US2011046606A1PendingUtilityA1

Catheter injectable depot compositions and uses thereof

45
Assignee: DURECT CORPPriority: Nov 14, 2001Filed: Oct 18, 2010Published: Feb 24, 2011
Est. expiryNov 14, 2021(expired)· nominal 20-yr term from priority
Inventors:Guohua ChenPaul R. HoustonLothar W. KleinerJohn Spaltro
A61P 43/00A61P 7/02A61P 37/06A61P 5/06A61P 31/00A61P 35/00A61P 27/02A61P 29/00A61K 47/10A61K 9/0024A61K 47/14A61K 47/34A61P 23/02A61K 9/08
45
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Claims

Abstract

Catheter injectable depot compositions are provided that include a bioerodible, biocompatible polymer, a solvent having miscibility in water of less than or equal to 7 wt. % at 25° C., in an amount effective to plasticize the polymer and form a gel therewith, a thixotropic agent, and a beneficial agent. The solvent comprises an aromatic alcohol, an ester of an aromatic acid, an aromatic ketone, or mixtures thereof. The compositions are have substantially improved the shear thinning behavior and reduced injection force, rendering the compositions readily implanted beneath a patient's body surface by injection.

Claims

exact text as granted — not AI-modified
1 . A catheter injectable depot composition comprising:
 (a) a bioerodible, biocompatible polymer;   (b) a solvent having miscibility in water of less than or equal to 7% at 25° C., in an amount effective to plasticize the polymer and form a gel therewith, wherein said solvent is an aromatic alcohol;   (c) a thixotropic amount of a thixotropic agent mixed with the polymer solution effective to form a thixotropic composition, the thixotropic agent being selected from the group consisting essentially of lower alkanols and said amount being less than 15 weight percent of the combined weight of the solvent and the thixotropic agent; and   (d) a beneficial agent.   
     
     
         2 . A catheter injectable depot composition comprising:
 (a) a bioerodible, biocompatible polymer;   (b) a solvent selected from the group consisting of aromatic alcohols, esters of aromatic acids, aromatic ketones, and mixtures thereof, said solvent having miscibility in water of less than or equal to 7% at 25° C., and present in an amount effective to plasticize the polymer and form a gel therewith;   (c) a thixotropic amount of a thixotropic agent mixed with the polymer solution effective to form a thixotropic composition, the thixotropic agent being selected from the group consisting essentially of lower alkanols and said amount being less than 15 weight percent of the combined weight of the solvent and the thixotropic agent; and   (d) a beneficial agent.   
     
     
         3 . The catheter injectable depot composition of  claim 1  or  claim 2 , wherein the aromatic alcohol has the structural formula (I)
   Ar-(L) n -OH 
 wherein Ar is aryl or heteroaryl, n is zero or 1, and L is a linking moiety. 
 
     
     
         4 . The catheter injectable depot composition of  claim 3 , wherein Ar is monocyclic aryl or heteroaryl, n is 1, and L is lower alkylene optionally containing at least one heteroatom. 
     
     
         5 . The catheter injectable depot composition of  claim 4 , wherein Ar is monocyclic aryl and L is lower alkylene. 
     
     
         6 . The catheter injectable depot composition of  claim 5 , wherein Ar is phenyl and L is methylene. 
     
     
         7 . The catheter injectable depot composition of  claim 2 , wherein the solvent is mixture of an aromatic alcohol and an ester of an aromatic acid. 
     
     
         8 . The catheter injectable depot composition of  claim 7 , wherein the aromatic alcohol is benzyl alcohol and the ester of an aromatic acid is a lower alkyl ester or an aralkyl ester of benzoic acid. 
     
     
         9 . The catheter injectable depot composition of  claim 8 , wherein the ester of an aromatic acid is benzyl benzoate and the lower alkyl ester of an aromatic acid is ethyl benzoate. 
     
     
         10 . The catheter injectable depot composition of  claim 1  or  claim 2  wherein the thixotropic agent is ethanol. 
     
     
         11 . The catheter injectable depot composition of  claim 10  wherein the amount of ethanol is greater than or equal to 0.01 weight percent and less than or equal to 15 weight percent of the combined weight of the solvent and the thixotropic agent. 
     
     
         12 . The catheter injectable depot composition of  claim 10  wherein the amount of ethanol is greater than or equal to 0.1 weight percent and less than or equal to 5 weight percent of the combined weight of the solvent and the thixotropic agent. 
     
     
         13 . The catheter injectable depot composition of  claim 10  wherein the amount of ethanol is greater than or equal to 0.5 weight percent and less than or equal to 5 weight percent of the combined weight of the solvent and the thixotropic agent. 
     
     
         14 . The catheter injectable depot composition of  claim 1  or  claim 2 , wherein the polymer is selected from the group consisting of polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamines, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyphosphoesters, polyorthocarbonates, polyphosphazenes, succinates, poly(malic acid), poly(amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, chitin, chitosan, hyaluronic acid, and copolymers, terpolymers and mixtures thereof. 
     
