Solid drug implants for intracochlear delivery of therapeutics for the treatment of otic disorders

Abstract

The present invention provides for pharmaceutical preparations, devices, systems and methods for the treatment of otic diseases and conditions. In various embodiments, the preparations, devices, systems and methods enable sustained drug release for the treatment or prevention of hearing loss, infections, and other pathological conditions of cochlea and inner ear.

1 . A method, comprising:
 providing a pharmaceutical preparation for sustained-release of an active pharmaceutical ingredient (API) after cochlear administration or implantation, comprising:
 one or more core particles adapted for administration or implantation into the cochlea, wherein each core particle comprises the API, wherein the pharmaceutical preparation is not in a liquid suspension; and 
   administering or implanting into the cochlea the pharmaceutical preparation to provide sustained-release administration of the API.   
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . The method of  claim 1 , wherein each core particle is one solid API crystal or each core particle comprises two or more API crystals, and the two or more API crystals are densely packed together. 
     
     
         5 . (canceled) 
     
     
         6 . The method of  claim 1 , wherein the API forms a saturated solution within the cochlear fluid after the administering or implanting into the cochlea, and wherein a sustained-release period of the API is determined by the solubility of the API in the cochlear fluid, the turnover of the API from the cochlear fluid, and the amount of the API administered. 
     
     
         7 . The method of  claim 1 , wherein the one or more core particles are each coated with a first polymeric coating formed from a first polymer-forming solution to form the one or more coated core particles. 
     
     
         8 . The method of  claim 7 , wherein the API forms a saturated solution within the first polymeric coating after the administering or implanting, and wherein the first polymeric coating is permeable to the API during a sustained-release period from administering the API until the concentration of the API contained within the first polymeric coating is unsaturated. 
     
     
         9 . The method of  claim 1 , wherein the pharmaceutical preparation comprises 1-15 core particles or coated core particles. 
     
     
         10 . (canceled) 
     
     
         11 . (canceled) 
     
     
         12 . The method of  claim 1 , wherein the core particle has a maximum dimension of between 100 μm to 300 μm. 
     
     
         13 . (canceled) 
     
     
         14 . (canceled) 
     
     
         15 . The method of  claim 1 , wherein the core particle has a high volume to surface area ratio. 
     
     
         16 . The method of  claim 7 , wherein diffusion of the API across the first polymeric coating exhibits pseudo-zero-order kinetics during said sustained-release period. 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . The method of  claim 7 , wherein the 1 to 15 coated core particles are administrable to the perilymph via cochlear implantation or injection. 
     
     
         20 . The method of  claim 7 , wherein each coated core particle has a maximum dimension between 20 μm and 800 μm and a maximum length of 4 mm. 
     
     
         21 . (canceled) 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . The method of  claim 7 , wherein the API is substantially insoluble in the first polymer-forming solution, the API is hydrophobic and the first polymer-forming solution is hydrophilic or the API is hydrophilic and the first polymer-forming solution is hydrophobic. 
     
     
         26 . (canceled) 
     
     
         27 . (canceled) 
     
     
         28 . (canceled) 
     
     
         29 . The method of  claim 7 , wherein each coated particle further comprises:
 a second polymeric coating on said first polymeric coating, wherein the second polymeric coating is formed from a second polymer-forming solution,   wherein said second polymeric coating is permeable to the API during said sustained-release period; or   a porous second polymeric coating on the first polymeric coating, wherein the porous second polymeric coating is formed from a second polymer-forming solution,   wherein the porous second polymeric coating defines pore regions which permit fluid communication between a pore portion of the first polymeric coating and an external environment, thereby allowing diffusion of the API across the first polymeric coating in the pore regions, and   wherein the porous second polymeric coating defines non-pore regions which prevent fluid communication between a non-pore portion of the first polymeric coating and an external environment, thereby inhibiting diffusion of the API across the first polymeric coating in the non-pore regions.   
     
     
         30 . (canceled) 
     
     
         31 . (canceled) 
     
     
         32 . (canceled) 
     
