TABLET-IN-TABLET COMPOSITIONS

• US 20080175908A1
• Filed: 01/11/2008
• Published: 07/24/2008
• Est. Priority Date: 01/12/2007
• Status: Abandoned Application

• Current Assignee: Wyeth (Pfizer Inc.)
• Original Assignee: Wyeth (Pfizer Inc.)
• Inventors: Baksh, Nizamuddin, Enever, Robin, Kresevic, John, Liu, Xiuying
• Application Number:
  US12/013,109
• Publication Number:
  US 20080175908A1
• Time in Patent Office: Days
• US Class Current: 424/465
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 31/57 substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/2013 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/2018 Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• CPC Class Codes: A61K 9/2054 Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• CPC Class Codes: A61K 9/209 containing drug in at least two layers or in the core and in at least one outer layer
• CPC Class Codes: A61P 15/12 for climacteric disorders
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 5/30 Oestrogens

Abstract

The present invention is directed to tablet-in-tablet compositions comprising one or more estrogens in a first layer and a therapeutic agent in a second layer, and processes for their preparation

Claims

1. A tablet-in-tablet composition comprising:

a) a core tablet comprising;

one or more estrogens;

a core filler/diluent component comprising from about 30% to about 85% by weight of said core tablet;

a core filler/binder component comprising from about 1% to about 30% by weight of said core tablet;

a core hydrophilic gel-forming polymer component comprising from about 1% to about 40% by weight of said core tablet; and

optionally, a core lubricant component comprising from about 0.01% to about 2% by weight of said core tablet; and

b) a compressed outer tablet layer comprising;

one or more therapeutic agents selected from the group consisting of selective estrogen receptor modulators and progestational agents;

an outer layer filler/diluent component comprising from about 10% to about 80% by weight of said compressed outer tablet layer;

an outer layer filler/binder component comprising from about 1% to about 60% by weight of said compressed outer tablet layer;

an outer layer hydrophilic gel-forming polymer component comprising from about 1% to about 70% by weight of said compressed outer tablet layer;

optionally, an antioxidant component comprising from about 0.01% to about 4% by weight of said compressed outer tablet layer; and

optionally, an outer layer lubricant component comprising from about 0.01% to about 2% by weight of said compressed outer tablet layer.

2. The tablet-in-tablet composition of claim 1 wherein:

said core tablet comprises from about 10% to about 50% by weight of said composition; and

said compressed outer tablet layer comprises from about 50% to about 90% by weight of said composition.

3. The tablet-in-tablet composition of claim 1 or claim 2 wherein said compressed outer tablet layer has a hardness from about 2 kp to about 7 kp.

4. The tablet-in-tablet composition of any one of claims 1 to 3 wherein said compressed outer tablet layer does not comprise a surfactant or wetting agent.

5. The tablet-in-tablet composition of claim 1 wherein:

said core tablet comprises from about 10% to about 50% by weight of said composition;

said compressed outer tablet layer comprises from about 50% to about 90% by weight of said composition;

said compressed outer tablet layer has a hardness from about 2 kp to about 7 kp; and

said compressed outer tablet layer does not comprise a surfactant or wetting agent.

6. The tablet-in-tablet composition of any one of claims 1 to 5 wherein said core tablet comprises at least one conjugated estrogen.

7. The tablet-in-tablet composition of any one of claims 1 to 6 wherein said compressed outer tablet layer comprises bazedoxifene, or pharmaceutically acceptable salt thereof.

8. The tablet-in-tablet composition of claim 7 wherein said compressed outer tablet layer comprises bazedoxifene acetate.

9. The tablet-in-tablet composition of any one of claims 1 to 6 wherein said compressed outer tablet layer comprises medroxyprogesterone acetate.

10. The tablet-in-tablet composition of claim 1 wherein:

said core tablet comprises at least one conjugated estrogen; and

said compressed outer tablet layer comprises medroxyprogestrone acetate or bazedoxifene acetate.

11. The tablet-in-tablet composition of any one of claims 1 to 10 wherein:

said core filler/diluent component comprises one or more of lactose, lactose monohydrate, mannitol, sucrose, maltodextrin, dextrin, maltitol, sorbitol, xylitol, powdered cellulose, cellulose gum, microcrystalline cellulose, starch, calcium phosphate, and a metal carbonate;

said core filler/binder component comprises one or more of microcrystalline cellulose, polyvinylpyrrolidone, copovidone, polyvinylalcohol, starch, gelatin, gum arabic, gum acacia, and gum tragacanth;

said core hydrophilic gel-forming polymer component comprises one or more of hydroxypropylmethylcellulose, polyethylene oxide, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, polyvinylpyrrolidone, xanthan gum, and guar gum;

said optional core lubricant component, if present, comprises one or more of stearic acid, metallic stearate, sodium stearyl fumarate, fatty acid, fatty alcohol, fatty acid ester, glyceryl behenate, mineral oil, vegetable oil, paraffin, leucine, talc, propylene glycol fatty acid ester, polyethylene glycol, polypropylene glycol, and polyalkylene glycol;

said outer layer filler/diluent component comprises one or more of lactose, lactose monohydrate, mannitol, sucrose, maltodextrin, dextrin, maltitol, sorbitol, xylitol, powdered cellulose, cellulose gum, microcrystalline cellulose, starch, calcium phosphate, and a metal carbonate;

said outer layer filler/binder component comprises one or more of microcrystalline cellulose, polyvinylpyrrolidone, copovidone, polyvinylalcohol, starch, gelatin, gum arabic, gum acacia, and gum tragacanth;

said outer layer hydrophilic gel-forming polymer comprises one or more of hydroxypropylmethylcellulose, polyethylene oxide, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, polyvinylpyrrolidone, xanthan gum, and guar gum;

said optional outer layer lubricant component, if present, comprises one or more of stearic acid, metallic stearate, sodium stearyl fumarate, fatty acid, fatty alcohol, fatty acid ester, glyceryl behenate, mineral oil, vegetable oil, paraffin, leucine, talc, propylene glycol fatty acid ester, polyethylene glycol, polypropylene glycol, and polyalkylene glycol;

said optional antioxidant component, if present, comprises one or more of ascorbic acid, sodium ascorbate, ascorbyl palmitate, vitamin E, vitamin E acetate, butylated hydroxytoluene, and butylated hydroxyanisole.

12. The tablet-in-tablet composition of claim 1 wherein:

said core filler/diluent component comprises one or more of lactose and lactose monohydrate;

said core filler/binder component comprises microcrystalline cellulose;

said core hydrophilic gel-forming polymer component comprises hydroxypropylmethylcellulose;

said optional core lubricant component, if present, comprises magnesium stearate;

said core filler/diluent component comprises one or more of lactose and lactose monohydrate;

said outer layer filler/binder component comprises microcrystalline cellulose;

said outer layer hydrophilic gel-forming polymer comprises hydroxypropylmethylcellulose;

said optional outer layer lubricant component, if present, comprises magnesium stearate;

said optional antioxidant component, if present, comprises one or more of ascorbic acid and vitamin E acetate;

said core tablet comprises at least one conjugated estrogen; and

said compressed outer tablet layer comprises medroxyprogesterone acetate or bazedoxifene acetate.

13. The tablet-in-tablet composition of any one of claims 1 to 12 wherein:

said core filler/diluent component comprises from about 50% to about 85% by weight of said core tablet;

said core filler/binder component comprises from about 10% to about 20% by weight of said core tablet;

said core hydrophilic gel-forming polymer component comprises from about 5% to about 15% by weight of said core tablet; and

said outer layer hydrophilic gel-forming polymer component comprises from about 1% to about 8% by weight of said compressed outer tablet layer.

