Doxycycline Formulations, and Methods of Treating Rosacea

Abstract

The present invention is directed to a pharmaceutical composition in unit dose form for orally delivering doxycycline to a human, the pharmaceutical composition comprising: a capsule, wherein the capsule is coated with a delayed release layer; wherein the delayed release layer comprises about 4 to 6 mg of doxycycline monohydrate and a binding agent, and wherein the delayed release layer is coated with an enteric coating; wherein the enteric coating dissolves at pH of about 5 to 6, and wherein the enteric coating is coated with an immediate release layer; wherein the immediate release layer comprises about 32 mg of doxycycline monohydrate and a binding agent, wherein the relative mean C max of the pharmaceutical composition is within 80.00% to 125.00% of a C max value of 510±220.7 ng/mL, after administration of a single dose of the pharmaceutical composition to humans in a fasting state; and wherein the relative mean AUC (0-∞) of the pharmaceutical composition is within 80.00% to 125.00% of a AUC (0-∞) value of 9227±3212.8 ng·hr/mL, after administration of a single dose of the pharmaceutical composition to humans in a fasting state.

We claim: 
     
         1 . A pharmaceutical composition in unit dose form for orally delivering doxycycline to a human, the pharmaceutical composition comprising:
 a capsule, wherein the capsule is coated with a delayed release layer;   wherein the delayed release layer comprises about 4 to 6 mg of doxycycline, or a pharmaceutically acceptable salt thereof, and a binding agent, and wherein the delayed release layer is coated with an enteric coating;   wherein the enteric coating dissolves at pH of about 5 to 6, and wherein the enteric coating is coated with an immediate release layer;   wherein the immediate release layer comprises about 32 mg of doxycycline, or a pharmaceutically acceptable salt thereof, and a binding agent,   wherein the relative mean C max  of the pharmaceutical composition is within 80.00% to 125.00% of a C max  value of 510±220.7 ng/mL, after administration of a single dose of the pharmaceutical composition to humans in a fasting state; and   wherein the relative mean AUC (0-∞)  of the pharmaceutical composition is within 80.00% to 125.00% of a AUC (0-∞)  value of 9227±3212.8 ng·hr/mL, after administration of a single dose of the pharmaceutical composition to humans in a fasting state.   
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the relative mean C max  of the pharmaceutical composition at steady state is within 80.00% to 125.00% of a C max  value of 600±194.2 ng/mL after administration to humans in a fasting state, and
 wherein the relative mean AUC (0-t)  of the pharmaceutical composition at steady state is within 80.00% to 125.00% of a AUC (0-t)  value of 7543±2443.9 ng·hr/mL, after administration to humans in a fasting state. 
 
     
     
         3 . The pharmaceutical composition of  claim 1  wherein the delayed release layer comprises about 4 mg of doxycycline monohydrate. 
     
     
         4 . The pharmaceutical composition of  claim 1  wherein the delayed release layer comprises about 6 mg of doxycycline monohydrate. 
     
     
         5 . The pharmaceutical composition of  claim 1  wherein the doxycycline salt is micronized. 
     
     
         6 . The pharmaceutical composition of  claim 5  wherein the micronized doxycycline salt has less than about 10 μm distribution for at least about 90% of particles. 
     
     
         7 . The pharmaceutical composition of  claim 1  further comprising a seal coating between the capsule and the delayed release coating. 
     
     
         8 . The pharmaceutical composition of  claim 7  wherein the seal coating comprises a pH dependent ingredient, wherein the pH dependent ingredient dissolves at pH of about 5 to 6. 
     
     
         9 . The pharmaceutical composition of  claim 1  wherein the capsule contains about 200 mg to about 260 mg of at least one inert ingredient. 
     
     
         10 . The pharmaceutical composition of  claim 9  wherein the capsule does not contain an active ingredient. 
     
     
         11 . The pharmaceutical composition of  claim 1  wherein the ratio of the binding agent to the doxycycline monohydrate in the delayed release layer is about 1:3. 
     
     
         12 . The pharmaceutical composition of  claim 1  wherein the ratio of the binding agent to the doxycycline monohydrate in the immediate release layer is about 1:3. 
     
     
         13 . The pharmaceutical composition of  claim 1  wherein the binding agent is hydroxypropyl methylcellulose (HPMC), hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), carboxy methyl cellulose (CMC), or mixtures thereof. 
     
     
         14 . The pharmaceutical composition of  claim 1 , having a dissolution profile such that about 80% to about 90% of the doxycycline monohydrate is dissolved after about 30 minutes at pH of about 1.1. 
     
     
         15 . The pharmaceutical composition of  claim 1 , having a dissolution profile such that about 90% of the doxycycline monohydrate is dissolved after about 120 minutes at pH of about 1.1 and 120 minutes at pH of about 6.0. 
     
