Drug-containing implants and methods of use thereof

Abstract

The present invention provides implants comprising a therapeutic drug and a polymer containing polylactic acid (PLA) and optionally polyglycolic acid (PGA). The present invention also provides methods of maintaining a therapeutic level of a drug in a subject, releasing a therapeutic drug at a substantially linear rate, and treating schizophrenia and other diseases and disorders, utilizing implants of the present invention.

What is claimed is: 
     
         1 . An implantable, long term delivery system for improving medication adherence in disorders associated with a likelihood of non-compliance, comprising: a therapeutic drug in an implantable, rod-shaped structure, wherein said rod-shaped structure further comprises a polymer, said polymer comprising polylactic acid (PLA) and optionally polyglycolic acid (PGA) in a PLA:PGA molar ratio between 50:50 and 100:0, thereby forming a long term delivery system for improving medication adherence in subjects having disorders associated with a likelihood of non-compliance. 
     
     
         2 . The implantable, long term delivery system of  claim 1 , wherein said rod-shaped structure is removable throughout the period of drug delivery. 
     
     
         3 . The implantable, long term delivery system of  claim 1 , wherein said therapeutic drug is present in an amount of 30%-60% of the mass of said implant. 
     
     
         4 . The implantable, long term delivery system of  claim 1 , wherein said therapeutic drug exhibits enhanced solubility in a reduced pH environment. 
     
     
         5 . The implantable, long term delivery system of  claim 1 , wherein said therapeutic drug is risperidone, 9-OH-risperidone, or an active metabolite thereof. 
     
     
         6 . The implantable, long term delivery system of  claim 1 , wherein therapeutic drug is thiothixene, haloperidol, hydrochlorothiazide (HCTZ), corticosterone, ibuprofen, aspirin, or an active metabolite thereof. 
     
     
         7 . The implantable, long term delivery system of  claim 1 , wherein said PLA:PGA molar ratio is between 75:25 and 100:0. 
     
     
         8 . The implantable, long term delivery system of  claim 1 , wherein said therapeutic drug is an anti-depressant. 
     
     
         9 . The implantable, long term delivery system of  claim 1 , wherein said therapeutic drug is an anti-anxiety agent. 
     
     
         10 . The implantable, long term delivery system of  claim 1 , wherein said therapeutic drug is an anti-psychotic agent. 
     
     
         11 . The implantable, long term delivery system of  claim 1 , wherein said therapeutic drug is a birth control drug. 
     
     
         12 . The implantable, long term delivery system of  claim 1 , wherein said implant has a surface area to volume ratio between 1 and 4 (millimeters [mm]) 2 /mm 3 . 
     
     
         13 . The implantable, long term delivery system of  claim 1 , wherein said implant has a length between 1-3 centimeters. 
     
     
         14 . The implantable, long term delivery system of  claim 1 , wherein said implant has a diameter between 2-4 millimeters. 
     
     
         15 . A biodegradable implant comprising a therapeutic drug and a polymer, said polymer comprising polylactic acid (PLA) and optionally polyglycolic acid (PGA) in a PLA:PGA molar ratio between 50:50 and 100:0, wherein said therapeutic drug is present in an amount of 10%-60% of the mass of said implant, and said polymer is present in an amount of 40%-90% of the mass of said implant. 
     
     
         16 . The biodegradable implant of  claim 15 , wherein said implant is rod-shaped. 
     
     
         17 . The biodegradable implant of  claim 15 , wherein said implant has a substantially circular cross-section. 
     
     
         18 . The biodegradable implant of  claim 15 , wherein said implant has a substantially elliptical cross-section. 
     
     
         19 . The biodegradable implant of  claim 15 , wherein said implant has a surface area to volume ratio between 1 and 4 (millimeters [mm]) 2 /mm 3 . 
     
     
         20 . The biodegradable implant of  claim 15 , wherein said implant has a length between 1-3 centimeters. 
     
