Extended Release Formulation and Method of Treating Adrenergic Dysregulation

Abstract

A composition and method of treating adrenergic dysregulation by administering the composition is disclosed, wherein the composition comprises a α 2 -adrenergic receptor agonist; a pharmaceutically acceptable hydrophilic matrix and a release-retardant of a metal alkyl sulfate. In embodiments, the composition provides a sustained release of the agonist, wherein after administration of the composition no more than once about every 12 hours to a subject having a steady state plasma concentration of the α 2 -adrenergic receptor agonist, the agonist's plasma concentration peak-to-trough ratio is no greater than about 1.9.

1 - 20 . (canceled) 
     
     
         21 . An oral dosage form comprising:
 (a) an α 2 -adrenergic receptor agonist in an amount between 0.001 wt % and 0.5 wt % of said oral dosage form; and   (b) a pharmaceutically acceptable hydrophilic matrix comprising:
 (i) at least one hydroxypropyl methylcellulose ether in an amount between 20 wt % and 80 wt % of said oral dosage form; 
 (ii) at least one of starch, lactose, or dextrose in an amount between 20 wt % and 80 wt % of said oral dosage form; and 
 (iii) a metal alkyl sulfate; 
   wherein after administration of said dosage form no more than once about every 24 hours to a subject having a steady state plasma concentration of said α 2 -adrenergic receptor agonist, said agonist's plasma concentration peak-to-trough ratio is no greater than about 1.9.   
     
     
         22 . The oral dosage form of  claim 21 , wherein said α 2 -adrenergic receptor agonist is clonidine or a pharmaceutically acceptable salt thereof. 
     
     
         23 . The oral dosage form of  claim 21 , wherein said α 2 -adrenergic receptor agonist is clonidine hydrochloride. 
     
     
         24 . The oral dosage form of  claim 22 , wherein said amount of clonidine is between about 0.025 wt % to about 0.40 wt % of said oral dosage form. 
     
     
         25 . The oral dosage form of  claim 21 , wherein said amount of said metal alkyl sulfate is between about 1 wt % and about 7 wt % of said oral dosage form. 
     
     
         26 . The oral dosage form of  claim 21 , wherein said amount of said metal alkyl sulfate is between about 2 wt % and about 6 wt % of said oral dosage form. 
     
     
         27 . The oral dosage form of  claim 21 , wherein said metal alkyl sulfate is sodium lauryl sulfate. 
     
     
         28 . The oral dosage form of  claim 21 , wherein said plasma concentration peak-to-trough ratio is no greater than about 1.6. 
     
     
         29 . The oral dosage form of  claim 21 , wherein said amount of α 2 -adrenergic receptor agonist is between about 0.1 mg to about 0.7 mg. 
     
     
         30 . An oral dosage form comprising:
 (a) an α 2 -adrenergic receptor agonist in an amount between 0.001 wt % and 0.5 wt % of the oral dosage form;   (b) a pharmaceutically acceptable hydrophilic matrix comprising,
 (i) at least one hydroxypropyl methylcellulose ether in an amount between 20 wt % and 80 wt % of the oral dosage form; 
 (ii) at least one of starch, lactose, or dextrose in an amount between 20 wt % and 80 wt % of the oral dosage form; and 
 (iii) a metal alkyl sulfate; and 
   (c) optionally a metal stearate and/or colloidal silica.   
     
     
         31 . The oral dosage form of  claim 30 , wherein said α 2 -adrenergic receptor agonist is clonidine or a pharmaceutically acceptable salt thereof. 
     
     
         32 . The oral dosage form of  claim 30 , wherein said α 2 -adrenergic receptor agonist is clonidine hydrochloride. 
     
     
         33 . The oral dosage form of  claim 31 , wherein the amount of clonidine is between about 0.025 wt % to about 0.40 wt % of the oral dosage form. 
     
     
         34 . The oral dosage form of  claim 30 , wherein the amount of the metal alkyl sulfate is between about 1 wt % and about 7 wt % of the oral dosage form. 
     
     
         35 . The oral dosage form of  claim 30 , wherein the amount of sodium lauryl sulfate is between about 2 wt % and about 6 wt %. 
     
     
         36 . The oral dosage form of  claim 30 , wherein the metal alkyl sulfate is sodium lauryl sulfate. 
     
     
         37 . The oral dosage form of  claim 30 , comprising:
 (a) clonidine hydrochloride in an amount between 0.025 wt % to about 0.40 wt % of the oral dosage form;   (b) a pharmaceutically acceptable hydrophilic matrix comprising,
 (i) at least one hydroxypropyl methylcellulose ether in an amount between 30 wt % and 50 wt % of the oral dosage form; 
 (ii) at least one of starch, lactose, or dextrose in an amount between 50 wt % and 70 wt % of the oral dosage form; and 
 (iii) a metal alkyl sulfate in an amount of between about 2 wt % and about 6 wt % of the oral dosage form; and 
   (c) a metal stearate and/or colloidal silica.   
     