     
         15 . The catheter injectable depot composition of  claim 1  or  claim 2 , wherein the polymer is a lactic acid-based polymer. 
     
     
         16 . The catheter injectable depot composition of  claim 15 , wherein the polymer is a copolymer of at least two of the following monomers: lactic acid, glycolic acid and caprolactone. 
     
     
         17 . The catheter injectable depot composition of  claim 1  or  claim 2 , further including at least one of the following: a pore former; a solubility modulator for the beneficial agent; and an osmotic agent. 
     
     
         18 . The catheter injectable depot composition of  claim 1  or  claim 2  wherein the beneficial agent is selected from a drug, proteins, enzymes, hormones, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, polypeptides, steroids, analgesics, local anesthetics, antibiotic agents, chemotherapeutic agents, immunosuppressive agents, anti-inflammatory agents, antiproliferative agents, antimitotic agents, angiogenic agents, anticoagulants, fibrinolytic agents, growth factors, antibodies, ocular drugs, and metabolites, analogs, derivatives, and fragments thereof. 
     
     
         19 . The catheter injectable depot composition of  claim 18  wherein the beneficial agent is a growth hormone. 
     
     
         20 . The catheter injectable depot composition of  claim 18  wherein the beneficial agent is a growth factor. 
     
     
         21 . The catheter injectable depot composition of  claim 20  wherein the growth factor is selected from epidermal growth factors (EGFs), platelet-derived growth factor (PDGFs), insulin-like growth factors (IGFs), fibroblast-growth factors (FGFs), transforming-growth factors (TGFs), interleukins (ILs), colony-stimulating factors (CSFs, MCFs, GCSFs, GMCSFs), Interferons (IFNs), endothelial growth factors (VEGF, EGFs), erythropoietins (EPOs), angiopoietins (ANGs), placenta-derived growth factors (PIGFs), and hypoxia induced transcriptional regulators (HIFs). 
     
     
         22 . The catheter injectable depot composition of  claim 18  wherein the beneficial agent is present in an amount of from 0.1 to 50% by weight of the combined amounts of the polymer, the solvent and the beneficial agent. 
     
     
         23 . The catheter injectable depot composition of  claim 18  wherein the beneficial agent is in the form of particles dispersed or dissolved in the viscous gel. 
     
     
         24 . The catheter injectable depot composition of  claim 23  wherein the beneficial agent is in the form of particles having an average particle size of from 0.1 to 250 microns. 
     
     
         25 . A catheter injectable depot composition comprising:
 (a) approximately 5 wt. % to approximately 90 wt. % of a bioerodible, biocompatible polymer;   (b) an aromatic alcohol having miscibility in water of less than or equal to 7% at 25° C., in an amount effective to plasticize the polymer and form a gel therewith, wherein the aromatic alcohol has the structural formula (I)
   Ar-(L) n -OH  (I)
 
   in which Ar is a substituted or unsubstituted aryl or heteroaryl group, n is zero or 1, and L is a linking moiety;   (c) a thixotropic amount of a thixotropic agent mixed with the polymer solution effective to form a thixotropic composition, the thixotropic agent being selected from the group consisting essentially of lower alkanols and said amount being less than 15 weight percent of the combined weight of the solvent and the thixotropic agent; and   (d) a beneficial agent.   
     
     
         26 . A catheter injectable depot composition comprising:
 (a) approximately 5 wt. % to approximately 90 wt. % of a biodegradable, biocompatible lactic acid-based polymer having a weight average molecular weight in the range of approximately 1,000 to approximately 120,000;   (b) an aromatic alcohol having miscibility in water of less than or equal to 7% at 25° C., in an amount effective to plasticize the polymer and form a gel therewith, wherein the aromatic alcohol has the structural formula (I)
   Ar-(L) n -OH  (I)
 
   in which Ar is a substituted or unsubstituted aryl or heteroaryl group, n is zero or 1, and L is a linking moiety;   (c) a thixotropic amount of a thixotropic agent mixed with the polymer solution effective to form a thixotropic composition, the thixotropic agent being selected from the group consisting essentially of lower alkanols and said amount being less than 15 weight percent of the combined weight of the solvent and the thixotropic agent; and   (d) a beneficial agent.   
     
     
         27 . A catheter injectable depot composition comprising:
 (a) approximately 5 wt. % to approximately 90 wt. % of a biodegradable, biocompatible lactic acid-based polymer having a weight average molecular weight in the range of approximately 1,000 to approximately 120,000;   (b) a solvent selected from the group consisting of an aromatic alcohol, an ester of an aromatic acid, and mixtures thereof, said solvent having miscibility in water of less than or equal to 7% at 25° C., and present in an amount effective to plasticize the polymer and form a gel therewith, wherein the aromatic alcohol has the structural formula (I)
   Ar-(L) n -OH  (I)
 
   in which Ar is a substituted or unsubstituted aryl or heteroaryl group, n is zero or 1, and L is a linking moiety;   (c) a thixotropic amount of a thixotropic agent mixed with the polymer solution effective to form a thixotropic composition, the thixotropic agent being selected from the group consisting essentially of lower alkanols and said amount being less than 15 weight percent of the combined weight of the solvent and the thixotropic agent; and   (d) a beneficial agent.   
     
