Drug cores for sustained release of therapeutic agents

Abstract

A solid drug core insert can be manufactured by injecting a liquid mixture comprising a therapeutic agent and a matrix precursor into a sheath body. The injection can be conducted at subambient temperatures. The mixture is cured to form a solid drug-matrix core. The therapeutic agent can be a liquid at about room temperature that forms a dispersion of droplets in the matrix material. A surface of the solid drug core is exposed, for example by cutting the tube, and the exposed surface of the solid drug core releases therapeutic quantities of the therapeutic agent when implanted into the patient. In some embodiments, the insert body inhibits release of the therapeutic agent, for example with a material substantially impermeable to the therapeutic agent, such that the therapeutic quantities are released through the exposed surface, thereby avoiding release of the therapeutic agent to non-target tissues.

1 . A drug core comprising.
 a therapeutic agent and a polymer matrix for disposition into, or configured as, a drug insert or an implant,   wherein the drug insert or the implant is adapted for disposition within or adjacent to a body cavity, tissue, duct or fluid of a patient, and   wherein an amount of the therapeutic agent in a first volumetric portion of the drug core is similar to an amount of the therapeutic agent in any other second, but equal volumetric portion of the drug core distinct from the first volumetric portion.   
   
   
       2 . The drug core of  claim 1 , wherein the drug insert or the implant is adapted for disposition within or adjacent to an eye of the patient. 
   
   
       3 . The drug core of  claim 1 , wherein: a) the therapeutic agent is uniformly and homogeneously dispersed throughout the polymer matrix; or b) the therapeutic agents at least in parts forms solid or liquid inclusions within the polymer matrix. 
   
   
       4 . The drug core of  claim 1 , wherein the amount of the therapeutic agent in the first volumetric portion of the drug core varies from the amount of the therapeutic agent in any other second, but equal volumetric portion of the drug core by no greater than about 30%. 
   
   
       5 . The drug core of  claim 1 , wherein the amount of the therapeutic agent in the first volumetric portion of the drug core varies from the amount of the therapeutic agent in any other second, but equal volumetric portion of the drug core by no greater than about 20%. 
   
   
       6 . The drug core of  claim 1 , wherein the amount of the therapeutic agent in the first volumetric portion of the drug core varies from the amount of the therapeutic agent in any other second, but equal volumetric portion of the drug core by no greater than about 10%. 
   
   
       7 . The drug core of  claim 1 , wherein the amount of the therapeutic agent in the first volumetric portion of the drug core varies from the amount of the therapeutic agent in any other second, but equal volumetric portion of the drug core by no greater than about 5%. 
   
   
       8 . The drug core of  claim 3 , wherein the therapeutic agent is uniformly and homogenously distributed throughout the polymer matrix. 
   
   
       9 . The drug core of  claim 3 , wherein the therapeutic agents at least in part, forms solid or liquid inclusions within the polymer matrix. 
   
   
       10 . The drug core of  claim 9 , wherein the solid or liquid inclusions have an average diameter of less than about 20 μm. 
   
   
       11 . The drug core of  claim 9 , wherein the solid or liquid inclusions have an average diameter of less than about 10 μm. 
   
   
       12 . The drug core of  claim 1 , wherein amounts of the therapeutic agent in equal volumetric portions located at about the proximal portion, at about the middle portion and at about the distal portion of the drug core are similar. 
   
   
       13 . The drug core of  claim 12 , wherein the amounts of the therapeutic agent in equal volumetric portions located at about the proximal portion, at about the middle portion and at about the distal portion of the drug core vary by no greater than about 30%. 
   
   
       14 . The drug core of  claim 12 , wherein the amounts of the therapeutic agent in equal volumetric portions located at about the proximal portion, at about the middle portion and at about the distal portion of the drug core vary by no greater than about 20%. 
   
   
       15 . The drug core of  claim 12 , wherein the amounts of the therapeutic agent in equal volumetric portions located at about the proximal portion, at about the middle portion and at about the distal portion of the drug core vary by no greater than about 10%. 
   
   
       16 . The drug core of  claim 12 , wherein the amounts of the therapeutic agent in equal volumetric portions located at about the proximal portion, at about the middle portion and at about the distal portion of the drug core vary by no greater than about 5%. 
   
