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 in combination with at least one other medication, and to combination products and compositions comprising the formulations and at least one other medication, such as neuroleptic (antipsychotic) and/or antidepressant drugs.

We claim: 
     
         1 . 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. 
     
     
         2 . The tablet of  claim 1  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. 
     
     
         3 . The tablet of  claim 1 , which tablet has a longest dimension within a range of 1-2 CM. 
     
     
         4 . The tablet of  claim 1 , 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. 
     
     
         5 . The tablet of  claim 1  or  claim 3 , wherein the tablet has a shape selected from the group consisting of spherical disc, oval, and oblong shape. 
     
     
         6 . 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.   
     
     
         7 . The composition of  claim 6 , wherein the prazosin is present in a pharmaceutically acceptable salt form. 
     
     
         8 . The pharmaceutical composition of  claim 6 , wherein the prazosin is released independent of pH over a pH range that spans at least pH 1.0 to pH 4.5. 
     
     
         9 . The pharmaceutical composition of  claim 6 , wherein the prazosin is released at a rate approximately linear with the square root of time. 
     
     
         10 . The pharmaceutical composition of  claim 6 , 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.   
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein the acamprosate is present in a pharmaceutically acceptable salt form. 
     
     
         12 . The pharmaceutical composition of  claim 11 , wherein the pharmaceutically acceptable salt form is or comprises acamprosate calcium. 
     
     
         13 . The pharmaceutical composition of  claim 6  or  claim 10 , wherein the swelling polymer comprises or consists of a carbomer, cellulosic hydrocolloid, polyethylene oxide, chitosan, xanthan gum, locustbean gum, klucel, or combinations thereof. 
     
     
         14 . The pharmaceutical composition of  claim 6  or  claim 10 , wherein the swelling polymer comprises or consists of a carbomer. 
     
     
         15 . The pharmaceutical composition of  claim 14 , wherein the carbomer comprises or consists of a carbomer selected from the group comprising carboxypolymethylene;
 carbomer homopolymer type A, and carbomer homopolymer type B.   
     
     
         16 . The pharmaceutical composition of  claim 14 , wherein the carbomer is present in an amount sufficient to provide a T max in plasma from about 1 hours to about 6 hours. 
     
     
         17 . The pharmaceutical composition of  claim 6 , which composition is characterized in that, when administered to a subject in a fasted state, achieves a plasma Cmax, a plasma Tmax, 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. 
     
     
         18 . A method comprising steps of:
 administering to a subject suffering from or susceptible to PTSD a combination of prazosin therapy and acamprosate therapy.   
     
     
         19 . The method of  claim 18 , 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. 
     
     
         20 . The method of  claim 18 , wherein the prazosin therapy comprises administering prazosin in the pharmaceutical composition of claim  114 . 
     
     
         21 . The method of  claim 18 , 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. 
     
     
         22 . The method of  claim 18 , wherein the prazosin therapy is administered independent of the subject's fed vs fasted state. 
     
     
         23 . The method of  claim 18 , wherein the step of administering comprises administering the composition of  claim 10 . 
     
     
         24 . 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.   
     
     
         25 . 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.   
     
     
         26 . The method of  claim 25 , wherein the acamprosate therapy regimen comprises administering the acamprosate in one or two doses per day. 
     
     
         27 . The method of  claim 25 , 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. 
     
     
         28 . The method of  claim 25 , 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. 
     
     
         29 . The method of  claim 25 , 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. 
     
     
         30 . The method of  claim 25 , wherein the subject is suffering from or susceptible to PTSD. 
     
     
         31 . The method of  claim 25 , 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. 
     
     
         32 . The method of  claim 25 , 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. 
     
     
         33 . The method of any one of  claims 18 - 32 , 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.   
     
     
         34 . A method comprising steps of:
 administering acamprosate therapy to a subject receiving prazosin therapy.   
     
     
         35 . 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. 
     
     
         36 . The method of  claim 35 , wherein the total daily dose is within a range of about 800 mg to about 3200 mg. 
     
     
         37 . A method comprising steps of
 administering to a subject a composition of  claim 6 , the administration being characterized in that it achieves a pK profile for prazosin characterized in that:   Cmax is decreased and Tmax is increased compared to that achieved by administration of prazosin in a reference composition associated with first order kinetics.   
     
     
         38 . The method of  claim 37  wherein:
 the administering comprises administering the composition according to a regimen characterized in that it achieves a plasma Cmax, a plasma Tmax, or a plasma AUC value for prazosin when administered to a subject in a fasted state that is substantially bioequivalent to that achieved when administered to the same subject in a fed state. 
 
     
     
         39 . The method of  claim 37  wherein:
 the administering comprises administering the composition according to a regimen characterized in that, when administered to a population of subjects in a fasted state, it achieves a plasma Cmax, a plasma Tmax, or a plasma AUC value for prazosin substantially bioequivalent to that achieved when it is administered to an otherwise comparable population of subjects in a fed state. 
 
     
     
         40 . The method of  claim 37 , further comprising a step of:
 administering acamprosate therapy to the subject.   
     
     
         41 . The method of any one of  claims 37 - 40 , wherein the composition further comprises acamprosate. 
     
     
         42 . The method of  claim 41 , wherein the administration is characterized in that it achieves a pK profile for acamprosate characterized in that:
 Cmax is about 200 to about 500 ng/mL;   Tmax is about 1 to about 6 hours; or   AUC is about 3400 to about 5800 h.ng/mL.   
     
     
         43 . The method of  claim 42 , wherein:
 the administering comprises administering the composition according to a regimen characterized in that it achieves a plasma Cmax, a plasma Tmax, or a plasma AUC value for acamprosate when administered to a subject in a fasted state that is substantially bioequivalent to that achieved when administered to the same subject in a fed state.