JP2005519917A5

JP2005519917A5 -

Info

Publication number: JP2005519917A5
Application number: JP2003563495A
Authority: JP
Filing date: 2003-01-31
Publication date: 2005-12-22

Claims

A targeted drug delivery system for cartilage protection comprising a plurality of cartilage protective agents contained in a delivery vehicle, wherein the delivery vehicle is an antibody specific for an antigenic determinant present in a joint Or linked to an antibody fragment, wherein the plurality of chondroprotective agents comprises at least one anabolic cartilage protectant and at least one cartilage catabolism inhibitor, each of which the plurality of cartilage protectants inhibit cartilage catabolism And a targeted drug delivery system included in a therapeutically effective amount to promote cartilage assimilation.

A targeted drug delivery system for cartilage protection, the delivery system comprising a plurality of cartilage protectants, wherein at least one of the cartilage protectants is contained within a delivery vehicle targeted to the joint; The plurality of cartilage protectors comprises at least one anabolic cartilage protectant and at least one cartilage catabolism inhibitor, wherein each of the plurality of cartilage protectants inhibits cartilage catabolism and A targeted drug delivery system comprising a therapeutically effective amount to promote cartilage anabolism.

The targeted drug delivery system of claim 2, wherein the targeted delivery vehicle is linked to an antibody or antibody fragment specific for an antigenic determinant present in the joint.

4. The targeted drug delivery system of claim 3, wherein the targeted antigenic determinant is present on or in articular cartilage.

5. The targeted drug delivery system of claim 4, wherein the targeted antigenic determinant is present on type II collagen of articular cartilage.

4. The targeted drug delivery system of claim 3, wherein the targeted antigenic determinant is present on cartilage collagen or cartilage proteoglycan.

The targeted antigenic determinants include type II collagen and type V, VI, type, type IX, type X, and type XI small collagens; large aggregate proteoglycans, aggrecans, decorins, biglycans, fibromodulins A cell selected from the group consisting of cartilage oligomeric matrix protein, glycoprotein 39; chondroitin sulfate proteoglycan and glycosaminoglycan; macrophage synovial cells and fibroblast synoviocytes; and chondrocytes, 4. The targeted drug delivery system of claim 3, found on or in a molecule, or structure.

4. The targeted drug delivery system of claim 3, wherein the targeted antigenic determinant is present on or in the synovium.

4. The targeted drug delivery system of claim 3, wherein the targeted antigenic determinant is an epitope or neoepitope associated with articular cartilage degeneration.

10. The targeted epitope or neoepitope is immunolocalized on the surface layer of articular cartilage in a patient diagnosed with osteoarthritis, rheumatoid arthritis, or other degenerative joint disease. Targeted drug delivery system.

10. The targeted drug delivery system of claim 9, wherein the targeted antigenic determinant is a neoepitope on type II collagen or type II collagen fragment of articular cartilage.

An individual action of the enzyme wherein the targeted neoepitope is selected from the group consisting of matrix metalloproteinase (MMP) -1, MMP-3, MMP-8, and MMP-13 and other members of the MMP family; 12. The targeted drug delivery system of claim 11, wherein the targeted drug delivery system is immunolocalized at a cleavage site generated by their combined action.

10. The targeted drug delivery system of claim 9, wherein the targeted epitope or neoepitope is present on aggrecan, biglycan, or decorin of articular cartilage.

10. The targeted drug delivery system of claim 9, wherein the targeted epitope or neoepitope is on an aggrecan or aggrecan fragment of articular cartilage.

The targeted neoepitope is immunolocalized at a cleavage site generated by the action of an enzyme belonging to the group consisting of a disintegrin having a thrombospondin motif and a metalloproteinase (ADAMTS) family and / or MMP family The targeted drug delivery system of claim 14.

16. The targeted neoepitope is immunolocalized at a cleavage site generated by individual or combined action of ADAMTS-4 and / or ADAMTS-5 / 11 enzymes. Targeted drug delivery system.

4. The targeted drug delivery system of claim 3, wherein the targeted antibody or antibody fragment is a humanized antibody, a chimeric antibody, or a human monoclonal antibody.

The targeted drug delivery system of claim 2, wherein the anabolic cartilage protective agent is included in the targeted delivery vehicle.