     
         28 . The catheter injectable depot composition of any one of  claim 25 ,  26  or  27 , wherein the polymer represents approximately 10 wt. % to approximately 85 wt. % of the composition. 
     
     
         29 . The catheter injectable depot composition of  claim 28 , wherein the polymer represents approximately 20 wt. % to approximately 75 wt. % of the composition. 
     
     
         30 . The catheter injectable depot composition of  claim 25 , wherein the polymer is selected from the group consisting of polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamines, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyphosphoesters, polyorthocarbonates, polyphosphazenes, succinates, poly(malic acid), poly(amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, chitin, chitosan, hyaluronic acid, and copolymers, terpolymers and mixtures thereof. 
     
     
         31 . The catheter injectable depot composition of any one of  claim 25 ,  26  or  27 , wherein the polymer is a copolymer of lactic acid and glycolic acid. 
     
     
         32 . The catheter injectable depot composition of  claim 31 , wherein the polymer is a copolymer of at least two of the following monomers: lactic acid, glycolic acid and caprolactone. 
     
     
         33 . The catheter injectable depot composition of any one of  claim 25 ,  26  or  27 , wherein Ar is monocyclic aryl or heteroaryl, n is 1, and L is lower alkylene optionally containing at least one heteroatom. 
     
     
         34 . The catheter injectable depot composition of  claim 33 , wherein Ar is monocyclic aryl and L is lower alkylene. 
     
     
         35 . The catheter injectable depot composition of  claim 34 , wherein Ar is phenyl and L is methylene. 
     
     
         36 . The catheter injectable depot composition of any one of  claim 25 ,  26  or  27 , wherein the aromatic alcohol is benzyl alcohol. 
     
     
         37 . The catheter injectable depot composition of  claim 27 , wherein the solvent is mixture of an aromatic alcohol and an ester of an aromatic acid. 
     
     
         38 . The catheter injectable depot composition of  claim 37 , wherein the aromatic alcohol is benzyl alcohol and the ester of an aromatic acid is a lower alkyl ester or an aralkyl ester of benzoic acid. 
     
     
         39 . The catheter injectable depot composition of  claim 38 , wherein the ester of an aromatic acid is benzyl benzoate and the lower alkyl ester of an aromatic acid is ethyl benzoate. 
     
     
         40 . The catheter injectable depot composition of  claim 37 , wherein the ratio of the aromatic alcohol to the ester of an aromatic acid is in the range of about 1% to about 99% by weight. 
     
     
         41 . The catheter injectable depot composition of  claim 40 , wherein the ratio of the aromatic alcohol to the ester of an aromatic acid is in the range of about 20% to about 80% by weight. 
     
     
         42 . The catheter injectable depot composition of any one of  claim 25 ,  26  or  27  wherein the thixotropic agent is ethanol. 
     
     
         43 . The catheter injectable depot composition of  claim 42  wherein the amount of ethanol is greater than or equal to 0.01 weight percent and less than or equal to 15 weight percent of the combined weight of the solvent and the thixotropic agent. 
     
     
         44 . The catheter injectable depot composition of  claim 43  wherein the amount of ethanol is greater than or equal to 0.1 weight percent and less than or equal to 5 weight percent of the combined weight of the solvent and the thixotropic agent. 
     
     
         45 . The catheter injectable depot composition of  claim 44  wherein the amount of ethanol is greater than or equal to 0.5 weight percent and less than or equal to 5 weight percent of the combined weight of the solvent and the thixotropic agent. 
     
     
         46 . The catheter injectable depot composition of  claim 36  wherein the thixotropic agent is ethanol. 
     
     
         47 . The catheter injectable depot composition of  claim 39  wherein the thixotropic agent is ethanol. 
     
     
         48 . The catheter injectable depot composition of any one of  claim 25 ,  26  or  27 , further including at least one of the following: a pore former; a solubility modulator for the beneficial agent; and an osmotic agent. 
     
     
         49 . The catheter injectable depot composition of any one of  claim 25 ,  26  or  27  wherein the beneficial agent is selected from a drug, proteins, enzymes, hormones, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, polypeptides, steroids, analgesics, local anesthetics, antibiotic agents, chemotherapeutic agents, immunosuppressive agents, anti-inflammatory agents, antiproliferative agents, antimitotic agents, angiogenic agents, anticoagulants, fibrinolytic agents, growth factors, antibodies, ocular drugs, and metabolites, analogs, derivatives, and fragments thereof. 
     
     
         50 . The catheter injectable depot composition of  claim 49  wherein the beneficial agent is a growth hormone. 
     
     
         51 . The catheter injectable depot composition of  claim 49  wherein the beneficial agent is a growth factor. 
     
