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Wo 2007/089878 A2 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date (10) International Publication Number 9 August 2007 (09.08.2007) PCT WO 2007/089878 A2 (51) International Patent Classification: (74) Agents: LIN, Qing et al.; Seed Intellectual Property Law A61K9/00 (2006.01) A61L 17/00 (2006.01) Group PLLC, Suite 5400, 701 Fifth Avenue, Seattle, Wash ington 98104-7064 (US). (21) International Application Number: PCT/US2007/002714 (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (22) International Filing Date: 3 1 January 2007 (31.01.2007) AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, FI, (25) Filing Language: English GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, LS, (26) Publication Language: English LT, LU, LV,LY, MA, MD, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, (30) Priority Data: RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, 60/763,945 31 January 2006 (3 1.0 1.2006) US TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW (71) Applicant (for all designated States except US): AN- (84) Designated States (unless otherwise indicated, for every GIOTECH PHARMACEUTICALS, INC. [CA/CA]; kind of regional protection available): ARIPO (BW, GH, 1618 Station Street, Vancouver, British Columbia V6A GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, 1B6 (CA). ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, (72) Inventors; and FR, GB, GR, HU, IE, IS, IT, LT, LU, LV,MC, NL, PL, PT, (75) Inventors/Applicants (for US only): AVELAR, Rui RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, [CA/CA]; 1989 King Edward Avenue West, Vancou GN, GQ, GW, ML, MR, NE, SN, TD, TG). ver, British Columbia V6J 2W7 (CA). MAITI, Arpita [CA/CA]; #21 1 - 2920 Ash Street, Vancouver, British Co Published: lumbia V5Z 4A6 (CA). TOLEIKIS, Philip, M. [US/CA]; — without international search report and to be republished 801 1 Laburnum Street, Vancouver, British Columbia V6P upon receipt of that report 5N8 (CA). CASHMAN, Johanne, Diane [CA/CA]; 6070 Blenheim Street, Vancouver, British Columbia V6N IRl For two-letter codes and other abbreviations, refer to the "G uid (CA). GRAVETT, David, M. [CA/CA]; 2255 23rd Av ance Notes on Codes and Abbreviations" appearing at the beg in enue West, Vancouver, British Columbia V60 1N3 (CA). ning of each regular issue of the PCT Gazette. (54) Title: SUTURES AND ANTI-SCARRING AGENTS (57) Abstract: Sutures are used in combination with anti-scarring agents to inhibit fibrosis between the sutures and the host tissues into which the sutures are inserted. Compositions and methods are described for use in reducing excessive scarring, surgical adhe sion, and other disorders. SUTURES AND ANTI-SCARRING AGENTS BACKGROUND OF THE INVENTION Field of the Invention The present invention relates generally to pharmaceutical agents and compositions for administration in association with sutures More specifically, the present invention relates to compositions and methods for preparing sutures that inhibits a fibrottc response between the sutures and the tissue in contact with the suture material. Description of the Related Art Surgical adhesions are abnormal, fibrous bands of scar tissue that can form inside the body as a result of the healing process that follows any open or minimally invasive surgical procedure including abdominal, gynecologic, cardiothoracic, spinal, plastic, vascular, ENT, ophthalmologic, urologic, neuro, or orthopedic surgery. Surgical adhesions are typically connective tissue structures that form between adjacent injured areas within the body. Briefly, localized areas of injury trigger an inflammatory and healing response that culminates in healing and scar tissue formation. If scarring results in the formation of fibrous tissue bands or adherence of adjacent anatomical structures (that should be separate), surgical adhesion formation is said to have occurred. Adhesions can range from flimsy, easily separable structures to dense, tenacious fibrous structures that can only be separated by surgical dissection. While many adhesions are benign, some can cause significant clinical problems and are a leading cause of repeat surgical intervention. Surgery to breakdown adhesions (adhesiolysis) often results in failure and recurrence because the surgical trauma involved in breaking down the adhesion triggers the entire process to repeat itself. Surgical breakdown of adhesions is a significant clinical problem and it is estimated that there were 473,000 adhesiolysis procedures in the US in 2002 According to the Diagnosis Related Groups (DRGs), the total hospital charges for these procedures is likely to