Acamprosate formulations, methods of using the same, and combinations comprising the same

Abstract

Embodiments disclosed herein generally relate to acamprosate formulations, methods of use of the formulations, to methods of using the formulations optionally in combination with at least one other medication, and to combination products and compositions comprising acamprosate and at least one other medication, such as neuroleptic (antipsychotic) and/or antidepressant drugs.

1 - 66 . (canceled) 
     
     
         67 . A tablet composition comprising:
 a polymer matrix comprised of at least one polymer;   a dose of prazosin dispersed within the polymer matrix, the dose being within a range of about 0.1 mg to about 50 mg; and   optionally at least one pharmaceutically acceptable excipient;   the at least one polymer being selected, and the polymer matrix being present at a level within the tablet so that:   
       when the tablet is exposed to a physiological buffer in vitro, it swells to a size within a range of between about 120% and about 150% of its initial size while remaining intact and firm. 
     
     
         68 . The tablet of  claim 67  wherein the tablet is considered to be firm when it has friability over a range of compression forces and/or firmness of at least level 4 on a 1-5 scale. 
     
     
         69 . The tablet of  claim 67 , which tablet has a longest dimension within a range of 1-2 cm. 
     
     
         70 . The tablet of  claim 67 , which tablet substantially retains its shape and dimensions in a subject's GI tract after administration to the subject, whether in the fed state or in the fasted state. 
     
     
         71 . The tablet of  claim 67  or  claim 69 , wherein the tablet has a shape selected from the group consisting of spherical disc, oval, and oblong shape. 
     
     
         72 . A pharmaceutical composition comprising:
 a dose of prazosin within the range of 0.1 mg to 50 mg, present in a sustained release formulation that comprises a polymer matrix comprised of a polymer that it swells rather than dissolving when placed in contact with water, wherein   the pharmaceutical composition is characterized in that it retains its integrity for at least several hours in an in vitro dissolution test, while releasing the prazosin either with zero-order kinetics or at a rate approximately linear with the square root of time, the releasing being substantially equivalent at pH 1.0 and pH 4.5.   
     
     
         73 . The composition of  claim 72 , wherein the prazosin is present in a pharmaceutically acceptable salt form. 
     
     
         74 . The pharmaceutical composition of  claim 72 , wherein the prazosin is released independent of pH over a pH range that spans at least pH 1.0 to pH 4.5. 
     
     
         75 . The pharmaceutical composition of  claim 72 , wherein the prazosin is released at a rate approximately linear with the square root of time. 
     
     
         76 . The pharmaceutical composition of  claim 72 , further comprising a dose of acamprosate, wherein:
 the dose of acamprosate is within a range of about 200 to about 1600 mg; or   the acamprosate is present at a level that is about 20% to about 90% of the total weight of the composition.   
     
     
         77 . The pharmaceutical composition of  claim 76 , wherein the acamprosate is present in a pharmaceutically acceptable salt form. 
     
     
         78 . The pharmaceutical composition of  claim 77 , wherein the pharmaceutically acceptable salt form is or comprises acamprosate calcium. 
     
     
         79 . The pharmaceutical composition of  claim 72  or  claim 76 , wherein the swelling polymer comprises or consists of a carbomer, cellulosic hydrocolloid, polyethylene oxide, chitosan, xanthan gum, locust bean gum, klucel, or combinations thereof. 
     
     
         80 . The pharmaceutical composition of  claim 72  or  claim 76 , wherein the swelling polymer comprises or consists of a carbomer. 
     
     
         81 . The pharmaceutical composition of  claim 80 , wherein the carbomer comprises or consists of a carbomer selected from the group comprising carboxypolymethylene; carbomer homopolymer type A, and carbomer homopolymer type B. 
     
     
         82 . The pharmaceutical composition of  claim 80 , wherein the carbomer is present in an amount sufficient to provide a T max  in plasma from about 1 hours to about 6 hours. 
     
     
         83 . The pharmaceutical composition of  claim 72 , which composition is characterized in that, when administered to a subject in a fasted state, achieves a plasma C max , a plasma T max , or a plasma AUC value for prazosin that is similar to the corresponding value it achieves when administered to the same subject in a fed state. 
     
     
         84 . A method comprising steps of:
 administering to a subject suffering from or susceptible to PTSD a combination of prazosin therapy and acamprosate therapy.   
     
     
         85 . The method of  claim 84 , wherein the prazosin therapy is characterized by a difference selected from the group consisting of reduced dosage, reduced administration frequency and/or reduced side effects such as hypotension as compared with a reference prazosin therapy. 
     
     
         86 . The method of  claim 84 , wherein the prazosin therapy comprises administering a pharmaceutical composition comprising:
 a dose of prazosin within the range of 0.1 mg to 50 mg, present in a sustained release formulation that comprises a polymer matrix comprised of a polymer that it swells rather than dissolving when placed in contact with water, wherein   the pharmaceutical composition is characterized in that it retains its integrity for at least several hours in an in vitro dissolution test, while releasing the prazosin either with zero-order kinetics or at a rate approximately linear with the square root of time, the releasing being substantially equivalent at pH 1.0 and pH 4.5.   
     