14. The tablet-in-tablet composition of any one of claims 1 to 12 wherein:

said core filler/diluent component comprises from about 50% to about 85% by weight of said core tablet;

said core filler/binder component comprises from about 10% to about 20% by weight of said core tablet;

said core hydrophilic gel-forming polymer component comprises from about 5% to about 15% by weight of said core tablet; and

said outer layer hydrophilic gel-forming polymer component comprises from about 8% to about 15% by weight of said compressed outer tablet layer.

15. The tablet-in-tablet composition of any one of claims 1 to 12 wherein:

said core filler/diluent component comprises from about 50% to about 85% by weight said core tablet;

said core filler/binder component comprises from about 10% to about 20% by weight of said core tablet;

said core hydrophilic gel-forming polymer component comprises from about 5% to about 15% by weight of said core tablet; and

said outer layer hydrophilic gel-forming polymer component comprises from about 15% to about 30% by weight of said compressed outer tablet layer.

16. The tablet-in-tablet composition of any one of claims 1 to 12 wherein:

said core filler/diluent component comprises from about 50% to about 85% by weight of said core tablet;

said core filler/binder component comprises from about 10% to about 20% by weight of said core tablet said;

said core hydrophilic gel-forming polymer component comprises from about 5% to about 15% by weight of said core tablet; and

said outer layer hydrophilic gel-forming polymer component comprises from about 30% to about 50% by weight of said compressed outer tablet layer.

17. The tablet-in-tablet composition of any one of claims 1 to 12 wherein:

said core filler/diluent component comprises from about 50% to about 85% by weight of said core tablet;

said core filler/binder component comprises from about 10% to about 20% by weight of said core tablet;

said core hydrophilic gel-forming polymer component comprises from about 15% to about 25% by weight of said core tablet; and

said outer layer hydrophilic gel-forming polymer component comprises from about 1% to about 8% by weight of said compressed outer tablet layer.

18. The tablet-in-tablet composition of any one of claims 1 to 12 wherein:

said core filler/diluent component comprises from about 50% to about 85% by weight of said core tablet;

said core filler/binder component comprises from about 10% to about 20% by weight of said core tablet;

said core hydrophilic gel-forming polymer component comprises from about 15% to about 25% by weight of said core tablet; and

said outer layer hydrophilic gel-forming polymer component comprises from about 8% to about 15% by weight of said compressed outer tablet layer.

19. The tablet-in-tablet composition of any one of claims 1 to 12 wherein:

said core filler/diluent component comprises from about 50% to about 85% by weight of said core tablet;

said core filler/binder component comprises from about 10% to about 20% by weight of said core tablet;

said core hydrophilic gel-forming polymer component comprises from about 15% to about 25% by weight of said core tablet; and

said outer layer hydrophilic gel-forming polymer component comprises from about 15% to about 30% by weight of said compressed outer tablet layer.

20. The tablet-in-tablet composition of any one of claims 1 to 12 wherein:

said core filler/diluent component comprises from about 50% to about 85% by weight of said core tablet;

said core filler/binder component comprises from about 10% to about 20% by weight of said core tablet;

said core hydrophilic gel-forming polymer component comprises from about 15% to about 25% by weight of said core tablet; and

said outer layer hydrophilic gel-forming polymer component comprises from about 30% to about 50% by weight of said compressed outer tablet layer.

21. The tablet-in-tablet composition of any one of claims 1 to 12 wherein:

said core filler/diluent component comprises from about 40% to about 75% by weight of said core tablet;

said core filler/binder component comprises from about 10% to about 20% by weight of said core tablet;

said core hydrophilic gel-forming polymer component comprises from about 25% to about 35% by weight of said core tablet; and

said outer layer hydrophilic gel-forming polymer component comprises from about 1% to about 8% by weight of said compressed outer tablet layer.

22. The tablet-in-tablet composition of any one of claims 1 to 12 wherein:

said core filler/diluent component comprises from about 40% to about 75% by weight of said core tablet;

said core filler/binder component comprises from about 10% to about 20% by weight of said core tablet;

said core hydrophilic gel-forming polymer component comprises from about 25% to about 35% by weight of said core tablet; and

said outer layer hydrophilic gel-forming polymer component comprises from about 8% to about 15% by weight of said compressed outer tablet layer.

23. The tablet-in-tablet composition of any one of claims 1 to 12 wherein:

said core filler/diluent component comprises from about 40% to about 75% by weight of said core tablet;

said core filler/binder component comprises from about 10% to about 20% by weight of said core tablet;

said core hydrophilic gel-forming polymer component comprises from about 25% to about 35% by weight of said core tablet; and

said outer layer hydrophilic gel-forming polymer component comprises from about 15% to about 30% by weight of said compressed outer tablet layer.

24. The tablet-in-tablet composition of any one of claims 1 to 12 wherein:

said core filler/diluent component comprises from about 40% to about 75% by weight of said core tablet;

said core filler/binder component comprises from about 10% to about 20% by weight of said core tablet;

said core hydrophilic gel-forming polymer component comprises from about 25% to about 35% by weight of said core tablet; and

said outer layer hydrophilic gel-forming polymer component comprises from about 30% to about 50% by weight of said compressed outer tablet layer.

25. A tablet-in-tablet composition selected from a plurality of compositions according to any one of claims 1 to 24, wherein the plurality has a mean dissolution profile wherein:

the mean of % of the estrogen released per composition after 1, 2, 3, 4, and 5 hours under estrogen dissolution conditions is substantially equal to the sum of b₁*X₁,b₂X₂, b₃*X₃, b₁₂*X₁*X₂, b₁₃*X₁*X₃, and b₂₃*X₂*X₃; and

the mean of % of the therapeutic agent per composition released after 0.25, 0.5, 1, 2, and 6 hours under type I therapeutic agent dissolution conditions is substantially equal to the sum of a₁*X₁,b₂X₂, a₃*X₃, a₁₂*X₁*X₂, a₁₃*X₁*X₃, and a₂₃*X₂*X₃;

X₁ is the % by weight of said outer layer hydrophilic gel-forming polymer component in said compressed outer tablet layer;

X₂ is the % by weight of said outer layer filler/diluent component in said compressed outer tablet layer;

X₃ is the % by weight of said outer layer filler/binder component in said compressed outer tablet layer;

b₁ at 1 hour is 157.4;

b₁ at 2 hours is 193.09;

b₁ at 3 hours is 184.1;

b₁ at 4 hours is 146.45;

b₁ at 5 hours is 100.25;

b₂ at 1 hour is 54.47;

b₂ at 2 hours is 80.09;

b₂ at 3 hours is 93.71;

b₂ at 4 hours is 101.05;

b₂ at 5 hours is 104.11;

b₃ at 1 hour is 46.75;

b₃ at 2 hours is 69.86;

b₃ at 3 hours is 84.19;

b₃ at 4 hours is 92.12;

b₃ at 5 hours is 95.89;

b₁₂ at 1 hour is −

437.12;

b₁₂ at 2 hours is −

557.91;

b₁₂ at 3 hours is −

561.48;

b₁₂ at 4 hours is −

489.08;

b₁₂ at 5 hours is −

383.44;

b₁₃ at 1 hour is −

414.17;

b₁₃ at 2 hours is −

542.65;

b₁₃ at 3 hours is −

569.13;

b₁₃ at 4 hours is −

518.63;

b₁₃ at 5 hours is −

441.05;

b₂₃ at 1 hour is 76.74;

b₂₃ at 2 hours is 79.7;

b₂₃ at 3 hours is 65.43;

b₂₃ at 4 hours is 43.23;

b₂₃ at 5 hours is 29.91;

a₁ at 0.25 hour is 217.8;

a₁ at 0.5 hour is 218.36;

a₁ at 1 hour is 188.75;

a₁ at 2 hours is 121.23;

a₁ at 6 hours is −

21.48;

a₂ at 0.25 hour is 87.91;

a₂ at 0.5 hour is 93.12;

a₂ at 1 hour is 96.98;

a₂ at 2 hours is 100.52;

a₂ at 6 hours is 100.91;

a₃ at 0.25 hour is 58.83;

a₃ at 0.5 hour is 75.08;

a₃ at 1 hour is 86.32;

a₃ at 2 hours is 92.04;

a₃ at 6 hours is 99.99;

a₁₂ at 0.25 hour is −

616.98;

a₁₂ at 0.5 hour is −

617.39;

a₁₂ at 1 hour is −

545.68;

a₁₂ at 2 hours is −

377.76;

a₁₂ at 6 hours is 69.72;

a₁₃ at 0.25 hour is −

536.63;

a₁₃ at 0.5 hour is −

576.95;

a₁₃ at 1 hour is −

540.35;

a₁₃ at 2 hours is −

397.91;

a₁₃ at 6 hours is 12.22;

a₂₃ at 0.25 hour is 30.77;

a₂₃ at 0.5 hour is 31.94;

a₂₃ at 1 hour is 32.68;

a₂₃ at 2 hours is 32.91; and

a₂₃ at 6 hours is 9.65.

