USOO6368613B1 (12) United States Patent (10) Patent No.: US 6,368,613 B1 Walters et al. (45) Date of Patent: *Apr. 9, 2002 (54) USE OF FLUOROCARBONS FOR 5,173,298. A 12/1992 Meadows ................... 424/423 DLAGNOSIS AND TREATMENT OF 5,470885. A 11/1995 Fuhrman et al. ARTICULAR DISORDERS 5,496.535 A 3/1996 Kirkland 5,799,660 A * 9/1998 Bertone (75) Inventors: Mark A. Walters, San Diego; Ronald FOREIGN PATENT DOCUMENTS M. Hopkins, Escondido; David H. Klein, Carlsbad, all of CA (US) EP O3O7863 3/1989 WO 9508985 4/1995 (73) Assignee: Alliance Pharmaceutical Corp., San Diego, CA (US) OTHER PUBLICATIONS - - - Tang-Liu, et al. Lenticular Uptake and Distribution of (*) Notice: This patent issued on a continued pros- Xenobiotics and Amino Acids. J. of Ocular Pharmacology ecution application filed under 37 CFR 1.53(d),a p. andM isS SubiectE. to thes twenty my 8(3):Hughes, 267-277 et al. Effect(1992). of Acylation On the Ocular Disposition 54(a)(2) p a a- - of Acyclovir II: Corneal Permeability and Anti-HSV 1 Z. Activity of 2'-Esters in Rabbit Epithelial Keratitis. J. of Subject to any disclaimer,- 0 the term of this Ocular Pharmacology 9(4): 299-309 (1993). R is Neil or adjusted under 35 Hageluken, et al. Lipophilic B-AdrenOceptor Antagonists U.S.C. 154(b) by 0 days. and Local Anesthetics Are Effective Direct Activators of G-Proteins. Biochemical Pharmacology 47(10): 1789–1795 This patent is Subject to a terminal dis- (1994). claimer. Moriguchi, et al. Simple method of Calculating Octanol/ Water Partition Coefficient Chem. Pharm. Bull. (21) Appl. No.: 09/217,491 40(1):127–130(1992). Yokogawa, et al. Relationships in the Structure-Tissue Dis (22) Filed: Dec. 21, 1998 tribution of Basic Drugs in the Rabbit Pharma. Res. Related U.S. ApplicationO O Data 7(7):691-696 (1990). cited by examiner (63) Continuation of application No. 08/616,260, filed on Mar. 15, 1996, now Pat. No. 5,861,175. Primary Examiner Edward J. Webman (51) Int. Cl." ........................ A61K 9/10; A61K 31/755; E. Agney Agent, or Firm- Knobbe, Martens, Olson & A61K 31/02; A61K 19/02 Ca (52) U.S. Cl. ........................................ 424/423: 514/825 (57) ABSTRACT (58) Field of Search ................................. 424/486, 423, 424/422; 514/825 Methods for the diagnosis and treatment of articular disor derS comprising the use of fluorocarbons are disclosed. The (56) References Cited methods provide for the introduction of a fluorocarbon into an articular region to replace or augment natural Synovial U.S. PATENT DOCUMENTS fluid. The introduced fluorocarbons, which may be in vari 3,697,653 A 10/1972 Ongley ous forms including liquids, gels or emulsions, provide 4,828,828 A 5/1989 Trager et al. articular lubrication and cushioning which is effective for 4,865,836 A 9/1989 Long, Jr. the treatment of disorderS Such as osteoarthritis and rheu 4,927,623 A 5/1990 Long, Jr. matoid arthritis. Additionally, the methods of the present 4.951,673 A 8/1990 Long invention may be used to provide high resolution articular 4,987,154 A 1/1991 Long, Jr. 4,993,415 A 2/1991 Long .......................... 128/653 images, reduce articular inflammation and introduce bioac 5,143,724 A 9/1992 Leshchiner et al. tive agents to the articular region. 5,145,841. A * 9/1992 Cullis-Hill et al. 5,149,319 A * 9/1992 Unger 12 Claims, No Drawings US 6,368,613 B1 1 2 USE OF FLUOROCARBONS FOR The Second major group of joints, the predominant form DLAGNOSIS AND TREATMENT OF of joint in the human body, are termed diarthroses or ARTICULAR DISORDERS synovial joints. Synovial joints, which allow for a wide range of motion, incorporate a fluid filled cavity (the articu RELATED APPLICATIONS lar cavity) having a membrane known as the Synovium. The This application is a continuation application of U.S. Ser. Synoviurn (or Synovial membrane), richly Supplied by both No. 08/616,260, filed Mar. 15, 1996, now U.S. Pat. No. blood vessels and lymphatics, terminates at the margin of 5,061,175. articular cartilage and is Supported by the fibrous tissue defining the cavity or capsule. Only a few cell layers thick FIELD OF THE INVENTION under normal circumstances, the Synovium helps regulate The present invention relates to therapeutic and diagnostic the amount of liquid in a joint by Secreting and absorbing methods for the management of orthopedic disorders. More synovial fluid. The synovial fluid plays an important role in particularly, the present invention relates to the administra lubricating and Separating the bone and cartilaginous Sur tion of fluorocarbons for the treatment or diagnosis of faces comprising the joint. More specifically, the bone various articular disorders. 