(19) & (11) EP 1 708 694 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: A61K 31/335 (2006.01) 11.07.2012 Bulletin 2012/28 (86) International application number: (21) Application number: 05722794.4 PCT/US2005/003800 (22) Date of filing: 31.01.2005 (87) International publication number: WO 2005/074913 (18.08.2005 Gazette 2005/33) (54) COMPOSITIONS AND METHODS FOR TREATING CONTRACTURE ZUSAMMENSETZUNGEN UND VERFAHREN ZUR BEHANDLUNG VON KONTRAKTUR COMPOSITIONS ET PROCEDES POUR LE TRAITEMENT DE LA CONTRACTURE (84) Designated Contracting States: • LOSS, Troy, A., E. AT BE BG CH CY CZ DE DK EE ES FI FR GB GR North Vancouver, British Columbia V7L 3G (CA) HU IE IS IT LI LT LU MC NL PL PT RO SE SI SK TR • GRAVETT, David, M. Vancouver, British Columbia V5Z 1Y8 (CA) (30) Priority: 30.01.2004 US 540660 P • MAITI, Arpita Vancouver, British Columbia V5Z 4A6 (CA) (43) Date of publication of application: 11.10.2006 Bulletin 2006/41 (74) Representative: Gowshall, Jonathan Vallance et al Forresters (73) Proprietor: ANGIOTECH INTERNATIONAL AG Skygarden 6304 Zug (CH) Erika-Mann-Strasse 11 80636 München (DE) (72) Inventors: • AVELAR, Rui (56) References cited: Vancouver, British Columbia V6J 2W7 (CA) EP-A- 1 508 331 WO-A-98/24427 • LIGGINS, Richard, T. WO-A-98/24427 US-A1- 2002 183 380 Coquitlam, British Columbia V3K 5K7 (CA) US-A1- 2002 183 380 US-A1- 2004 001 872 • TOLEIKIS, Philip, M. Vancouver, British Columbia V6P 5N8 (CA) Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 1 708 694 B1 Printed by Jouve, 75001 PARIS (FR) EP 1 708 694 B1 Description Technical Field 5 [0001] The present invention relates generally to pharmaceutical compositions and methods for preventing conditions associated with reduced mobility or loss of function and articulation. Background of the Invention 10 [0002] The normal function of a joint and its movement can be severely impaired by scar and abnormal tissue formation that takes place both inside and outside the joint. The result is reduced mobility of a joint or extra- articular structure such as a muscle, tendon, or ligament. Reduced mobility can involve permanently shortened distances between tissues or a reduced maximum possible lengthening or shortening of tissues. When the impaired mobility results from one of these conditions, it is generally referred to as a contracture. The term "contracture" is often used interchangeably with the 15 terms such as "stiff joint" or arthrofibrosis. [0003] Contractures can be associated with or caused by a variety of conditions, for example, metabolic disorders, ischemia, burns, injury (e.g., to joint, capsule, bone, cartilage, tendon, ligament or muscle), fractures, subluxation, dis- locations, crush injuries, prolonged immobilization ( e.g., immobilization of a joint in a cast or splint), and paralysis. Surgical procedures may also precipitate contractures, as in the case of operations involving the shoulder ( e.g., rotator cuff repair 20 or diagnostic inspection), elbow, and hand. Other procedures involving joint reduction after a dislocation, or repairs of tendon, ligament, capsule and bone may also induce joint contractures. Procedures to remove scar and abnormal tissue in contracted joints often fail because the surgery itself represents a controlled injury. Thus, the process of removing abnormal and scarred tissue further stimulates the formation of scarred and abnormal tissue. As a result, the procedures offered today have limited success and at times, can actually make a patient worse. 25 [0004] Certain joints and procedures have higher tendencies for contractures. For example, a hip or knee arthroplasty generally has a low rate of joint stiffness after a procedure, but a shoulder has a significantly higher rate. An anterior cruciate repair has an incidence of arthrofibrosis ranging from 3% to 15% depending on the surgeon and repair performed (e.g., semi-tendinous/gracilis or bone-patellar tendon bone repair). Joints such as the elbow have a high tendency and can form some degree of contracture in 30% to 70% of patients. Shoulders may form contractures not only in response 30 to trauma, but can also form spontaneously, for example, a frozen shoulder with a capsule that has thickened without any obvious precipitant. [0005] In certain cases, the contracture may have a hereditary basis and have the primary scar and abnormal tissue growth take place outside of the joint. Dupytren’s contracture represents a condition whereby the connective tissue in the palmer aspect of the hand begins to scar and thicken leading to deformation of the hand at