Composition and device for in vivo cartilagerepair

Abstract

The composition as described serves for in vivo cartilage repair. It basically consists of a naturally derived osteoinductive and/or chondroinductive mixture of factors (e.g. derived from bone) or of a synthetic mimic of such a mixture combined with a nanosphere delivery system. A preferred mixture of factors is the combination of factors isolated from bone, known as BP and described by Poser and Benedict (WO 95/13767). The nanosphere delivery system consists of nanospheres defined as polymer particles of less than 1000 nm in diameter (whereby the majority of particles preferably ranges between 200-400 nm) in which nanospheres the combination of factors is encapsulated. The nano-spheres are loaded with the mixture of factors in a weight ratio of 0.001 to 17% (w/w), preferably of 1 to 4% (w/w) and have a release profile with an initial burst of 10 to 20% of the total load over the first 24 hours and a long time release of at least 0.1 per day during at least seven following days. The nanospheres are composed of e.g. ((D,L)-lactic acid/glycolic acid)-copolymer (PLGA). The loaded nanospheres are e.g. made by phase inversion. The composition is advantageously utilized as a device comprising any biodegradable matrix in which the nanospheres loaded with the factor combination is contained.

1 . Composition for inducing in vivo cartilage repair comprising an osteoinductive and/or chondroinductive mixture of factors derived from natural tissue or a sythetic mimic of such a mixture encapsulated in nanospheres, whereby the nanospheres are polymer particles having a size of less than 1000 nm and an in vitro analytically determined release rate profile with an initial burst of 10 to 20% of the total load over the first 24 hours and a long time release of at least 0.1% per day during at least seven following days and whereby the nanospheres are loaded with between 0.001 and 17% weight percent of the mixture of factors.  
     
     
         2 . Composition according to  claim 1 , characterized in that the long term release is between 0.1 and 1% of the total load per day over between 40 and 70 days.  
     
     
         3 . Composition according to  claim 1  or  2 , characterized in that the osteoinductive and/or chondroinductive mixture of factors is derived from bone, cartilage, tendon, meniscus or ligament.  
     
     
         4 . Composition according to  claim 1  or  2 , characterized in that the osteoinductive and/or chondroinductive mixture of factors is the mixture known as BP (bone protein) derived from bovine long bones and partly purified.  
     
     
         5 . Composition according to  claim 4 , characterized, in that the nanospheres are loaded with between 1 and 4% weight percent of BP.  
     
     
         6 . Composition according to one of  claims 1  to  5 , characterized in that the nanospheres consist of ((D,L)lactic acid/glycolic acid)-copolymer containing 20 to 80% of lactic acid and 80 to 20% of glycolic acid.  
     
     
         7 . Composition according to one of  claims 1  to  5 , characterized in that the ((D,L)lactic acid/glycolic acid)-copolymer contains 50% of lactic acid and 50% of glycolic acid.  
     
     
         8 . Composition according to one of  claims 1  to  7 , characterized in that the nanospheres are made by phase inversion.  
     
     
         9 . Device containing the composition according to one of  claims 1  to  8  and further comprising a porous biodegradable matrix.  
     
     
         10 . Device according to  claim 9 , characterized in that it contains at least 2 μg of loaded nanospheres per ml.  
     
     
         11 . Device according to  claim 9 , characterized in that it contains at least 20 ng of the osteoinductive and/or chondroinductive mixture of factors per ml.  
     
     
         12 . Device according to one of  claims 9  to  11 , characterized in that the matrix has the form of a sponge, membrane, film or gel.  
     
     
         13 . Device according to one of  claims 9  to  12 , characterized in that the matrix consists of collagen type I, collagen type II or hyaluronic acid.  
     
     
         14 . Use of the composition according to one of  claims 1  to  8  for preparing a device for in vivo cartilage repair.  
     
     
         15 . Use according to  claim 14 , characterized in that the cartilage is articular cartilage or meniscus cartilage.  
     
     
         16 . Use of the composition according to one of  claims 1  to  8  for cartilage repair on an animal with a degenerative disease.  
     
     
         17 . Use of the device according to one of  claims 9  to  13  for cartilage repair on an animal with a degenerative disease.  
     
     
         18 . Method for in vivo cartilage repair comprising the step of filling a cartilage defect with a device according to one of  claims 9  to  13 .  
     
     
         19 . Method according to  claim 18 , characterized in that the defect is dressed before filling.  
     
     
         20 . Method for in vitro cartilage repair comprising the step of applying to the cartilage defect a composition according to one of  claims 1  to  8 .  
     
     
         21 . Method according to  claim 20 , characterized in that the composition is applied by injection.  
     
     
         22 . Method according to  claim 20  or  21 , characterized in that the composition is applied in an amount of at least 2 μg per ml defect size.  
     
     
         23 . Method according to  claim 20  or  21 , characterized in that the composition is applied in an amount such that the osteoinductive and/or chondroinductive mixture is present in the defect in an amount of at least 20 ng per ml defect size.