Methods and compositions employing bicifadine for treating disability or functional impairment associated with acute pain, chronic pain, or neuropathic disorders

Abstract

Methods and compositions are provided for formulating and administering bicifadine and related compounds to treat or prevent functional impairment and disabilities associated with acute pain, chronic pain, and neuropathic disorders.

1 . A method for treating a disability or reducing a functional impairment in a mammalian subject associated with acute pain, chronic pain, or a neuropathic disorder, comprising administering a pre-determined dosage amount of an active therapeutic agent selected from a compound of Formula I  
       
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates, and prodrugs of said compound, whereby said disability is substantially reduced or said function or activity is significantly enhanced in said subject.  
     
     
         2 . The method of  claim 1 , wherein one or more functional indices of impairment or disability is reduced in treated subjects compared to placebo-treated subjects by at least 20%.  
     
     
         3 . The method of  claim 1 , wherein one or more functional indices of impairment or disability is reduced in treated subjects compared to placebo-treated subjects by at least 50%.  
     
     
         4 . The method of  claim 1 , wherein a baseline functional disability index or score of subjects prior to treatment is improved after treatment by at least 20%.  
     
     
         5 . The method of  claim 1 , wherein a baseline functional disability index or score of subjects prior to treatment is improved after treatment by at least 50%.  
     
     
         6 . The method of  claim 1 , which is effective for treating a disability or reducing a functional impairment associated with a chronic pain condition or symptom in said subject.  
     
     
         7 . The method of  claim 6 , wherein said chronic pain condition or symptom is selected from the group consisting of osteoarthritis pain; rheumatoid arthritis pain; cancer pain; and various other chronic pain conditions of non-neuropathic origin, including chronic low back pain, chronic lumbar and cervical pain, chronic fibromyalgia pain, chronic pain from arteriovenuous malformation, arachnoiditis, chronic pain from root avulsion, chronic postthoracotomy pain, and chronic postmastectomy pain of non-neuropathic origin.  
     
     
         8 . The method of  claim 1 , which is effective for treating a disability or reducing a functional impairment associated with chronic low back pain (CLBP) in said subject.  
     
     
         9 . The method of  claim 8 , wherein treated subjects exhibit at least a 20% decrease in a Roland-Morris Disability Questionnaire (RDQ) score following treatment compared to a control RDQ score of placebo-treated subjects.  
     
     
         10 . The method of  claim 8 , wherein treated subjects exhibit at least a 30% decrease in a Roland-Morris Disability Questionnaire (RDQ) score following treatment compared to a control RDQ score of placebo-treated subjects.  
     
     
         11 . The method of  claim 8 , wherein treated subjects exhibit at least a 50% decrease in a Roland-Morris Disability Questionnaire (RDQ) score following treatment compared to a control RDQ score of placebo-treated subjects.  
     
     
         12 . The method of  claim 1 , wherein said compound of Formula I is formulated for oral delivery with a sustained release vehicle, matrix, binder, or coating material  
     
     
         13 . The method of  claim 12 , wherein the sustained release vehicle, matrix, binder, or coating material comprises a sustained release polymer.  
     
     
         14 . The method of  claim 13 , wherein the sustained release polymer is selected from the group consisting of consisting of ethylcellulose, hydroxyethyl cellulose; hydroxyethylmethyl cellulose; hydroxypropyl cellulose; hydroxypropylmethyl cellulose; hydroxypropylmethyl cellulose phthalate; hydroxypropylmethylcellulose acetate succinate; hydroxypropylmethylcellulose acetate phthalate; sodium carboxymethylcellulose; cellulose acetate phthalate; cellulose acetate trimellitate; polyoxyethylene stearates; polyvinyl pyrrolidone; polyvinyl alcohol; copolymers of polyvinyl pyrrolidone and polyvinyl alcohol; polymethacrylate copolymers; and mixtures thereof.  
     
     
         15 . The method of  claim 1 , which is effective for treating a disability or reducing a functional impairment associated with an acute pain condition or symptom in said subject.  
     
