Immediate release formulations of 1-aminocyclohexane compounds, memantine and neramexane

Abstract

The present invention relates to an immediate release solid oral dosage form containing 1-aminocyclohexanes, preferably memantine or neramexane, and optionally a pharmaceutically acceptable coating, wherein the active ingredient exhibits dose proportionality and is released at a dissolution rate of more than about 80% within about the first 60 minutes following entry of said form into a use environment. The dosage form is direct compressed and has a hardness within the range of between about 3 and about 40 Kp, exhibits an average T max within the range of about 2 to about 8 hours with an active ingredient load within the range of about 2.5 to about 150 mg. The formulation allows for dose-proportional compositions for once daily or b.i.d. dosing, while maintaining a steady average range of T max .

1 - 38 . (canceled) 
   
   
       39 . A method of treating a disorder selected from the group consisting of mild, moderate, and severe Alzheimer's dementia, wherein the method consists of administering an immediate release solid oral dosage form comprising (i) about 2.5 to about 150 mg of an active ingredient consisting essentially of memantine or a pharmaceutically acceptable salt thereof and (ii) optionally, a pharmaceutically acceptable coating, the dosage form exhibiting dose-proportionality and releasing the active ingredient at a rate of more than about 80% within about the first 60 minutes after administration of the immediate release oral dosage form to a patient in need thereof, wherein the dosage form exhibits an average T max  within the range of about 2 to about 8 hours. 
   
   
       40 . The method of  claim 39 , wherein the oral dosage form comprises about 2.5 mg to about 40 mg of the active ingredient. 
   
   
       41 . The method of  claim 39 , wherein the oral dosage form comprises about 5 mg of the active ingredient. 
   
   
       42 . The method of  claim 39 , wherein the oral dosage form comprises about 10 mg of the active ingredient. 
   
   
       43 . The method of  claim 39 , wherein the oral dosage form comprises about 20 mg of the active ingredient. 
   
   
       44 . The method of  claim 39 , wherein the oral dosage form releases the active ingredient at a rate of more than about 80% within the first 30 minutes after administration of the immediate release oral dosage form to a patient in need thereof. 
   
   
       45 . The method of  claim 39 , wherein the oral dosage form releases the active ingredient at a rate of more than about 80% within the first 15 minutes after administration of the immediate release oral dosage form to a patient in need thereof. 
   
   
       46 . The method of  claim 39 , wherein the active ingredient is memantine hydrochloride. 
   
   
       47 . The method of  claim 39 , wherein the oral dosage form is lactose free. 
   
   
       48 . The method of  claim 39 , wherein the pharmaceutically acceptable coating contains hydroxypropyl methylcellulose. 
   
   
       49 . The method of  claim 39 , wherein the pharmaceutically acceptable coating contains a methacrylic acid-ethyl acrylate copolymer. 
   
   
       50 . The method of  claim 39 , wherein the immediate release oral dosage form further comprises one or more pharmaceutically acceptable carriers, excipients, anti-adherants, fillers, stabilizing agents, binders, colorants, disintegrants, glidants, and lubricants. 
   
   
       51 . The method of  claim 39 , wherein the immediate release oral dosage form exhibits less than 3% w/w lactose adduct formation. 
   
   
       52 . The method of  claim 39 , wherein the immediate release oral dosage form exhibits less than 2.5% w/w lactose adduct formation. 
   
   
       53 . The method of  claim 39 , wherein the immediate release oral dosage form exhibits less than 0.5% w/w lactose adduct formation. 
   
   
       54 . The method of  claim 39 , wherein the immediate release oral dosage form further comprises a pharmaceutically acceptable filler. 
   
   
       55 . The method of  claim 54 , wherein the pharmaceutically acceptable filler is microcrystalline cellulose. 
   
   
       56 . The method of  claim 55 , wherein the microcrystalline cellulose is present in an amount within the range from about 20% w/w to about 95% w/w. 
   
   
       57 . The method of  claim 39 , wherein the immediate release oral dosage form exhibits less than 3% w/w adduct formation, wherein the oral dosage form comprises a) between about 2% w/w and about 10% w/w of memantine hydrochloride; b) between about 2% w/w to about 5% w/w of hydroxypropyl methylcellulose; c) between about 20% w/w and about 95% w/w of microcrystalline cellulose; d) between about 0% w/w and about 3% w/w of colloidal silicon dioxide; e) between about 0% w/w and about 5% w/w of talc; f) between about 0% w/w and about 2% w/w of magnesium stearate; and g) between about 0% w/w and about 3% w/w of croscarmellose sodium. 
   
