Biodegradable, semi-crystalline, phase separated, thermoplastic multi block copolymers for controlled release of biologically active compounds

Abstract

This invention is directed to a biodegradable, semi-crystalline, phase separated thermoplastic multi-block copolymer, a process for preparing said multi-block copolymer, a composition for the delivery of at least one biological active compound, and to a method for delivering a biologically active compound to a subject in need thereof. A multi-block copolymer of the invention is characterised in that: a) it comprises at least one hydrolysable pre-polymer (A) segment and at least one hydrolysable pre-polymer (B) segment, b) said multi-block copolymer having a T g of 37° C. or less and a T m of 110-250° C. under physiological conditions; c) the segments are linked by a multifunctional chain-extender; d) the segments are randomly distributed over the polymer chain; e) at least part of the pre-polymer (A) segment is derived from a water-soluble polymer.

1 . Biodegradable, semi-crystalline, phase separated, thermoplastic multi-block copolymer, the copolymer being characterised in that:
 a) it comprises at least one hydrolysable pre-polymer (A) segment and at least one hydrolysable pre-polymer (B) segment,   b) said multi-block copolymer having a Tg of 37° C. or less and a Tm of 110-250° C. under physiological conditions;   c) the segments are linked by a multifunctional chain-extender;   d) the segments are randomly distributed over the polymer chain;   e) at least part of the pre-polymer (A) segment is derived from a water-soluble polymer.   
     
     
         2 . Biodegradable, semi-crystalline, phase separated, thermoplastic multi-block copolymer according to  claim 1 , wherein said chain-extender is a difunctional aliphatic chain-extender, preferably a diisocyanate, such as 1,4-butane diisocyanate. 
     
     
         3 . Biodegradable, semi-crystalline, phase separated, thermoplastic multi-block copolymer according to  claim 1 , wherein pre-polymer (A) comprises reaction products of cyclic monomers and/or non cyclic monomers, wherein said non cyclic monomers are preferably selected from the group consisting of succinic acid, glutaric acid, adipic acid, sebacic acid, lactic acid, glycolic acid, hydroxybutyric acid, ethylene glycol, diethylene glycol, 1,4-butanediol and/or 1,6-hexanediol, and wherein said cyclic monomers are preferably selected from the group consisting of glycolide, lactide, ε-caprolactone, δ-valerolactone, trimethylene carbonate, tetramethylenecarbonate, 1,5-dioxepane-2-one, 1,4-dioxane-2-one (para-dioxanone) and/or cyclic anhydrides such as oxepane-2,7-dione. 
     
     
         4 . Biodegradable, semi-crystalline, phase separated, thermoplastic multi-block copolymer according to  claim 1 , wherein said water-soluble polymer is selected from the group consisting of polyethers such as polyethylene glycol (PEG), polytetramethyleneoxide (PTMO) and polypropyleneglycol (PPG); polyvinylalcohol (PVA) polyvinylpyrrolidone (PVP), polyvinylcaprolactam, poly(hydroxyethylmethacrylate) (poly-(HEMA)), polyphosphazenes, polyorthoesters, polyorthoesteramides or copolymers of the previous polymers, preferably said water-soluble polymer is derived from poly(ethylene glycol) (PEG) having a Mn of 150-5000 g/mol. 
     
     
         5 . Biodegradable, semi-crystalline, phase separated, thermoplastic multi-block copolymer according to  claim 1 , wherein a water-soluble polymer is present as an additional pre-polymer. 
     
     
         6 . Biodegradable, semi-crystalline, phase separated, thermoplastic multi-block copolymer according to  claim 1 , wherein said pre-polymer (B) segment comprises a crystallisable polymer derived from hydroxyalkanoate, glycolide, 1-lactide or d-lactide, preferably said pre-polymer (B) segment comprises 1-lactide pre-polymers and d-lactide pre-polymers in such amounts and ratio that stereocomplexation between 1-lactide and d-lactide is achieved,
 preferably said pre-polymer (B) is poly(1-lactic acid) with an Mn of 1000 g/mol or more, preferably 2000 g/mol or more, more preferably 3000 g/mol or more.   
     
     
         7 . Biodegradable, semi-crystalline, phase separated, thermoplastic multi-block copolymer according to  claim 1 , having a swelling ratio under physiological conditions varies from 1 to 4, more preferably 1 to 2, most preferably 1 to 1.5. 
     
     
         8 . Biodegradable, semi-crystalline, phase separated, thermoplastic multi-block copolymer according to  claim 1 , wherein said copolymer has an intrinsic viscosity of at least 0.1 dl/g, and preferably between 0.2 and 2 dl/g. 
     
