within 4 to 5 days follow diothoracic, spinal, plastic, vascular, ENT, opthalmologic, ing Surgery, then adhesion formation may be inhibited. urologic, neuro, or orthopedic Surgery. Surgical adhesions are 0008 Various modes of adhesion prevention have been typically connective tissue structures that form between adja examined, including (1) prevention of fibrin deposition, (2) cent injured areas within the body. Briefly, localized areas of reduction of local tissue inflammation and (3) removal of injury trigger an inflammatory and healing response that cul fibrin deposits. Fibrin deposition is prevented through the use minates in healing and scar tissue formation. If scarring of physical barriers that are either mechanical or comprised of results in the formation offibrous tissue bands or adherence of Viscous solutions. Barriers have the added advantage of adjacent anatomical structures (that should be separate), Sur physically preventing adjacent tissues from contacting each gical adhesion formation is said to have occurred. Adhesions can range from flimsy, easily separable structures to dense, other and thereby reducing the probability that they will scar tenacious fibrous structures that can only be separated by together. Although many investigators and commercial prod Surgical dissection. While many adhesions are benign, some ucts utilize adhesion prevention barriers, a number of techni can cause significant clinical problems and are a leading cal difficulties exist and significant failure rates have been cause of repeat surgical intervention. Surgery to breakdown reported. Inflammation is reduced by the administration of adhesions (adhesiolysis) often results in failure and recur drugs such as corticosteroids and non-steroidal anti-inflam rence because the Surgical trauma involved in breaking down matory drugs. However, the results from the use of these the adhesion triggers the entire process to repeat itself. Sur drugs in animal models have not been encouraging due to the gical breakdown of adhesions is a significant clinical problem extent of the inflammatory response and dose restriction due and it is estimated that there were 473,000 adhesiolysis pro to systemic side effects.