26. The tablet-in-tablet composition of claim 1 wherein:

said core tablet comprises at least one conjugated estrogen;

said compressed outer tablet layer comprises bazedoxifene acetate;

said dissolution profile of said estrogen from said tablet under estrogen dissolution conditions is substantially as shown in any one of FIGS. 30 to 32 or 48 to 54; and

said dissolution profile of said therapeutic agent from said tablet under type II therapeutic agent dissolution conditions is substantially as shown in any one of FIGS. 27 to 29 or 41 to 47.

27. The tablet-in-tablet composition of claim 1 wherein:

said core tablet comprises at least one conjugated estrogen;

said compressed outer tablet layer comprises medroxyprogesterone acetate;

said dissolution profile of said estrogen from said tablet under estrogen dissolution conditions is substantially as shown in any one of FIGS. 4-6, FIG. 33 (Example

     9), FIG. 34 (Example

     13), FIG. 35 (Example

     15), FIG. 35 (Example

     16), FIG. 35 (Example

     18) or FIG. 36 (Example

     20); and

said dissolution profile of said therapeutic agent from said tablet under type I therapeutic agent dissolution conditions is substantially as shown in any one of FIGS. 1-3, FIG. 37 (Example

     9), FIG. 38 (Example

     13), FIG. 39 (Example

     15), FIG. 39 (Example

     16), FIG. 39 (Example

     18) or FIG. 40 (Example

     20).

28. A tablet-in-tablet composition selected from a plurality of tablet-in-tablet compositions according to any one of claims 1 to 27, wherein said plurality has a content uniformity for said therapeutic agent about equal to or less than 3.5%.

29. A tablet-in-tablet composition selected from a plurality of tablet-in-tablet compositions according to any one of claims 1 to 27, wherein said plurality has a content uniformity for said therapeutic agent about equal to or less than 2.5%.

30. A tablet-in-tablet composition selected from a plurality of tablet-in-tablet compositions according to any one of claims 1 to 27, wherein said plurality has a weight variation of about equal to or less than 2%.

31. A tablet-in-tablet composition selected from a plurality of tablet-in-tablet compositions according to any one of claims 1 to 27, wherein said plurality has a weight variation of about equal to or less than 1.5%.

32. A tablet-in-tablet composition comprising:

a) a core tablet comprising;

one or more estrogens;

a core filler/diluent component comprising from about 30% to about 85% by weight by weight of said core tablet;

a core filler/binder component comprising from about 1% to about 30% by weight of said core tablet;

a core hydrophilic gel-forming polymer component comprising from about 1% to about 40% by weight of said core tablet; and

optionally, a core lubricant component comprising from about 0.01% to about 2% by weight of said core tablet; and

b) a compressed outer tablet layer comprising;

one or more therapeutic agents selected from the group consisting of selective estrogen receptor modulators and progestational agents;

a pharmaceutically acceptable carrier component comprising from about 60% to about 99.9% by weight of said compressed outer tablet layer, wherein said pharmaceutically acceptable carrier component optionally comprises one or more of an outer layer filler/diluent component, an outer layer filler/binder component, and an outer layer hydrophilic gel-forming polymer component;

optionally, an outer layer lubricant component comprising from about 0.01% to about 2% by weight of said compressed outer tablet layer; and

optionally, an antioxidant component comprising from about 0.01% to about 4% by weight of said compressed outer tablet layer.

33. The tablet-in-tablet composition of claim 32 wherein:

said core tablet comprises from about 10% to about 50% by weight of said composition; and

said compressed outer tablet layer comprises from about 50% to about 90% by weight of said composition.

34. The tablet-in-tablet composition of claim 32 or claim 33 wherein said compressed outer tablet layer has a hardness from about 2 kp to about 7 kp.

35. The tablet-in-tablet composition of any one of claims 32 to 34 wherein said compressed outer tablet layer does not comprise a surfactant or wetting agent.

36. The tablet-in-tablet composition of claim 32 wherein:

said core tablet comprises from about 10% to about 50% by weight of said composition;

said compressed outer tablet layer comprises from about 50% to about 90% by weight of said composition;

said compressed outer tablet layer has a hardness from about 2 kp to about 7 kp; and

said compressed outer tablet layer does not comprise a surfactant or wetting agent.

37. The tablet-in-tablet composition of any one of claims 32 to 36 wherein said pharmaceutically acceptable carrier component comprises an outer layer filler/diluent component.

38. The tablet-in-tablet composition of any one of claims 32 to 37 wherein said pharmaceutically acceptable carrier component comprises an outer layer filler/binder component.

39. The tablet-in-tablet composition of any one of claims 32 to 38 wherein said pharmaceutically acceptable carrier component comprises an outer layer hydrophilic gel-forming polymer component.

40. The tablet-in-tablet composition of any one of claims 32 to 36 wherein said pharmaceutically acceptable carrier component comprises:

from about 30% to about 99.9% by weight of an outer layer filler/diluent component; and

from about 1% to about 70% by weight of an outer layer filler/binder component.

41. The tablet-in-tablet composition of any one of claims 32 to 36 wherein said pharmaceutically acceptable carrier component comprises:

from about 30% to about 99.9% by weight of an outer layer filler/diluent component; and

from about 1% to about 70% by weight of an outer layer hydrophilic gel-forming polymer component.

42. The tablet-in-tablet composition of any one of claims 32 to 36 wherein said pharmaceutically acceptable carrier component comprises:

from about 30% to about 99.9% by weight of an outer layer filler/binder component; and

from about 1% to about 70% by weight of an outer layer hydrophilic gel-forming polymer component.

43. The tablet-in-tablet composition of any one of claims 32 to 42 wherein:

said core filler/diluent component comprises one or more of lactose, lactose monohydrate, mannitol, sucrose, maltodextrin, dextrin, maltitol, sorbitol, xylitol, powdered cellulose, cellulose gum, microcrystalline cellulose, starch, calcium phosphate, and a metal carbonate;

said core filler/binder component comprises one or more of microcrystalline cellulose, polyvinylpyrrolidone, copovidone, polyvinylalcohol, starch, gelatin, gum arabic, gum acacia, and gum tragacanth;

said core hydrophilic gel-forming polymer component comprises one or more of hydroxypropylmethylcellulose, polyethylene oxide, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, polyvinylpyrrolidone, xanthan gum, and guar gum;

said optional core lubricant component, if present, comprises one or more of stearic acid, metallic stearate, sodium stearyl fumarate, fatty acid, fatty alcohol, fatty acid ester, glyceryl behenate, mineral oil, vegetable oil, paraffin, leucine, talc, propylene glycol fatty acid ester, polyethylene glycol, polypropylene glycol, and polyalkylene glycol;

