Low-Dose Doxepin Formulations And Methods Of Making And Using The Same

Abstract

The invention disclosed herein generally relates to low-dose oral doxepin pharmaceutical formulations and the use of these formulations to promote sleep.

We claim: 
     
         1 . A pharmaceutical composition comprising from about 0.5 to about 7 mg of doxepin, or a pharmaceutically acceptable salt or prodrug thereof, and from about 20% to about 99.9% w/w silicified microcrystalline cellulose, the composition having one or more of the characteristics selected from the group consisting of: a hardness value of at least 2 Kp, a friability value of 1% or less, a disintegration time of about 1 minute as per USP protocols, at least an 80% release of doxepin within 15 minutes using compendial method for measuring dissolution of doxepin, at least an 85 percent release of doxepin within 30 minutes using U.S. Pharmacopeia (USP) Apparatus I at 100 rpm (or Apparatus II at 50 rpm) in 0.1 N HCl or Simulated Gastric Fluid USP without enzymes, at least an 85 percent release of doxepin within 30 minutes using U.S. Pharmacopeia (USP) Apparatus I at 100 rpm (or Apparatus II at 50 rpm) in a pH 4.5 buffer, and at least an 85 percent release of doxepin within 30 minutes using U.S. Pharmacopeia (USP) Apparatus I at 100 rpm (or Apparatus II at 50 rpm) in a pH 6.8 buffer or Simulated Intestinal Fluid USP without enzymes. 
     
     
         2 . The composition of  claim 1 , wherein the silicified microcrystalline cellulose (SMCC) is provided in an amount of about 92% to about 99.8% w/w. 
     
     
         3 . The composition of  claim 1 , further comprising from about 0.1 to about 1.5% w/w colloidal silicon dioxide. 
     
     
         4 . The composition of  claim 1 , further comprising from about 0.25 to about 1.5% w/w magnesium stearate. 
     
     
         5 . The composition of  claim 1 , wherein the doxepin is provided in an amount of about 2.5 to about 4 mg. 
     
     
         6 . The composition of  claim 5 , wherein the doxepin is provided in an amount of about 3 mg. 
     
     
         7 . The composition of  claim 1 , wherein the doxepin is provided in an amount of about 6 mg. 
     
     
         8 . A method of manufacturing a doxepin dosage, doxepin salt or doxepin prodrug form comprising,
 forming a drug substance pre-blend by mixing a first filler and doxepin, doxepin salt or doxepin prodrug;   forming a final blend by mixing a second filler and the drug substance pre-blend;   forming a doxepin, doxepin salt or doxepin prodrug dosage form from the final blend.   
     
     
         9 . The method of  claim 8 , wherein the first filler and the second filler are selected from the group consisting of silicified microcrystalline cellulose, microcrystalline cellulose, lactose, compressible sugars, xylitol, sorbitol, mannitol, pregelatinized starch, maltodextrin, calcium phosphate dibasic, calcium phosphate tribasic, and calcium carbonate DC. 
     
     
         10 . The method of  claim 9 , wherein the first and second fillers are not the same. 
     
     
         11 . The method of  claim 10 , wherein the first or the second filler is silicified microcrystalline cellulose. 
     
     
         12 . The method of  claim 9 , wherein the first and second fillers are the same. 
     
     
         13 . The method of  claim 12 , wherein the first and the second filler is silicified microcrystalline cellulose. 
     
     
         14 . The method of  claim 8 , wherein the drug substance pre-blend or the final blend comprises an additional filler. 
     
     
         15 . The method of  claim 14 , wherein the additional filler is selected from the group consisting of silicified microcrystalline cellulose, microcrystalline cellulose, lactose, compressible sugars, xylitol, sorbitol, mannitol, pregelatinized starch, maltodextrin, calcium phosphate dibasic, calcium phosphate tribasic, and calcium carbonate DC. 
     
     
         16 . A pharmaceutical unit dosage form, comprising:
 doxepin, a pharmaceutically-acceptable salt thereof or a prodrug thereof in an amount equivalent to about 3 or 6 mg doxepin hydrochloride;   one or more pharmaceutically-acceptable excipients; and optionally,   a capsule or coating;   wherein the excipients and any capsule or coating are selected to provide a swallowable unit dosage that is at least externally solid and that has dissolution and bioavailability characteristics such that after administration to a 70 kg human, the dosage form provides a plasma concentration of at least 0.1 ng/mL doxepin within a time frame of not more than about 60 minutes.   
     
     
         17 . The unit dosage form of  claim 16 , wherein the time frame to provide a plasma concentration of at least 0.1 ng/mL is not more than about 50 minutes. 
     
     
         18 . The unit dosage form of  claim 16 , wherein the doxepin, the pharmaceutically-acceptable salt thereof or the prodrug thereof is in an amount equivalent to about 3 mg doxepin hydrochloride. 
     
     
         19 . The unit dosage form of  claim 16 , wherein the doxepin, the pharmaceutically-acceptable salt thereof or the prodrug thereof is in an amount equivalent to about 6 mg doxepin hydrochloride. 
     
     
         20 . The method of  claim 16 , wherein the excipients comprises silicified microcrystalline cellulose.