PHARMACEUTICAL COMPOSITIONS COMPRISING CONJUGATED ESTROGENS

• US 20090232897A1
• Filed: 03/13/2009
• Published: 09/17/2009
• Est. Priority Date: 03/14/2008
• Status: Abandoned Application

• Current Assignee: Dr. Reddy's Lab., Inc. (Dr. Reddy's Laboratories Ltd.), Dr. Reddy's Laboratories Ltd.
• Original Assignee: Dr. Reddy's Lab., Inc. (Dr. Reddy's Laboratories Ltd.), Dr. Reddy's Laboratories Ltd.
• Inventors: Sahoo, Bijayananda, Gore, Subhash, Ghosh, Pradip Kumar, Buhary, S.H. Seyed Mohamed, Agrawal, Pratit Premchand, Sankaranarayanan, Anand
• Application Number:
  US12/403,401
• Publication Number:
  US 20090232897A1
• Time in Patent Office: Days
• US Class Current: 424/490
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 9/1623 Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• CPC Class Codes: A61K 9/2077 Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
• CPC Class Codes: A61K 9/2866 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Abstract

Pre-mix compositions containing conjugated estrogens and a pharmaceutical carrier, and pharmaceutical formulations containing a pre-mix composition. Further, the invention includes processes for preparing the premix compositions and pharmaceutical formulations containing pre-mix compositions.

Claims

1. A pre-mix composition, prepared by spray drying or spray coating a solution comprising conjugated estrogens, or a dispersion comprising conjugated estrogens in solution and a solid pharmaceutical carrier, or by spray coating a solution or dispersion comprising conjugated estrogens onto a solid pharmaceutical carrier.

2. The premix composition of claim 1, wherein a solution or dispersion comprises an organic solvent.

3. The premix composition of claim 1, wherein a pharmaceutical carrier comprises one or more of lactose, dextrose, mannitol, and sorbitol.

4. The premix composition of claim 1, wherein a pharmaceutical carrier comprises lactose.

5. The premix composition of claim 1, wherein a pharmaceutical carrier comprises an inorganic compound.

6. The premix composition of claim 1, having a moisture content not exceeding about 4 percent by weight.

7. The pre-mix composition of claim 1, wherein the concentration of conjugated estrogens is at least about 0.1 percent by weight of the total composition.

8. The premix composition of claim 1, in which 90 percent of particles have sizes about 20 μ

m to 150 μ

m.

9. The premix composition of claim 1, having bulk density about 0.2 to 0.6 grams per mL.

10. A pharmaceutical formulation comprising a pre-mix composition of claim 1.

11. The pharmaceutical formulation of claim 10, having a moisture content not exceeding about 6 percent by weight.

12. The pharmaceutical formulation of claim 10, providing, following immersion of a single unit dosage form into pH 4.5 acetate buffer, when tested in USP Apparatus II with 50 rpm stirring:

a) release of about 2 to about 30 percent of contained conjugated estrogens within about one hour;

b) release of about 5 to about 55 percent of contained conjugated estrogens within about 2 hours;

c) release of about 60 to about 100 percent of contained conjugated estrogens within about 5 hours; and

d) release of not less than about 70 percent of contained conjugated estrogens within about 8 hours.

13. The pharmaceutical formulation of claim 10, providing, following immersion of a single unit dosage form into degassed purified water, when tested in USP Apparatus II with 50 rpm stirring:

a) release of less than about 35 percent of contained conjugated estrogens within about one hour;

b) release of less than about 65 percent of contained conjugated estrogens within about 2 hours;

c) release of about 30 to about 100 percent of contained conjugated estrogens within about 5 hours; and

d) release of not less than about 60 percent of contained conjugated estrogens within about 8 hours.

14. The pharmaceutical formulation of claim 10, containing 0.625 mg of conjugated estrogen and producing:

estrone C_max values about 58 pg/mL to about 90 pg/mL, AUC_0-t values about 2340 pg·

hour/mL to about 3658 pg·

hour/mL, and AUC_0-∞

values about 5754 pg·

hour/mL to about 8991 pg·

hour/mL; and

equilin C_max values about 10 pg/mL to about 16 pg/mL, AUC_0-t values about 187 pg·

hour/mL to about 292 pg·

hour/mL, and AUC_0-∞

values about 242 pg·

hour/mL to about 378 pg·

hour/mL;

in plasma after oral administration of a single dose to healthy humans under fasting conditions.

15. The pharmaceutical formulation of claim 10, containing 0.625 mg of conjugated estrogen and producing:

estrone C_max values about 57 pg/mL to about 89 pg/mL, AUC_0-t values about 1903 pg·

hour/mL to about 2974 pg·

hour/mL, and AUC_0-∞

values about 2989 pg·

hour/mL to about 4670 pg·

hour/mL; and

equilin C_max values about 11 pg/mL to about 18 pg/mL, AUC_0-t values about 174 pg·

hour/mL to about 272 pg·

hour/mL, and AUC_0-∞

values about 216 pg·

hour/mL to about 338 pg·

hour/mL;

in plasma after oral administration of a single dose to healthy humans under fed conditions.

16. The pharmaceutical formulation of claim 10, providing C_max and AUC_0-t values that do not vary by more than about 20% between fed state administration and fasted state administration, to healthy humans.

17. A process for preparing a pre-mix composition, comprising spray drying a dispersion comprising a solution of conjugated estrogens in solution and a solid pharmaceutical carrier.

18. The process of claim 17, wherein a solution comprises an organic solvent.

19. A process for preparing a pre-mix composition, comprising spray coating a solution or dispersion comprising conjugated estrogens onto a solid pharmaceutical carrier.

20. The process of claim 19, wherein a solution or dispersion comprises an organic solvent.

21. The process of claim 19, wherein 90 percent of particles in the premix composition have sizes about 20 μ

m to 150 μ

m.