said pharmaceutically acceptable carrier component comprises one or more of lactose, lactose monohydrate, mannitol, sucrose, maltodextrin, dextrin, maltitol, sorbitol, xylitol, powdered cellulose, cellulose gum, microcrystalline cellulose, starch, calcium phosphate, a metal carbonate, polyvinylpyrrolidone, copovidone, polyvinylalcohol, gelatin, gum arabic, gum acacia, gum tragacanth, hydroxypropylmethylcellulose, polyethylene oxide, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, xanthan gum, and guar gum;

said optional outer layer lubricant component, if present, comprises one or more of stearic acid, metallic stearate, sodium stearyl fumarate, fatty acid, fatty alcohol, fatty acid ester, glyceryl behenate, mineral oil, vegetable oil, paraffin, leucine, talc, propylene glycol fatty acid ester, polyethylene glycol, polypropylene glycol, and polyalkylene glycol;

said optional antioxidant component, if present, comprises one or more of ascorbic acid, sodium ascorbate, ascorbyl palmitate, vitamin E, vitamin E acetate, butylated hydroxytoluene, and butylated hydroxyanisole;

said core tablet comprises at least one conjugated estrogen; and

said compressed outer tablet layer comprises medroxyprogesterone acetate or bazedoxifene acetate.

44. The tablet-in-tablet composition of any one of claims 32 to 42 wherein:

said core filler/diluent component comprises one or more of lactose and lactose monohydrate;

said core filler/binder component comprises microcrystalline cellulose;

said core hydrophilic gel-forming polymer component comprises hydroxypropylmethylcellulose;

said optional core lubricant component, if present, comprises magnesium stearate;

said pharmaceutically acceptable carrier component comprises one or more of lactose, lactose monohydrate, microcrystalline cellulose, and hydroxypropylmethylcellulose;

said optional outer layer lubricant component, if present, comprises magnesium stearate;

said optional antioxidant component, if present, comprises one or more of ascorbic acid and vitamin E acetate;

said core tablet comprises at least one conjugated estrogen; and

said compressed outer tablet layer comprises medroxyprogesterone acetate or bazedoxifene acetate.

45. A tablet-in-tablet composition selected from a plurality of compositions according to any one of claims 32 to 44, wherein the plurality has a mean dissolution profile wherein:

the mean of % of the estrogen released per composition after 1, 2, 3, 4, and 5 hours under estrogen dissolution conditions is substantially equal to the sum of b₁*X₁,b₂X₂, b₃*X₃, b₁₂*X₁*X₂, b₁₃*X₁*X₃, and b₂₃*X₂*X₃;

the mean of % of the therapeutic agent per composition released after 0.25, 0.5, 1, 2, and 6 hours under type I therapeutic agent dissolution conditions is substantially equal to the sum of a₁*X₁,b₂X₂, a₃*X₃, a₁₂*X₁*X₂, a₁₃*X₁*X₃, and a₂₃*X₂*X₃;

X₁ is the % by weight of said optional outer layer hydrophilic gel-forming polymer component, if present, in said compressed outer tablet layer;

X₂ is the % by weight of said optional outer layer filler/diluent component, if present, in said compressed outer tablet layer; and

X₃ is the % by weight of said optional outer layer filler/binder component, if present, in said compressed outer tablet layer;

wherein;

b₁ at 1 hour is 157.4;

b₁ at 2 hours is 193.09;

b₁ at 3 hours is 184.1;

b₁ at 4 hours is 146.45;

b₁ at 5 hours is 100.25;

b₂ at 1 hour is 54.47;

b₂ at 2 hours is 80.09;

b₂ at 3 hours is 93.71;

b₂ at 4 hours is 101.05;

b₂ at 5 hours is 104.11;

b₃ at 1 hour is 46.75;

b₃ at 2 hours is 69.86;

b₃ at 3 hours is 84.19;

b₃ at 4 hours is 92.12;

b₃ at 5 hours is 95.89;

b₁₂ at 1 hour is −

437.12;

b₁₂ at 2 hours is −

557.91;

b₁₂ at 3 hours is −

561.48;

b₁₂ at 4 hours is −

489.08;

b₁₂ at 5 hours is −

383.44;

b₁₃ at 1 hour is −

414.17;

b₁₃ at 2 hours is −

542.65;

b₁₃ at 3 hours is −

569.13;

b₁₃ at 4 hours is −

518.63;

b₁₃ at 5 hours is −

441.05;

b₂₃ at 1 hour is 76.74;

b₂₃ at 2 hours is 79.7;

b₂₃ at 3 hours is 65.43;

b₂₃ at 4 hours is 43.23;

b₂₃ at 5 hours is 29.91;

a₁ at 0.25 hour is 217.8;

a₁ at 0.5 hour is 218.36;

a₁ at 1 hour is 188.75;

a₁ at 2 hours is 121.23;

a₁ at 6 hours is −

21.48;

a₂ at 0.25 hour is 87.91;

a₂ at 0.5 hour is 93.12;

a₂ at 1 hour is 96.98;

a₂ at 2 hours is 100.52;

a₂ at 6 hours is 100.91;

a₃ at 0.25 hour is 58.83;

a₃ at 0.5 hour is 75.08;

a₃ at 1 hour is 86.32;

a₃ at 2 hours is 92.04;

a₃ at 6 hours is 99.99;

a₁₂ at 0.25 hour is −

616.98;

a₁₂ at 0.5 hour is −

617.39;

a₁₂ at 1 hour is −

545.68;

a₁₂ at 2 hours is −

377.76;

a₁₂ at 6 hours is 69.72;

a₁₃ at 0.25 hour is −

536.63;

a₁₃ at 0.5 hour is −

576.95;

a₁₃ at 1 hour is −

540.35;

a₁₃ at 2 hours is −

397.91;

a₁₃ at 6 hours is 12.22;

a₂₃ at 0.25 hour is 30.77;

a₂₃ at 0.5 hour is 31.94;

a₂₃ at 1 hour is 32.68;

a₂₃ at 2 hours is 32.91; and

a₂₃ at 6 hours is 9.65.

46. The tablet-in-tablet composition of claim 32 wherein:

said core tablet comprises at least one conjugated estrogen;

said compressed outer tablet layer comprises medroxyprogesterone acetate;

said dissolution profile of said estrogen from said tablet under estrogen dissolution conditions is substantially as shown in any one of FIG. 33 (Example

     8), FIG. 33 (Example

     10), FIG. 33 (Example

     11), FIG. 34 (Example

     12), FIG. 34 (Example

     14), FIG. 35 (Example

     17), FIG. 36 (Example

     19) or FIG. 36 (Example

     21); and

said dissolution profile of said therapeutic agent from said tablet under type I therapeutic agent dissolution conditions is substantially as shown in any one of FIG. 37 (Example

     8), FIG. 37 (Example

     10), FIG. 38 (Example

     11), FIG. 38 (Example

     12), FIG. 38 (Example

     14), FIG. 39 (Example

     17), FIG. 40 (Example

     19) or FIG. 40 (Example

     21).

47. A tablet-in-tablet composition selected from a plurality of tablet-in-tablet compositions according to claim 32, wherein said plurality has a content uniformity for said therapeutic agent about equal to or less than 3.5%.

48. A tablet-in-tablet composition selected from a plurality of tablet-in-tablet compositions according to claim 32, wherein said plurality has a content uniformity for said therapeutic agent about equal to or less than 2.5%.

49. A tablet-in-tablet composition selected from a plurality of tablet-in-tablet compositions according to claim 32, wherein said plurality has a weight variation of about equal to or less than 2%.

50. A tablet-in-tablet composition selected from a plurality of tablet-in-tablet compositions according to of claim 32, wherein said plurality has a weight variation of about equal to or less than 1.5%.