     
         52 . The catheter injectable depot composition of  claim 51  wherein the growth factor is selected from epidermal growth factors (EGFs), platelet-derived growth factor (PDGFs), insulin-like growth factors (IGFs), fibroblast-growth factors (FGFs), transforming-growth factors (TGFs), interleukins (ILs), colony-stimulating factors (CSFs, MCFs, GCSFs, GMCSFs), Interferons (IFNs), endothelial growth factors (VEGF, EGFs), erythropoietins (EPOs), angiopoietins (ANGs), placenta-derived growth factors (PIGFs), and hypoxia induced transcriptional regulators (HIFs). 
     
     
         53 . The catheter injectable depot composition of  claim 49  wherein the beneficial agent is present in an amount of from 0.1 to 50% by weight of the combined amounts of the polymer, the solvent and the beneficial agent. 
     
     
         54 . The catheter injectable depot composition of  claim 49  wherein the beneficial agent is in the form of particles dispersed or dissolved in the viscous gel. 
     
     
         55 . The catheter injectable depot composition of  claim 54  wherein the beneficial agent is in the form of particles having an average particle size of from 0.1 to 250 microns. 
     
     
         56 . A catheter injectable depot composition comprising:
 (a) approximately 5 wt. % to approximately 90 wt. % a poly(lactide-co-glycolide) (PLGA) copolymer having a weight average molecular weight in the range of approximately 1,000 to approximately 120,000;   (b) approximately 5 wt. % to approximately 90 wt. % an aromatic alcohol solvent having miscibility in water of less than or equal to 7% at 25° C., in an amount effective to plasticize the polymer and form a gel therewith;   (c) a thixotropic amount of thixotropic agent mixed with the polymer solution effective to form a thixotropic composition, wherein the thixotropic agent is ethanol and the amount of ethanol is greater than or equal to 0.01 weight percent and less than or equal to 15 weight percent of the combined weight of the solvent and the thixotropic agent; and   (d) a beneficial agent.   
     
     
         57 . The catheter injectable depot composition of  claim 56 , wherein the aromatic alcohol is benzyl alcohol. 
     
     
         58 . A catheter injectable depot composition comprising:
 (a) approximately 5 wt. % to approximately 90 wt. % of a poly(lactide-co-glycolide) (PLGA) copolymer having a weight average molecular weight in the range of approximately 1,000 to approximately 120,000;   (b) approximately 5 wt. % to approximately 90 wt. % of a solvent selected from the group consisting of an aromatic alcohol, an ester of an aromatic acid, and mixtures thereof, said solvent having miscibility in water of less than or equal to 7% at 25° C., and present in an amount effective to plasticize the polymer and form a gel therewith,   (c) a thixotropic amount of thixotropic agent mixed with the polymer solution effective to form a thixotropic composition, wherein the thixotropic agent is ethanol and the amount of ethanol is greater than or equal to 0.01 weight percent and less than or equal to 15 weight percent of the combined weight of the solvent and the thixotropic agent; and   (d) a beneficial agent.   
     
     
         59 . The catheter injectable depot composition of  claim 58 , wherein the aromatic alcohol is benzyl alcohol and the ester of an aromatic acid is benzyl benzoate. 
     
     
         60 . A catheter injectable depot composition comprising:
 a bioerodible, biocompatible polymer;   an aromatic alcohol having miscibility in water of less than or equal to 7 wt. % at 25° C., in an amount effective to plasticize the polymer and form a gel therewith; and   a beneficial agent,   wherein the composition is free of monohydric lower alkanols.   
     
     
         61 . A catheter injectable depot composition comprising:
 a bioerodible, biocompatible polymer;   a solvent selected from the group consisting of esters of aromatic acids, aromatic ketones, and mixtures thereof, said solvent having miscibility in water of less than or equal to 7% at 25° C., and present in an amount effective to plasticize the polymer and form a gel therewith;   an effective thixotropic amount of an aromatic alcohol having miscibility in water of less than or equal to 7%; and   a beneficial agent,   wherein the composition is free of monohydric lower alkanols.   
     
     
         62 . A catheter injectable depot composition comprising:
 (a) approximately 5 wt. % to approximately 90 wt. % of a biodegradable, biocompatible lactic acid-based polymer having a weight average molecular weight in the range of approximately 1,000 to approximately 120,000;   (b) an aromatic alcohol having miscibility in water of less than or equal to 5% at 25° C., in an amount effective to plasticize the polymer and form a gel therewith, wherein the aromatic alcohol has the structural formula (I)
   Ar-(L) n -OH 
   in which Ar is a substituted or unsubstituted aryl or heteroaryl group, n is zero or 1, and L is a linking moiety; and   (c) a beneficial agent,   wherein the composition is free of monohydric lower alkanols.   
     
     
         63 . The catheter injectable depot composition of  claim 62 , wherein Ar is monocyclic aryl or heteroaryl, n is 1, and L is lower alkylene optionally containing at least one heteroatom. 
     
     
         64 . The catheter injectable depot composition of  claim 63 , wherein Ar is monocyclic aryl and L is lower alkylene. 
     
     
         65 . The catheter injectable depot composition of  claim 64 , wherein Ar is phenyl and L is methylene. 
     