be at least US $ 10 billion annually Since all interventions involve a certain degree of trauma to the operative tissues, virtually any procedure (no matter how well executed) has the potential to result in the formation of clinically significant adhesion formation Adhesions can be triggered by surgical trauma such as cutting, manipulation, retraction or suturing, as well as from inflammation, infection (e g , fungal or mycobacterium), bleeding or the presence of a foreign body. Surgical trauma may also result from tissue drying, ischemia, or thermal injury. Due to the diverse etiology of surgical adhesions, the potential for formation exists regardless of whether the surgery is done in a so-called minimally invasive fashion (e.g., catheter-based therapies, laparoscopy) or in a standard open technique involving one or more relatively large incisions. Although a potential complication of any surgical intervention, surgical adhesions are particularly problematic in Gl surgery (causing bowel obstruction), gynecological surgery (causing pain and/or infertility), tendon repairs (causing shortening and flexion deformities), joint capsule procedures (causing capsular contractures), and nerve and muscle repair procedures (causing diminished or lost function). Surgical adhesions may cause various, often serious and unpredictable clinical complications; some of which manifest themselves only years after completion of the original procedure. Complications from surgical adhesions are a major cause of failed surgical therapy and are the leading cause of bowel obstruction and infertility. Other adhesion-related complications include chronic back or pelvic pain, intestinal obstruction, urethral obstruction and voiding dysfunction. Relieving the post-surgical complications caused by adhesions generally requires another surgery. However, the subsequent surgery is further complicated by adhesions formed as a result of the previous surgery. In addition, the second surgery is likely to result in further adhesions and a continuing cycle of additional surgical complications Adhesions generally begin to form within the fust several days after surgery Generally, adhesion formation is an inflammatory reaction in which factors are released, increasing vascular permeability and resulting in fibrinogen influx and fibrin deposition This deposition forms a matrix that bridges the abutting tissues Fibroblasts accumulate, attach to the matrix, deposit collagen and induce aπgiogenesis If this cascade of events can be prevented within 4 to 5 days following surgery, then adhesion formation may be inhibited Various modes of adhesion prevention have been examined, including (1) prevention of fibrin deposition, (2) reduction of local tissue inflammation and (3) removal of fibrin deposits. Fibrin deposition is prevented through the use of physical barriers that are either mechanical or comprised of viscous solutions. Barriers have the added advantage of physically preventing adjacent tissues from contacting each other and thereby reducing the probability that they will scar together Although many investigators and commercial products utilize adhesion prevention barriers, a number of technical difficulties exist and significant failure rates have been reported. Inflammation is reduced by the administration of drugs such as corticosteroids and non¬ steroidal anti-inflammatory drugs. However, the results from the use of these drugs in animal models have not been encouraging due to the extent of the inflammatory response and dose restriction due to systemic side effects. Finally, the removal of fibrin deposits has been investigated using proteolytic and fibrinolytic enzymes. A potential complication to the clinical use of these enzymes is the possibility for post-surgical excessive bleeding (surgical hemostasis is critical for procedural success). Accordingly, there is need for developing new prevention or treatment methods for surgical adhesion. The present invention fulfils this need and also provides additional related advantages. SUMMARY O F THE INVENTION Briefly stated, the present invention provides sutures (including plain and self-retaining sutures) that comprise an anti-scar πng agent, as well as methods for making and using such sutures In addition the present invention also provides compositions that comprise anti-scarring agents and methods for using such compositions in combination with sutures (including plain and self- retaining sutures) in various applications (e.g , reducing excessive scarring or surgical adhesion). In one aspect, the present invention provides an anti-scarring suture
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