Controlled Release Doxycycline

Abstract

The disclosure provides controlled release compositions comprising tetracyclines and in some embodiments, doxycycline. The controlled release doxycycline compositions of the invention exhibit a superior dissolution profile and provide reduce side effects such as nausea and irritation.

What is claimed is: 
     
         1 . A dosage form, comprising: doxycycline and a controlled release composition,
 wherein said dosage form comprises 60, 90, or 120 mg of doxycycline and maintains doxycycline release levels measured under USP <711> conditions at pH 5 that provides a clinically effective plasma level of doxycycline.   
     
     
         2 . The dosage form of  claim 1 , wherein the doxycycline release levels, measured under USP <711> conditions at pH 5, do not exceed about 70% release at about 30 minutes. 
     
     
         3 . The dosage form of  claim 1 , wherein when the amount of doxycycline of said dosage form is 60 mg, after administration of a single dose under fasting conditions to a patient in need thereof, the average C max  is about 80% to about 125% of about 625-1600 ng/ml;
 or   wherein when the amount of doxycycline of said dosage form is 90 mg, after administration of a single dose under fasting conditions to a patient in need thereof, the average C max  is about 80% to about 125% of about 940-2400 ng/ml;   or   wherein when the amount of doxycycline of said dosage form is 120 mg, after administration of a single dose under fasting conditions to a patient in need thereof, the average C max  is about 80% to about 125% of about 1250-3200 ng/ml.   
     
     
         4 . The dosage form of  claim 1 , wherein when the amount of doxycycline of said dosage form is 60 mg, after administration of a single dose to a patient in need thereof, the average AUC 0-∞  is about 80% to about 125% of about 10000-24000 ng·hr/ml; or
 wherein when the amount of doxycycline of said dosage form is 90 mg, after administration of a single dose to a patient in need thereof, the average AUC 0-∞  is about 80% to about 125% of about 15000-36500 ng·hr/ml; or 
 wherein when the amount of doxycycline of said dosage form is 120 mg, after administration of a single dose to a patient in need thereof, the average AUC 0-∞  is about 80% to about 125% of about 20000-48500 ng·hr/ml. 
 
     
     
         5 . The dosage form of  claim 3 , wherein when the amount of doxycycline of said dosage form is 60 mg, after administration of a single dose to a patient in need thereof, the average AUC 0-∞  is about 80% to about 125% of about 10000-24000 ng·hr/ml; or
 wherein when the amount of doxycycline of said dosage form is 90 mg, after administration of a single dose to a patient in need thereof, the average AUC 0-∞  is about 80% to about 125% of about 15000-36500 ng·hr/ml; or 
 wherein when the amount of doxycycline of said dosage form is 120 mg, after administration of a single dose to a patient in need thereof, the average AUC 0-∞  is about 80% to about 125% of about 20000-48500 ng·hr/ml. 
 
     
     
         6 . The dosage form of  claim 1 , wherein the release of doxycycline at pH 5 measured under USP <711> conditions is at least one of the following:
 about 45% to about 50% after 10 minutes; 
 about 55% to about 65% at 20 minutes; 
 about 65% to about 70% at 30 minutes; 
 about 70% to about 75% at 45 minutes; and 
 about 75% to about 80% at 60 minutes. 
 
     
     
         7 . The dosage form of  claim 1 , wherein the dosage form maintains release levels measured under USP <711> conditions that are low at pH values up to pH 4.5. 
     
     
         8 . The dosage form of  claim 3 , wherein the dosage form maintains release levels measured under USP <711> conditions that are low at pH values up to pH 4.5. 
     
     
         9 . The dosage form of  claim 4 , wherein the dosage form maintains release levels measured under USP <711> conditions that are low at pH values up to pH 4.5. 
     
     
         10 . The dosage form of  claim 5 , wherein the dosage form maintains release levels measured under USP <711> conditions that are low at pH values up to pH 4.5. 
     
     
         11 . The dosage form of  claim 1 , wherein the release of doxycycline at pH 5 measured under USP <711> conditions is at least two of the following:
 about 45% to about 50% after 10 minutes; 
 about 55% to about 65% at 20 minutes; 
 about 65% to about 70% at 30 minutes; 
 about 70% to about 75% at 45 minutes; and 
 about 75% to about 80% at 60 minutes. 
 
     
     
         12 . The dosage form of  claim 1 , wherein the release of doxycycline at pH 5 measured under USP <711> conditions is at least three of the following:
 about 45% to about 50% after 10 minutes; 
 about 55% to about 65% at 20 minutes; 
 about 65% to about 70% at 30 minutes; 
 about 70% to about 75% at 45 minutes; and 
 about 75% to about 80% at 60 minutes. 
 
     
     
         13 . The dosage form of  claim 1 , wherein the release of doxycycline at pH 5 measured under USP <711> conditions is at least four of the following:
 about 45% to about 50% after 10 minutes; 
 about 55% to about 65% at 20 minutes; 
 about 65% to about 70% at 30 minutes; 
 about 70% to about 75% at 45 minutes; and 
 about 75% to about 80% at 60 minutes. 
 
     
     
         14 . The dosage form of  claim 1 , wherein the release of doxycycline at pH 5 measured under USP <711> conditions is:
 about 45% to about 50% after 10 minutes; 
 about 55% to about 65% at 20 minutes; 
 about 65% to about 70% at 30 minutes; 
 about 70% to about 75% at 45 minutes; and 
 about 75% to about 80% at 60 minutes. 
 