     
         66 . The catheter injectable depot composition of  claim 60  or  claim 61 , wherein the polymer is selected from the group consisting of polylactides, polyglycolides, polycaprolactones, polyanhydrides, polyamines, polyurethanes, polyesteramides, polyorthoesters, polydioxanones, polyacetals, polyketals, polycarbonates, polyphosphoesters, polyorthocarbonates, polyphosphazenes, succinates, poly(malic acid), poly(amino acids), polyvinylpyrrolidone, polyethylene glycol, polyhydroxycellulose, chitin, chitosan, hyaluronic acid, and copolymers, terpolymers and mixtures thereof. 
     
     
         67 . The catheter injectable depot composition of  claim 60  or  claim 61 , wherein the polymer is a lactic acid-based polymer. 
     
     
         68 . The catheter injectable depot composition of any one of  claim 60 ,  61  or  62 , wherein the polymer is a copolymer of at least two of the following monomers: lactic acid, glycolic acid and caprolactone. 
     
     
         69 . The catheter injectable depot composition of any one of  claim 60 ,  61  or  62 , further including at least one of the following: a pore former; a solubility modulator for the beneficial agent; and an osmotic agent. 
     
     
         70 . The catheter injectable depot composition of any one of  claim 60 ,  61  or  62 , wherein the composition is free of solvents having miscibility in water that is greater than 7 wt. % at 25° C. 
     
     
         71 . The catheter injectable depot composition of  claim 68 , wherein the polymer represents approximately 10 wt. % to approximately 85 wt. % of the composition. 
     
     
         72 . The catheter injectable depot composition of  claim 71 , wherein the polymer represents approximately 20 wt. % to approximately 75 wt. % of the composition. 
     
     
         73 . The catheter injectable depot composition of  claim 68 , wherein the aromatic alcohol is benzyl alcohol and the ester of an aromatic acid is a lower alkyl ester or an aralkyl ester of benzoic acid. 
     
     
         74 . The catheter injectable depot composition of  claim 73 , wherein the ester of an aromatic acid is benzyl benzoate and the lower alkyl ester of an aromatic acid is ethyl benzoate. 
     
     
         75 . The catheter injectable depot composition of  claim 73 , wherein the ratio of the aromatic alcohol to the ester of an aromatic acid is in the range of about 1% to about 99% by weight. 
     
     
         76 . The catheter injectable depot composition of  claim 75 , wherein the ratio of the aromatic alcohol to the ester of an aromatic acid is in the range of about 20% to about 80% by weight. 
     
     
         77 . The catheter injectable depot composition of any one of  claim 60 ,  61  or  62  wherein the beneficial agent is selected from a drug, proteins, enzymes, hormones, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, polypeptides, steroids, analgesics, local anesthetics, antibiotic agents, chemotherapeutic agents, immunosuppressive agents, anti-inflammatory agents, antiproliferative agents, antimitotic agents, angiogenic agents, anticoagulants, fibrinolytic agents, growth factors, antibodies, ocular drugs, and metabolites, analogs, derivatives, and fragments thereof. 
     
     
         78 . The catheter injectable depot composition of  claim 77  wherein the beneficial agent is a growth hormone. 
     
     
         79 . The catheter injectable depot composition of  claim 77  wherein the beneficial agent is a growth factor. 
     
     
         80 . The catheter injectable depot composition of  claim 79  wherein the growth factor is selected from epidermal growth factors (EGFs), platelet-derived growth factor (PDGFs), insulin-like growth factors (IGFs), fibroblast-growth factors (FGFs), transforming-growth factors (TGFs), interleukins (ILs), colony-stimulating factors (CSFs, MCFs, GCSFs, GMCSFs), Interferons (IFNs), endothelial growth factors (VEGF, EGFs), erythropoietins (EPOs), angiopoietins (ANGs), placenta-derived growth factors (PIGFs), and hypoxia induced transcriptional regulators (HIFs). 
     
     
         81 . The catheter injectable depot composition of  claim 77  wherein the beneficial agent is present in an amount of from 0.1 to 50% by weight of the combined amounts of the polymer, the solvent and the beneficial agent. 
     
     
         82 . The catheter injectable depot composition of  claim 77  wherein the beneficial agent is in the form of particles dispersed or dissolved in the viscous gel. 
     
     
         83 . The catheter injectable depot composition of  claim 82  wherein the beneficial agent is in the form of particles having an average particle size of from 0.1 to 250 microns. 
     
     
         84 . A catheter injectable depot composition comprising:
 (a) approximately 5 wt. % to approximately 90 wt. % a poly(lactide-co-glycolide) (PLGA) copolymer having a weight average molecular weight in the range of approximately 1,000 to approximately 120,000;   (b) approximately 5 wt. % to approximately 90 wt. % an aromatic alcohol solvent having miscibility in water of less than or equal to 7% at 25° C., in an amount effective to plasticize the polymer and form a gel therewith; and   (c) a beneficial agent;   
       wherein the composition is free of monohydric lower alkanols 
     
     
         85 . The catheter injectable depot composition of  claim 84 , wherein the aromatic alcohol is benzyl alcohol. 
     
