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 . An immediate release solid oral dosage form comprising (i) an active ingredient selected from the group consisting of an 1-aminocyclohexane compound and a pharmaceutically acceptable salt thereof and (ii) optionally, a pharmaceutically acceptable coating, said dosage form exhibiting dose-proportionality and releasing said active ingredient at a rate of more than about 80% within about the first 60 minutes following entry of said form into a use environment, wherein said dosage form 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, and wherein said dosage form is obtained through direct compression.  
     
     
         2 . The immediate release solid oral dosage form according to  claim 1  wherein said oral dosage form releases said active ingredient at a rate of more than about 80% within the first 30 minutes following entry of said form into a use environment.  
     
     
         3 . The immediate release solid oral dosage form according to  claim 2  wherein said oral dosage form releases said active ingredient at a rate of more than about 80% within the first 15 minutes following entry of said form into a use environment.  
     
     
         4 . The immediate release solid oral dosage form according to  claim 1 , wherein said active ingredient is memantine hydrochloride.  
     
     
         5 . The immediate release solid oral dosage form according to  claim 1 , wherein said active ingredient is neramexane mesylate.  
     
     
         6 . The immediate release solid oral dosage form according to  claim 4 , wherein the active ingredient is present in an amount within the range from about 2% w/w to about 20% w/w.  
     
     
         7 . The immediate release solid oral dosage form according to  claim 6 , wherein the active ingredient is present in an amount within the range from about 3.2% w/w to about 10% w/w.  
     
     
         8 . The immediate release solid oral dosage form according to  claim 6 , wherein the active ingredient is present in an amount within the range from about 3.9% w/w to about 8.4% w/w.  
     
     
         9 . The immediate release solid oral dosage form according to  claim 1 , wherein the pharmaceutically acceptable coating contains hydroxypropyl methylcellulose.  
     
     
         10 . The immediate release solid oral dosage form according to  claim 1 , wherein the pharmaceutically acceptable coating contains a methacrylic acid-ethyl acrylate copolymer.  
     
     
         11 . The immediate release solid oral dosage form according to  claim 1 , wherein the pharmaceutically acceptable coating is present in an amount within the range from about 2% w/w to about 7% w/w.  
     
     
         12 . The immediate release solid oral dosage form according to  claim 11 , wherein the pharmaceutically acceptable coating is present in an amount within the range from about 2% w/w to about 5% w/w.  
     
     
         13 . The immediate release solid oral dosage form according to  claim 1 , further comprising one or more pharmaceutically acceptable carriers, excipients, anti-adherants, fillers, stabilizing agents, binders, colorants, disintegrants, glidants, and lubricants.  
     
     
         14 . The immediate release solid oral dosage form according to  claim 1 , further comprising a pharmaceutically acceptable filler.  
     
     
         15 . The immediate release solid oral dosage form according to  claim 1  exhibiting adduct formation to an extent less than 3% w/w.  
     
     
         16 . The immediate release solid oral dosage form according to  claim 1  exhibiting adduct formation to an extent less than 2.5% w/w.  
     
     
         17 . The immediate release solid oral dosage form according to  claim 1  exhibiting adduct formation to an extent less than 0.5% w/w.  
     
     
         18 . The immediate release solid oral dosage form according to  claim 14 , wherein the pharmaceutically acceptable filler is microcrystalline cellulose.  
     
     
         19 . The immediate release solid oral dosage form according to  claim 18 , wherein the microcrystalline cellulose is present in an amount within the range from about 10% w/w to about 35% w/w, and wherein the solid oral dosage form additionally comprises lactose monohydrate.  
     
     
         20 . The immediate release solid oral dosage form according to  claim 19 , wherein the microcrystalline cellulose is present in an amount within the range from about 18% w/w to about 22% w/w.  
     
     
         21 . The immediate release solid oral dosage form according to  claim 18 , wherein the microcrystalline cellulose is present in an amount within the range from about 20% w/w to about 95% w/w, wherein the solid oral dosage form is lactose free.  
     
     
         22 . The immediate release solid oral dosage form according to  claim 21 , wherein the microcrystalline cellulose is present in amounts ranging from about 60% w/w to about 90% w/w.  
     
     
         23 . The immediate release solid oral dosage form according to  claim 1 , wherein the solid oral dosage form has a hardness within the range of between about 3 and about 40 Kp.  
     
     
         24 . The immediate release solid oral dosage form according to  claim 23 , wherein the solid oral dosage form has a hardness within the range of between about 4 and about 30 Kp.  
     
     
         25 . The immediate release solid oral dosage form according to  claim 1 , further comprising a lubricant.  
     
     
         26 . The immediate release solid oral dosage form according to  claim 25 , wherein the lubricant is magnesium stearate.  
     
     
         27 . The immediate release solid oral dosage form according to  claim 26 , wherein the magnesium stearate is present in an amount within the range from about 0% to about 2% w/w.  
     
     
         28 . The immediate release solid oral dosage form according to  claim 27 , wherein the magnesium stearate is present in an amount within the range from about 0.2% to about 0.5% W/W.  
     
     
         29 . The immediate release solid oral dosage form according to  claim 1  wherein said solid oral dosage form is a tablet.  
     
     
         30 . The immediate release solid oral dosage form of  claim 1 , wherein the solid 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 10% w/w and about 35% w/w of microcrystalline cellulose;    d) between about 50% w/w and about 70% w/w of lactose monohydrate;    e) between about 0% w/w and about 3% w/w of colloidal silicon dioxide;    f) between about 3% w/w and about 5% w/w of talc; and    g) between about 0% w/w and about 2% w/w of magnesium stearate.    
     
     
         31 . The immediate release solid oral dosage form of  claim 1 , wherein the solid 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 18% w/w and about 22% w/w of microcrystalline cellulose;    d) between about 65% w/w and about 70% w/w of lactose monohydrate;    e) between about 0% w/w and about 0.5% w/w of colloidal silicon dioxide;    f) between about 4% w/w and about 5% w/w of talc; and    g) between about 0.2% w/w and about 0.5% w/w of magnesium stearate.    
     
     
         32 . The immediate release solid oral dosage form of  claim 1 , wherein the solid 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; and    f) between about 0% w/w and about 2% w/w of magnesium stearate.    g) between about 0% w/w and about 3% w/w of croscarmellose sodium.    
     
     
         33 . The immediate release solid oral dosage form of  claim 1 , wherein the solid 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; and    f) between about 0.2% w/w and about 0.5% w/w of magnesium stearate.    g) between about 1.8% w/w and about 2.2% w/w of croscarmellose sodium.    
     
     
         34 . The immediate release solid oral dosage form according to  claim 1 , wherein the solid oral dosage form does not contain lactose.  
     
     
         35 . A method of treating a disorder selected from the group consisting of mild, moderate, and sever Alzheimer's dementia, and neuropathic pain, wherein the method comprises administering the immediate release solid oral dosage form of  claim 1 .  
     
     
         36 . The method of  claim 35 , wherein the administration is once daily.  
     
     
         37 . The method of  claim 35 , wherein the administration is twice a day dosing.  
     
     
         38 . The method of  claim 37 , wherein the dosage form is administered about 4 hours apart.