51. A tablet-in-tablet composition comprising:

a) a core tablet comprising;

one or more estrogens;

a core filler/diluent component comprising from about 30% to about 85% by weight by weight of said core tablet;

a core filler/binder component comprising from about 1% to about 30% by weight of said core tablet;

a core hydrophilic gel-forming polymer component comprising from about 1% to about 40% by weight of said core tablet; and

optionally, a core lubricant component comprising from about 0.01% 10 to about 2% by weight of said core tablet; and

b) a compressed outer tablet layer comprising;

one or more therapeutic agents selected from the group consisting of selective estrogen receptor modulators and progestational agents;

an outer layer filler/diluent component comprising from about 25% to about 65% by weight of said compressed outer tablet layer;

an outer layer filler/binder component comprising from about 20% to about 50% by weight of said compressed outer tablet layer;

a disintegrant component comprising from about 2% to about 15% by weight of said compressed outer tablet layer;

optionally, an outer layer wetting agent component comprising from about 0.01% to about 4% of said compressed outer tablet layer;

optionally, an outer layer lubricant component comprising from about 0.01% to about 2% by weight of said compressed outer tablet layer; and

optionally, an antioxidant component comprising from about 0.01% to about 4% by weight of said compressed outer tablet layer.

52. The tablet-in-tablet composition of claim 51 wherein:

said core filler/diluent component comprises one or more of lactose, lactose monohydrate, mannitol, sucrose, maltodextrin, dextrin, maltitol, sorbitol, xylitol, powdered cellulose, cellulose gum, microcrystalline cellulose, starch, calcium phosphate, and a metal carbonate;

said core filler/binder component comprises one or more of microcrystalline cellulose, polyvinylpyrrolidone, copovidone, polyvinylalcohol, starch, gelatin, gum arabic, gum acacia, and gum tragacanth;

said core hydrophilic gel-forming polymer component comprises one or more of hydroxypropylmethylcellulose, polyethylene oxide, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, polyvinylpyrrolidone, xanthan gum, and guar gum;

said optional core lubricant component, if present, comprises one or more of stearic acid, metallic stearate, sodium stearyl fumarate, fatty acid, fatty alcohol, fatty acid ester, glyceryl behenate, mineral oil, vegetable oil, paraffin, leucine, talc, propylene glycol fatty acid ester, polyethylene glycol, polypropylene glycol, and polyalkylene glycol;

said outer layer filler/diluent component comprises one or more of lactose, lactose monohydrate, mannitol, sucrose, maltodextrin, dextrin, maltitol, sorbitol, xylitol, powdered cellulose, cellulose gum, microcrystalline cellulose, starch, calcium phosphate, and a metal carbonate;

said outer layer filler/binder component comprises one or more of silicified microcrystalline cellulose, microcrystalline cellulose, polyvinylpyrrolidone, copovidone, polyvinylalcohol, starch, gelatin, gum arabic, gum acacia, and gum tragacanth;

said outer layer disintegrant component comprises one or more of croscarmellose sodium, carmellose calcium, crospovidone, alginic acid, sodium alginate, potassium alginate, calcium alginate, starch, pregelatinized starch, sodium starch glycolate, cellulose floc, and carboxymethylcellulose;

said optional outer layer wetting agent component, if present, comprises one or more of a polyethylene glycol-polypropylene glycol copolymer, sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid ester, polyethylene glycol, polyoxyethylene castor oil derivative, docusate sodium, quaternary ammonium amine compound, sugar esters of fatty acid, polyethoxylated fatty acid esters, and polyglycolized glycerides;

said optional outer layer lubricant component, if present, comprises one or more of stearic acid, metallic stearate, sodium stearyl fumarate, fatty acid, fatty alcohol, fatty acid ester, glyceryl behenate, mineral oil, vegetable oil, paraffin, leucine, talc, propylene glycol fatty acid ester, polyethylene glycol, polypropylene glycol, and polyalkylene glycol;

said optional antioxidant component, if present, comprises one or more of ascorbic acid, sodium ascorbate, ascorbyl palmitate, vitamin E, vitamin E acetate, butylated hydroxytoluene, and butylated hydroxyanisole;

said core tablet comprises at least one conjugated estrogen; and

said compressed outer tablet layer comprises medroxyprogesterone acetate or bazedoxifene acetate.

53. The tablet-in-tablet composition of claim 51 wherein:

said core filler/diluent component comprises one or more of lactose and lactose monohydrate;

said core filler/binder component comprises microcrystalline cellulose;

said core hydrophilic gel-forming polymer component comprises hydroxypropylmethylcellulose;

said optional core lubricant component, if present, comprises magnesium stearate;

said outer layer filler/diluent component comprises lactose monohydrate;

said outer layer filler/binder component comprises microcrystalline cellulose;

said outer layer disintegrant component comprises one or more of pregelatinized starch and sodium starch glycolate;

said optional outer layer wetting agent component, if present, comprises a polyethylene glycol-polypropylene glycol copolymer;

said optional outer layer lubricant component, if present, comprises magnesium stearate;

said optional antioxidant component, if present, comprises one or more of ascorbic acid and vitamin E acetate;

said core tablet comprises at least one conjugated estrogen; and

said compressed outer tablet layer comprises medroxyprogesterone acetate or bazedoxifene acetate.

54. A tablet-in-tablet composition selected from a plurality of tablet-in-tablet compositions according to any one of claims 51 to 53, wherein said plurality has a content uniformity for said therapeutic agent about equal to or less than 3.5%.

55. A tablet-in-tablet composition selected from a plurality of tablet-in-tablet compositions according to any one of claims 51 to 53, wherein said plurality has a content uniformity for said therapeutic agent about equal to or less than 2.5%.

56. A tablet-in-tablet composition selected from a plurality of tablet-in-tablet compositions according to any one of claims 51 to 53, wherein said plurality has a weight variation of about equal to or less than 2%.

57. A tablet-in-tablet composition selected from a plurality of tablet-in-tablet compositions according to of any one of claims 51 to 53, wherein said plurality has a weight variation of about equal to or less than 1.5%.

58. A process for producing a tablet-in-tablet composition comprising:

compressing a first solid mixture to form a core tablet; and

compressing a second solid mixture onto said core tablet to form a compressed outer tablet layer;

wherein;

(a) said first solid mixture comprises;

one or more estrogens;

a first solid mixture filler/diluent component comprising from about 30% to about 85% by weight of said first solid mixture;

a first solid mixture filler/binder component comprising from about 1% to about 30% by weight of said first solid mixture;

a first solid mixture hydrophilic gel-forming polymer component comprising from about 1% to about 40% by weight of said first solid mixture; and

optionally, a first solid mixture lubricant component comprising from about 0.01% to about 2% by weight of said first solid mixture; and

(b) said second solid mixture comprises;

one or more therapeutic agents selected from the group consisting of selective estrogen receptor modulator and a progestational agent;

a second solid mixture filler/diluent component comprising from about 10% to about 80% by weight of said second solid mixture;

a second solid mixture filler/binder component comprising from about 1% to about 70% by weight of said second solid mixture;

a second solid mixture hydrophilic gel-forming polymer component comprising from about 1% to about 60% of said compressed outer tablet layer;

optionally, a second solid mixture antioxidant component comprising from about 0.01% to about 4% of said second solid mixture; and

optionally, a second solid mixture lubricant component comprising from about 0.01% to about 2% of said second solid mixture.

59. The process of claim 58 further comprising blending said one or more therapeutic agents, said second solid mixture filler/binder component, said second solid mixture filler/diluent component, and said second solid mixture hydrophilic gel-forming polymer component to form said second solid mixture.

60. The process of claim 59 wherein said blending further comprises:

blending said one or more therapeutic agents and said second solid mixture filler/binder component to form an initial mixture; and

blending said initial mixture with said second solid mixture filler/diluent component and said second solid mixture hydrophilic gel-forming polymer component to form said second solid mixture.