     
         86 . A catheter injectable depot composition comprising:
 (a) approximately 5 wt. % to approximately 90 wt. % of a poly(lactide-co-glycolide) (PLGA) copolymer having a weight average molecular weight in the range of approximately 1,000 to approximately 120,000;   (b) approximately 5 wt. % to approximately 90 wt. % of a solvent selected from the group consisting of an aromatic alcohol, an ester of an aromatic acid, and mixtures thereof, said solvent having miscibility in water of less than or equal to 7% at 25° C., and present in an amount effective to plasticize the polymer and form a gel therewith; and   (c) a beneficial agent;   
       wherein the composition is free of monohydric lower alkanols. 
     
     
         87 . The catheter injectable depot composition of  claim 86 , wherein the aromatic alcohol is benzyl alcohol and the ester of an aromatic acid is benzyl benzoate. 
     
     
         88 . A method of administering a beneficial agent to a subject comprising the steps of:
 (1) providing a catheter having an injectable depot composition, said catheter injectable depot composition comprising:
 (a) a bioerodible, biocompatible polymer; 
 (b) a solvent having miscibility in water of less than or equal to 7% at 25° C., in an amount effective to plasticize the polymer and form a gel therewith, wherein said solvent is an aromatic alcohol; 
 (c) a thixotropic amount of a thixotropic agent mixed with the polymer solution effective to form a thixotropic composition, the thixotropic agent being selected from the group consisting essentially of lower alkanols and said amount being less than 15 weight percent of the combined weight of the solvent and the thixotropic agent; and 
 (d) a beneficial agent; 
   (2) delivering the depot composition to said subject at a site within the subject; and   (3) forming an implant at the site wherein the implant provides sustained release of the beneficial agent at the site.   
     
     
         89 . A method of administering a beneficial agent to a subject comprising the steps of:
 (1) providing a catheter having an injectable depot composition, said catheter injectable depot composition comprising:
 (a) a bioerodible, biocompatible polymer; 
 (b) a solvent selected from the group consisting of aromatic alcohols, esters of aromatic acids, aromatic ketones, and mixtures thereof, said solvent having miscibility in water of less than or equal to 7% at 25° C., and present in an amount effective to plasticize the polymer and form a gel therewith; 
 (c) a thixotropic amount of a thixotropic agent mixed with the polymer solution effective to form a thixotropic composition, the thixotropic agent being selected from the group consisting essentially of lower alkanols and said amount being less than 15 weight percent of the combined weight of the solvent and the thixotropic agent; and 
 (d) a beneficial agent; 
   (2) delivering the depot composition to said subject at a site within the subject; and   (3) forming an implant at the site wherein the implant provides sustained release of the beneficial agent at the site.   
     
     
         90 . A method of administering a beneficial agent to a subject comprising the steps of:
 (1) providing a catheter having an injectable depot composition, said catheter injectable depot composition comprising:
 (a) approximately 5 wt. % to approximately 90 wt. % of a bioerodible, biocompatible polymer; 
 (b) an aromatic alcohol having miscibility in water of less than or equal to 7% at 25° C., in an amount effective to plasticize the polymer and form a gel therewith, wherein the aromatic alcohol has the structural formula (I)
   Ar-(L) n -OH  (I)
 
 
   in which Ar is a substituted or unsubstituted aryl or heteroaryl group, n is zero or 1, and L is a linking moiety;
 (c) a thixotropic amount of a thixotropic agent mixed with the polymer solution effective to form a thixotropic composition, the thixotropic agent being selected from the group consisting essentially of lower alkanols and said amount being less than 15 weight percent of the combined weight of the solvent and the thixotropic agent; and 
 (d) a beneficial agent; 
   (2) delivering the depot composition to said subject at a site within the subject; and   (3) forming an implant at the site wherein the implant provides sustained release of the beneficial agent at the site.   
     
     
         91 . A method of administering a beneficial agent to a subject comprising the steps of:
 (1) providing a catheter having an injectable depot composition, said catheter injectable depot composition comprising:
 (a) approximately 5 wt. % to approximately 90 wt. % of a biodegradable, biocompatible lactic acid-based polymer having a weight average molecular weight in the range of approximately 1,000 to approximately 120,000; 
 (b) an aromatic alcohol having miscibility in water of less than or equal to 7% at 25° C., in an amount effective to plasticize the polymer and form a gel therewith, wherein the aromatic alcohol has the structural formula (I)
   Ar-(L) n -OH  (I)
 
 
   in which Ar is a substituted or unsubstituted aryl or heteroaryl group, n is zero or 1, and L is a linking moiety;
 (c) a thixotropic amount of a thixotropic agent mixed with the polymer solution effective to form a thixotropic composition, the thixotropic agent being selected from the group consisting essentially of lower alkanols and said amount being less than 15 weight percent of the combined weight of the solvent and the thixotropic agent; and 
 (d) a beneficial agent; 
   (2) delivering the depot composition to said subject at a site within the subject; and   (3) forming an implant at the site wherein the implant provides sustained release of the beneficial agent at the site.   
     
