Method for morselizing and/or targeting pharmaceutically active principles to synovial tissue

Abstract

A method of targeting to the synovial tissue biodegradable drug delivery compositions or morselizing biodegradable drug delivery compositions are described. The biodegradable drug composition comprises a triblock copolymer containing a polyester and a polyethylene glycol and a diblock copolymer containing a polyester and an end-capped polyethylene glycol, as well as at least one pharmaceutically active principle is disclosed.

1 . A method for morselizing a biodegradable drug delivery composition comprising at least one pharmaceutically active principle comprising:
 (1) formulating a biodegradable drug composition comprising   (a) a biodegradable triblock copolymer having the formula:
   PLA v -PEG w -PLA x    
   
       wherein v and x are the number of repeat units ranging from 24 to 682 and w is the number of repeat units ranging from 4 to 273 and v=x or v≠x;
 (b) a biodegradable diblock copolymer having the formula:
   mPEG y -PLA z    
 
 wherein y are the number of repeat units with y ranging from 3 to 45 and z ranging from 7 to 327, d wherein the ratio of the biodegradable triblock copolymer of (a) and the biodegradable diblock copolymer of (b) is 3:2 to 1:19 in said biodegradable drug composition the and (c) at least one pharmaceutically active principle; 
 (2) administering said formulated biodegradable drug delivery composition in at least one joint of a patient, such that it is contained within the articulating joint capsule. 
 
     
     
         2 . The method for morselizing according to  claim 1 , wherein said formulation of said biodegradable drug delivery composition is taken up by syringe for administration and injected into said joint or manually formed in into a solid bolus by exposing the formulation to aqueous liquid and manual placement into the joint. 
     
     
         3 . The method for morselizing according to  claim 1 , wherein said formulation of said biodegradable drug delivery composition is subjected to a mechanical challenge. 
     
     
         4 . The method for morselizing according to  claim 3 , wherein said mechanical challenge is obtained by internal structures of the joints, articulation, weight bearing and/or by synovial tissue pressure. 
     
     
         5 . The method for morselizing according to  claim 1 , wherein the formulation of said biodegradable drug delivery composition is broken into pieces. 
     
     
         6 . The method for morselizing according to  claim 1 , wherein said at least one pharmaceutically active principle is present in said formulation in an amount of 1% to 85% w %/w %. 
     
     
         7 . The method for morselizing according to  claim 1 , wherein the polyethylene glycol chain in the triblock and the diblock ranges from 300 Da to 12 kDa. 
     
     
         8 . The method for morselizing according to  claim 7 , wherein the polyethylene glycol chain in the triblock or the diblock is 2 kDa. 
     
     
         9 . The method for morselizing according to  claim 1 , wherein the polylactic repeat unit to ethylene oxide molar ratio is 1.6 to 7.2 in the triblock and 1.9 to 4.8 in the diblock. 
     
     
         10 . The method for morselizing according to  claim 1 , wherein the degree of polymerization in the triblock is 72 to 324 and the degree of polymerization in the diblock is 85.5 to 216. 
     
     
         11 . The method for morselizing according to  claim 1 , wherein the triblock is present in an amount of 6% to 24% (wt %/wt %) and the diblock is present in an amount of 12% to 40% (wt %/wt %). 
     
     
         12 . The method for morselizing according to  claim 1 , wherein the formulation of said biodegradable drug composition comprises mixing the triblock copolymer with the diblock copolymer in a biocompatible organic solvent to form a triblock copolymer and diblock copolymer mixture. 
     
     
         13 . The method for morselizing according to  claim 12 , further comprising adding to said triblock copolymer and diblock copolymer mixture at least one pharmaceutically active principle. 
     
     
         14 . The method for morselizing according to  claim 12 , wherein the solvent is evaporated off. 
     
     
         15 . The method for morselizing according to  claim 13 , wherein said triblock copolymer and diblock copolymer mixture is further exposed to an aqueous liquid to form a solid bolus. 
     