     
     
         15 . The dosage form of  claim 1 , wherein said dosage form comprises a pellet that has a controlled release polymer composition disposed over the doxycycline. 
     
     
         16 . The dosage form of  claim 1 , wherein said dosage form comprises a plurality of pellets and each pellet has a controlled release polymer composition comprising an enteric polymer disposed over the doxycycline. 
     
     
         17 . The dosage form of  claim 1 , wherein said dosage form comprises a plurality of pellets and each pellet has a controlled release polymer composition comprising a blend of an enteric polymer and a water soluble polymer disposed over the doxycycline. 
     
     
         18 . The dosage form of  claim 16 , wherein said plurality of pellets are contained within a capsule or tablet. 
     
     
         19 . The dosage form of  claim 17 , wherein said plurality of pellets are contained within a capsule or tablet. 
     
     
         20 . The dosage form of  claim 1 , wherein said dosage form is a matrix composition. 
     
     
         21 . The dosage form of  claim 1 , wherein said dosage form is a matrix tablet or caplet. 
     
     
         22 . The dosage form of  claim 1 , wherein the amount of doxycycline of said dosage form is 60 mg. 
     
     
         23 . The dosage form of  claim 1 , wherein the amount of doxycycline of said dosage form is 90 mg. 
     
     
         24 . The dosage form of  claim 1 , wherein the amount of doxycycline of said dosage form is 120 mg. 
     
     
         25 . The dosage form of  claim 3 , wherein said dosage form comprises a pellet that has a controlled release polymer composition disposed over the doxycycline. 
     
     
         26 . The dosage form of  claim 3 , wherein said dosage form comprises a plurality of pellets and each pellet has a controlled release polymer composition comprising an enteric polymer disposed over the doxycycline. 
     
     
         27 . The dosage form of  claim 3 , wherein said dosage form comprises a plurality of pellets and each pellet has a controlled release polymer composition comprising a blend of an enteric polymer and a water soluble polymer disposed over the doxycycline. 
     
     
         28 . The dosage form of  claim 26 , wherein said plurality of pellets are contained within a capsule or tablet. 
     
     
         29 . The dosage form of  claim 27 , wherein said plurality of pellets are contained within a capsule or tablet. 
     
     
         30 . The dosage form of  claim 3 , wherein said dosage form is a matrix composition. 
     
     
         31 . The dosage form of  claim 3 , wherein said dosage form is a matrix tablet or caplet. 
     
     
         32 . The dosage form of  claim 3 , wherein the amount of doxycycline of said dosage form is 60 mg. 
     
     
         33 . The dosage form of  claim 3 , wherein the amount of doxycycline of said dosage form is 90 mg. 
     
     
         34 . The dosage form of  claim 3 , wherein the amount of doxycycline of said dosage form is 120 mg. 
     
     
         35 . The dosage form of  claim 4 , wherein said dosage form comprises a pellet that has a controlled release polymer composition disposed over the doxycycline. 
     
     
         36 . The dosage form of  claim 4 , wherein said dosage form comprises a plurality of pellets and each pellet has a controlled release polymer composition comprising an enteric polymer disposed over the doxycycline. 
     
     
         37 . The dosage form of  claim 4 , wherein said dosage form comprises a plurality of pellets and each pellet has a controlled release polymer composition comprising a blend of an enteric polymer and a water soluble polymer disposed over the doxycycline. 
     
     
         38 . The dosage form of  claim 36 , wherein said plurality of pellets are contained within a capsule or tablet. 
     
     
         39 . The dosage form of  claim 37 , wherein said plurality of pellets are contained within a capsule or tablet. 
     
     
         40 . The dosage form of  claim 4 , wherein said dosage form is a matrix composition. 
     
     
         41 . The dosage form of  claim 4 , wherein said dosage form is a matrix tablet or caplet. 
     
     
         42 . The dosage form of  claim 4 , wherein the amount of doxycycline of said dosage form is 60 mg. 
     
     
         43 . The dosage form of  claim 4 , wherein the amount of doxycycline of said dosage form is 90 mg. 
     
     
         44 . The dosage form of  claim 4 , wherein the amount of doxycycline of said dosage form is 120 mg. 
     
     
         45 . A method of treating a skin condition in a patient, comprising: orally administering the dosage form according to  claim 1  to a patient in need thereof. 
     
     
         46 . The method of  claim 45 , wherein said skin condition is at least one condition selected from the group consisting of: a skin infection, rosacea, acne, papules, pustules, open comedo, closed comedo, or a combination thereof. 
     
     
         47 . A method of treating a skin condition in a patient, comprising: orally administering the dosage form according to  claim 3  to a patient in need thereof. 
     
     
         48 . The method of  claim 47 , wherein said skin condition is at least one condition selected from the group consisting of: a skin infection, rosacea, acne, papules, pustules, open comedo, closed comedo, or a combination thereof. 
     
     
         49 . A method of treating a skin condition in a patient, comprising: orally administering the dosage form according to  claim 4  to a patient in need thereof. 
     
     
         50 . The method of  claim 49 , wherein said skin condition is at least one condition selected from the group consisting of: a skin infection, rosacea, acne, papules, pustules, open comedo, closed comedo, or a combination thereof.