| Treatment of arthritis and other musculoskeletal disorders with crosslinked hyaluronic acid -> Monitor Keywords |
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Treatment of arthritis and other musculoskeletal disorders with crosslinked hyaluronic acidRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), O-glycoside, PolysaccharideTreatment of arthritis and other musculoskeletal disorders with crosslinked hyaluronic acid description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070203095, Treatment of arthritis and other musculoskeletal disorders with crosslinked hyaluronic acid. Brief Patent Description - Full Patent Description - Patent Application Claims
INCORPORATION BY REFERENCE [0001] This application claims the benefit of U.S. Provisional Application Nos. 60/751,237; 60/751,381; and 60/751,414, all of which were filed Dec. 14, 2005. The entire teachings of the above-mentioned applications are incorporated herein by reference. BACKGROUND OF THE INVENTION [0002] Arthritis is a musculoskeletal disorder which is one of the leading causes of disability in the United States of America and the rest of the world. In particular, osteoarthritis (OA) is one of the most frequent articular pathologies in humans, and a common condition leading to total joint arthroplasty (artificial joint placement) in elderly individuals. Osteoarthritis is typically characterized by degenerative changes in the surface of the articular cartilage which results in cartilage thinning. It usually presents a pain, which worsens with exercise. Commonly affected joints are the knee, hips, spine, ankles, shoulders, fingers and toes. [0003] To date, no therapies have been shown to unequivocally alter the clinical course of OA. The primary treatment goals are thus so far to relieve the OA symptoms, i.e., adequate pain relief and maintain mobility. Current treatments for OA include use of non-steroidal anti-inflammatory drugs (NSAIDs) and intra-articular injections of corticosteroids. Prolonged use of NSAIDs can, however, lead to gastric ulcers, kidney damage, hearing loss and even inhibit cartilage formation. Corticosteroids provide short-term improvement of OA symptoms with quick onset of pain relief in the arthritic joints but their repeated use is limited due to the known side-effects of steroids. [0004] Therefore, there is a need for development of new therapies for treating arthritis (e.g., osteoarthritis) that overcome or minimize the above-mentioned problems. SUMMARY OF THE INVENTION [0005] The invention generally is directed to a method of treating a subject having a musculoskeletal disorder with a hyaluronic acid (HA) derivative, such as a crosslinked HA gel. [0006] In one embodiment, the method includes administering to a subject's articular site in need thereof an effective amount of an hyaluronic acid composition. The hyaluronic acid composition includes a hyaluronic acid derivative, wherein carboxyl functionalities of the hyaluronic acid derivative are each independently derivatized to include an N-acylurea or O-acyl isourea, or both N-acylurea and O-acyl isourea. [0007] In another embodiment, the method includes co-administering to an articular site of the subject an effective amount of a hyaluronic acid derivative as described above, and an effective amount of at least one second bioactive agent other than the HA derivative. The bioactive agent includes at least one member selected from the group consisting of cells, nucleic acids, proteins, antibodies, peptides and pharmaceuticals, such as growth factors, antibiotics, analgesics, anesthetics, steroidal and non-steroidal anti-inflammatory agents, chondroregenerative agents, chondroprotective agents, matrix metalloproteinase (MMP) inhibitors, tissue inhibitors of matrix metalloproteinase (TIMP), bone protective agents, bone regenerating agents, bone anabolic agents, bone resorption inhibitors, and bone osteoclast inhibiting agents. [0008] In yet another embodiment, the present invention is directed to a method of treating a subject having a musculoskeletal disorder that includes the step of inserting a needle into a subject's articular site in need