     
         87 . The method of  claim 84 , wherein the prazosin therapy is characterized by a reduced level of hypotension observed across a population receiving the therapy as compared with that observed with a reference prazosin therapy at the same dose. 
     
     
         88 . The method of  claim 84 , wherein the prazosin therapy is administered independent of the subject's fed vs fasted state. 
     
     
         89 . The method of  claim 84 , wherein the step of administering comprises administering a pharmaceutical composition comprising:
 a dose of acamprosate within a range of about 200 to about 1600 mg; or a dose of acamprosate present at a level that is about 20% to about 90% of the total weight of the composition; and   a dose of prazosin within the range of 0.1 mg to 50 mg, present in a sustained release formulation that comprises a polymer matrix comprised of a polymer that it swells rather than dissolving when placed in contact with water, wherein   the pharmaceutical composition is characterized in that it retains its integrity for at least several hours in an in vitro dissolution test, while releasing the prazosin either with zero-order kinetics or at a rate approximately linear with the square root of time, the releasing being substantially equivalent at pH 1.0 and pH 4.5.   
     
     
         90 . A method comprising steps of administering to a subject suffering from or susceptible to an anxiety disorder, PTSD, or insomnia, a combination of prazosin therapy and acamprosate therapy. 
     
     
         91 . A method comprising steps of administering to a patient receiving prazosin therapy for PTSD, an anxiety disorder, or a sleep disorder, an acamprosate therapy regimen selected from the group consisting of:
 administration of acamprosate at a total daily dose between 1 gram and 4 grams per day, given as a single daily dose;   administration of acamprosate in a pharmaceutical composition comprising a swelling polymer selected so that the acamprosate is released from the composition with either zero-order kinetics, first-order kinetics, or at a rate approximately proportional with the square root of time; and   combinations thereof.   
     
     
         92 . The method of  claim 91 , wherein the acamprosate therapy regimen comprises administering the acamprosate in one or two doses per day. 
     
     
         93 . The method of  claim 91 , wherein the prazosin therapy comprises administering prazosin according to a regimen that differs from that according to which prazosin is administered to treat PTSD, anxiety disorder, or sleep disorder when prazosin is administered alone in that it involves reduced dosage, reduced administration frequency and/or reduced side effects. 
     
     
         94 . The method of  claim 91 , wherein the acamprosate therapy regimen comprises administering acamprosate in a pharmaceutical composition that comprises acamprosate in a dose of at least 800 mg or comprises acamprosate at a lower dose and also comprises citric acid at a level sufficient to achieve a pH comparable to that provided when acamprosate is present in the dose of at least 800 mg. 
     
     
         95 . The method of  claim 91 , wherein the acamprosate therapy regimen comprises administration of the pharmaceutical composition providing substantially the same PK profile in said patient whether it is administered in a fed state or in a fasted state. 
     
     
         96 . The method of  claim 91 , wherein the subject is suffering from or susceptible to PTSD. 
     
     
         97 . The method of  claim 91 , wherein the acamprosate therapy regimen is administered for a period of time until a reduction is observed in one or more symptoms selected from the group consisting of: symptoms of PTSD (re-experiencing phenomena, hyperarousal, an emotional numbing), depression, difficulty initiating or maintaining sleep, generalized anxiety disorder, suicidal ideation, alcohol overuse, and combinations thereof. 
     
     
         98 . The method of  claim 91 , wherein the subject displays one or more side effects selected from the group comprising: syncope, symptomatic orthostatic hypotension, drowsiness, dizziness, and combinations thereof, which one or more side effects are associated with the prazosin therapy, and further wherein, upon administration of the acamprosate therapy regimen, the subject experiences a reduction in one or more of the displayed side effects. 
     
     
         99 . The method of  claim 84 , wherein: the prazosin therapy comprises administering one or more doses of a pharmaceutical composition comprising:
 a dose of prazosin within the range of 0.1 mg to 50 mg; or   the acamprosate therapy comprises administering one or more doses of a pharmaceutical composition comprising a polymer matrix comprised of a swelling polymer and a dose of acamprosate within the range 400 mg to 1600 mg; or   both.   
     
     
         100 . A method comprising steps of:
 administering acamprosate therapy to a subject receiving prazosin therapy.   
     
     
         101 . A method of administering acamprosate to a subject receiving prazosin therapy, the method comprising administration of acamprosate at a total daily dose of 800 mg or more. 
     
     
         102 . The method of  claim 101 , wherein the total daily dose is within a range of about 800 mg to about 3200 mg. 
     
     
         103 . A method comprising steps of administering to a subject a composition of  claim 72 , the administration being characterized in that it achieves a pK profile for prazosin characterized in that: C max  is decreased and T max  is increased compared to that achieved by administration of prazosin in a reference composition associated with first order kinetics.