     
         9 . Process for preparing a biodegradable, semi-crystalline, phase separated, thermoplastic multi-block copolymer according to  claim 1 , comprising
 i) performing a chain extension reaction of pre-polymer (A) and pre-polymer (B) in the presence of a multifunctional chain-extender, wherein pre-polymer (A) and (B) are both diol or diacid terminated and the chain-extender is di-carboxylic acid or diol terminated; or   ii) performing a chain extension reaction using a coupling agent, wherein pre-polymer (A) and (B) are both diol or diacid terminated and the coupling agent is preferably dicyclohexyl carbodiimide.   
     
     
         10 . Use of a biodegradable, semi-crystalline, phase separated, thermoplastic multi-block copolymer according to  claim 1 , preferably in the form of microspheres, microparticles, nanoparticles, nanospheres, rods, implants, gels, coatings, films, sheets, sprays, tubes, membranes, meshes, fibres, or plugs. 
     
     
         11 . A composition for the delivery of at least one biologically active compound to a host, comprising at least one biologically active compound encapsulated in a matrix, wherein said matrix comprises at least one biodegradable, semi-crystalline, phase separated, thermoplastic multi-block copolymer according to  claim 1 . 
     
     
         12 . A composition according to  claim 11 , wherein said at least one biologically active compound is a non-peptide non-protein small sized drug, or a biologically active polypeptide. 
     
     
         13 . A composition according to  claim 12 , wherein said non-peptide, non-protein small sized drug comprises one or more selected from the group consisting of an anti-tumour agent, an anti-microbial agent, a sephalosporin, an aminoglycoside, a macrolide, a tetracycline, a chemotherapeutic agent, a urinary tract antiseptic, a drug for anaerobic infections, a drug for tuberculosis, a drug for leprosy, an antifungal agent, an antiviral agent, an anti-helminthiasis agent, an anti-inflammatory agent, an anti-gout agent, a centrally acting (opoid) analgesic, a local anaesthetic, a drug for Parkinson's disease, a centrally acting muscle relaxant, a hormone or hormone anti-agonist, a corticosteroid, a glucocorticosteroid, an androgen, an androgenic steroid, an anabolic steroid, an anti-androgen, an estrogen, an estrogenic steroid, an anti-estrogen, a progestin, a thyroid drug and an anti-thyroid drug. 
     
     
         14 . A composition according to  claim 12 , wherein said biologically active polypeptide comprises one or more selected from the group consisting of a protein/peptide drug, an enzyme, a receptor ligand, a neurotransmitter, an inhibitory peptide, a regulatory peptide, an activator peptide, a cytokine, a growth factor, a monoclonal antibody, a monoclonal antibody fragment, an anti-tumour peptide, an antibiotic, an antigen, a vaccine, and a hormone. 
     
     
         15 . Composition according to  claim 11 , wherein said biologically active compound is a non-peptide, non-protein small molecule having an Mn which is 1000 Da or less, preferably said multi-block copolymer contains poly(ethylene glycol), as a segment of pre-polymer (A) and/or as an additional pre-polymer, wherein said poly(ethylene glycol)
 i) has a molecular weight of from 200 to 1500 g/mol, preferably from 600 to 1000 g/mol; and/or   ii) is present in an amount of from 5 wt. % to 20 wt. %, preferably of from 5 wt. % to 10 wt. %.   
     
     
         16 . Composition according to  claim 11 , wherein said biologically active compound is a biologically active polypeptide having a molecular weight which is 10 000 Da or less,
 preferably said multi-block copolymer contains poly(ethylene glycol), as a segment of pre-polymer (A) and/or as an additional pre-polymer, and wherein said poly(ethylene glycol)   i) has a molecular weight of from 400 to 3000 g/mol, preferably from 600 to 1500 g/mol; and/or   ii) is present in an amount of from 5 wt. % to 60 wt. %, preferably of from 5 wt. % to 40 wt. %.   
     
     
         17 . Composition according  claim 11 , wherein said biologically active compound is a biologically active polypeptide having a molecular weight of 10 000 Da or more, preferably said multi-block copolymer contains poly(ethylene glycol), as a segment of pre-polymer (A) and/or as an additional pre-polymer, and wherein said poly(ethylene glycol)
 i) has a molecular weight of from 600 to 5000 g/mol, preferably of from 1000 to 3000 g/mol; and/or   ii) is present in an amount of from 5 wt. % to 70 wt. %, more preferably of from 10 wt. % to 50 wt. %.   
     
     
         18 . Composition according to  claim 11 , in the form of microspheres, microparticles, nanoparticles, nanospheres, rods, implants, gels, coatings, films, sheets, sprays, tubes, membranes, meshes, fibres, or plugs. 
     
     
         19 . Composition according to  claim 11 , wherein the average diameter of the microspheres and/or microparticles is preferably in the range of 0.1-1000 μm, more preferably in the range of 1-100 μm, even more preferably in the range of 10-50 μm. 
     