15 Surfaces are typically covered by articular cartilage, a spe cialized form of hyaline cartilage, which has a very low BACKGROUND OF THE INVENTION coefficient of friction. Sliding contact is facilitated by the One of the most significant events in the evolution of presence of the Synovial fluid, which, among other animal physiology was the internalization of the skeletal functions, provides for lubrication and maintenance of the framework. In a broad sense, it allowed for Substantial living cells in the cartilage. Where the congruity between the increases in Size while retaining the mobility necessary to bones is low there may also be an articular disc or meniscus exploit new environments. Moreover, in higher organisms of fibrocartilage. The purpose of this fibrocartilage is uncer the skeletal System carries out Several important functions. tain although it has been Suggested that it plays a part in Fundamentally, it provides mechanical Support for the tis Shock absorption, improvement of fit between Surfaces and SueS of the body and assists in the maintaining the body's 25 Spreading of weight over a larger area. In any case, the natural mineral balance. It also exhibits a protective nature, Synovial joints allow an impressive array of movements reducing the potential for harm to delicate internal organs. while Successfully Supporting immense loads. Perhaps most importantly, the skeletal System is a dynamic The presence of healthy cartilaginous tissue is critical for Structure incorporating numerous joints and providing a the effective operation of synovial joints. Bathed by synovial framework on which muscles can act to allow motion. fluid, cartilage provides a Smooth, relatively malleable Sur Responsive to neural Signals, this coordinated interaction is face allowing for almost frictionle SS movement. the basis for all voluntary movement. Histologically, articular cartilage is a vascular and lacking in The adult human skeleton is made up of 206 individual nerve structures. It contains a relatively Small number of bones. The Sites where the bones come together are com cells (chondrocytes) in a stiff, gel-like extracellular matrix monly called joints (arthroses) or points of articulation. In 35 that is permeated by a network of collagen fibers. Synthesis, normal operation, joints efficiently function to provide and to Some extent degradation, of the cartilage matrix is Smooth, painless, Stable, force transmission between one undertaken by the chondrocytes. The unusual mechanical bone and the next with little effort. For the average adult characteristics of cartilage are a result of the unique archi individual, the joints cycle more than one million times a tectural combination as well as chemical interactions year, typically without injury or mishap. The hip, knee and 40 between the components. Mechanically, articular cartilage ankle joints transmit forces of three times body weight with can be considered to be a fluid-filled, permeable, porous the Simplest of activities Such as walking, and over Seven Solid. It is efficient at resisting the large compressive forces times the body weight when undergoing motion related to generated by weight transmission during movement and its climbing Stairs. Because much of the force transmitted elasticity dissipates the effect of concussion. During normal acroSS a joint is due to agonistic muscle contraction, the 45 joint operation, the cartilage is Subjected to both mechanical force per unit area carried by all extremity joints is similar. distortion of the matrix and, as a result of movement of Based on the nature of their connective tissue, joints are interstitial fluid in and out of the tissue, changes in Volume. generally classified as belonging to one of two principal The movement of synovial fluid, both within the cartilage groups. In the first group, connective tissues remain Solid and in the articular cavity, is extremely important to proper (Synarthroses). These Solid joints are further classified as 50 joint function. being fibrous joints or cartilaginous joints based on the most Synovial fluid is a dialysate of blood plasma into which prevalent type of connective tissue. Fibrous joints tend to be hyaluronate, a glycosaminoglycan of high molecular weight articulations in which the Surfaces of the bones are fastened is secreted by the synovial membrane. The high levels of together by intervening fibrous tissue. Such joints, including hyaluronate dissolved in the synovial fluid tend to make it those between cranial bones, tend to allow little appreciable 55 fairly Viscous under normal physiological conditions. In motion. Cartilaginous joints include Synchondroses humans, the volume of synovial fluid found in the joints is (primary cartilaginous joints) and Symphyses (Secondary typically on the order of a few tenths of a milliliter to several cartilaginous joints) each of which may allow limited move milliliters which is deposited on, and permeates, the carti ment. The former are essentially growth mechanisms and are lage and other Surfaces within the articular cavity. Besides found where two separate but adjacent regions of OSSifica 60 providing the articular cartilage its Smooth texture and tion occur within a continuous mass of hyaline cartilage.