61. The process of claim 60 further comprising granulating and then milling said second solid mixture after said blending and prior to said compressing to form said compressed outer tablet layer.

62. The process of claim 61 further comprising blending said second solid mixture antioxidant component and, optionally, at least a portion of said optional second solid mixture lubricant component with said one or more therapeutic agents, said second solid mixture filler/binder component, said second solid mixture filler/diluent component, and said second solid mixture hydrophilic gel-forming polymer component to form said second solid mixture.

63. The process of any one of claims 58 to 62 further comprising blending said first solid mixture filler/diluent component, said first solid mixture filler/binder component, said first solid mixture hydrophilic gel-forming polymer component, and said estrogen to form said first solid mixture.

64. The process of claim 63 further comprising granulating and then milling said first solid mixture after said blending.

65. The process of claim 64 further comprising the steps of:

(a) adding water to said first solid mixture during said granulating; and

(b) drying said first granulated mixture before said milling.

66. The process of claim 65 wherein said drying comprises drying said first granulated mixture to loss on drying (LOD) of from about 1% to about 3%.

67. The process of claim 58 further comprising the steps of:

(i) blending said first solid mixture filler/diluent component, said first solid mixture filler/binder component, said first solid mixture hydrophilic gel-forming polymer component, and said estrogen to form a first solid mixture;

(ii) granulating said first solid mixture of step (i) in the presence of water;

(iiii) drying the first solid mixture of step (ii)

(iv) milling the first solid mixture of step (iii);

(v) optionally, blending said first solid mixture of step (iv) with said optional first solid mixture lubricant component, if present;

(vi) compressing said first solid mixture of step (iv) or step (v), if utilized, to form said core tablet;

(vii) blending said one or more therapeutic agents and said second solid mixture filler/binder component to form an initial mixture;

(viii) blending said initial mixture with said second solid mixture filler/diluent component and said second solid mixture hydrophilic gel-forming polymer component to form a second solid mixture;

(ix) optionally, granulating the second solid mixture of step (viii);

(x) optionally, blending the second solid mixture of step (viii) or step (ix), if utilized, with at least a portion of said optional second solid mixture lubricant component; and

(xi) after step (viii) or steps (ix) or (x), if utilized, compressing the second solid mixture of (vi) onto said core tablet of step (iv) to form said compressed outer tablet layer.

68. The process of any one of claims 58 to 67 wherein:

said first solid mixture filler/diluent component comprises one or more of lactose, lactose monohydrate, mannitol, sucrose, maltodextrin, dextrin, maltitol, sorbitol, xylitol, powdered cellulose, cellulose gum, microcrystalline cellulose, starch, calcium phosphate, and a metal carbonate;

said first solid mixture filler/binder component comprises one or more of microcrystalline cellulose, polyvinylpyrrolidone, copovidone, polyvinylalcohol, starch, gelatin, gum arabic, gum acacia, and gum tragacanth;

said first solid mixture hydrophilic gel-forming polymer component comprises one or more of hydroxypropylmethylcellulose, polyethylene oxide, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, polyvinylpyrrolidone, xanthan gum, and guar gum;

said optional first solid mixture lubricant component, if present, comprises one or more of stearic acid, metallic stearate, sodium stearyl fumarate, fatty acid, fatty alcohol, fatty acid ester, glyceryl behenate, mineral oil, vegetable oil, paraffin, leucine, talc, propylene glycol fatty acid ester, polyethylene glycol, polypropylene glycol, and polyalkylene glycol;

said second solid mixture filler/diluent component comprises one or more of lactose, lactose monohydrate, mannitol, sucrose, maltodextrin, dextrin, maltitol, sorbitol, xylitol, powdered cellulose, cellulose gum, microcrystalline cellulose, starch, calcium phosphate, and a metal carbonate;

said second solid mixture filler/binder component comprises one or more of microcrystalline cellulose, polyvinylpyrrolidone, copovidone, polyvinylalcohol, starch, gelatin, gum arabic, gum acacia, and gum tragacanth;

said second solid mixture hydrophilic gel-forming polymer component comprises one or more of hydroxypropylmethylcellulose, polyethylene oxide, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, polyvinylpyrrolidone, xanthan gum, and guar gum;

said optional second solid mixture lubricant component, if present, comprises one or more of stearic acid, metallic stearate, sodium stearyl fumarate, fatty acid, fatty alcohol, fatty acid ester, glyceryl behenate, mineral oil, vegetable oil, paraffin, leucine, talc, propylene glycol fatty acid ester, polyethylene glycol, polypropylene glycol, and polyalkylene glycol;

said optional second solid mixture antioxidant component, if present, comprises one or more of ascorbic acid, sodium ascorbate, ascorbyl palmitate, vitamin E, vitamin E acetate, butylated hydroxytoluene, and butylated hydroxyanisole;

said core tablet comprises at least one conjugated estrogen; and

said compressed outer tablet layer comprises medroxyprogesterone acetate or bazedoxifene acetate.

69. The tablet-in-tablet composition of any one of claims 58 to 67 wherein:

said first solid mixture filler/diluent component comprises one or more of lactose and lactose monohydrate;

said first solid mixture filler/binder component comprises microcrystalline cellulose;

said first solid mixture hydrophilic gel-forming polymer component comprises hydroxypropylmethylcellulose;

said optional first solid mixture lubricant component, if present, comprises magnesium stearate;

said second solid mixture filler/diluent component comprises one or more of lactose and lactose monohydrate;

said second solid mixture filler/binder component comprises microcrystalline cellulose;

said second solid mixture hydrophilic gel-forming polymer component comprises hydroxypropylmethylcellulose;

said optional second solid mixture lubricant component, if present, comprises magnesium stearate;

said optional second solid mixture antioxidant component, if present, comprises one or more of ascorbic acid and vitamin E acetate;

said core tablet comprises at least one conjugated estrogen; and

said compressed outer tablet layer comprises medroxyprogesterone acetate or bazedoxifene acetate.

70. The process of any one of claims 58 to 69 wherein said process produces a plurality of tablet-in-tablet compositions having a content uniformity for said therapeutic agent about equal to or less than 3.5%.

71. The process of any one of claims 58 to 69 wherein said process produces a plurality of tablet-in-tablet compositions having a content uniformity for said therapeutic agent about equal to or less than 2.5%.

72. The process of any one of claims 58 to 69 wherein said process produces a plurality of tablet-in-tablet compositions having a weight variation about equal to or less than 2%.

73. The process of any one of claims 58 to 69 wherein said process produces a plurality of tablet-in-tablet compositions having a weight variation about equal to or less than 1.5%.

74. A product of the process of any one of claims 58 to 73.

75. A plurality of products according to claim 74.

76. A product according to claim 74 or claim 75 wherein said compressed outer tablet layer has a hardness from about 2 kp to about 7 kp.

77. A process for producing a tablet-in-tablet composition comprising:

compressing a first solid mixture to form a core tablet; and

compressing a second solid mixture onto said core tablet to form a compressed outer tablet layer;

wherein;

a) said first solid mixture comprises;

one or more estrogens;

a first solid mixture filler/diluent component comprising from about 30% to about 85% by weight by weight of said core tablet;

a first solid mixture filler/binder component comprising from about 1% to about 30% by weight of said core tablet;

a first solid mixture hydrophilic gel-forming polymer component comprising from about 1% to about 40% by weight of said core tablet; and

optionally, a first solid mixture lubricant component comprising from about 0.01% to about 2% by weight of said core tablet; and

b) said second solid mixture comprises;

one or more therapeutic agents selected from the group consisting of selective estrogen receptor modulators and progestational agents;

a pharmaceutically acceptable carrier component comprising from about 60% to about 99.9% by weight of said compressed outer tablet layer, wherein said outer pharmaceutically acceptable carrier component optionally comprises one or more of a second solid mixture filler/diluent component, a second solid mixture filler/binder component, and a second solid mixture hydrophilic gel-forming polymer component;

optionally, a second solid mixture lubricant component comprising from about 0.01% to about 2% by weight of said compressed outer tablet layer; and

optionally, a second solid mixture antioxidant component comprising from about 0.01% to about 4% by weight of said compressed outer tablet layer.