     
         38 . A method of treating adrenergic dysregulation in a subject in need thereof, comprising:
 administering the oral dosage form of  claim 21  to said subject no more than once about every 24 hours, wherein said subject has a steady state plasma concentration of said α 2 -adrenergic receptor agonist, and wherein after said administering, said agonist's plasma concentration peak-to-trough ratio is no greater than about 1.9;   wherein said adrenergic dysregulation is treated.   
     
     
         39 . The method of  claim 38 , wherein said adrenergic dysregulation is manifested in a condition selected from the group consisting of hypertension, atrial fibrillation, congestive heart failure, orthostatic hypotension, postoperative pain, intractable cancer pain, headaches, labor pain, reflex sympathetic dystrophy, akathisia, peripheral neuropathy, neuropathic orofacial pain, diabetic gastroparesis, essential tremor, postepidural shivering, postanesthesia shivering, restless legs syndrome, hypertonicity, hyperkinetic movement disorders, tourette's syndrome, substance withdrawal, acute anorexia nervosa, attention-deficit/hyperactivity disorder, conduct disorder, bipolar disorder, aggression, narcolepsy, panic disorder, posttraumatic stress disorder, sleep disorders, social phobia, schizophrenia, ulcerative colitis and proctitis, emesis, cyclosporine-induced nephrotoxicity, hyperthyroidism, growth delay in children, excessive sweating, post-menopausal flushing and hot flashes. 
     
     
         40 . The method of  claim 38 , wherein said adrenergic dysregulation is manifested in attention-deficit hyperactivity disorder. 
     
     
         41 . The method of  claim 38 , wherein said adrenergic dysregulation is manifested in hypertension. 
     
     
         42 . The method of  claim 38 , wherein said adrenergic dysregulation is manifested in post-menopausal flushing or hot flashes. 
     
     
         43 . The method of  claim 38 , wherein said α 2 -adrenergic receptor agonist is clonidine or a pharmaceutically acceptable salt thereof. 
     
     
         44 . The method of  claim 38 , wherein said α 2 -adrenergic receptor agonist is clonidine hydrochloride. 
     
     
         45 . The method of  claim 38 , wherein said metal alkyl sulfate of said oral dosage form is sodium lauryl sulfate. 
     
     
         46 . The method of  claim 38 , wherein said plasma concentration peak-to-trough ratio is between about 1.3 to about 1.6. 
     
     
         47 . The method of  claim 38 , wherein said amount of α 2 -adrenergic receptor agonist present in said oral dosage form is between about 0.1 mg to about 0.7 mg. 
     
     
         48 . A method of treating adrenergic dysregulation in a subject in need thereof, comprising:
 administering the oral dosage form of  claim 30  to said subject no more than once about every 24 hours;   wherein said adrenergic dysregulation is treated.   
     
     
         49 . The method of  claim 48 , wherein said adrenergic dysregulation is manifested in a condition selected from the group consisting of hypertension, atrial fibrillation, congestive heart failure, orthostatic hypotension, postoperative pain, intractable cancer pain, headaches, labor pain, reflex sympathetic dystrophy, akathisia, peripheral neuropathy, neuropathic orofacial pain, diabetic gastroparesis, essential tremor, postepidural shivering, postanesthesia shivering, restless legs syndrome, hypertonicity, hyperkinetic movement disorders, tourette's syndrome, substance withdrawal, acute anorexia nervosa, attention-deficit/hyperactivity disorder, conduct disorder, bipolar disorder, aggression, narcolepsy, panic disorder, posttraumatic stress disorder, sleep disorders, social phobia, schizophrenia, ulcerative colitis and proctitis, emesis, cyclosporine-induced nephrotoxicity, hyperthyroidism, growth delay in children, excessive sweating, post-menopausal flushing and hot flashes. 
     
     
         50 . The method of  claim 48 , wherein said adrenergic dysregulation is manifested in attention-deficit hyperactivity disorder. 
     
     
         51 . The method of  claim 48 , wherein said adrenergic dysregulation is manifested in hypertension. 
     
     
         52 . The method of  claim 48 , wherein said adrenergic dysregulation is manifested in post-menopausal flushing or hot flashes. 
     
     
         53 . The method of  claim 48 , wherein said α 2 -adrenergic receptor agonist is clonidine or a pharmaceutically acceptable salt thereof. 
     
     
         54 . The method of  claim 48 , wherein said α 2 -adrenergic receptor agonist is clonidine hydrochloride. 
     
     
         55 . The method of  claim 48 , wherein said metal alkyl sulfate of said oral dosage form is sodium lauryl sulfate. 
     
     
         56 . The method of  claim 48 , wherein said amount of α 2 -adrenergic receptor agonist present in said oral dosage form is between about 0.1 mg to about 0.7 mg.