     
         16 . The method of  claim 15 , wherein said acute pain condition or symptom results from a trauma, injury or condition selected from the group consisting of burns; cuts; wounds; trauma; surgery; headaches; sprains; bone fractures; fibromyalgia; acute lower back pain; dorsopathy; dysmenorrhea; infection; dysfunction of the liver, pancreas, endocrine glands, kidney, bladder, gall bladder, spleen, hematopoetic system, vasculature or other body organ or tissue; torn or injured muscle, ligament, or tendon; acute exacerbation of a chronic or intermittent pain condition, including arthritic flare, migraine attack, and acute worsening of chronic lower back pain or chronic neuropathic pain.  
     
     
         17 . The method of  claim 1 , which is effective for treating a disability or reducing a functional impairment associated with a neuropathic disorder in said subject.  
     
     
         18 . The method of  claim 17 , wherein said neuropathic disorder or related symptom is selected from the group consisting of diabetic neuropathy; peripheral neuropathy; distal symmetrical polyneuropathy; post-herpetic neuralgia; trigeminal neuralgia; alcoholism-related neuropathy; HIV sensory neuropathy; sciatica; spinal cord injury; post-stroke neuropathy; multiple sclerosis; Parkinson's disease; idiopathic or post-traumatic neuropathy; mononeuritis; cancer-associated neuropathy; peripheral nerve trauma; nerve transection; carpal tunnel injury; neuropathy associated with Fabry's disease; vasculitic neuropathy; neuropathy associated with Guillain-Barre syndrome; entrapment neuropathy; phantom limb syndrome; and neuropathic conditions associated with fibromyalgia, Wallenberg's syndrome, connective tissue disease, plexus irradiation, ischemic irradiation, hematomyelia, dyscraphism, tumor compression, arteriovenuous malformation, syphilitic myelitis, commissural myelotomy, arachnoiditis, root avulsion, chronic lower back pain syndromes of neuropathic origin, and reflex sympathic dystrophy.  
     
     
         19 . The method of  claim 1 , wherein the active therapeutic agent comprises bicifadine HCl.  
     
     
         20 . The method of  claim 1 , wherein the active therapeutic agent comprises a (+) enantiomer of bicifadine.  
     
     
         21 . The method of  claim 1 , wherein the active therapeutic agent is substantially free of a (−) enantiomer of bicifadine.  
     
     
         22 . The method of  claim 1 , wherein the active therapeutic agent comprises a (−) enantiomer of bicifadine.  
     
     
         23 . The method of  claim 1 , wherein the active therapeutic agent is substantially free of a (+) enantiomer of bicifadine.  
     
     
         24 . The method of  claim 1 , wherein the active therapeutic agent comprises a polymorph B form of bicifadine.  
     
     
         25 . The method of  claim 1 , wherein the active therapeutic agent is substantially free of a polymorph A form of bicifadine.  
     
     
         26 . The method of  claim 1 , wherein the active therapeutic agent comprises a polymorph A form of bicifadine.  
     
     
         27 . The method of  claim 1 , wherein the composition is substantially free of a polymorph B form of bicifadine.  
     
     
         28 . The method of  claim 1 , wherein said pre-determined dosage amount of the active therapeutic agent is between about 25 to 1200 mg.  
     
     
         29 . The method of  claim 1 , wherein said pre-determined dosage amount of the active therapeutic agent is between about 50 to 1000 mg.  
     
     
         30 . The method of  claim 1 , wherein said pre-determined dosage amount of the active therapeutic agent is between about 75 to 800 mg.  
     
     
         31 . The method of  claim 1 , wherein said pre-determined dosage amount of the active therapeutic agent is between about 100 to 600 mg.  
     
     
         32 . The method of  claim 1 , wherein said pre-determined dosage amount of the active therapeutic agent is between about 100 to 400 mg.  
     
     
         33 . The method of  claim 1 , wherein said pre-determined dosage amount of the active therapeutic agent is between about 100 to 200 mg.  
     
