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 .- 48 . (canceled) 
     
     
         49 . An oral pharmaceutical composition comprising 25 mg to 50 mg of total doxycycline, the composition consisting of (i) 70 to 80 percent of the doxycycline formulated in an immediate release formulation (IR) and 20 to 30 percent of the doxycycline formulated as a delayed release formulation (DR); and (ii) one or more pharmaceutically acceptable excipients, wherein a once-daily dosing of the composition will exhibit a pharmacokinetic profile at steady state blood levels of doxycycline according to  FIG. 5  of the application. 
     
     
         50 . The composition of  claim 49 , wherein the weight ratio of IR to DR is 75:25. 
     
     
         51 . The composition of  claim 49 , which is in the form of a granule, tablet, pellet, powder, sachet, capsule, gel, dispersion or suspension. 
     
     
         52 . The composition of  claim 49 , wherein the DR formulation is in the form of granules, pellets, or tablet. 
     
     
         53 . The composition of  claim 49 , wherein the one or more pharmaceutically acceptable excipients is incorporated in the IR formulation, the DR formulation, or both. 
     
     
         54 . The composition of  claim 53 , wherein the one or more pharmaceutically acceptable excipients is a binder, a disintegration agent, a filling agent, a surfactant, a solubilizer, a stabilizer, and combinations thereof. 
     
     
         55 . The composition of  claim 54 , wherein the binder is selected from the group consisting of methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, and polyvinylpyrrolidone/vinyl acetate copolymer. 
     
     
         56 . The composition of  claim 54 , wherein the disintegration agent is selected from the group consisting of cornstarch, pregelatinized starch, cross-linked carboxymethylcellulose, sodium starch glycolate, and cross-linked polyvinylpyrrolidone. 
     
     
         57 . The composition of  claim 54 , wherein the filling agents are selected from the group consisting of lactose, calcium carbonate, calcium phosphate, calcium sulfate, microcrystalline cellulose, dextran, starches, sucrose, xylitol, lactitol, mannitol, sorbitol, sodium chloride, and polyethylene glycol. 
     
     
         58 . The composition of  claim 54 , wherein the surfactants are selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, bile salts, and glyceryl monostearate. 
     
     
         59 . The composition of  claim 54 , wherein the solubilizers are selected from the group consisting of citric acid, succinic acid, fumaric acid, malic acid, tartaric acid, maleic acid, glutaric acid, sodium bicarbonate, and sodium carbonate. 
     
     
         60 . The composition of  claim 54 , wherein the stabilizers are selected from the group consisting of antioxidation agents, buffers, and acids. 
     
     
         61 . A method for treating rosacea in a mammal in need thereof, comprising administering an oral pharmaceutical composition comprising 25 mg to 50 mg of total doxycycline, the composition consisting of (i) 70 to 80 percent of the doxycycline formulated in an immediate release formulation (IR) and 20 to 30 percent of the doxycycline formulated as a delayed release formulation (DR); and (ii) one or more pharmaceutically acceptable excipients, wherein a once-daily dosing of the composition will exhibit a pharmacokinetic profile at steady state blood levels of doxycycline according to  FIG. 5  of the application. 
     
     
         62 . The method of  claim 61 , wherein the mammal is a human.