78. The process of claim 77 further comprising blending said one or more therapeutic agents and said pharmaceutically acceptable carrier component to form said second solid mixture.

79. The process of claim 78 further comprising granulating and then milling said second solid mixture prior to compressing to form said compressed outer tablet layer.

80. The process of any one of claims 77 to 79 further comprising blending said first solid mixture filler/diluent component, said first solid mixture filler/binder component, said first solid mixture hydrophilic gel-forming polymer component, and said estrogen to form said first solid mixture.

81. The process of claim 80 further comprising granulating and then milling said first solid mixture prior to said compressing to form said core tablet.

82. The process of claim 81 further comprising the steps of:

(a) adding water to said first solid mixture during said granulating; and

(b) drying said first granulated mixture before said milling.

83. The process of claim 77 further comprising the steps of:

(i) blending said first solid mixture filler/diluent component, said first solid mixture filler/binder component, said first solid mixture hydrophilic gel-forming polymer component, and said estrogen to form a first solid mixture;

(ii) granulating said first solid mixture of step (i) in the presence of water;

(iii) milling said first solid mixture of step (iii) after said granulating;

(iv) optionally, blending said first solid mixture of step (iii) with said optional first solid mixture lubricant component, if present;

(v) compressing said first solid mixture of step (iiii) or optional step (iv), if utilized, to form said core tablet;

(vi) blending said one or more therapeutic agents and said pharmaceutically acceptable carrier component to form an initial mixture;

(vii) optionally, granulating and then milling the second solid mixture of step (vi);

(viii) optionally, blending the second solid mixture of step (vi) or optional step (vii), if utilized, with at least a portion of said optional second solid mixture lubricant component; and

(ix) after step (vi) or optional steps (vi) and (vii), if utilized, compressing the second solid mixture of (vi) onto said core tablet of step (iv) to form said compressed outer tablet layer.

84. The process of any one of claims 77 to 83 wherein:

said first solid mixture filler/diluent component comprises one or more of lactose, lactose monohydrate, mannitol, sucrose, maltodextrin, dextrin, maltitol, sorbitol, xylitol, powdered cellulose, cellulose gum, microcrystalline cellulose, starch, calcium phosphate, and a metal carbonate;

said first solid mixture filler/binder component comprises one or more of microcrystalline cellulose, polyvinylpyrrolidone, copovidone, polyvinylalcohol, starch, gelatin, gum arabic, gum acacia, and gum tragacanth;

said first solid mixture hydrophilic gel-forming polymer component comprises one or more of hydroxypropylmethylcellulose, polyethylene oxide, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, polyvinylpyrrolidone, xanthan gum, and guar gum;

said optional first solid mixture lubricant component, if present, comprises one or more of stearic acid, metallic stearate, sodium stearyl fumarate, fatty acid, fatty alcohol, fatty acid ester, glyceryl behenate, mineral oil, vegetable oil, paraffin, leucine, talc, propylene glycol fatty acid ester, polyethylene glycol, polypropylene glycol, and polyalkylene glycol;

said pharmaceutically acceptable carrier component comprises one or more of lactose, lactose monohydrate, mannitol, sucrose, maltodextrin, dextrin, maltitol, sorbitol, xylitol, powdered cellulose, cellulose gum, microcrystalline cellulose, starch, calcium phosphate, a metal carbonate, polyvinylpyrrolidone, copovidone, polyvinylalcohol, gelatin, gum arabic, gum acacia, gum tragacanth, hydroxypropylmethylcellulose, polyethylene oxide, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, xanthan gum, and guar gum;

said optional second solid mixture lubricant component, if present, comprises one or more of stearic acid, metallic stearate, sodium stearyl fumarate, fatty acid, fatty alcohol, fatty acid ester, glyceryl behenate, mineral oil, vegetable oil, paraffin, leucine, talc, propylene glycol fatty acid ester, polyethylene glycol, polypropylene glycol, and polyalkylene glycol;

said optional second solid mixture antioxidant component, if present, comprises one or more of ascorbic acid, sodium ascorbate, ascorbyl palmitate, vitamin E, vitamin E acetate, butylated hydroxytoluene, and butylated hydroxyanisole;

said core tablet comprises at least one conjugated estrogen; and

said compressed outer tablet layer comprises medroxyprogesterone acetate or bazedoxifene acetate.

85. The tablet-in-tablet composition of any one of claims 77 to 83 wherein:

said first solid mixture filler/diluent component comprises one or more of lactose and lactose monohydrate;

said first solid mixture filler/binder component comprises microcrystalline cellulose;

said first solid mixture hydrophilic gel-forming polymer component comprises hydroxypropylmethylcellulose;

said optional first solid mixture lubricant component, if present, comprises magnesium stearate;

said pharmaceutically acceptable carrier component comprises one or more of lactose, lactose monohydrate, microcrystalline cellulose, and hydroxypropylmethylcellulose;

said optional second solid mixture lubricant component, if present, comprises magnesium stearate;

said optional second solid mixture antioxidant component, if present, comprises one or more of ascorbic acid and vitamin E acetate;

said core tablet comprises at least one conjugated estrogen; and

said compressed outer tablet layer comprises medroxyprogesterone acetate or bazedoxifene acetate.

86. The process of any one of claims 77 to 85 wherein said process produces a plurality of tablet-in-tablet compositions having a content uniformity for said therapeutic agent about equal to or less than 3.5%.

87. The process of any one of claims 77 to 85 wherein said process produces a plurality of tablet-in-tablet compositions having a content uniformity for said therapeutic agent about equal to or less than 2.5%.

88. The process of any one of claims 77 to 85 wherein said process produces a plurality of tablet-in-tablet compositions having a weight variation about equal to or less than 2%.

89. The process of any one of claims 77 to 85 wherein said process produces a plurality of tablet-in-tablet compositions having a weight variation about equal to or less than 1.5%.

90. A product of the process of any one of claims 77 to 89.

91. A plurality of products according to claim 90.

92. A product according to claim 90 or claim 91 wherein said compressed outer tablet layer has a hardness from about 2 kp to about 7 kp.

93. A process for producing a tablet-in-tablet composition comprising:

compressing a first solid mixture to form a core tablet; and

compressing a second solid mixture onto said core tablet to form a compressed outer tablet layer;

wherein;

a) said first solid mixture comprises;

one or more estrogens;

a first solid mixture filler/diluent component comprising from about 30% to about 85% by weight by weight of said core tablet;

a first solid mixture filler/binder component comprising from about 1% to about 30% by weight of said core tablet;

a first solid mixture hydrophilic gel-forming polymer component comprising from about 1% to about 40% by weight of said core tablet; and

optionally, a first solid mixture lubricant component comprising from about 0.01% to about 2% by weight of said core tablet; and

b) said second solid mixture comprises;

one or more therapeutic agents selected from the group consisting of selective estrogen receptor modulators and progestational agents;

a second solid mixture filler/diluent component comprising from about 25% to about 65% by weight of said compressed outer tablet layer;

a second solid mixture filler/binder component comprising from about 20% to about 50% by weight of said compressed outer tablet layer;

a second solid mixture disintegrant component comprising from about 2% to about 15% by weight of said compressed outer tablet layer;

optionally, a second solid mixture wetting agent component comprising from about 0.01% to about 4% of said compressed outer tablet layer;

optionally, a second solid mixture lubricant component comprising from about 0.01% to about 2% by weight of said compressed outer tablet layer; and

optionally, a second solid mixture antioxidant component comprising from about 0.01% to about 4% by weight of said compressed outer tablet layer.