     
         34 . A method for treating a disability or reducing a functional impairment in a mammalian subject associated with acute pain, chronic pain, or a neuropathic disorder, comprising administering a pharmaceutical composition comprising a pre-determined dosage amount of an active therapeutic agent selected from a compound of Formula I  
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates, and prodrugs of said active compound, formulated with a sustained release vehicle, matrix, binder or coating material,  
         which, following administration of said pharmaceutical composition to said subject, provides a mean maximum plasma concentration (Cmax) of said active therapeutic agent in said subject which is less than about 80% of a Cmax provided in a control subject after administration of the same amount of the active agent in an immediate release formulation, whereby said disability is substantially reduced or said function or activity is significantly enhanced in said subject.  
       
     
     
         35 . A method for treating a disability or reducing a functional impairment in a mammalian subject associated with acute pain, chronic pain, or a neuropathic disorder, comprising administering a pharmaceutical composition comprising a pre-determined dosage amount of an active therapeutic agent selected from a compound of Formula I  
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates, and prodrugs of said active compound, formulated with a sustained release vehicle, matrix, binder or coating material,  
         which, following administration of said pharmaceutical composition to a mammalian treatment subject, yields an Area Under the Curve (AUC) of said active therapeutic agent in said treatment subject which is less than about 80% of an AUC provided in a control subject following administration of the same amount of the active agent in an immediate release formulation, whereby said disability is substantially reduced or said function or activity is significantly enhanced in said subject.  
       
     
     
         36 . A method for treating a disability or reducing a functional impairment in a mammalian subject associated with acute pain, chronic pain, or a neuropathic disorder, comprising administering a pharmaceutical composition comprising a pre-determined dosage amount of an active therapeutic agent selected from a compound of Formula I  
       
         
           
           
               
               
           
         
         and pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates, and prodrugs of said active compound, formulated with a sustained release vehicle, matrix, binder or coating material,  
         which, following administration of said pharmaceutical composition to a mammalian treatment subject, yields a mean maximum plasma concentration (Cmax) and an Area Under the Curve (AUC) of said active therapeutic agent in said treatment subject which are each, respectively, less than about 80% of a Cmax and an AUC provided in a control subject following administration of the same amount of the active agent in an immediate release formulation, whereby said disability is substantially reduced or said function or activity is significantly enhanced in said subject.  
       
     
     
         37 . A pharmaceutical composition for treating a disability or reducing a functional impairment in a mammalian subject associated with acute pain, chronic pain, or a neuropathic disorder comprising: 
 a predetermined dosage amount of an active therapeutic agent selected from a compound of Formula I                          and pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates, and prodrugs of said active compound, and combinations thereof; and    a sustained release vehicle, matrix, binder or coating material,    which, following administration of said pharmaceutical composition to a mammalian treatment subject, provides a mean maximum plasma concentration (Cmax) of said active therapeutic agent in said treatment subject which is less than about 80% of a Cmax provided in a control subject after administration of the same amount of the active agent in an immediate release formulation, and which is effective to substantially reduce said disability or significantly enhance said function or activity in said subject.    
     
     
         38 . A pharmaceutical composition for treating a disability or reducing a functional impairment in a mammalian subject associated with acute pain, chronic pain, or a neuropathic disorder comprising: 
 a pre-determined dosage amount of an active therapeutic agent selected from a compound of Formula I                          and pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates, and prodrugs of said active compound, and combinations thereof; and    a sustained release vehicle, matrix, binder or coating material,    which, following administration of said pharmaceutical composition to a mammalian treatment subject, yields an Area Under the Curve (AUC) of said active therapeutic agent in said treatment subject which is less than about 80% of an AUC provided in a control subject following administration of the same amount of the active agent in an immediate release formulation, and which is effective to substantially reduce said disability or significantly enhance said function or activity in said subject.    
     