     
         16 . The method for morselizing according to  claim 1 , wherein said pieces are broken down to smaller and smaller pieces. 
     
     
         17 . The method according to  claim 1 , wherein said at least one pharmaceutically active principle can be applied to post-surgical applications which are total knee replacements (TKR), total hip replacements (THR), joint surgeries, arthroscopic joint surgeries, open joint surgeries or non-surgical applications such as intra-articular injection for inflammatory diseases, mosaicplasty, microfracture, autologous chondrocyte implantation, osteoarticular transfer system, ligament and tendon repair, meniscus repair or unicompartmental knee replacement. 
     
     
         18 . The method according to  claim 1 , wherein the at least one pharmaceutically active principle can be applied to post-surgical applications which are total or partial knee replacements, total or partial hip replacements, total or partial ankle replacements, arthroscopic or open joint surgeries, microfracture, autologous chondrocyte implantation, mosaicplasty, debridement and lavage, ligament repair, tendon repair, rotator cuff repair, meniscus surgery, synovectomy or non-surgical applications by intra-articular injections for inflammatory disease or joint pain. 
     
     
         19 . The method for morselizing according to  claim 1 , wherein said administration to said patient is 0.1 to 6 ml for the knee, 0.1 to 6 ml for the hip, 0.1 to 4 ml for the ankle, 0.1 to 6 ml for the shoulder and 0.1 to 2 ml for the elbow. 
     
     
         20 . A biodegradable drug delivery composition comprising at least one pharmaceutically active principle comprising:
 (1) formulating a biodegradable drug composition comprising   (a) a biodegradable triblock copolymer having the formula:
   PLA v -PEG w -PLA x    
   
       wherein v and x are the number of repeat units ranging from 24 to 682 and w is the number of repeat units ranging from 4 to 273 and v=x or v≠x;
 (b) a biodegradable diblock copolymer having the formula:
   mPEG y -PLA z    
 
 wherein y are the number of repeat units with y ranging from 3 to 45 and z ranging from 7 to 327, the and wherein the ratio of the biodegradable triblock copolymer of (a) and the biodegradable diblock copolymer of (b) is 3:2 to 1:19 in said biodegradable drug composition; and 
 (c) at least one pharmaceutically active principle principle for morselization of said biodegradable drug delivery composition; 
 wherein said formulated biodegradable drug delivery is contained within the articulating joint capsule for morselization. 
 
     
     
         21 . A method for targeting at least one pharmaceutically active principle to at least one joint said method comprising administering to a mammal or animal in need of such treatment a biodegradable drug delivery composition comprising:
 (a) a biodegradable triblock copolymer having the formula:
   PLA v -PEG w -PLA x    
   
       wherein v and x are the number of repeat units ranging from 24 to 682 and w is the number of repeat units ranging from 4 to 273 and v=x or v≠x;
 (b) a biodegradable diblock copolymer having the formula:
   mPEG y -PLA z    
 
 
       wherein y and z are the number of repeat units with y ranging from 3 to 45 and z ranging from 7 to 327, wherein the ratio of the biodegradable triblock copolymer of (a) and the biodegradable diblock copolymer of (b) is 3:2 to 1:19 in said biodegradable drug composition; and (c) at least one pharmaceutically active principle. 
     
     
         22 . The method according to  claim 21 , wherein in the triblock copolymer v and x are ester repeat units and are ethylene oxide repeat units and in the diblock copolymer y are the number of ethylene oxide repeat units and z are the number of ester repeat units. 
     
     
         23 . The method according to  claim 21 , wherein the triblock copolymer is present in an amount of 2.0% to 45% (w %/w %) of the total composition and the diblock copolymer is present in an amount of 8.0% to 50% (w %/w %) of the total composition. 
     
     
         24 . The method according to  claim 21 , wherein the active principle is present in an amount of 1% to 20% (w %/w %) of the total composition. 
     