thereof, wherein the needle is coupled to a syringe loaded with a HA composition as described above. Force is applied to the syringe, whereby at least a portion of the HA composition is delivered to the articular site. [0009] The present invention also provides a method of treating a subject having a musculoskeletal disorder with an effective amount of an HA composition including a crosslinked hyaluronic acid (HA) gel that is prepared by reacting an uncrosslinked HA with a biscarbodiimide in the presence of a pH buffer in a range of between about 4 and about 8 is also included in the invention. [0010] With the present invention, the residence time of HA in the joints can be improved, providing longer therapeutic effect, which in turn can reduce the frequency of administration, e.g., intra-articular injections, in OA patients, but yet effecting the efficiency and safety typical of uncrosslinked HA. In particular, co-therapy of the crosslinked HA in combination with a corticosteroid can provide rapid pain relief due to the presence of the corticosteroid, and prolonged pain relief due to the presence of the crosslinked HA. DETAILED DESCRIPTION OF THE INVENTION [0011] The foregoing and other objects, features and advantages of the invention will be apparent from the following more particular description of preferred embodiments of the invention. [0012] The method of the invention which employs a hyaluronic acid derivative, such as a crosslinked hyaluronic acid gel, can treat a subject having a musculoskeletal disorder, such as arthritis. In a preferred embodiment, the musculoskeletal disorder is osteoarthritis (OA). [0013] As used herein, the term "hyaluronic acid derivative" means hyaluronic acid derivatized in that carboxyl functionalities of the hyaluronic acid (HA) (a portion or all) are each independently derivatized to include an N-acylurea or O-acyl isourea, or both N-acylurea and O-acyl isourea. As used herein, hyaluronic acid, and any of its salts which are often referred to as "hyaluronan" (e.g., sodium, potassium, magnesium, calcium or ammonium salts) are represented by the term "HA." Typically, HA comprises disaccharide units of D-glucuronic acid (GlcUA) and N-acetyl-D-glucosamine (GlcNAc), which are alternately linked, forming a linear polymer. [0014] N-acylurea and O-acyl isourea derivatives for the invention are as shown in the bracketed fragments in the following structural formulas (I) and (II): [0015] In structural formulas (I) and (II), each R.sub.1 can be the same or different. Each R.sub.1 is selected from the group consisting of hydrogen; substituted or unsubstituted hydrocarbyl groups (linear or branched, or cyclic or acyclic) optionally interrupted by one or more heteroatoms; substituted or unsubstituted alkoxy; substituted or unsubstituted aryloxy; and substituted or unsubstituted aralkyloxy. Examples of substituted or unsubstituted hydrocarbyl groups (linear or branched, or cyclic or acyclic) optionally interrupted by one or more heteroatoms include optionally substituted aliphatic groups (e.g., alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl and cycloaliphaticalkyl); optionally substituted aryl groups (including heteroaryl groups); optionally substituted aliphatic groups interrupted by one or more heteroatoms (e.g., heterocyclyl, cycloaliphaticalkyl and heterocyclylalkyl); and optionally substituted, partially aromatic and partially aliphatic groups (e.g., aralkyl and heteroaralkyl). Suitable optional substituents are those that do not substantially interfere with the properties of the resulting crosslinked HA composition. Suitable substituents for carbon atoms of hydrocarbyl groups include --OH, halogens (--Br, --Cl, --l, --F), --OR.sup.a, --O--COR.sup.a, --COR.sup.a, --CN, --NCS, --NO.sub.2, --COOH, --SO.sub.3H, --NH.sub.2, --NHR.sup.a, --N(R.sup.aR.sup.b), --COOR.sup.a, --CHO, --CONH.sub.2, --CONHR.sup.a, --CON(R.sup.aR.sup.b), --NHCOR.sup.a, --NR.sup.bCOR.sup.a, --NHCONH.sub.2, --NHCONR.sup.aH, --NHCON(R.sup.aR.sup.b), --NR.sup.bCONH.sub.2, --NR.sup.bCONR.sup.aH, --NR.sup.cCON(R.sup.aR.sup.b), --C(.dbd.NH)--NH.sub.2, --C(.dbd.NH)--NHR.sup.a, --C(.dbd.NH)--N(R.sup.aR.sup.b), --C(.dbd.NR.sup.c)--NH.sub.2, --C(.dbd.NR.sup.c)--NHR.sup.a, --C(.dbd.NR.sup.c)--N(R.sup.aR.sup.b), --NH--C(.dbd.NH)--NH.sub.2, --NH--C(.dbd.NH)--NHR.sup.a, --NH--C(.dbd.NH)--N(R.sup.aR.sup.b), --NH--C(.dbd.NR.sup.c)--NH.sub.2, --NH--C(.dbd.NR.sup.c)--NHR.sup.a, --NH--C(.dbd.NR.sup.c)--N(R.sup.aR.sup.b), --NR.sup.dH--C(.dbd.NH)--NH.sub.2, --NR.sup.d--C(.dbd.NH)--N(R.sup.aR.sup.b), --NR.sup.d--C(.dbd.NR.sup.c)--NH.sub.2, --NR.sup.d--C(.dbd.NR.sup.c)--NHR.sup.a, --NR.sup.d--C(.dbd.NR.sup.c)--N(R.sup.aR.sup.b), --NHNH.sub.2, --NHNHR.sup.a, --NHR.sup.aR.sup.b, --SO.sub.2NH.sub.2, --SO.sub.2NHR.sup.a, --SO.sub.2NR.sup.aR.sup.b, --SH, --SR.sup.a, --S(O)R.sup.a, and --S(O).sub.2R.sup.a. In addition, an alkyl, alkylene, alkenyl or alkenylene group can be substituted with substituted or unsubstituted aryl group to form, for example, an aralkyl group such as benzyl. Similarly, aryl groups can be substituted with a substituted or unsubstituted alkyl or alkenyl group. [0016] R.sup.a-R.sup.d are each independently an alkyl group, aryl group, including heteroaryl group, non-aromatic heterocyclic group or --N(R.sup.aR.sup.b), taken together, form a substituted or unsubstituted non-aromatic heterocyclic group. The alkyl, aromatic and non-aromatic heterocyclic group represented by R.sup.a-R.sup.d and the non-aromatic heterocyclic group represented by --N(R.sup.aR.sup.b) can optionally be substituted. [0017] In other embodiments, R.sub.1 is an optionally substituted aliphatic group (cyclic or acyclic, or linear or branched). More preferably, R.sub.1 is an alkyl group, such as C1-C6 alkyl (e.g., methyl, ethyl, propyl, butyl, 2-propyl, tert-butyl, and the like). Preferably, each R.sub.1 is ethyl. [0018] Each R.sub.2 is independently a substituted or unsubstituted linking group including one or more of hydrocarbylene groups (cyclic or acyclic, or linear or branched) optionally interrupted by one or more heteroatoms. Examples include optionally substituted aliphatic groups (e.g., alkylene, alkenylene, alkynylene, cycloalkylene, cycloalkenylene, cycloalkynylene and cycloaliphaticalkylene); optionally substituted arylene (including heteroaryl groups); optionally substituted aliphatic groups interrupted by one or more heteroatoms (e.g., heterocyclylene, cycloaliphaticalkylene and heterocyclylalkylene); and optionally substituted, partially aromatic and partially aliphatic groups (e.g., aralkylene and heteroaralkylene). Suitable optional substituents are as those described above for R.sub.1. [0019] In some embodiments, R.sub.2 includes or is interrupted by other groups, e.g, carbonyl, amide, oxy, sulfide, disulfide, and the like. In other embodiments, R.sub.2 is a cycloaliphatic, arylene, heteroarylene, or heterocyclylene group. In still other embodiments, R.sub.2 is 1,6-hexamethylene, octamethylene, decamethylene, dodecamethylene, PEG, --CH.sub.2CH.sub.2--S--S--CH.sub.2CH.sub.2--, para-phenylene-S-S-para-phenylene, meta-phenylene-S-S-mela-phenylene, ortho-phenylene-S-S-ortho-phenylene, ortho-phenylene, meta-phenylene or para-phenylene. More preferably, R.sub.2 is phenylene. Preferably, R.sub.2 is para-phenylene. [0020] In one embodiment, the wavy line connected to R.sub.2 in structural formulas (I) and (II) represents hydrogen, substituted or unsubstituted hydrocarbyl groups (linear or branched, or cyclic or acyclic) optionally interrupted by one or more heteroatoms; alkoxy; aryloxy; or aralkyloxy, as described for R.sub.1. In another embodiment, the wavy line connected to R.sub.2 in structural formulas (I) and (II) represents optionally substituted N-acyl urea group or O-acyl isourea group, as shown below in structural formulas VI-VIII. Continue reading about Treatment of arthritis and other musculoskeletal disorders with crosslinked hyaluronic acid... Full patent description for Treatment of arthritis and other musculoskeletal disorders with crosslinked hyaluronic acid Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Treatment of arthritis and other musculoskeletal disorders with crosslinked hyaluronic acid patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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