94. The process of claim 93 further comprising blending said first solid mixture filler/diluent component, said first solid mixture filler/binder component, said first solid mixture hydrophilic gel-forming polymer component, and said estrogen to form said first solid mixture.

95. The process of claim 94 further comprising granulating and then milling said first solid mixture after said blending.

96. The process of claim 95 further comprising the steps of:

(a) adding water to said first solid mixture during said granulating; and

(b) drying said first granulated mixture before said milling.

97. The process of any one of claims 93 to 96 further comprising blending said one or more therapeutic agents, said optional second solid mixture wetting agent component, if present, and said optional second solid mixture antioxidant component, if present, with at least a portion of each of said second solid mixture filler/diluent component, said second solid mixture filler/binder component, and said second solid mixture disintegrant component to form an initial mixture.

98. The process of claim 97 further comprising granulating and then milling said initial mixture after said blending to form a granulated mixture.

99. The process of claim 98 further comprising blending said granulated mixture with any remaining portion of said second solid mixture filler/diluent component, said second solid mixture filler/binder component and said second solid mixture disintegrant component to form said second solid mixture.

100. The process of claim 99 further comprising blending said second solid mixture with said optional second solid mixture lubricant component, if present, prior to compressing said second solid mixture onto said core tablet.

101. The process of claim 93 further comprising (i) blending said first solid mixture filler/diluent component, said first solid mixture filler/binder component, said first solid mixture hydrophilic gel-forming polymer component, and said estrogen to form a first solid mixture;

(ii) granulating said first solid mixture of step (i) in the presence of water;

(iiii) drying said first solid mixture of step (ii)

(iv) milling said first solid mixture of step (iii);

(v) optionally, blending said first solid mixture of step (iv) with said optional first solid mixture lubricant component, if present;

(vi) compressing said first solid mixture of step (iv) or step (v), if utilized, to form said core tablet;

(vii) blending said one or more therapeutic agents, said optional second solid mixture wetting agent component, if present, and said optional second solid mixture antioxidant component, if present, with at least a portion of each of said second solid mixture filler/diluent component, said second solid mixture filler/binder component, and said second solid mixture disintegrant component to form an initial mixture;

(viii) optionally, granulating and milling said second solid mixture of step

(vii) to form a granulated mixture;

(ix) blending either said initial mixture of (vii) or said granulated mixture of

(viii) with any remaining portion of said second solid mixture filler/diluent component, said second solid mixture filler/binder component and said second solid mixture disintegrant component to form said second solid mixture;

(x) optionally, blending said second solid mixture of step (ix) with at least a portion of said optional second solid mixture lubricant component; and

(xi) compressing said second solid mixture of either step (ix) or step (x) onto said core tablet of step (vi) to form said compressed outer tablet layer.

102. The process of any one of claims 93 to 101 wherein:

said first solid mixture filler/diluent component comprises one or more of lactose, lactose monohydrate, mannitol, sucrose, maltodextrin, dextrin, maltitol, sorbitol, xylitol, powdered cellulose, cellulose gum, microcrystalline cellulose, starch, calcium phosphate, and a metal carbonate;

said first solid mixture filler/binder component comprises one or more of microcrystalline cellulose, polyvinylpyrrolidone, copovidone, polyvinylalcohol, starch, gelatin, gum arabic, gum acacia, and gum tragacanth;

said first solid mixture hydrophilic gel-forming polymer component comprises one or more of hydroxypropylmethylcellulose, polyethylene oxide, hydroxypropylcellulose, hydroxyethylcellulose, methylcellulose, polyvinylpyrrolidone, xanthan gum, and guar gum;

said first solid mixture lubricant component, if present, comprises one or more of stearic acid, metallic stearate, sodium stearyl fumarate, fatty acid, fatty alcohol, fatty acid ester, glyceryl behenate, mineral oil, vegetable oil, paraffin, leucine, talc, propylene glycol fatty acid ester, polyethylene glycol, polypropylene glycol, and polyalkylene glycol;

said second solid mixture filler/diluent component comprises one or more of lactose, lactose monohydrate, mannitol, sucrose, maltodextrin, dextrin, maltitol, sorbitol, xylitol, powdered cellulose, cellulose gum, microcrystalline cellulose, starch, calcium phosphate, and a metal carbonate;

said second solid mixture filler/binder component comprises one or more of microcrystalline cellulose, polyvinylpyrrolidone, copovidone, polyvinylalcohol, starch, gelatin, gum arabic, gum acacia, and gum tragacanth;

said second solid mixture disintegrant component comprises one or more of croscarmellose sodium, carmellose calcium, crospovidone, alginic acid, sodium alginate, potassium alginate, calcium alginate, starch, pregelatinized starch, sodium starch glycolate, cellulose floc, and carboxymethylcellulose;

said optional second solid mixture wetting agent component, if present, comprises one or more of a polyethylene glycol-polypropylene glycol copolymer, sodium lauryl sulfate, polyoxyethylene sorbitan fatty acid ester, polyethylene glycol, polyoxyethylene castor oil derivative, docusate sodium, quaternary ammonium amine compound, sugar esters of fatty acid, polyethoxylated fatty acid esters, and polyglycolized glycerides;

said optional second solid mixture lubricant component, if present, comprises one or more of stearic acid, metallic stearate, sodium stearyl fumarate, fatty acid, fatty alcohol, fatty acid ester, glyceryl behenate, mineral oil, vegetable oil, paraffin, leucine, talc, propylene glycol fatty acid ester, polyethylene glycol, polypropylene glycol, and polyalkylene glycol;

said optional second solid mixture antioxidant component, if present, comprises one or more of ascorbic acid, sodium ascorbate, ascorbyl palmitate, vitamin E, vitamin E acetate, butylated hydroxytoluene, and butylated hydroxyanisole;

said core tablet comprises at least one conjugated estrogen; and

said compressed outer tablet layer comprises medroxyprogesterone acetate or bazedoxifene acetate.

103. The process of any one of claims 93 to 101 wherein:

said first solid mixture filler/diluent component comprises one or more of lactose and lactose monohydrate;

said first solid mixture filler/binder component comprises microcrystalline cellulose;

said first solid mixture hydrophilic gel-forming polymer component comprises hydroxypropylmethylcellulose;

said optional first solid mixture lubricant component, if present, comprises magnesium stearate;

said second solid mixture filler/diluent component comprises one or more of lactose and lactose monohydrate;

said second solid mixture filler/binder component comprises microcrystalline cellulose;

said second solid mixture disintegrant component comprises one or more of pregelatinized starch and sodium starch glycolate;

said optional second solid mixture wetting agent component, if present, comprises a polyethylene glycol-polypropylene glycol copolymer;

said optional second solid mixture lubricant component, if present, comprises magnesium stearate;

said optional second solid mixture component, if present, comprises one or more of ascorbic acid and vitamin E acetate;

said core tablet comprises at least one conjugated estrogen; and

said compressed outer tablet layer comprises medroxyprogesterone acetate or bazedoxifene acetate.

104. The process of any one of claims 93 to 103 wherein said process produces a plurality of tablet-in-tablet compositions having a content uniformity for said therapeutic agent about equal to or less than 3.5%.

105. The process of any one of claims 93 to 103 wherein said process produces a plurality of tablet-in-tablet compositions having a content uniformity for said therapeutic agent about equal to or less than 2.5%.

106. The process of any one of claims 93 to 103 wherein said process produces a plurality of tablet-in-tablet compositions having a weight variation about equal to or less than 2%.

107. The process of any one of claims 93 to 103 wherein said process produces a plurality of tablet-in-tablet compositions having a weight variation about equal to or less than 1.5%.

108. A product of the process of any one of claims 93 to 107.

109. A plurality of products according to claim 108.