     
         25 . The method according to  claim 21 , wherein the total polymer content ranges from 20% to 50% (w %/w %) of the total composition and the at least one pharmaceutically active principle is present in an amount of 10% to 20% (w %/w %) of the total composition. 
     
     
         26 . The method according to  claim 21 , wherein said composition is a liquid that can be injected into at least one joint or are small solid particles that can be injected into the at least one joint or are rod implants or spatial formulations. 
     
     
         27 . The method according to  claim 21 , wherein the size of the polyethylene glycol chain ranges from 200 Da to 12 kDa or 194 Da to 12 kDa and the size of the end-capped polyethylene glycol chain ranges from 100 Da to 2 kDa or 164 Da to 2 kDa. 
     
     
         28 . The method to  claim 21 , further comprising a pharmaceutically acceptable vehicle. 
     
     
         29 . The method according to  claim 21 , wherein the polyester repeat unit to ethylene oxide molar ratio in the composition is between 0.5 to 3.5 or 0.5 to 22.3 in the triblock and 2 to 6 or 0.8 to 13 in the diblock. 
     
     
         30 . The method for targeting at least one pharmaceutically active principle to synovial tissue using biodegradable drug delivery compositions, wherein a lactic acid to ethylene oxide molar ratio in the composition is between 0.5 to 22.3 for the triblock copolymer and between 0.8 to 13 for the diblock copolymer. 
     
     
         31 . The method according to  claim 21 , wherein said synovial joint is a knee joint, an ankle joint, an elbow joint, an humerus joint, an ulna joint, pivot joints, ball and socket joints, hinge joints, shoulder joints, scapula joints, leg joints, fibula joints, saddle joints, wrist joints, finger joints and tibia joints. 
     
     
         32 . The method according to  claim 20 , wherein said pharmaceutically active principle can be applied to post-surgical applications which are total knee replacements (TKR), total hip replacements (THR), joint surgeries, arthroscopic joint surgeries, open joint surgeries or non-surgical applications, intra-articular injection for inflammatory diseases, mosaicplasty, microfracture, autologous chondrocyte implantation, osteoarticular transfer system, ligament and tendon repair, meniscus repair or unicompartmental knee replacement, total or partial knee replacements, total or partial hip replacements, total or partial ankle replacements, arthroscopic or open joint surgeries, debridement and lavage, rotator cuff repair, synovectomy or non-surgical applications by intra-articular injections for inflammatory disease or joint pain. 
     
     
         33 . The method according to  claim 21 , wherein said at least one pharmaceutically active principle is a peptide drug, a protein drug, a desensitizing agent, an antigen, a non-steroidal anti-inflammatory agent, an anti-inflammatory drug, an anaesthetic, an anti-oxidant agent, an anti-infective agent, a chemotherapeutic agents, an anti-nociceptive agent, DMOAD, anabolic agents, anti-catabolic agents, autophagy regulation agents, anti-osteoclast-mediated bone loss agents, nutraceutical agents, analgesic agents, biologicsi and mixtures thereof. 
     
     
         34 . The method according to  claim 33 , wherein said non-steroidal anti-inflammatory agent is etofenamate, celecoxib, apricoxib, rofecoxib, nabumetone, benorilate, etoricoxib, ampiroxicam, aminophemazone, valdecoxib, acetominophen, bufexamac, nimesulide, parecoxib, mefenamic acid, dexibuprofen, ibuprofen, flurbiprofen, aspirin, dexdetoprofen, diclofenac, diflunisal, etodolac, fenoprofen, firocoxib, flurbiprofen, indomethacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, loxomac, lumiracoxib, meclofenamic acid, meloxicam, naproxen, naprosyn, nimalox, oxaporozin, piroxicam, salsalate, sulindac, tenoxicam, tolfenamic acid, ropivicaine and mixtures thereof.