Compositions and methods for systemic inhibition of cartilage degradation

Abstract

Methods and compositions for inhibiting articular cartilage degradation. The compositions preferably include multiple chondroprotective agents, including at least one agent that promotes cartilage anabolic activity and at least one agent that inhibits cartilage catabolism. The compositions may also include one or more pain and inflammation inhibitory agents. The compositions may be administered systemically, such as to treat patients at risk of cartilage degradation at multiple joints, and suitably may be formulated in a carrier or delivery vehicle that is targeted to the joints. Alternatively the compositions may be injected or infused directly into the joint.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] The present application is a continuation of copending U.S. patent application Ser. No. 10 / 356,649, filed Jan. 21, 2003, which claims the benefit of U.S. Provisional Application No. 60 / 353,552 filed Feb. 1, 2002 and is a continuation-in-part of U.S. application Ser. No. 10 / 031,546 filed Jan. 18, 2002, which is a U.S. National phase of International Application No. PCT / US00 / 19864 filed Jul. 21, 2000 designating the United States, which claims priority from U.S. Provisional Application No. 60 / 144,904 filed Jul. 21, 1999, and also is a continuation-in-part of U.S. application Ser. No. 09 / 839,633 filed Apr. 20, 2001, which is a continuation-in-part of International Application No. PCT / US99 / 26330 filed Nov. 5, 1999 designating the United States, which claims priority from U.S. Provisional Application No. 60 / 107,256 filed Nov. 5, 1998, and of International Application No. PCT / US99 / 24625 filed Oct. 20, 1999 designating the United States, which...

AI Technical Summary

Benefits of technology

[0018] This local delivery aspect of the present invention provides a solution constituting a mixture of multiple agents in low concentrations directed at inhibiting locally the mediators of pain, inflammation, and cartilage degradation in a physiologic electrolyte carrier fluid. The invention also provides a method for perioperative delivery of the irrigation solution containing these agents directly to a surgical site, where it works locally at the receptor and enzyme levels to preemptively limit pain, inflammation, and cartilage degradation at the site. Due to the local perioperative delivery method of the present invention, a desired therapeutic effect can be achieved with lower doses of agents than are necessary when employing other methods of delivery (i.e., intravenous, intramuscular, subcutaneous and oral).

[0023] The advantages of low dose applications of agents in accordance with this aspect of the invention are three-fold. The most important is the absence of systemic side effects that often limit the usefulness of these agents. Additionally, the agents selected for particular applications in the solutions of the present invention are highly specific with regard to the mediators and mediation targets on which they work. This specificity is maintained by the low dosages utilized. Finally, the cost of these active agents per procedure is low.

[0024] The advantages of local administration of the agents via irrigation or other fluid application in accordance with this aspect of the invention are the following: (1) local administration guarantees a known concentration at the target site, regardless of interpatient variability in metabolism, blood flow, etc.; (2) because of the direct mode of delivery, a therapeutic concentration is obtained instantaneously and, thus, improved dosage control is provided; and (3) local administration of the active agents directly to a wound or operative site also substantially reduces degradation of the agents through systemic processes (e.g., first- and second-pass metabolism) that would otherwise occur if the agents were given orally, intravenously, subcutaneously or intramuscularly. This is particularly true for those active agents that are proteins and peptides, which are metabolized rapidly. Thus, local administration permits the use of compounds or agents which otherwise could not be employed therapeutically. For example, some agents in the following classes are peptidic: bradykinin receptor antagonists; tachykinin receptor antagonists; opioid receptor agonists; CGRP receptor antagonists; and interleukin receptor antagonists, TNF-receptor antagonists; TGF-β receptor agonists; BMP-2 and BMP-7 receptor agonists; IL4, IL10 and IL-13 receptor agonists; and integrin receptor agonists and antagonists. Local, continuous delivery to the wound or operative site minimizes drug degradation or metabolism while also providing for the continuous replacement of that portion of the agent that may be degraded, to ensure that a local therapeutic concentration, sufficient to maintain receptor occupancy or enzymatic saturation, is maintained throughout the duration of the operative procedure.

[0025] Local administration of the solution perioperatively throughout a surgical procedure in accordance with this aspect of the present invention produces a preemptive analgesic, anti-inflammatory and cartilage protective effect. As used herein, the term “perioperative” encompasses application intraprocedurally, pre- and intraprocedurally, intra- and postprocedurally, and pre-, intra- and postprocedurally. To maximize the preemptive anti-inflammatory, analgesic (for certain applications) and cartilage protective (for certain applications) effects, the solutions of the present invention are most preferably applied pre-, intra- and postoperatively. By occupying the target receptors or inactivating or activating targeted enzymes prior to the initiation of significant operative trauma locally, the agents of the present solution modulate specific pathways to preemptively inhibit the targeted pathologic process. If inflammatory mediators and processes are preemptively inhibited in accordance with the present invention before they can exert tissue damage, the benefit is more substantial than if given after the damage has been initiated.

[0027] Used perioperatively, the solution should result in a clinically significant decrease in operative site pain and inflammation, and of cartilage degradation, relative to currently-used irrigation fluids, thereby decreasing the patient's postoperative analgesic (i.e., opiate) requirement and, where appropriate, allowing earlier patient mobilization of the operative site. No extra effort on the part of the surgeon and operating room personnel is required to use the present solution relative to conventional irrigation fluids. For optimum chondroprotection in accordance with this aspect of the invention, the solutions of the invention are administered directly to a joint prior to, during and / or after a surgical procedure.

Problems solved by technology

Although various therapeutic approaches may provide relief of symptoms, no therapeutic regimen has been proven to retard progression of articular cartilage degradation.

The progressive deterioration and loss of articular cartilage leads to an irreversible impairment of joint motion.

Cartilage destructive processes may also be associated with or initiated by surgical procedures of the joint.

Conventional physiologic irrigation fluids do not provide analgesic, anti-inflammatory or anti-cartilage degradation effects.

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