Once daily formulations of tetracyclines
View Patent ↗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 consisting of (i) an immediate release formulation (IR) comprising about 30 mg doxycycline; a delayed release formulation (DR) comprising about 10 mg doxycycline; and optionally, (iii) one or more pharmaceutically acceptable excipients.
2. An oral pharmaceutical composition comprising doxycycline, which at a once-daily dosage will give blood levels of the doxycycline of a minimum of 0.1 μg/ml and a maximum of 1.0 μg/ml, the composition consisting of (i) an immediate release formulation (IR) comprising about 30 mg doxycycline; as a delayed release formulation (DR) comprising about 10 mg doxycycline; and optionally, (iii) one or more pharmaceutically acceptable excipients.
3. The composition of claim 2 , which at a once-daily dosage will give blood levels of the doxycycline of between 0.3 μg/ml to 0.8 μg/ml.
4. The composition of claim 2 , which is in the form of a granule, tablet, pellet, powder, sachet, capsule, gel, dispersion or suspension.
5. The composition according to claim 2 , wherein the DR formulation comprises at least one enteric polymer.
6. The composition of claim 2 , 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; shellac; poly(methacylic acid-co-ethyl acrylate) 1:1, or combinations thereof.
7. The composition according to claim 2 , wherein the DR formulation is in the form of granules, pellets, or tablet.
8. The composition according to claim 2 , wherein the one or more pharmaceutically acceptable excipients is incorporated in the IR formulation, the DR formulation, or both.
9. The composition of claim 8 , 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.
10. The composition of claim 9 , wherein the binder is selected from the group consisting of methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, and polyvinylpyrrolidone/vinyl acetate copolymer.
11. The composition of claim 9 , wherein the disintegration agent is selected from the group consisting of cornstarch, pregelatinized starch, cross-linked carboxymethylcellulose, sodium starch glycolate, and cross-linked polyvinylpyrrolidone.
12. The composition of claim 9 , 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.
13. The composition of claim 9 , wherein the surfactants are selected from the group consisting of sodium lauryl sulfate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, bile salts, and glyceryl monostearate.
14. The composition of claim 9 , 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.
15. The composition of claim 9 , wherein the stabilizers are selected from the group consisting of antioxidation agents, buffers, and acids.
16. A method for treating rosacea in a mammal in need thereof, comprising administering an oral pharmaceutical composition consisting of (i) an immediate release formulation (IR) comprising about 30 mg doxycycline; a delayed release formulation (DR) comprising about 10 mg doxycycline; and optionally, (iii) one or more pharmaceutically acceptable excipients.
17. A method for treating rosacea in a mammal in need thereof, comprising administering an oral pharmaceutical composition comprising doxycycline, which at a once-daily dosage will give blood levels of the doxycycline of a minimum of 0.1 μg/ml and a maximum of 1.0 μg/ml, the composition consisting of (i) an immediate release formulation (IR) comprising about 30 mg doxycycline; as a delayed release foi ululation (DR) comprising about 10 mg doxycycline; and optionally, (iii) one or more pharmaceutically acceptable excipients.
18. The method of claim 17 , wherein the mammal is a human.
19. The method of claim 17 , which at a once-daily dosage, administration of the composition will give blood levels of the doxycycline of between 0.3 μg/ml to 0.8 μg/ml.