     
         20 . Composition according to  claim 19 , wherein the biologically active compound is dissolved or dispersed throughout the polymer matrix. 
     
     
         21 . Composition according to  claim 19 , wherein the microsphere comprises a reservoir wherein biologically active compound is contained, surrounded by a polymer in mononuclear or polynuclear state. 
     
     
         22 . Composition according to  claim 11  for treating rheumatoid arthritis, hepatitis, diabetes, metabolic syndromes, osteoarthritis, renal disease, inflammation, local pain processes, local infections, local skin diseases, tumours (or their sites after surgical removal as a postoperative treatment to destroy any tumour cells possibly remaining), prostate or breast cancer, agromegaly, ocular diseases such as age-related macular degeneration, local brain diseases such as Parkinson's disease, and cardiovascular diseases such as acute myocardial infarction, chronic heart failure or arthrosclerosis. 
     
     
         23 . A method for delivering a biologically active compound to a subject in need thereof, comprising administering an effective dose of a composition according to  claim 11 . 
     
     
         24 . A method of manufacturing a composition according to  claim 19 , comprising the successive steps of
 a) emulsifying an aqueous solution of a water-soluble biologically active compound in a solution of a biodegradable, semi-crystalline, phase separated, thermoplastic multi-block copolymer comprising at least one hydrolysable pre-polymer (A) segment and at least one hydrolysable pre-polymer (B) segment; said multi-block copolymer having a Tg of 37° C. or less and a Tm of 110-250° C. under physiological conditions; the segments are linked by a multifunctional chain-extender; the segments are randomly distributed over the polymer chain; and at least part of the pre-polymer (A) segment is derived from a water-soluble polymer, in an organic solvent, such as dichloromethane or ethyl acetate;   b) subsequently emulsifying the resultant emulsion of a) in an aqueous solution comprising a surfactant such as polyvinyl alcohol, thereby yielding a water-in-oil-in-water (W/O/W) emulsion; and   c) extracting the organic solvent to solidify microspheres.   
     
     
         25 . A method of manufacturing a composition according to  claim 19 , comprising the successive steps of
 a) dispersing the biologically active compound as a solid powder in a solution of a biodegradable, semi-crystalline, phase separated, thermoplastic multi-block copolymer comprising at least one hydrolysable pre-polymer (A) segment and at least one hydrolysable pre-polymer (B) segment: said multi-block copolymer having a Tg of 37° C. or less and a Tm of 110-250° C. under physiological conditions; the segments are linked by a multifunctional chain-extender; the segments are randomly distributed over the polymer chain; and at least part of the pre-polymer (A) segment is derived from a water-soluble polymer, in an organic solvent, such as dichloromethane or ethyl acetate;   b) emulsifying the resultant dispersion of a) in an aqueous solution comprising a surfactant such as polyvinyl alcohol, thereby yielding a solid-in-oil-in-water (S/O/W) emulsion; and   c) extracting the organic solvent to solidify the microspheres.   
     
     
         26 . A method of manufacturing a composition according to  claim 1 , comprising the successive steps of
 a) emulsifying an aqueous solution of a water-soluble biologically active compound in a solution of a biodegradable, semi-crystalline, phase separated, thermoplastic multi-block copolymer comprising at least one hydrolysable pre-polymer (A) segment and at least one hydrolysable pre-polymer (B) segment; said multi-block copolymer having a Tg of 37° C. or less and a Tm of 110-250° C. under physiological conditions; the segments are linked by a multifunctional chain-extender; the segments are randomly distributed over the polymer chain; and at least part of the pre-polymer (A) segment is derived from a water-soluble polymer, in an organic solvent, such as dichloromethane or ethyl acetate;   b) adding a polymer precipitant, such as silicon oil, to the resultant emulsion of a) to form embryonic microparticles; and   c) extracting the polymer precipitant and the organic solvent to solidify the microspheres.   
     
     
         27 . A method of manufacturing a composition according to  claim 19 , comprising the successive steps of
 a) dispersing the biologically active compound as a solid powder in a solution of a biodegradable, semi-crystalline, phase separated, thermoplastic multi-block copolymer comprising at least one hydrolysable pre-polymer (A) segment and at least one hydrolysable pre-polymer (B) segment: said multi-block copolymer having a Tg of 37° C. or less and a Tm of 110-250° C. under physiological conditions; the segments are linked by a multifunctional chain-extender; the segments are randomly distributed over the polymer chain; and at least part of the pre-polymer (A) segment is derived from a water-soluble polymer, in an organic solvent, such as dichloromethane or ethyl acetate;   b) adding a polymer precipitant, such as silicon oil, to the resultant dispersion of a) to form embryonic microparticles; and   c) extracting the polymer precipitant and the organic solvent to solidify the microspheres.