     
         21 . The biodegradable implant of  claim 15 , wherein said implant has a diameter between 2-4 millimeters. 
     
     
         22 . The biodegradable implant of  claim 15 , wherein said PLA:PGA molar ratio is between 75:25 and 100:0. 
     
     
         23 . The biodegradable implant of  claim 15 , wherein said implant is removable throughout the period of drug delivery. 
     
     
         24 . The biodegradable implant of  claim 15 , wherein said implant exhibits a reduced pH internal environment. 
     
     
         25 . The biodegradable implant of  claim 24 , wherein said reduced pH internal environment facilitates the release of a drug with enhanced solubility at reduced pH. 
     
     
         26 . The biodegradable implant of  claim 15 , wherein said implant is manufactured by a process comprising a step selected from solvent casting, melt-mixing, or a melt mix extrusion method that does not require use of a surfactant or an emulsion. 
     
     
         27 . The biodegradable implant of  claim 15 , wherein said therapeutic drug is present in an amount of 30%-60% of the mass of said implant 
     
     
         28 . The biodegradable implant of  claim 15 , wherein said therapeutic drug is risperidone, 9-OH-risperidone, or an active metabolite thereof. 
     
     
         29 . The biodegradable implant of  claim 15 , wherein therapeutic drug is thiothixene, haloperidol, hydrochlorothiazide (HCTZ), corticosterone, ibuprofen, aspirin, or an active metabolite thereof. 
     
     
         30 . The biodegradable implant of  claim 15 , wherein said therapeutic drug is an anti-depressant. 
     
     
         31 . The biodegradable implant of  claim 15 , wherein said therapeutic drug is an anti-anxiety agent. 
     
     
         32 . The biodegradable implant of  claim 15 , wherein said therapeutic drug is an anti-psychotic agent. 
     
     
         33 . The biodegradable implant of  claim 15 , wherein said therapeutic drug is a birth control drug. 
     
     
         34 . A method for treating a schizophrenia in a human, comprising administering the biodegradable implant of  claim 14  to said human, thereby treating a schizophrenia in a human. 
     
     
         35 . A method for treating a bipolar disorder, dementia, delirium, agitation, impulse control disorder, or psychotic depression in a human, comprising administering the biodegradable implant of  claim 14  5o said human, thereby treating a bipolar disorder, dementia, delirium, agitation, impulse control disorder, or psychotic depression in a human. 
     
     
         36 . A method for treating a subject for a disorder associated with a likelihood of non-compliance, comprising administering to said subject a therapeutic drug in a long term delivery system, wherein said long term delivery system comprises an implantable, rod-shaped structure, said implantable, rod-shaped structure comprising the target therapeutic drug and a polymer, said polymer comprising polylactic acid (PLA) and optionally polyglycolic acid (PGA) in a PLA:PGA molar ratio between 50:50 and 100:0, such that said subject is treated for said disorder associated with a likelihood of non-compliance. 
     
     
         37 . The method of  claim 36 , wherein said subject is human. 
     
     
         38 . The method of  claim 36 , wherein said step of administering is reversible throughout the period of drug delivery. 
     
     
         39 . The method of  claim 36 , wherein said therapeutic drug is present in an amount of 30%-60% of the mass of said individual biodegradable implants 
     
     
         40 . The method of  claim 36 , wherein said therapeutic drug is risperidone, 9-OH-risperidone, or an active metabolite thereof. 
     
     
         41 . The method of  claim 36 , wherein said PLA:PGA molar ratio is between 85:15 and 100:0. 
     
     
         42 . The method of  claim 36 , wherein said rod-shaped structure has a surface area to volume ratio between 1 and 4 (millimeters [mm]) 2 /mm 3 . 
     
     
         43 . The method of  claim 36 , wherein said rod-shaped structure has a length between 1-3 centimeters. 
     
     
         44 . The method of  claim 36 , wherein said rod-shaped structure has a diameter between 2-4 millimeters. 
     