the site of the thickening 35 and loss of range of motion of the fingers. Equivalent scenarios exist in the penis (Peyronie’s disease), and on the plantar aspect of the foot (Ledderhose’s disease). [0006] Treatment for contractures today only addresses the issue after a contracture is already established. Interven- tions including only physiotherapy and range of motion exercises are used but have very limited success. Surgical interventions include manipulation under anesthesia ( i.e., essentially putting the patient to sleep and then breaking down 40 the adhesion by forcing the joint). Unfortunately, this often reignites the inflammation and proliferation in the tissue and the reformation of the scar and stiffness. Surgery may involve an open procedure, releasing and removing the restricting scar and abnormal tissue or the operation can also be done through an arthroscope, whereby the scar and restricting tissue is released and removed using special tools. Surgical interventions often fail, and may actually make the condition worse, since the surgery itself is a controlled injury or trauma, which can cause the tissue to lay down even more scar 45 in response to the surgical injury. [0007] Pharmacological therapy has been attempted with limited or no success. Agents most often used include non- steriodal anti-inflammatories, steroids and radiation. Pharmacological treatments for various types of contracture have included administration of hyaluronic acid ( i.e., HEALON-R, Pharmacia Inc., Piscataway, NJ) into joints (Clin. Rheumatol. 20: 98-103, 2001; Acta Orthop. Scand. 62: 323-6, 1991); oral administration of antihistamines to rabbits (J. Hand Surg. 50 18: 1080-5, 1993); and intra-articular injection of dimethlysulfoxide, systemic steroids, and non- steroidal anti-inflamma- tories. Recombinant human superoxide dismutase (U.S. 6,312,720), calmodulin blockertrifluroperizine (U.S. 6,525,100), collagenase and calcium channel blockers have been disclosed as therapy for patients suffering from Peyronie’s disease; matrix metalloproteinase inhibitors have been disclosed for inhibiting contraction (see, e.g., U.S. Patent No. 6,093,398); and use of dimethylsulfoxide, oxygen free radical scavengers, including colchicine, allopurinol, and methylhydrazine, 55 interferon, collagenases, steroids, such as triamcinolone and clobetasol(Hand Clinics 15: 97-107, 1999), verapamil, nifedipine, diltiazem, amalodipine, felodipine, isradipine, nicardipine, nimodipine, nisoldipine, bepridil (see,e.g ., U.S. Patent Nos. 6,353,028 and 6,031,005) and fluroquinolone (U.S. Patent No. 6,060,474) have been injected locally into fibrous tissue in an attempt to treat Dupuytren’s contracture. To date, however, none of the pharmacological treatments 2 EP 1 708 694 B1 described above have been approved for treating contracture in human patients. SUMMARY OF THE INVENTION 5 [0008] The present invention provides the claimed compositions, for use in devices and methods for the treatment of contracture, and in particular, for use in human and animal patients. The compositions described herein may be used after an injury in order to prevent or minimize contracture formation. In the case of established contracture, the compo- sitions of the invention can be used to complement a release proceduree.g (., forced manipulation, open release, arthroscopic release, or debulking of scar) to prevent the recurrence of scarred and abnormal tissue which can lead to 10 a contracture. The administration may be intra-articular in cases where the contracture is caused by an intra-articular scar, or may used peri-articularly where the contracture is caused by not only scarring within the joints, but also by scar tissue outside the joint. An example of the latter would include interphalangeal contractures, not only is the scar within the joint, the outside volar plate is also involved. The use or administration of the instant compositions provides for an efficacious treatment which is reasonably safe and well tolerated and may further provide other related advantages. The 15 drug contained in the compositions of the invention may be selected from a variety of therapeutically active compounds which will provide symptomatic, disease modifying or prophylaxis effect in conditions associated with contracture. The method of use of such compositions may also vary, but includes all routes of administration, doses, and dosing frequencies which will provide such a benefit. [0009] In one aspect, a method for treating contracture is provided that includes administering to a patient