     
         92 . A method of administering a beneficial agent to a subject comprising the steps of:
 (1) providing a catheter having an injectable depot composition, said catheter injectable depot composition comprising:
 (a) approximately 5 wt. % to approximately 90 wt. % of a biodegradable, biocompatible lactic acid-based polymer having a weight average molecular weight in the range of approximately 1,000 to approximately 120,000; 
 (b) a solvent selected from the group consisting of an aromatic alcohol, an ester of an aromatic acid, and mixtures thereof, said solvent having miscibility in water of less than or equal to 7% at 25° C., and present in an amount effective to plasticize the polymer and form a gel therewith, wherein the aromatic alcohol has the structural formula (I)
   Ar-(L) n -OH  (I)
 
 
   in which Ar is a substituted or unsubstituted aryl or heteroaryl group, n is zero or 1, and L is a linking moiety;
 (c) a thixotropic amount of a thixotropic agent mixed with the polymer solution effective to form a thixotropic composition, the thixotropic agent being selected from the group consisting essentially of lower alkanols and said amount being less than 15 weight percent of the combined weight of the solvent and the thixotropic agent; and 
 (d) a beneficial agent; 
   (2) delivering the depot composition to said subject at a site within the subject; and   (3) forming an implant at the site wherein the implant provides sustained release of the beneficial agent at the site.   
     
     
         93 . A method of administering a beneficial agent to a subject comprising the steps of:
 (1) providing a catheter having an injectable depot composition, said catheter injectable depot composition comprising:
 (a) approximately 5 wt. % to approximately 90 wt. % a poly(lactide-co-glycolide) (PLGA) copolymer having a weight average molecular weight in the range of approximately 1,000 to approximately 120,000; 
 (b) approximately 5 wt. % to approximately 90 wt. % an aromatic alcohol solvent having miscibility in water of less than or equal to 7% at 25° C., in an amount effective to plasticize the polymer and form a gel therewith; 
 (c) a thixotropic amount of thixotropic agent mixed with the polymer solution effective to form a thixotropic composition, wherein the thixotropic agent is ethanol and the amount of ethanol is greater than or equal to 0.01 weight percent and less than or equal to 15 weight percent of the combined weight of the solvent and the thixotropic agent; and 
 (d) a beneficial agent; 
   (2) delivering the depot composition to said subject at a site within the subject; and   (3) forming an implant at the site wherein the implant provides sustained release of the beneficial agent at the site.   
     
     
         94 . A method of administering a beneficial agent to a subject comprising the steps of:
 (1) providing a catheter having an injectable depot composition, said catheter injectable depot composition comprising:
 (a) approximately 5 wt. % to approximately 90 wt. % of a poly(lactide-co-glycolide) (PLGA) copolymer having a weight average molecular weight in the range of approximately 1,000 to approximately 120,000; 
 (b) approximately 5 wt. % to approximately 90 wt. % of a solvent selected from the group consisting of an aromatic alcohol, an ester of an aromatic acid, and mixtures thereof, said solvent having miscibility in water of less than or equal to 7% at 25° C., and present in an amount effective to plasticize the polymer and form a gel therewith, 
 (c) a thixotropic amount of thixotropic agent mixed with the polymer solution effective to form a thixotropic composition, wherein the thixotropic agent is ethanol and the amount of ethanol is greater than or equal to 0.01 weight percent and less than or equal to 15 weight percent of the combined weight of the solvent and the thixotropic agent; and 
 (d) a beneficial agent; 
   (2) delivering the depot composition to said subject at a site within the subject; and   (3) forming an implant at the site wherein the implant provides sustained release of the beneficial agent at the site.   
     
     
         95 . A method of administering a beneficial agent to a subject comprising the steps of:
 (1) providing a catheter having an injectable depot composition, said catheter injectable depot composition comprising:
 (a) a bioerodible, biocompatible polymer; 
 (b) an aromatic alcohol having miscibility in water of less than or equal to 7 wt. % at 25° C., in an amount effective to plasticize the polymer and form a gel therewith; and 
 (c) a beneficial agent; wherein the composition is free of monohydric lower alkanols; 
   (2) delivering the depot composition to said subject at a site within the subject; and   (3) forming an implant at the site wherein the implant provides sustained release of the beneficial agent at the site.   
     
     
         96 . A method of administering a beneficial agent to a subject comprising the steps of:
 (1) providing a catheter having an injectable depot composition, said catheter injectable depot composition comprising:
 (a) a bioerodible, biocompatible polymer; 
 (b) a solvent selected from the group consisting of esters of aromatic acids, aromatic ketones, and mixtures thereof, said solvent having miscibility in water of less than or equal to 7% at 25° C., and present in an amount effective to plasticize the polymer and form a gel therewith; 
 (c) an effective thixotropic amount of an aromatic alcohol having miscibility in water of less than or equal to 7%; and 
 (d) a beneficial agent; wherein the composition is free of monohydric lower alkanols; 
   (2) delivering the depot composition to said subject at a site within the subject; and   (3) forming an implant at the site wherein the implant provides sustained release of the beneficial agent at the site.   
     