     
         39 . A pharmaceutical composition for treating a disability or reducing a functional impairment in a mammalian subject associated with acute pain, chronic pain, or a neuropathic disorder comprising: 
 a predetermined dosage amount of an active therapeutic agent selected from a compound of Formula I                          and pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates, and prodrugs of said active compound, and combinations thereof; and    a sustained release vehicle, matrix, binder or coating material,    which, following administration of said pharmaceutical composition to a mammalian treatment subject, yields a mean maximum plasma concentration (Cmax) and an Area Under the Curve (AUC) of said active therapeutic agent in said treatment subject which are each, respectively, less than about 80% of a Cmax and an AUC provided in a control subject following administration of the same amount of the active agent in an immediate release formulation, and which is effective to substantially reduce said disability or significantly enhance said function or activity in said subject.    
     
     
         40 . A pharmaceutical composition according to any of claims  37 ,  38 , or  39 , wherein the sustained release vehicle, matrix, binder, or coating material, comprises a sustained release polymer.  
     
     
         41 . A pharmaceutical composition according to  claim 40 , wherein the sustained release polymer is selected from the group consisting of consisting of ethylcellulose, hydroxyethyl cellulose; hydroxyethylmethyl cellulose; hydroxypropyl cellulose; hydroxypropylmethyl cellulose; hydroxypropylmethyl cellulose phthalate; hydroxypropylmethylcellulose acetate succinate; hydroxypropylmethylcellulose acetate phthalate; sodium carboxymethylcellulose; cellulose acetate phthalate; cellulose acetate trimellitate; polyoxyethylene stearates; polyvinyl pyrrolidone; polyvinyl alcohol; copolymers of polyvinyl pyrrolidone and polyvinyl alcohol; polymethacrylate copolymers; and mixtures thereof.  
     
     
         42 . A pharmaceutical composition according to any of claims  37 ,  38 , or  39 , which is effective for preventing or treating an acute pain condition or symptom in said subject.  
     
     
         43 . A pharmaceutical composition according to  claim 42 , wherein said acute pain condition or symptom results from a trauma, injury or condition selected from the group consisting of burns; cuts; wounds; trauma; surgery; headaches; sprains; bone fractures; fibromyalgia; acute lower back pain; dorsopathy; dysmenorrhea; infection; dysfunction of the liver, pancreas, endocrine glands, kidney, bladder, gall bladder, spleen, hematopoetic system, vasculature or other body organ or tissue; torn or injured muscle, ligament, or tendon; acute exacerbation of a chronic or intermittent pain condition, including arthritic flare, migraine attack, and acute worsening of chronic lower back pain or chronic neuropathic pain.  
     
     
         44 . A pharmaceutical composition according to any of claims  37 ,  38 , or  39 , which is effective for preventing or treating a chronic pain condition or symptom in said subject.  
     
     
         45 . A pharmaceutical composition according to  claim 44 , wherein said chronic pain condition or symptom is selected from the group consisting of 
 osteoarthritis pain; rheumatoid arthritis pain; cancer pain; and various other chronic pain conditions of non-neuropathic origin, including chronic low back pain, chronic lumbar and cervical pain, chronic fibromyalgia pain, chronic pain from arteriovenuous malformation, arachnoiditis, chronic pain from root avulsion, chronic postthoracotomy pain, and chronic postmastectomy pain of non-neuropathic origin.    
     
     
         46 . A pharmaceutical composition according to any of claims  37 ,  38 , or  39 , which is effective for treating or preventing a neuropathic disorder or related symptom in said subject.  
     
