Crystalline form of estradiol and pharmaceutical formulations comprising same

• US 5,928,666 A
• Filed: 11/10/1997
• Issued: 07/27/1999
• Est. Priority Date: 11/12/1996
• Status: Expired due to Term

• Current Assignee: Ortho-McNeil Pharmaceutical Incorporated (Johnson & Johnson)
• Original Assignee: Cygnus, Inc. (Johnson & Johnson)
• Inventors: Jayalakshmi, Yalia, Lee, Susanne M., Farinas, Kathleen C., Soni, Pravin L.
• Primary Examiner(s): Webman, Edward J.
• Application Number:
  US08/968,769
• Time in Patent Office: 624 Days
• Field of Search: 424/487, 424/486, 424/448, 424/449, 424/464-465, 424/469, 514/182, 514/843, 514/946-947, 552/625
• US Class Current: 424/449
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 9/7053 obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
• CPC Class Codes: A61K 9/7061 Polyacrylates

Abstract

The present invention is directed to a stable crystalline form of estradiol suitable for incorporation into pharmaceutical formulations. The invention further provides methods of preparing said crystalline form of estradiol. The invention further provides pharmaceutical formulations comprising said crystalline form of estradiol. The invention further provides a method of treatment of an individual in need of such administration by the transdermal administration of estradiol from a polymeric matrix comprising the crystal structure of estradiol of the present invention.

Claims

1. A method for preparing a crystalline form of estradiol characterized by possessing at least one diffraction peak having a 2θ

angle of 11.2°

±

0.2°

, 12.7°

±

0.2°

, 17.4°

±

0.2°

or 19.6°

±

0.2°

, said method comprising the steps of;

a) preparing a supersaturated suspension of estradiol hemihydrate crystals in an adhesive and solvent;

b) removing the solvent;

c) heating the suspension to a temperature sufficient to dissolve the estradiol hemihydrate crystals in the adhesive; and

d) transferring the suspension to conditions wherein the supersaturation ratio is greater than or equal to about 12.

4. The method of claim 1, further comprising the step of e) incorporating the suspension into a pharmaceutical formulation.

5. The method of claim 4, wherein the pharmaceutical formulation comprises a transdermal drug delivery device.

6. The method of claim 5 wherein the pharmaceutical formulation further comprises a skin permeation enhancer.

7. The method of claim 5, wherein the pharmaceutical formulation further comprises a progestin.

8. The method of claim 1, wherein the adhesive is chosen from the group consisting of acrylates, silicones, and polyisobutylenes.

2. A method for preparing a crystalline form of of estradiol characterized by possessing at least one diffraction peak having a 2θ

angle of 11.2°

±

0.2°

, 12.7°

±

0.2°

, 17.4°

±

0.2°

or 19.6°

±

0.2°

, said method comprising the steps of;

a) preparing a supersaturated suspension of estradiol hemihydrate crystals in an adhesive and solvent;

b) removing the solvent;

c) heating the suspension of to a temperature sufficient to dissolve the estradiol hemihydrate crystals in the adhesive; and

d) transferring the suspension to conditions of approximately 32°

C. and 80% relative humidity.

9. The method of claim 2, further comprising the step of e) incorporating the suspension into a pharmaceutical formulation.

10. The method of claim 9 wherein the pharmaceutical formulation comprises a transdermal drug delivery device.

11. The method of claim 10, wherein the pharmaceutical formulation further comprises a skin permeation enhancer.

12. The method of claim 10, wherein the pharmaceutical formulation further comprises a progestin.

13. The method of claim 2, wherein the adhesive is chosen from the group consisting of acrylates, silicones, and polyisobutylenes.

3. A method for preparing a crystalline form of of estradiol characterized by possessing at least one diffraction peak having a 2θ

angle of 11.2°

±

0.2°

, 12.7°

±

0.2°

, 17.4°

±

0.2°

or 19.6°

±

0.2°

from micronized estradiol hemihydrate (E2-HH) crystals said method comprising the steps of;

a.) preparing a sample of pure micronized E2-HH in an sealed container in the absence of extraneous water;

b.) heating the sample to the melting temperature of the micronized E2-HH and

c.) cooling the sample at a controlled rate so as to form Crystal X.

14. The method of claim 3 wherein the controlled rate of cooling is approximately 5°

C. per minute.

15. The method of claim 3, further comprising the step of d) incorporating the sample into a pharmaceutical formulation.

16. The method of claim 15 wherein the pharmaceutical formulation further comprises a pharmaceutical excipient.

17. The method of claim 16, wherein the pharmaceutical formulation comprises tablets.

18. The method of claim 15, wherein the pharmaceutical formulation further comprises a progestin.