Controlled release doxycycline

• US 9,446,057 B2
• Filed: 11/12/2015
• Issued: 09/20/2016
• 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): YOUNG, MICAH PAUL
• Application Number:
  US14/939,936
• Publication Number:
  US 20160101119A1
• Time in Patent Office: 313 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 maintains doxycycline release levels measured under USP <

711>

conditions at pH 5 that provide a clinically effective plasma level of doxycycline.

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 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.

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 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.

4. The dosage form of claim 2, 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 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.

6. 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.

7. The dosage form of claim 2, 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 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.

11. The dosage form of claim 5, 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.

12. The dosage form of claim 5, 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.

13. The dosage form of claim 5, 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.

14. 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.

15. The dosage form of claim 14, wherein the controlled release polymer composition comprises a blend of an enteric polymer and a water soluble polymer.

16. The dosage form of claim 15, wherein the controlled release polymer composition further comprises a plasticizer.

17. The dosage form of claim 16, wherein the controlled release polymer composition consists essentially of a blend of an enteric polymer, a water soluble polymer, and a plasticizer.

18. The dosage form of claim 14, further comprising a stabilizing coating disposed between the core and the controlled release polymer composition layer.

19. 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.

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

21. The method of claim 19, 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.

22. The method of claim 20, 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.

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

24. The method of claim 20, wherein said administering is once-per-day.

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

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

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