     
         33 . The method of  claim 7 , wherein the first polymeric coating comprises a polymer or co-polymer including at least one monomer selected from the group consisting of sugar phosphates, alkylcellulose, hydroxyalkylcelluloses, lactic acid, glycolic acid, β-propiolactone, β-butyrolactone, γ-butyrolactone, pivalolactone, α-hydroxy butyric acid, α-hydroxyethyl butyric acid, α-hydroxy isovaleric acid, α-hydroxy-β-methyl valeric acid, α-hydroxy caproic acid, α-hydroxy isocaproic acid, α-hydroxy heptanic acid, α-hydroxy octanic acid, α-hydroxy decanoic acid, α-hydroxy myristic acid, α-hydroxy stearic acid, α-hydroxy lignoceric acid, para-xylene (parylene N), halogenated para-xylene, β-phenol lactic acid and polyvinyl alcohol and the second polymeric coating comprises a polymer or co-polymer including at least one monomer selected from the group consisting of sugar phosphates, alkylcellulose, hydroxyalkylcelluloses, lactic acid, glycolic acid, β-propiolactone, β-butyrolactone, γ-butyrolactone, pivalolactone, α-hydroxy butyric acid, α-hydroxyethyl butyric acid, α-hydroxy isovaleric acid, α-hydroxy-β-methyl valeric acid, α-hydroxy caproic acid, α-hydroxy isocaproic acid, α-hydroxy heptanic acid, α-hydroxy octanic acid, α-hydroxy decanoic acid, α-hydroxy myristic acid, α-hydroxy stearic acid, α-hydroxy lignoceric acid, para-xylene (parylene N), halogenated para-xylene, β-phenol lactic acid and polyvinyl alcohol. 
     
     
         34 . (canceled) 
     
     
         35 . (canceled) 
     
     
         36 . (canceled) 
     
     
         37 . (canceled) 
     
     
         38 . The method of  claim 7 , wherein the weight of said first polymeric coating is between 0.001% and 60% of the weight of said core particle or the volume of said first polymeric coating is between 0.001% and 60% of the volume of said core particle. 
     
     
         39 . (canceled) 
     
     
         40 . (canceled) 
     
     
         41 . (canceled) 
     
     
         42 . The method of  claim 1 , wherein the pharmaceutical preparation is administered or implanted by injecting the pharmaceutical preparation through the round window or the oval window for delivery of API into the cochlea or is administered during a stapedectomy procedure. 
     
     
         43 . (canceled) 
     
     
         44 . The method of  claim 1 , wherein the method protects against ototoxicity, reduces the risk of sensorineural hearing loss, treats of sensorineural hearing loss, protects against inflammation, treats autoimmune inner ear disease, treats Meniere's disease, reduces the risk of noise induced hearing loss, treats of noise induced hearing loss, treats infection, or treats inner ear vestibular dis-function. 
     
     
         45 . A sustained-release drug delivery system for delivering a medicament to the cochlea, comprising:
 1 to 15 devices adapted for administration or implantation into the cochlea, each device comprising:
 a solid drug core particle comprising the medicament, the solid drug core particle having a maximum dimension between 20 μm and 800 μm and a maximum length of 4 mm, wherein the device is capable of releasing said medicament at a rate which maintains a pharmacologically effective concentration of said medicament within the cochlea 
 wherein the 1 to 15 devices are not in a liquid suspension. 
   
     
     
         46 . (canceled) 
     
     
         47 . (canceled) 
     
     
         48 . The sustained-release drug delivery system of  claim 42 , wherein the solid drug core is one solid medicament crystal or the solid drug core comprises two or more medicament crystals, and the two or more medicament crystals are densely packed together. 
     
     
         49 . (canceled) 
     
     
         50 . (canceled) 
     
     
         51 . (canceled) 
     
     
         52 . The sustained-release drug delivery system of  claim 45 , wherein the solid drug core particle has a maximum dimension of between 100 μm to 300 μm. 
     
     
         53 . (canceled) 
     
     
         54 . (canceled) 
     
     
         55 . (canceled) 
     
     
         56 . The sustained-release drug delivery system of  claim 45 , wherein the device is capable of maintaining a pharmacologically effective concentration of said medicament within the inner ear for a period of at least 4, 7, 14, 20, or 180 days or for a period of at least one year. 
     
     
         57 . (canceled) 
     
     
         58 . (canceled) 
     
     
         59 . (canceled) 
     
     
         60 . (canceled) 
     
     
         61 . (canceled) 
     
     
         62 . The sustained-release drug delivery system of  claim 45 , wherein the medicament is selected from the group consisting of:
 an agent for the protection against ototoxicity,   an agent for the prevention of sensorineural hearing loss,   an agent for the treatment of sensorineural hearing loss,   an agent for the protection against inflammation,   an agent for the treatment of autoimmune inner ear disease,   an agent for the treatment of Meniere's disease,   an agent for the prevention of noise induced hearing loss,   an agent for the treatment of noise induced hearing loss,   an agent for the treatment of infection,   an agent for the treatment of inner ear vestibular dis-functional growth factor,   an antioxidant,   a TNF-α inhibitor,   a corticosteroid, an antibiotic,   an anti-inflammatory drug, and   a non-steroidal anti-inflammatory drug.   
     
     
         63 . (canceled) 
     
     
         64 . (canceled) 
     
     
         65 . A packaged pharmaceutical product, comprising:
 the sustained release drug delivery system of  claim 45 ; and   instructions for using the system in conjunction with administration of an ototoxic chemotherapeutic drug or instructions for using the system in conjunction with the implantation of a medical device into the cochlea.   
     