The anabolic cartilage protective agent includes an interleukin (IL) agonist that promotes cartilage anabolism, a member of the transforming growth factor β superfamily that promotes cartilage anabolism (TGF-β agonist and bone morphogenetic protein (BMP) agonist) ), An insulin-like growth factor that promotes cartilage anabolism, and a fibroblast growth factor that promotes cartilage anabolism.

The anabolic cartilage protective agent is IL-4, IL-10, IL-13, TGFβ1, TGFβ2, TGFβ3, BMP-2, BMP-4, BMP-6, BMP-7, IGF-1, bFGF, and natural. The targeted drug delivery system of claim 2, wherein the targeted drug delivery system is selected from the group consisting of fragments, deletions, adducts, amino acid substitutions, variants, and variants that retain the biological characteristics of the drug present in .

A member of the transforming growth factor β superfamily (TGF-β agonist and bone morphogenetic protein (BMP) agonist) in which the anabolic cartilage protective agent promotes cartilage anabolism; an insulin-like growth factor that promotes cartilage anabolism; and cartilage 3. The targeted drug delivery system of claim 2, wherein the targeted drug delivery system is selected from the group consisting of fibroblast growth factors that promote assimilation.

The targeted drug delivery system of claim 2, wherein the cartilage catabolism inhibitor is included in the targeted delivery vehicle.

IL-1 receptor antagonist inhibiting cartilage catabolism, TNF-α receptor antagonist inhibiting cartilage catabolism, cyclooxygenase-2 specific inhibitor inhibiting cartilage catabolism, MAP kinase inhibitor inhibiting cartilage catabolism, cartilage 3. The targeted drug delivery system of claim 2, selected from the group consisting of nitric oxide synthase inhibitors that inhibit catabolism and nuclear factor kappa B inhibitors that inhibit cartilage catabolism.

A matrix metalloproteinase inhibitor that inhibits cartilage catabolism; cell adhesion molecules that inhibit cartilage catabolism (including integrin agonists and integrin antagonists); intracellular signaling inhibitors that inhibit cartilage catabolism (protein kinase C inhibitors and 3. A targeted drug delivery system according to claim 2 selected from the group consisting of: protein tyrosine kinase inhibitors); and SH2 domain inhibitors that inhibit cartilage catabolism.

The targeted drug delivery system of claim 2, wherein the cartilage catabolism inhibitor comprises an agent selected from an IL-1 receptor antagonist that inhibits cartilage catabolism and a TNF-α receptor antagonist that inhibits cartilage catabolism.

The targeted drug delivery system of claim 2, wherein each of the anabolic cartilage protective agent and cartilage catabolism inhibitor comprises a protein.

3. The targeted drug delivery system of claim 2, wherein both the anabolic cartilage protectant and the cartilage catabolism inhibitor are included in a targeted delivery vehicle.

The targeted drug delivery system includes a plurality of targeted delivery vehicles, wherein the anabolic cartilage protective agent and cartilage catabolism inhibitor are respectively in first and second vehicles of the plurality of targeted delivery vehicles. The targeted drug delivery system of claim 2, which is separately contained in

29. The targeted drug delivery system of claim 28, wherein the first and second targeted delivery vehicles are selected to produce temporarily different release rates for the anabolic chondroprotectant and cartilage catabolism inhibitor included. .

The targeted drug delivery system of claim 2, wherein the targeted delivery vehicle comprises targeted immune particles.

32. The targeted drug delivery system of claim 30, wherein the targeted immune particle comprises a nanoparticle.

32. The targeted drug delivery system of claim 31, wherein the nanoparticles have a diameter in the range of 5 nanometers to 750 nanometers.

32. The targeted drug delivery system of claim 31, wherein the nanoparticles have a diameter in the range of 10 nanometers to 500 nanometers.

32. The targeted drug delivery system of claim 31, wherein the nanoparticles have a diameter in the range of 20 nanometers to 200 nanometers.

32. The target of claim 31, wherein the nanoparticles are formed from a polymer selected from the group consisting of hyaluronan, chitosan, collagen, gelatin, alginate, polylactic acid (PLLA), polyglycolic acid (PGA), and PLGA. Drug delivery system.

32. The targeted drug delivery system of claim 31, wherein the nanoparticles provide a sustained release of the chondroprotectant over a period of 1 day to 4 weeks.

The targeted drug delivery system of claim 2, further comprising a carrier suitable for intravenous, intramuscular, subcutaneous, or inhalation administration.

