Once Daily Formulations Of Tetracyclines

Abstract

Disclosed are once-daily formulations containing tetracyclines, especially doxycycline. Such formulations are useful, for instance, for the treatment of collagenase destructive enzyme-dependent diseases, such as periodontal disease and acne, and acute and chronic inflammatory disease states, such as rosacea and arthritis.

1 . An oral pharmaceutical composition containing a tetracycline, which at a once-daily dosage will give steady state blood levels of the tetracycline of a minimum of about 0.1 μg/ml and a maximum of about 1.0 μg/ml, wherein 70 to 80 Percent of the tetracycline is formulated as an immediate release (IR) formulation and 20 to 30 percent of the tetracycline is formulated as a delayed release (DR) formulation. 
     
     
         2 . The composition of  claim 1 , which at a once-daily dosage will give steady state blood levels of the tetracycline of between about 0.3 μg/ml to about 0.8 μg/ml. 
     
     
         3 . The composition of  claim 1 , wherein the tetracycline is doxycycline. 
     
     
         4 - 9 . (canceled) 
     
     
         11 . The composition of  claim 1 , wherein the ratio of immediate release formulation to delayed release formulation is 75:25. 
     
     
         12 . The composition of  claim 1 , which is in the form of a granule, tablet, pellet, powder, sachet, capsule, gel, dispersion or suspension. 
     
     
         13 . The composition of  claim 12 , which is in a dosage form of a combination of pellets, wherein a portion of the pellets are of the immediate release formulation and the remaining pellets are of the delayed release formulation. 
     
     
         14 . The composition of  claim 1 , wherein the DR formulation is in the form of granules, pellets, or tablets. 
     
     
         15 - 25 . (canceled) 
     
     
         26 . A method for treating rosacea in a mammal in need thereof, comprising administering to the mammal an oral pharmaceutical composition containing a tetracycline, which at a once-daily dosage will give steady state blood levels of the tetracycline of a minimum of about 0.1 μg/ml and a maximum of about 1.0 μg/ml, wherein 70 to 80 percent of the tetracycline is formulated as an immediate release (IR) formulation and 20 to 30 percent of the tetracycline is formulated as a delayed release (DR) formulation. 
     
     
         27 . The method of  claim 26 , wherein the mammal is a human. 
     
     
         28 - 46 . (canceled) 
     
     
         47 . A process for preparing a once-daily oral pharmaceutical composition containing a tetracycline, which at a once-daily dosage will give steady state blood levels of the tetracycline of a minimum of about 0.1 μg/ml and a maximum of about 1.0 μg/ml, comprising combining an immediate release formulation comprising 70 to 80 percent of the tetracycline with a delayed release formulation comprising 20 to 30 percent of the tetracycline. 
     
     
         48 . (canceled) 
     
     
         49 . The composition of  claim 1 , wherein the DR formulation comprises at least one enteric polymer. 
     
     
         50 . The composition of  claim 49 , wherein the enteric polymer is cellulose acetate phthalate; hydroxypropyl methylcellulose phthalate; polyvinyl acetate phthalate; hydroxypropyl methylcellulose acetate succinate; cellulose acetate trimellitate; hydroxypropyl methylcellulose succinate; cellulose acetate succinate; cellulose acetate hexahydrophthalate; cellulose propionate phthalate; a copolymer of methylmethacrylic acid and methyl methacrylate; a copolymer of methyl acrylate, methylmethacrylate and methacrylic acid; a copolymer of methylvinyl ether and maleic anhydride; ethyl methyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylate copolymer; zein; or shellac; or any combination of two or more of the foregoing. 
     
     
         51 . The composition of  claim 1 , wherein one or more pharmaceutically acceptable excipients is incorporated in the IR formulation, the DR formulation, or both. 
     
     
         52 . The composition of  claim 51 , wherein the one or more pharmaceutically acceptable excipients is a binder, a disintegration agent, a filling agent, a surfactant, a solubilizer or a stabilizer, or any combination of the foregoing. 
     
     
         53 . The composition of  claim 52 , wherein the binder is selected from methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone or polyvinylpyrrolidone/vinyl acetate copolymer. 
     
     
         54 . The composition of  claim 52 , wherein the disintegration agent is selected from cornstarch, pregelatinized starch, cross-linked carboxymethylcellulose, sodium starch glycolate or cross-linked polyvinylpyrrolidone. 
     
     
         55 . The composition of  claim 52 , wherein the filling agent is selected from lactose, calcium carbonate, calcium phosphate, calcium sulfate, microcrystalline cellulose, dextran, starches, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride or polyethylene glycol. 
     
     
         56 . The composition of  claim 52 , wherein the surfactant is selected from sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, bile salts or glyceryl monostearate. 
     
     
         57 . The composition of  claim 52 , wherein the solubilizer is selected from citric acid, succinic acid, fumaric acid, malic acid, tartaric acid, maleic acid, glutaric acid, sodium bicarbonate or sodium carbonate. 
     
     
         58 . The composition of  claim 52 , wherein the stabilizer is selected from antioxidation agents, buffers or acids.