Controlled release doxycycline

• US 9,295,652 B1
• Filed: 10/23/2014
• Issued: 03/29/2016
• Est. Priority Date: 10/08/2014
• Status: Active Grant

• Current Assignee: Mayne Pharma International Pty Limited (Mayne Pharma)
• Original Assignee: Mayne Pharma International Pty Limited (Mayne Pharma)
• Inventors: Lukas, Stefan, Lepore, Angelo, Mudge, Stuart
• Primary Examiner(s): Hartley, Michael G
• Assistant Examiner(s): Young, Micah-Paul
• Application Number:
  US14/521,998
• Publication Number:
  US 20160101052A1
• Time in Patent Office: 523 Days
• Field of Search: 424489-502
• US Class Current: 1/1
• CPC Class Codes: A61K 31/65 Tetracyclines
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/167 with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface with further drug-free outer coating A61K9/5073
• CPC Class Codes: A61K 9/4808 characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release capsules filled with granules or microparticles A61K9/16; filled with microcapsules or coated microparticles A61K9/50; with mixture of different granules, microcapsules, (coated) microparticles A61K9/5084
• CPC Class Codes: A61K 9/5042 Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5047 Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/5073 having two or more different coatings optionally including drug-containing subcoatings

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.

Claims

1. A dosage form, comprising a plurality of modified release doxycycline pellets, wherein each doxycycline pellet comprises:

doxycycline; and

a controlled release polymer composition disposed over the doxycycline,

wherein said dosage form comprises 60, 90, or 120 mg of doxycycline and releases less than about 15% of the doxycycline at pH 1.2, and less than 40% of the doxycycline at pH 4.5 after 60 minutes, measured under USP <

711>

conditions; and

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.

2. 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.

3. The dosage form of claim 1, wherein the doxycycline pellets comprise a doxycycline-containing core, and the controlled release polymer composition is disposed as a layer over the core.

4. The dosage form of claim 3, wherein the controlled release polymer composition comprises a blend of an enteric polymer and a water soluble polymer.

5. The dosage form of claim 4, wherein the controlled release polymer composition further comprises a plasticizer.

6. The dosage form of claim 5, wherein the controlled release polymer composition consists essentially of a blend of an enteric polymer, a water soluble polymer, and a plasticizer.

7. The dosage form of claim 4, wherein the enteric polymer is selected from the group consisting of hydroxypropyl methylcellulose phthalate, poly(methacrylic acid-co-ethyl acrylate), poly(methacrylic acid-co-methyl methacrylate), poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid), hydroxypropylmethyl cellulose acetate succinate, cellulose acetate succinate, polyvinyl acetate phthalate, shellac, cellulose acetate trimellitate, sodium alginate, and combinations thereof.

8. The dosage form of claim 4, wherein the water soluble polymer is selected from the group consisting of hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polyethylene glycol, polyvinyl alcohol, and combinations thereof.

9. The dosage form of claim 5, wherein the plasticizer is selected from the group consisting of citric acid esters, tartaric acid esters, glycerol, glycerol esters, phthalic acid esters, adipic acid esters, sebacic acid esters, polyethylene glycol esters, sorbitan esters, and combinations thereof.

10. The dosage form of claim 6, wherein the controlled release polymer composition consists essentially of hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose, and triethyl citrate.

11. The dosage form of claim 10, wherein the ratio of hydroxypropyl methylcellulose phthalate to hydroxypropyl methylcellulose ranges from about 3.5:

1 to about 6;

1.

12. The dosage form of claim 3, further comprising a stabilizing coating disposed between the core and the controlled release polymer composition layer.

13. The dosage form of claim 12, wherein the stabilizing coating comprises a water soluble polymer and talc.

14. A method of treating a skin condition in a patient, comprising orally administering the dosage form of claim 1 to a patient in need thereof.

15. A method of treating a skin condition in a patient, comprising orally administering the dosage form of claim 3 to a patient in need thereof.

16. The method of claim 14, 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.

17. The method of claim 15, 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.

18. The method of claim 14, wherein said administering is once-per-day.

19. The method of claim 15, wherein said administering is once-per-day.

20. The dosage form of claim 1, wherein the amount of doxycycline of said dosage form is 60 mg.

21. The dosage form of claim 1, wherein the amount of doxycycline of said dosage form is 90 mg.

22. The dosage form of claim 1, wherein the amount of doxycycline of said dosage form is 120 mg.

23. The dosage form of claim 2, wherein the amount of doxycycline of said dosage form is 60 mg.

24. The dosage form of claim 2, wherein the amount of doxycycline of said dosage form is 90 mg.

25. The dosage form of claim 2, wherein the amount of doxycycline of said dosage form is 120 mg.

26. The dosage form of claim 3, wherein the controlled release polymer composition comprises a blend of an enteric polymer and a plasticizer.