     
         45 . The method of  claim 36 , wherein said rod-shaped structure has a mass of about 0.75 grams or less. 
     
     
         46 . The method of  claim 36 , wherein said long term delivery system further comprises a starter set of one or more different biodegradable rod-shaped structures, wherein said different rod-shaped structures differ from the set of biodegradable rod-shaped structure of  claim 36  in drug load, PLA:PGA ratio, or surface area to volume ratio, mass, length, diameter, or inherent viscosity and whereby said different rod-shaped structures reach steady-state levels of drug release faster than the set of rod-shaped structure of  claim 36 . 
     
     
         47 . The method of  claim 46 , wherein said one or more different biodegradable rod-shaped structures, if more than one in number, differ substantially from one another in said PLA:PGA molar ratio. 
     
     
         48 . A method for treating a schizophrenia in a human, comprising performing the method of  claim 36  on said human, thereby treating a schizophrenia in a human. 
     
     
         49 . A method for maintaining a therapeutic level of a therapeutic drug in a subject for a period of at least about 1 month, comprising administering to said subject a set of biodegradable implants, said set of biodegradable implants consisting of one or more individual biodegradable implants, said individual biodegradable implants each comprising said therapeutic drug and a polymer, said polymer comprising polylactic acid (PLA) and optionally polyglycolic acid (PGA) in a PLA:PGA molar ratio between 50:50 and 100:0, wherein said therapeutic drug is present in an amount of 10%-60% of the mass of said individual biodegradable implants, and said polymer is present in an amount of 40%-90% of the mass of said individual biodegradable implants, and wherein said individual biodegradable implants, if more than one in number, do not differ substantially from one another in said PLA:PGA molar ratio, thereby maintaining a therapeutic level of a therapeutic drug in a subject for a period of at least about 1 month. 
     
     
         50 . The method of  claim 49 , wherein said subject is human. 
     
     
         51 . The method of  claim 49 , wherein said step of administering is reversible throughout the period of drug delivery. 
     
     
         52 . The method of  claim 49 , wherein said individual biodegradable implants each exhibit a reduced pH internal environment. 
     
     
         53 . The method of  claim 52 , wherein said reduced pH internal environment facilitates the release of a drug with enhanced solubility at reduced pH. 
     
     
         54 . The method of  claim 49 , wherein said individual biodegradable implants are rod-shaped. 
     
     
         55 . The method of  claim 49 , wherein said therapeutic drug is present in an amount of 30%-60% of the mass of said individual biodegradable implants 
     
     
         56 . The method of  claim 49 , wherein said therapeutic drug is risperidone, 9-OH-risperidone, or an active metabolite thereof. 
     
     
         57 . The method of  claim 49 , wherein said PLA:PGA molar ratio is between 85:15 and 100:0. 
     
     
         58 . The method of  claim 49 , wherein said individual biodegradable implants have a surface area to volume ratio between 1 and 4 (millimeters [mm]) 2 /mm 3 . 
     
     
         59 . The method of  claim 49 , wherein said individual biodegradable implants have a length between 1-3 centimeters. 
     
     
         60 . The method of  claim 49 , wherein said individual biodegradable implants have a diameter between 2-4 millimeters. 
     
     
         61 . The method of  claim 49 , wherein said individual biodegradable implants have a combined mass of about 0.75 grams or less. 
     
     
         62 . The method of  claim 49 , further comprising administering to said subject a starter set of one or more different biodegradable implants, wherein said different biodegradable implants differ from the set of biodegradable implants of  claim 46  in drug load, PLA:PGA ratio, or surface area to volume ratio, mass, length, diameter, or inherent viscosity and whereby said different biodegradable implants reach steady-state levels of drug release faster than the set of biodegradable implants of  claim 49 . 
     
     
         63 . The method of  claim 62 , wherein said different biodegradable implants, if more than one in number, differ substantially from one another in said PLA:PGA molar ratio. 
     