   
       17 . The drug core of  claim 1 , wherein the polymer matrix comprises a non-biodegradable silicone or polyurethane, or a combination thereof. 
   
   
       18 . The drug core of  claim 1 , wherein the therapeutic agent comprises a glaucoma medication, a muscarinic agent, a beta blocker, an alpha agonist, a carbonic anhydrase inhibitor, a prostaglandin or prostaglandin analog, an anti-inflammatory agent, an anti-infective agent, a dry eye medication or any combination thereof. 
   
   
       19 . The drug core of  claim 2 , wherein the polymer matrix comprises silicone and the therapeutic agent comprises latanoprost. 
   
   
       20 . The drug core of  claim 2 , wherein the therapeutic agent comprises cyclosporine and the polymer matrix comprises a polyurethane. 
   
   
       21 . The drug core of  claim 1 , further comprising a release rate modifying material combined in the polymer matrix, the release rate modifying material comprising an inert filler material, a salt, a surfactant, a dispersant, a second polymer, an oligomer, or a combination thereof. 
   
   
       22 . A drug insert adapted for disposition within an implant disposable within or adjacent to a body cavity, tissue, duct or fluid, the insert comprising-a drug core comprising a therapeutic agent and a polymer matrix; and
 a sheath body disposed over a portion the drug core, the sheath body inhibiting release of the therapeutic agent from said portion and defining at least one exposed surface of the drug core adapted to release the therapeutic agent to the body cavity, duct, tissue or fluid, when the implant is implanted, and   wherein an amount of the therapeutic agent in a first volumetric portion of the drug core is similar to an amount of the therapeutic agent in any other second, but equal volumetric portion of the drug core distinct from the first volumetric portion.   
   
   
       23 . (canceled) 
   
   
       24 . The drug insert of  claim 22 , wherein the drug core and the sheath body are cut from a longitudinally-extending precursor sheath body containing a precursor drug core, the precursor drug core comprising the therapeutic agent and the polymer matrix, the precursor sheath body substantially impermeable to the therapeutic agent; and
 wherein an amount of the therapeutic agent in a first volumetric portion of the precursor drug core is similar to an amount of the therapeutic agent in any other second, but equal volumetric portion of the precursor drug core distinct from the first volumetric portion.   
   
   
       25 - 26 . (canceled) 
   
   
       27 . The drug insert of  claim 22 , wherein an outer surface of the sheath body is sized and shaped to be received by a channel of the implant, the sheath body being received such that an exposed surface of the drug core will be exposed to the body cavity, tissue, duct or fluid when the implant is implanted. 
   
   
       28 - 29 . (canceled) 
   
   
       30 . A method of manufacturing a drug insert for an implant body disposable within or adjacent to a body cavity, tissue, duct or fluid of a patient, the method comprising:
 injecting into a precursor sheath body, at a temperature of less than about 25° C., a mixture comprising a therapeutic agent and a precursor matrix such that the precursor sheath is substantially filled therewith, the precursor sheath body being substantially impermeable to the therapeutic agent;   curing the mixture in the precursor sheath body to provide a cured, filled precursor sheath body containing a precursor drug core; and   dividing the cured, filled precursor sheath into a plurality of drug inserts, each drug insert being adapted to fit within a respective implant body,   wherein each drug insert comprises a drug core and a sheath body disposed over a portion of the drug core, the sheath body inhibiting release of the therapeutic agent from said portion and defining at least one exposed surface of the drug core adapted to release the therapeutic agent when the insert is disposed with the implant body and the implant body is inserted into the patient, and wherein an amount of the therapeutic agent in a first volumetric portion of the drug core is similar to an amount of the therapeutic agent in any other second, but equal volumetric portion of the drug core distinct from the first volumetric portion.   
   
   
       31 . The method of  claim 30 , wherein each of the plurality of drug inserts is of substantially the same length, and wherein an amount of the therapeutic agent in a first insert of the plurality is similar to an amount of the therapeutic agent in any other insert of the plurality. 
   
   
       32 - 36 . (canceled) 
   
   
       37 . The drug insert of  claim 22 , adapted for disposition within a lacrimal implant and providing sustained release of latanoprost to an eye of a patient in need of treatment of glaucoma, the therapeutic agent comprising latanoprost and the polymer matrix comprising a silicone polymer. 
   
   
       38 - 41 . (canceled)