     
         47 . A pharmaceutical composition according to  claim 46 , wherein said neuropathic disorder or related symptom is selected from the group consisting of diabetic neuropathy; peripheral neuropathy; distal symmetrical polyneuropathy; post-herpetic neuralgia; trigeminal neuralgia; alcoholism-related neuropathy; HIV sensory neuropathy; sciatica; spinal cord injury; post-stroke neuropathy; multiple sclerosis; Parkinson's disease; idiopathic or post-traumatic neuropathy; mononeuritis; cancer-associated neuropathy; peripheral nerve trauma; nerve transection; carpal tunnel injury; neuropathy associated with Fabry's disease; vasculitic neuropathy; neuropathy associated with Guillain-Barre syndrome; entrapment neuropathy; phantom limb syndrome; and neuropathic conditions associated with fibromyalgia, Wallenberg's syndrome, connective tissue disease, plexus irradiation, ischemic irradiation, hematomyelia, dyscraphism, tumor compression, arteriovenuous malformation, syphilitic myelitis, commissural myelotomy, arachnoiditis, root avulsion, chronic lower back pain syndromes of neuropathic origin, and reflex sympathic dystrophy.  
     
     
         48 . A pharmaceutical composition according to any of claims  37 ,  38 , or  39 , wherein the active therapeutic agent comprises bicifadine HCl.  
     
     
         49 . A pharmaceutical composition according to any of claims  37 ,  38 , or  39 , wherein the active therapeutic agent comprises a (+) enantiomer of bicifadine.  
     
     
         50 . A pharmaceutical composition according to  claim 49 , wherein the composition is substantially free of a (−) enantiomer of bicifadine.  
     
     
         51 . A pharmaceutical composition according to any of claims  37 ,  38 , or  39 , wherein the active therapeutic agent comprises a (−) enantiomer of bicifadine.  
     
     
         52 . A pharmaceutical composition according to  claim 51 , wherein the composition is substantially free of a (+) enantiomer of bicifadine.  
     
     
         53 . A pharmaceutical composition according to any of claims  37 ,  38 , or  39 , wherein the active therapeutic agent comprises a polymorph B form of bicifadine.  
     
     
         54 . A pharmaceutical composition according to  claim 53 , wherein the composition is substantially free of a polymorph A form of bicifadine.  
     
     
         55 . A pharmaceutical composition according to any of claims  37 ,  38 , or  39 , wherein the active therapeutic agent comprises a polymorph A form of bicifadine.  
     
     
         56 . A pharmaceutical composition according to  claim 55 , wherein the composition is substantially free of a polymorph B form of bicifadine.  
     
     
         57 . A pharmaceutical composition according to any of claims  37 ,  38 , or  39 , wherein said pre-determined dosage amount of the active therapeutic agent is between about 25 to 1200 mg.  
     
     
         58 . A pharmaceutical composition according to  claim 57 , wherein said pre-determined dosage amount of the active therapeutic agent is between about 75 to 800 mg.  
     
     
         59 . A pharmaceutical composition according to  claim 57 , wherein said pre-determined dosage amount of the active therapeutic agent is between about 100 to 600 mg.  
     
     
         60 . A pharmaceutical composition according to  claim 57 , wherein said pre-determined dosage amount of the active therapeutic agent is between about 100 to 400 mg.  
     
     
         61 . A pharmaceutical composition according to any of claims  37 ,  38 , or  39 , wherein the composition comprises a unit oral dosage form containing from about 25 to 600 mg of an active ingredient selected from the group consisting of a compound of Formula I  
       
         
           
           
               
               
           
         
       
       and a pharmaceutically acceptable salt thereof; and  
       from about 5% to about 75% by weight of said composition of a sustained release polymer.  
     
     
         62 . A pharmaceutical composition according to  claim 61 , wherein the sustained release polymer is selected from the group consisting of consisting of ethylcellulose, hydroxyethyl cellulose; hydroxyethylmethyl cellulose; hydroxypropyl cellulose; hydroxypropylmethyl cellulose; hydroxypropylmethyl cellulose phthalate; hydroxypropylmethylcellulose acetate succinate; hydroxypropylmethylcellulose acetate phthalate; sodium carboxymethylcellulose; cellulose acetate phthalate; cellulose acetate trimellitate; polyoxyethylene stearates; polyvinyl pyrrolidone; polyvinyl alcohol; copolymers of polyvinyl pyrrolidone and polyvinyl alcohol; polymethacrylate copolymers; and mixtures thereof.  
     