     
         97 . A method of administering a beneficial agent to a subject comprising the steps of:
 (1) providing a catheter having an injectable depot composition, said catheter injectable depot composition comprising:
 (a) approximately 5 wt. % to approximately 90 wt. % of a biodegradable, biocompatible lactic acid-based polymer having a weight average molecular weight in the range of approximately 1,000 to approximately 120,000; 
 (b) an aromatic alcohol having miscibility in water of less than or equal to 5% at 25° C., in an amount effective to plasticize the polymer and form a gel therewith, wherein the aromatic alcohol has the structural formula (I)
   Ar-(L) n -OH 
 
   in which Ar is a substituted or unsubstituted aryl or heteroaryl group, n is zero or 1, and L is a linking moiety; and
 (c) a beneficial agent; wherein the composition is free of monohydric lower alkanols; 
   (2) delivering the depot composition to said subject at a site within the subject; and   (3) forming an implant at the site wherein the implant provides sustained release of the beneficial agent at the site.   
     
     
         98 . A method of administering a beneficial agent to a subject comprising the steps of:
 (1) providing a catheter having an injectable depot composition, said catheter injectable depot composition comprising:
 (a) approximately 5 wt. % to approximately 90 wt. % a poly(lactide-co-glycolide) (PLGA) copolymer having a weight average molecular weight in the range of approximately 1,000 to approximately 120,000; 
 (b) approximately 5 wt. % to approximately 90 wt. % an aromatic alcohol solvent having miscibility in water of less than or equal to 7% at 25° C., in an amount effective to plasticize the polymer and form a gel therewith; and 
 (c) a beneficial agent; wherein the composition is free of monohydric lower alkanols; 
   (2) delivering the depot composition to said subject at a site within the subject; and   (3) forming an implant at the site wherein the implant provides sustained release of the beneficial agent at the site.   
     
     
         99 . A method of administering a beneficial agent to a subject comprising the steps of:
 (1) providing a catheter having an injectable depot composition, said catheter injectable depot composition comprising:
 (a) approximately 5 wt. % to approximately 90 wt. % of a poly(lactide-co-glycolide) (PLGA) copolymer having a weight average molecular weight in the range of approximately 1,000 to approximately 120,000; 
 (b) approximately 5 wt. % to approximately 90 wt. % of a solvent selected from the group consisting of an aromatic alcohol, an ester of an aromatic acid, and mixtures thereof, said solvent having miscibility in water of less than or equal to 7% at 25° C., and present in an amount effective to plasticize the polymer and form a gel therewith; and 
 (c) a beneficial agent; wherein the composition is free of monohydric lower alkanols; 
   (2) delivering the depot composition to said subject at a site within the subject; and   (3) forming an implant at the site wherein the implant provides sustained release of the beneficial agent at the site.   
     
     
         100 . The method according to any one of  claims 88  to  99 , wherein the catheter further comprises a needle having a diameter greater than 16 gauge. 
     
     
         101 . The method according to  claim 100 , wherein the needle has a diameter greater than 20 gauge. 
     
     
         102 . The method according to  claim 101 , wherein the needle has a diameter greater than 22 gauge. 
     
     
         103 . The method according to  claim 102 , wherein the needle has a diameter greater than 24 gauge. 
     
     
         104 . The method according to  claim 100 , wherein the catheter has a length of less than 8 feet. 
     
     
         105 . The method according to  claim 104  wherein the catheter has a length ranging from about 3 feet to about 6 feet. 
     
     
         106 . The method according to  claim 104 , wherein the catheter has an outer diameter range of less than 2 mm. 
     
     
         107 . The method according to  claim 106 , wherein the catheter has an inner diameter range of less than 2 mm. 
     
     
         108 . The method according to  claim 100 , wherein the needle is made from a metallic, non-metallic, ceramic, and polymeric material and composites thereof. 
     
     
         109 . The method of  claim 100  wherein the beneficial agent is selected from a drug, proteins, enzymes, hormones, polynucleotides, nucleoproteins, polysaccharides, glycoproteins, lipoproteins, polypeptides, steroids, analgesics, local anesthetics, antibiotic agents, chemotherapeutic agents, immunosuppressive agents, anti-inflammatory agents, antiproliferative agents, antimitotic agents, angiogenic agents, anticoagulants, fibrinolytic agents, growth factors, antibodies, ocular drugs, and metabolites, analogs, derivatives, and fragments thereof. 
     
     
         110 . The catheter injectable depot composition of  claim 23  wherein the beneficial agent is in the form of particles wherein the particle further comprises a component selected from the group consisting of a stabilizing agent, bulking agent, chelating agent and a buffering agent. 
     
     
         111 . The catheter injectable depot composition of  claim 54  wherein the beneficial agent is in the form of particles wherein the particle further comprises a component selected from the group consisting of a stabilizing agent, bulking agent, chelating agent and a buffering agent. 
     
     
         112 . The catheter injectable depot composition of  claim 82  wherein the beneficial agent is in the form of particles wherein the particle further comprises a component selected from the group consisting of a stabilizing agent, bulking agent, chelating agent and a buffering agent.

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