     
         66 . (canceled) 
     
     
         67 . A pharmaceutical preparation for sustained-release of an active pharmaceutical ingredient (API) after cochlear administration or implantation, comprising:
 1 to 15 core particles adapted for administration or implantation into the cochlea, wherein each core particle comprises the API, wherein the pharmaceutical preparation is not in a liquid suspension.   
     
     
         68 . (canceled) 
     
     
         69 . (canceled) 
     
     
         70 . The pharmaceutical preparation of  claim 67 , wherein each core particle is one solid API crystal or each core particle comprises two or more API crystals, and the two or more API crystals are densely packed together. 
     
     
         71 . (canceled) 
     
     
         72 . The pharmaceutical preparation of  claim 67 , wherein the 1 to 15 core particles are each coated with a first polymeric coating formed from a first polymer-forming solution to form 1 to 15 coated core particles. 
     
     
         73 . (canceled) 
     
     
         74 . (canceled) 
     
     
         75 . The pharmaceutical preparation of  claim 67 , wherein the core particle has a maximum dimension of between 100 μm to 300 μm. 
     
     
         76 . (canceled) 
     
     
         77 . (canceled) 
     
     
         78 . (canceled) 
     
     
         79 . The pharmaceutical preparation of  claim 72 , wherein the API is substantially insoluble in the first polymer-forming solution, the API is hydrophobic and the first polymer-forming solution is hydrophilic or the API is hydrophilic and the first polymer-forming solution is hydrophobic. 
     
     
         80 . (canceled) 
     
     
         81 . (canceled) 
     
     
         82 . The pharmaceutical preparation of  claim 72 , wherein each coated particle further comprises:
 a second polymeric coating on said first polymeric coating, wherein the second polymeric coating is formed from a second polymer-forming solution,   wherein said second polymeric coating is permeable to the API during said sustained-release period; or   a porous second polymeric coating on the first polymeric coating, wherein the porous second polymeric coating is formed from a second polymer-forming solution,   wherein the porous second polymeric coating defines pore regions which permit fluid communication between a pore portion of the first polymeric coating and an external environment, thereby allowing diffusion of the API across the first polymeric coating in the pore regions, and   wherein the porous second polymeric coating defines non-pore regions which prevent fluid communication between a non-pore portion of the first polymeric coating and an external environment, thereby inhibiting diffusion of the API across the first polymeric coating in the non-pore regions.   
     
     
         83 . (canceled) 
     
     
         84 . (canceled) 
     
     
         85 . (canceled) 
     
     
         86 . The pharmaceutical preparation of  claim 72 , wherein the first polymeric coating comprises a polymer or co-polymer including at least one monomer selected from the group consisting of sugar phosphates, alkylcellulose, hydroxyalkylcelluloses, lactic acid, glycolic acid, β-propiolactone, β-butyrolactone, γ-butyrolactone, pivalolactone, α-hydroxy butyric acid, α-hydroxyethyl butyric acid, α-hydroxy isovaleric acid, α-hydroxy-(β-methyl valeric acid, α-hydroxy caproic acid, α-hydroxy isocaproic acid, α-hydroxy heptanic acid, α-hydroxy octanic acid, α-hydroxy decanoic acid, α-hydroxy myristic acid, α-hydroxy stearic acid, α-hydroxy lignoceric acid, para-xylene (parylene N), halogenated para-xylene, β-phenol lactic acid and polyvinyl alcohol and wherein the second polymeric coating comprises a polymer or co-polymer including at least one monomer selected from the group consisting of sugar phosphates, alkylcellulose, hydroxyalkylcelluloses, lactic acid, glycolic acid, β-propiolactone, β-butyrolactone, γ-butyrolactone, pivalolactone, α-hydroxy butyric acid, α-hydroxyethyl butyric acid, α-hydroxy isovaleric acid, α-hydroxy-(β-methyl valeric acid, α-hydroxy caproic acid, α-hydroxy isocaproic acid, α-hydroxy heptanic acid, α-hydroxy octanic acid, α-hydroxy decanoic acid, α-hydroxy myristic acid, α-hydroxy stearic acid, α-hydroxy lignoceric acid, para-xylene (parylene N), halogenated para-xylene, β-phenol lactic acid and polyvinyl alcohol. 
     
     
         87 . (canceled) 
     
     
         88 . The pharmaceutical preparation of  claim 72 , wherein the weight of said first polymeric coating is between 0.001% and 60% of the weight of said core particle or the volume of said first polymeric coating is between 0.001% and 60% of the volume of said core particle. 
     
     
         89 . (canceled) 
     
     
         90 . (canceled) 
     
     
         91 . (canceled)