   
       58 . The method of  claim 39 , wherein the immediate release oral dosage form exhibits less than 3% w/w adduct formation, wherein the oral dosage form comprises a) between about 3.2% w/w and about 10% w/w of memantine hydrochloride; b) between about 2% w/w to about 4% w/w of hydroxypropyl methylcellulose; c) between about 60% w/w and about 90% w/w of microcrystalline cellulose; d) between about 0% w/w and about 0.5% w/w of colloidal silicon dioxide; e) between about 4% w/w and about 5% w/w of talc; f) between about 0.2% w/w and about 0.5% w/w of magnesium stearate; and g) between about 1.8% w/w and about 2.2% w/w of croscarmellose sodium. 
   
   
       59 . A method of treating a disorder selected from the group consisting of mild, moderate, and severe Alzheimer's dementia, wherein the method consists of administering an immediate release solid oral dosage form consisting essentially of 10 mg of memantine or a salt thereof, the dosage form exhibiting dose-proportionality and wherein the dosage form provides an in vivo plasma profile comprising a mean Tmax of about 3 or more hours; a mean Cmax of less than about 60 ng/ml; and a mean AUC 0-24  of more than about 350 ng h/ml. 
   
   
       60 . The method of  claim 59 , wherein the Tmax is about 6 or more hours. 
   
   
       61 . The method of  claim 59 , wherein the Cmax is less than about 50 ng/ml. 
   
   
       62 . The method of  claim 59 , wherein the mean AUC 0-24  is more than about 425 ng h/ml. 
   
   
       63 . The method of  claim 59 , wherein the immediate release oral dosage form releases the memantine or a salt thereof at a rate of more than about 80% within about 30 minutes. 
   
   
       64 . The method of  claim 59 , wherein the immediate release oral dosage form releases the memantine or a salt thereof at a rate of more than about 80% within about 15 minutes. 
   
   
       65 . A method of treating a disorder selected from the group consisting of mild, moderate, and severe Alzheimer's dementia, wherein the method consists of administering an immediate release solid oral dosage form consisting essentially of 10 mg of memantine or a salt thereof, the dosage form exhibiting dose-proportionality and wherein the dosage form provides an in vivo plasma profile comprising a mean Tmax of about 3 or more hours; a mean Cmax of less than about 30 ng/ml; and a mean AUC 0-∞  of more than about 500 ng h/ml. 
   
   
       66 . The method of  claim 65 , wherein the Tmax is about 6 or more hours. 
   
   
       67 . The method of  claim 65 , wherein the Cmax is less than about 25 ng/ml. 
   
   
       68 . The method of  claim 65 , wherein the mean AUC 0-∞  is more than about 2000 ng h/ml. 
   
   
       69 . The method of  claim 65 , wherein the immediate release oral dosage form releases the memantine or a salt thereof at a rate of more than about 80% within about 30 minutes. 
   
   
       70 . The method of  claim 65 , wherein the immediate release oral dosage form releases the memantine or a salt thereof at a rate of more than about 80% within about 15 minutes. 
   
   
       71 . A method of treating a disorder selected from the group consisting of mild, moderate, and severe Alzheimer's dementia, wherein the method consists of administering an immediate release solid oral dosage form consisting essentially of 5 mg of memantine or a salt thereof, the dosage form exhibiting dose-proportionality and wherein the dosage form provides an in vivo plasma profile comprising a mean T max  of about 3 or more hours; a mean Cmax of less than about 15 ng/ml; and a mean AUC 0-∞  of more than about 250 ng h/ml. 
   
   
       72 . The method of  claim 71 , wherein the Tmax is about 6 or more hours. 
   
   
       73 . The method of  claim 71 , wherein the Cmax is less than about 10 ng/ml. 
   
   
       74 . The method of  claim 71 , wherein the mean AUC 0-∞  is more than about 1000 ng h/ml. 
   
   
       75 . The method of  claim 71 , wherein the immediate release oral dosage form releases the memantine or a salt thereof at a rate of more than about 80% within about 60 minutes. 
   
   
       76 . The method of  claim 71 , wherein the immediate release oral dosage form releases the memantine or a salt thereof at a rate of more than about 80% within about 30 minutes.