     
         64 . A method for treating a schizophrenia in a human, comprising performing the method of  claim 49  on said human, thereby treating a schizophrenia in a human. 
     
     
         65 . A method for maintaining a therapeutic level of a drug in a subject for a period of at least about 3 months, comprising
 a. administering to said subject an initial set of one or more biodegradable implants, wherein said initial set consists of one or more individual biodegradable implants, said individual biodegradable implants each comprising a therapeutic drug and a polymer, said polymer comprising polylactic acid (PLA) and optionally polyglycolic acid (PGA) in a PLA:PGA molar ratio between 50:50 and 100:0, wherein said therapeutic drug is present in an amount of 10%-60% of the mass of said individual biodegradable implants, and said polymer is present in an amount of 40%-90% of the mass of said individual biodegradable implants, and wherein said individual biodegradable implants, if more than one in number, do not differ substantially from one another in said PLA:PGA molar ratio;   b. administering to said subject a maintenance set of one or more biodegradable implants to said subject near the point of peak release of said initial set of biodegradable implants, wherein said maintenance set of biodegradable implants consists of additional individual biodegradable implants equivalent in said PLA:PGA molar ratio to the individual biodegradable implants in said initial set of biodegradable implants; and   c. repeating step (b) as necessary,   thereby maintaining a therapeutic level of a drug in a subject for a period of at least about 3 months.   
     
     
         66 . The method of  claim 65 , wherein said subject is human. 
     
     
         67 . The method of  claim 65 , wherein said step of administering is reversible throughout the period of drug delivery. 
     
     
         68 . The method of  claim 65 , wherein said individual biodegradable implants of said initial set each exhibit a reduced pH internal environment. 
     
     
         69 . The method of  claim 68 , wherein said reduced pH internal environment facilitates the release of a drug with enhanced solubility at reduced pH. 
     
     
         70 . The method of  claim 65 , wherein said individual biodegradable implants of said initial set are rod-shaped. 
     
     
         71 . The method of  claim 65 , wherein said individual biodegradable implants of said initial set are disk-shaped. 
     
     
         72 . The method of  claim 65 , wherein said therapeutic drug is present in an amount of 30%-60% of the mass of said individual biodegradable implants of said initial set. 
     
     
         73 . The method of  claim 65 , wherein said therapeutic drug is risperidone, 9-OH-risperidone, or an active metabolite thereof. 
     
     
         74 . The method of  claim 65 , wherein said PLA:PGA molar ratio is between 85:15 and 100:0. 
     
     
         75 . The method of  claim 65 , wherein said individual biodegradable implants of said initial set have a surface area to volume ratio between 1 and 4 (millimeters [mm]) 2 /mm 3 . 
     
     
         76 . The method of  claim 65 , wherein said individual biodegradable implants of said initial set have a length between 1-5 millimeters. 
     
     
         77 . The method of  claim 65 , wherein said individual biodegradable implants of said initial set have a diameter between 2-4 millimeters. 
     
     
         78 . The method of  claim 65 , wherein said individual biodegradable implants of said initial set have a combined mass of about 0.75 grams or less. 
     
     
         79 . The method of  claim 65 , further comprising administering, together with said initial set of biodegradable implants, a starter set of one or more different biodegradable implants, wherein said different biodegradable implants differ from said initial set of biodegradable implants in drug load, PLA:PGA ratio, surface area to volume ratio, mass, length, diameter, or inherent viscosity, and whereby said different biodegradable implants reach steady-state levels of drug release faster than said initial set of biodegradable implants. 
     
     
         80 . The method of  claim 79 , wherein said one or more different biodegradable implants, if more than one in number, differ substantially from one another in said PLA:PGA molar ratio. 
     
     
         81 . A method for treating a schizophrenia in a human, comprising performing the method of  claim 65  to said human, thereby treating a schizophrenia in a human.