Pharmaceutical Compositions

• US 20090130202A1
• Filed: 12/15/2006
• Published: 05/21/2009
• Est. Priority Date: 12/15/2005
• Status: Active Grant

• Current Assignee: Archimedes Development Limited (Kirin Holdings Company Limited)
• Original Assignee: Archimedes Development Limited (Kirin Holdings Company Limited)
• Inventors: Dyer, Ann Margaret, Smith, Alan
• Granted Patent: US 8,460,702 B2
• Time in Patent Office: Days
• US Class Current: 424/456
• CPC Class Codes: A61K 31/195 having an amino group
• CPC Class Codes: A61K 9/1611 Inorganic compounds
• CPC Class Codes: A61K 9/2009 Inorganic compounds
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/2095 Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing mechanical aspects A61J3/00
• CPC Class Codes: A61K 9/2866 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 9/04 Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

Sustained release pharmaceutical compositions contain a drug; microcrystalline cellulose; a diluent (such as starch); a glidant (such as talc); and one or more of ethylcellulose, stearic acid and a salt of stearic acid. Preferred drugs include those that exhibit a low degree of solubility combined with a high potency, particularly thyroid hormones, such as liothyronine.

Claims

1. A sustained release pharmaceutical composition comprising:

(a) a drug;

(b) microcrystalline cellulose;

(c) a diluent;

(d) a glidant; and

(e) one or more of ethylcellulose, stearic acid and a salt of stearic acid.

2. A composition as claimed in claim 1 obtained by a process comprising extrusion-spheronisation.

3. A composition as claimed in claim 1, which comprises from 20 to about 50% w/w of ethylcellulose, stearic acid or salt of stearic acid or a combination thereof.

4. A composition as claimed in claim 1, wherein component (e) is ethylcellulose only.

5. A composition as claimed in claim 1, wherein the ethylcellulose has an ethoxyl substitution of from 44 to 51%.

6. A composition as claimed in claim 1, wherein the ethylcellulose has a viscosity (5% solution in 80/20 toluene/ethanol) of from 2 to 40 cps.

7. A composition as claimed in claim 1, wherein the ethylcellulose has an ethoxyl substitution in the range 49.6 to 51.0% and a viscosity (5% solution in 80/20 toluene/ethanol) of 8 to 11 cps.

8. A composition as claimed in claim 1, wherein the amount of stearic acid present is 30% w/w or below.

9. A composition as claimed in claim 5, wherein the amount of stearic acid is from 10 to 25% w/w.

10. A composition as claimed in claim 1, wherein the amount of stearic acid salts present is 50% w/w or below.

11. A composition as claimed in claim 1, wherein the amount of microcrystalline cellulose is from 20 to 50% w/w.

12. A composition as claimed in claim 1, wherein the glidant is talc.

13. A composition as claimed in claim 1, wherein the amount of glidant is from 10 to 20% w/w.

14. A composition as claimed in any claim 1, wherein the diluent is starch.

15. A composition as claimed in claim 1, wherein the amount of diluent is from 15 to 35% w/w.

16. A composition as claimed in claim 1, wherein the drug is one that possesses a solubility in aqueous media of less than 1 mg/ml at a temperature of 37°

C. and at atmospheric pressure.

17. A composition as claimed in claim 1, wherein the amount of the drug is from 0.002 to 50% w/w.

18. A composition as claimed in claim 1, wherein the drug is liothyronine or a salt thereof.

19. A composition as claimed in claim 1, which exhibits a release in an in vitro dissolution test of at least 50% of drug within a period of around 4 hours, and at least 70% within a period of around 6 hours.

20. A composition as claimed in claim 1, which exhibits a release in an in vitro dissolution test of at least 50% of drug within a period of around 8 hours, and at least 70% within a period of around 12 hours.

21. A composition as claimed in claim 19, which comprises ethylcellulose, starch (as the diluent) and talc (as the glidant).

22. A composition as claimed in claim 21, which comprises 0.001 to 1% w/w of liothyronine or a salt thereof;

20 to 40% w/w of microcrystalline cellulose;

15 to 55% w/w of starch, 10-20% w/w of talc; and

15 to 25% w/w of ethylcellulose.

23. A composition as claimed in claim 20, which comprises stearic acid and/or a salt thereof, starch (as the diluent) and talc (as the glidant).

24. A composition as claimed in claim 23, which comprises 0.001 to 1% w/w of liothyronine or a salt thereof;

20 to 40% w/w of microcrystalline cellulose;

15 to 35% w/w of starch, 5 to 20% w/w of talc;

10 to 30% w/w of calcium stearate; and

5 to 15% w/w of stearic acid.

25. A composition as claimed in claim 1 which is in the form of pellets.

26. A composition as claimed in claim 23, wherein the pellet diameter is from 0.1 to 2 mm.

27. A composition as claimed in claim 23, wherein the pellets are contained within hard capsules made from gelatin, hydroxypropylmethylcellulose, pullulan or starch.

28. A composition as claimed in claim 25, wherein the pellets consist essentially of a drug, microcrystalline cellulose, a diluent, a glidant and ethylcellulose.

29. A process for the preparation of a composition as defined in claim 1, which comprises preparing a heavy granule or wet mass by mixing the ingredients with sufficient water to form a paste, passing the paste through an extruder, transferring the extrudate to a spheronizer, and then drying the particles so formed.

32. A method of providing sustained release of a drug into systemic circulation, which comprises administration of a composition as defined in claim 1 to a patient in need of such sustained release.

33. A method of treatment of hypothyroidism or congestive heart failure which comprises administration of a composition as defined in claim 1 to a patient in need of such treatment.

30-31. -31. (canceled)