The targeted drug delivery system of claim 2 further comprising one or more additional therapeutic agents.

The targeted drug delivery system of claim 2, further comprising one or more pain inhibitors or inflammation inhibitors.

The pain inhibitor or inflammation inhibitor is a serotonin receptor antagonist, serotonin receptor agonist, histamine receptor antagonist, bradykinin receptor antagonist, kallikrein inhibitor, tachykinin receptor antagonist, calcitonin gene-related peptide (CGRP) receptor antagonist, interleukin receptor antagonist, arachidonic acid Inhibitors of enzymes active in metabolic synthesis pathways, prostanoid receptor antagonists, leukotriene receptor antagonists, opioid receptor agonists, purinoceptor agonists and antagonists, adenosine triphosphate (ATP) sensitive potassium channel openers, and calcium channel antagonists It is selected from Ranaru group, targeted drug delivery system according to claim 39.

A targeted drug delivery system for cartilage protection, the delivery system comprising a plurality of cartilage protectants, at least one of which is targeted to a hyaline cartilage molecule, cell or structure. And wherein the plurality of chondroprotective agents includes at least one anabolic cartilage protectant and at least one cartilage catabolism inhibitor, each of the plurality of cartilage protectants comprising the plurality of cartilage protectants. A targeted drug delivery system wherein is included in a therapeutically effective amount to inhibit cartilage catabolism and promote cartilage assimilation.

A targeted drug delivery system for cartilage protection comprising a therapeutically effective amount of at least one cartilage protectant, wherein the cartilage protectant is an anabolic cartilage protectant or a cartilage catabolism inhibitor; A targeted drug delivery system comprised in a targeted immune particle coupled to an antibody or antibody fragment specific for an antigenic determinant present in a joint.

A targeted drug delivery system for cartilage protection, the delivery system comprising a therapeutically effective amount of an anabolic cartilage protectant contained in a delivery vehicle targeted to the joint.

A targeted drug delivery system for cartilage protection comprising a therapeutically effective amount of an anabolic cartilage protectant contained in a delivery vehicle targeted to a hyaline cartilage molecule, cell, or structure , Targeted drug delivery systems.

A kit for protecting the patient's cartilage, the kit includes a targeted drug delivery system, the delivery system includes a plurality of chondroprotective agents contained in the delivery vehicle, said delivery vehicle, intraarticular Wherein the plurality of chondroprotective agents comprises at least one anabolic cartilage protectant and at least one cartilage catabolism inhibitor, each of which comprises A kit comprising a plurality of cartilage protective agents in a therapeutically effective amount to inhibit cartilage catabolism and promote cartilage assimilation.

A kit for protecting the patient's cartilage, the kit comprises a plurality of chondroprotective agents, wherein at least one of said chondroprotective agent is contained within a delivery vehicle which is targeted to joint The plurality of cartilage protectants comprises at least one anabolic cartilage protectant and at least one cartilage catabolism inhibitor, wherein each of the plurality of cartilage protectants inhibits cartilage catabolism. And a kit comprising a therapeutically effective amount to promote cartilage anabolism , and wherein the plurality of cartilage protective agents are administered simultaneously to the patient .

A kit for protecting the patient's cartilage, the kit comprises a plurality of chondroprotective agents, wherein at least one of chondroprotective agents, targeted to neo-epitopes associated with degeneration of articular cartilage Wherein the plurality of cartilage protectors comprises at least one anabolic cartilage protectant and at least one cartilage catabolism inhibitor, each of the plurality of cartilage protectants comprising the plurality of cartilage protectors A kit wherein the agent is included in a therapeutically effective amount to inhibit cartilage catabolism and promote cartilage assimilation , and the plurality of cartilage protective agents are administered to the patient simultaneously .

A kit for protecting the patient's cartilage, the kit comprises a plurality of chondroprotective agents, wherein at least one of chondroprotective agents, targeting to a molecule of hyaline cartilage, cells or structures, Wherein the plurality of cartilage protectors comprises at least one anabolic cartilage protectant and at least one cartilage catabolism inhibitor, each of the plurality of cartilage protectants comprising the plurality of cartilage protectors A kit wherein the agent is included in a therapeutically effective amount to inhibit cartilage catabolism and promote cartilage assimilation , and the plurality of cartilage protective agents are administered to the patient simultaneously .