     
         16 . The pharmaceutical composition of  claim 1 , having a dissolution profile as shown in  FIG. 8 . 
     
     
         17 . The pharmaceutical composition of  claim 1 , wherein the capsule is hydroxypropyl methylcellulose. 
     
     
         18 . The pharmaceutical composition of  claim 1 , wherein the 90% Confidence Interval of the relative mean C max , AUC (0-t)  and AUC (0-∞)  of the pharmaceutical composition to a reference formulation is within 80.00% to 125.00% upon administration to humans in a fasting state, wherein the reference formulation is a gelatin capsule filled with beads of doxycycline monohydrate, wherein the beads consist of 30 mg of immediate release beads and 10 mg of delayed release beads. 
     
     
         19 . A method for treating papules and pustules of rosacea in a human in need thereof, comprising orally administering a once a day dose of a pharmaceutical composition to the human, the pharmaceutical composition comprising:
 a capsule, wherein the capsule is coated with a delayed release layer;   wherein the delayed release layer comprises about 4 to 6 mg of doxycycline, or a pharmaceutically acceptable salt thereof, and a binding agent, and wherein the delayed release layer is coated with an enteric coating;   wherein the enteric coating dissolves at pH of about 5 to 6, and wherein the enteric coating is coated with an immediate release layer;   wherein the immediate release layer comprises about 32 mg of doxycycline, or a pharmaceutically acceptable salt thereof, and a binding agent,   wherein the relative mean C max  of the pharmaceutical composition is within 80.00% to 125.00% of a C max  value of 510±220.7 ng/mL, after administration of a single dose of the pharmaceutical composition to humans in a fasting state; and   wherein the relative mean AUC (0-∞)  of the pharmaceutical composition is within 80.00% to 125.00% of a AUC (0-∞)  value of 9227±3212.8 ng·hr/mL, after administration of a single dose of the pharmaceutical composition to humans in a fasting state.   
     
     
         20 . The method of  claim 19 , wherein the relative mean C max  of the pharmaceutical composition at steady state is within 80.00% to 125.00% of a C max  value of 600±194.2 ng/mL after administration to humans in a fasting state, and
 wherein the relative mean AUC (0-t)  of the pharmaceutical composition at steady state is within 80.00% to 125.00% of a AUC (0-t)  value of 7543±2443.9 ng·hr/mL, after administration to humans in a fasting state. 
 
     
     
         21 . The method of  claim 19 , wherein the pharmaceutical composition further comprises a seal coating between the capsule and the delayed release coating, wherein the seal coating comprises a pH dependent ingredient, wherein the pH dependent ingredient dissolves at pH of about 5 to 6. 
     
     
         22 . The method of  claim 19  wherein the delayed release layer comprises about 4 mg of doxycycline monohydrate. 
     
     
         23 . The method of  claim 19  wherein the delayed release layer comprises about 6 mg of doxycycline monohydrate. 
     
     
         24 . The method of  claim 19 , wherein the pharmaceutical composition has a dissolution profile such that about 80% to about 90% of the doxycycline salt is dissolved after about 30 minutes at pH of about 1.1. 
     
     
         25 . The method of  claim 19 , wherein the pharmaceutical composition has a dissolution profile such that about 90% of the doxycycline salt is dissolved after about 120 minutes at pH of about 1.1 and 120 minutes at pH of about 6.0. 
     
     
         26 . The method of  claim 19 , wherein pharmaceutical composition has a dissolution profile as shown in  FIG. 8 . 
     
     
         27 . A pharmaceutical composition in unit dose form for orally delivering doxycycline to a human, the pharmaceutical composition comprising:
 a capsule, wherein the capsule is coated with a delayed release layer;   wherein the delayed release layer comprises about 4 to 6 mg of doxycycline, or a pharmaceutically acceptable salt thereof, and a binding agent, and wherein the delayed release layer is coated with an enteric coating;   wherein the enteric coating dissolves at pH of about 5 to 6, and wherein the enteric coating is coated with an immediate release layer;   wherein the immediate release layer comprises about 32 mg of doxycycline, or a pharmaceutically acceptable salt thereof;   and wherein after administration of a single dose to humans in a fasting state, the C max  has a range of about 230 ng/mL to about 1120 ng/mL, and the AUC (0-∞)  has a range of about 4800 ng·hr/mL to about 15,600 ng·hr/mL.   
     
     
         28 . The pharmaceutical composition of  claim 27  wherein at steady state the C max , has a range of about 325 ng/mL to about 1000 ng/mL, and the AUC (0-∞)  has a range of about 3500 ng·hr/mL to about 12,500 ng·hr/mL.