     
         63 . A pharmaceutical composition according to  claim 62 , wherein the sustained release polymer is a hydrophilic slow release polymer matrix.  
     
     
         64 . A pharmaceutical composition according to  claim 63 , wherein the slow release polymer matrix comprises a hydroxypropyl methyl cellulose matrix.  
     
     
         65 . A pharmaceutical composition according to  claim 64 , wherein the hydroxypropyl methyl cellulose matrix is present in an amount of from about 20% to 40% by weight of said composition.  
     
     
         66 . A method for treating a disability or reducing a functional impairment in a mammalian subject associated with acute pain, chronic pain, or a neuropathic disorder, comprising administering to said subject a pharmaceutical composition comprising: 
 a therapeutically effective amount of an active therapeutic agent selected from a compound of Formula I                          and pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates, and prodrugs of said active compound, and combinations thereof; and    a sustained release vehicle, matrix, binder or coating material,    wherein, following administration of said pharmaceutical composition to said subject, a mean maximum plasma concentration (Cmax) of said active therapeutic agent is obtained in said subject which is less than or equal to about 80% of a Cmax obtained in a control subject after administration of the same amount of the active agent in an immediate release formulation, whereby said disability is substantially reduced or said function or activity is significantly enhanced in said subject.    
     
     
         67 . A method for treating a disability or reducing a functional impairment in a mammalian subject associated with acute pain, chronic pain, or a neuropathic disorder, comprising administering to said subject a pharmaceutical composition comprising: 
 a therapeutically effective amount of an active therapeutic agent selected from a compound of Formula I                          and pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates, and prodrugs of said active compound, and combinations thereof; and    a sustained release vehicle, matrix, binder or coating material,    wherein, following administration of said pharmaceutical composition to said subject, an Area Under the Curve (AUC) of said active therapeutic agent is obtained in said subject which is less than or equal to about 80% of an AUC obtained in a control subject after administration of the same amount of the active agent in an immediate release formulation, whereby said disability is substantially reduced or said function or activity is significantly enhanced in said subject.    
     
     
         68 . A method for treating a disability or reducing a functional impairment in a mammalian subject associated with acute pain, chronic pain, or a neuropathic disorder, comprising administering to said subject a pharmaceutical composition comprising: 
 a therapeutically effective amount of an active therapeutic agent selected from a compound of Formula I                          and pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates, and prodrugs of said active compound, and combinations thereof; and    a sustained release vehicle, matrix, binder or coating material,    wherein, following administration of said pharmaceutical composition to said subject, a mean maximum plasma concentration (Cmax) and an Area Under the Curve (AUC) of said active therapeutic agent are obtained in said subject which are each, respectively, less than or equal to about 80% of a Cmax and an AUC obtained in a control subject after administration of the same amount of the active agent in an immediate release formulation, whereby said disability is substantially reduced or said function or activity is significantly enhanced in said subject.    
     
     
         69 . A method according to  claim 1 , wherein said compound of Formula I is formulated in a sustained release composition having an in vitro dissolution profile wherein about 15% to about 40% of the compound of Formula I is dissolved within 1 hour, measured in a <711> dissolution test, Apparatus 1, USP 28, 2005, at 37.0° C.±0.5° C., using 900 ml 0.05M potassium phosphate monobasic buffer pH 6.8 and a basket or paddle speed of 75 rpm.  
     
     
         70 . A method for treating a disability or reducing a functional impairment in a mammalian subject associated with acute pain, chronic pain, or a neuropathic disorder, comprising: 
 administering to said subject a therapeutically effective amount of an active therapeutic agent selected from a compound of Formula I                          and pharmaceutically acceptable salts, enantiomers, polymorphs, solvates, hydrates, and prodrugs of said active compound, and combinations thereof, in a daily dosing regimen consisting of one or two doses of the active agent per day, which is effective to substantially reduce said disability or significantly enhance said function or activity in said subject over approximately a 24 hour period.