Vaginally administrable progesterone containing tablets and method for preparing the same

1 . A method for preparing a tablet for the vaginal administration of: progesterone for systemic use, comprising the steps of:

(i) preparing a mixture consisting of water and micronized progesterone to obtain wetted micronized progesterone;

(ii) drying the wetted micronized progesterone to obtain dry micronized progesterone;

(iii) mixing the dried micronized progesterone with at least one pharmaceutically acceptable excipient or diluent to form a second mixture; and

(iv) forming a tablet by direct compaction of the second mixture.

2 . The method of claim 1 , wherein step (iii) comprises mixing the dry micronized progesterone with

(a) a pharmaceutically acceptable non-effervescent excipient or diluent; and

(b) an effervescent.

3 . The method of claim 2 , wherein the micronized progesterone is present in from about 6% to about 20% by weight of the tablet.

4 . The method of claim 2 , wherein the micronized progesterone is present in from about 8% to about 12% by weight of the tablet.

5 . The method of claim 2 , wherein the effervescent is a mixture of a pharmaceutically acceptable carboxylic or dicarboxylic acid and a pharmaceutically acceptable salt of HCO 3 − .

6 . The method of claim 5 , wherein the pharmaceutically acceptable salt of HCO 3 − is sodium bicarbonate.

7 . The method of claim 2 , wherein the pharmaceutically acceptable carboxylic or dicarboxylic acid is adipic acid or tartaric acid.

8 . The method of claim 7 , wherein the pharmaceutically acceptable carboxylic or dicarboxylic acid and said bicarbonate are present in an amount providing a molar excess of —COOH groups.

9 . The method of claim 2 , wherein the effervescent comprises a mixture ofadipic acid and sodium bicarbonate.

10 . The method of claim 2 , wherein the effervescent comprises between about 5% and about 12% by weight of the tablet.

11 . The method of claim 10 , wherein the effervescent comprises about 8% by weight of the tablet.

12 . The method of claim 2 , wherein the amount of water mixed with the micronized progesterone is between about 25% and 28% by weight of the amount of micronized progesterone.

13 . The method of claim 12 , wherein the amount of water mixed with the micronized progesterone is about 28% by weight of the amount of micronized progesterone.

14 . The method according to claim 2 , wherein the dried micronized

15 . The method according to claim 2 , wherein step (iii) comprises:

(i) sieving a first lubricant to obtain a sieved first lubricant;

(ii) mixing the dry micronized progesterone with the sieved first lubricant and a material selected from a first filler or a disintegrant to form a first mixture;

(iii) mixing a binder which binds dry particles with the first mixture to form a second mixture;

(iv) intimately mixing the effervescent and a first quantity of a second filler to form a third mixture;

(v) sieving the third mixture to obtain a sieved third mixture, and then intimately mixing the sieved third mixture and the second mixture to form a fourth mixture;

(vi) intimately mixing the fourth mixture with a second quantity of the second filler to form a fifth mixture;

(vii) sieving a second lubricant and a material selected from a saponificant or a third lubricant to obtain, respectively, sieved second lubricant and sieved third lubricant; and

(viii) intimately mixing the sieved second lubricant and said sieved third lubricant with said fifth mixture to form a sixth mixture.

16 . The method of claim 15 , wherein said first lubricant is silicon dioxide.

17 . A method according to claim 15 , wherein the material in step (ii) is a disintegrant, and wherein the disintegrant is a starch derived from corn, potatoes or wheat.

18 . The method of claim 17 , wherein said starch is cornstarch.

19 . The method of claim 15 , wherein the binder is polyvinylpyrrolidone.

20 . The method of claim 15 , wherein the second filler is selected from lactose or a composition consisting essentially of lactose.

21 . A method according to claim 15 , wherein the second lubricant is selected from the group consisting of magnesium stearate, talc, sodium lauryl sulfate, and phosphates.

22 . The method of claim 15 , wherein the material selected from a saponificant or a third lubricant in step (vii) is sodium lauryl sulfate.

23 . A method for preparing a tablet useful for vaginal administration of progesterone which comprises (i) mixing water with micronized progesterone, prior to adding any other ingredients, to obtain wetted micronized progesterone;

(ii) drying the wetted micronized progesterone;

(iii) mixing a pharmaceutically acceptable excipient or diluent with the micronized progesterone after the drying step to form a tabletting mixture; and

(iv) directly compacting the tabletting mixture to form the tablet.

24 . The method of claim 23 for preparing a tablet for the vaginal administration of progesterone for systemic use, wherein the mixture in step (i) consists essentially of water and micronized progesterone.

25 . A method for preparing a tablet for the vaginal administration of progesterone for systemic use, comprising the following sequential steps:

(i) first mixing water with micronized progesterone, in the absence of a pharmaceutically acceptable excipient or diluent, to obtain wetted micronized progesterone;

(ii) drying said wetted micronized progesterone to form dry micronized progesterone;

(iii) mixing said dry micronized progesterone with

(a) a pharmaceutically acceptable non effervescent excipient or diluent; and

(b) an effervescent to form a mixture; and

(iv) forming a tablet by direct compaction of said mixture.