Flexible, compressed intravaginal rings, methods of making and using the same, and apparatus for making the same

• US 7,910,126 B2
• Filed: 03/20/2007
• Issued: 03/22/2011
• Est. Priority Date: 03/20/2006
• Status: Expired due to Fees

• Current Assignee: Teva Women's Health Incorporated (Teva Pharmaceutical Industries Limited)
• Original Assignee: Teva Women's Health Incorporated (Teva Pharmaceutical Industries Limited)
• Inventors: Luo, Yi, Chowdhury, Tahseen A., Ahmed, Salah U.
• Primary Examiner(s): Wax; Robert A
• Assistant Examiner(s): Al-Awadi; Danah
• Application Number:
  US11/725,563
• Publication Number:
  US 20070254014A1
• Time in Patent Office: 1,463 Days
• Field of Search: None
• US Class Current: 424/430
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/20 having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 9/0036 Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms
• CPC Class Codes: A61P 15/02 for disorders of the vagina
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 23/02 Local anaesthetics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics

Abstract

The present invention is directed to flexible, compressed intravaginal rings comprising a substantially homogeneous compressed mixture comprising a polymethacrylate, a plasticizer, and an active agent, and methods of making and using the same, and apparatus for making the same.

Claims

1. A flexible, compressed intravaginal ring comprising a substantially homogeneous compressed mixture comprising a polymethacrylate, a plasticizer, a thickener, and an active agent, wherein the thickener is present in a concentration of about 2% to about 20% by weight of the flexible, compressed intravaginal ring, and wherein the polymethacrylate has a glass transition temperature of about 10°

C. to about 50°

C.

2. The flexible, compressed intravaginal ring of claim 1, wherein the polymethacrylate is selected from the group consisting of:

poly(n-butyl) methacrylate, poly(isopropyl)methacrylate, poly(ethyl)methacrylate, poly(butyl) methacrylate, poly(propyl)methacrylate, poly(hexyl)methacrylate, and combinations thereof.

3. The flexible, compressed intravaginal ring of claim 1, wherein the plasticizer is selected from the group consisting of:

dibutyl sebacate, triethyl citrate, castor oil, triacetin, propylene glycol, polyethylene glycol, hydrogenated vegetable oil, cetyl alcohol, cetylstearyl alcohol, fatty acids, glycerides and triglycerides, polyoxyethylene glycols, butyl lactate, ethyl glycolate, ethyl lactate, sorbitol lactate, 1,2-butylene glycol, block polymers, and combinations thereof.

4. The flexible, compressed intravaginal ring of claim 1, wherein the polymethacrylate and the plasticizer are present in a ratio of about 1:

1 to about 9;

1 by weight.

5. The flexible, compressed intravaginal ring of claim 4, wherein the polymethacrylate and the plasticizer are present in a ratio of about 2:

1 to about 7;

1 by weight.

6. The flexible, compressed intravaginal ring of claim 4, wherein the polymethacrylate and the plasticizer are present in a ratio of about 3:

1 to about 6;

1 by weight.

7. The flexible, compressed intravaginal ring of claim 4, wherein the polymethacrylate and the plasticizer are present in a ratio of about 3:

1 to about 5;

1 by weight.

8. The flexible, compressed intravaginal ring of claim 4, wherein the polymethacrylate and the plasticizer are present in a ratio of about 4:

1 by weight.

9. The flexible, compressed intravaginal ring of claim 1, wherein the thickener is selected from the group consisting of:

fumed silica, colloidal silica, calcium silicate, gelatinized starch, microcrystalline cellulose, talc, magnesium stearate, and combinations thereof.

10. The flexible, compressed intravaginal ring of claim 1, wherein the active agent is selected from the group consisting of:

a prostaglandin, a urinary incontinence agent, an analgesic, an anti-inflammatory agent, a hormonal agent, an anti-microbial, an anesthetic, an anti-osteoporosis agent, a peptide hormone, an enzyme, and combinations thereof.

11. The flexible, compressed intravaginal ring of claim 1, further comprising a pharmaceutically acceptable excipient selected from the group consisting of:

a diluent, a binder, a lubricant, an antioxidant, and combinations thereof.

13. A therapeutic kit comprising:

(a) the flexible, compressed intravaginal ring of claim 1; and

(b) instructions for administering the flexible, compressed intravaginal ring to a female subject.

12. A method of providing an active agent to a subject, the method comprising vaginally administering a flexible, compressed intravaginal ring to the subject, wherein the flexible, compressed intravaginal ring comprises a substantially homogeneous compressed mixture comprising a polymethacrylate, a plasticizer, a thickener, and an active agent wherein the thickener is present in a concentration of about 2% to about 20% by weight of the flexible, compressed intravaginal ring, and wherein the polymethacrylate has a glass transition temperature of about 10°

C. to about 50°

C.

14. A process for preparing a flexible, compressed intravaginal ring, the process comprising:

mixing a polymethacrylate having a glass transition temperature, a plasticizer, a thickener, and an active agent at a temperature above the glass transition temperature of the polymethacrylate to form a substantially homogeneous mixture; and

compressing the substantially homogeneous mixture at a temperature below the glass transition temperature of the mixture to form a flexible, compressed intravaginal ring wherein the thickener is present in a concentration of about 2% to about 20% by weight of the flexible, compressed intravaginal ring, and wherein the polymethacrylate has a glass transition temperature of about 10°

C. to about 50°

C.

15. The process of claim 14, further comprising cooling the substantially homogeneous mixture to a temperature below the glass transition temperature of the mixture.

16. The process of claim 14, further comprising curing the flexible, compressed intravaginal ring.

17. The process of claim 14, wherein curing comprises heating the flexible, compressed intravaginal ring to a temperature above the glass transition temperature of the mixture.

18. The process of claim 14, wherein the polymethacrylate is selected from the group consisting of:

poly(n-butyl)methacrylate, poly(isopropyl) methacrylate, poly(ethyl)methacrylate, poly(butyl)methacrylate, poly(propyl) methacrylate, poly(hexyl)methacrylate, and combinations thereof.

19. The process of claim 14, wherein the plasticizer is selected from the group consisting of:

dibutyl sebacate, triethyl citrate, castor oil, triacetin, propylene glycol, polyethylene glycol, hydrogenated vegetable oil, cetyl alcohol, cetylstearyl alcohol, fatty acids, glycerides and triglycerides, polyoxyethylene glycols, butyl lactate, ethyl glycolate, ethyl lactate, sorbitol lactate, 1,2-butylene glycol, block polymers, and mixtures thereof.

20. The process of claim 14, wherein the thickener is selected from the group consisting of:

fumed silica, colloidal silica, calcium silicate, gelatinized starch, microcrystalline cellulose, talc, magnesium stearate, and combinations thereof.

21. The process of claim 14, wherein the active agent is selected from the group consisting of:

a prostaglandin, a urinary incontinence agent, an analgesic, an anti-inflammatory agent, a hormonal agent, an anti-microbial, an anesthetic, an anti-osteoporosis agent, a peptide hormone, an enzyme, and combinations thereof.

22. The process of claim 14, wherein the compressing comprises:

providing a compression tooling apparatus comprising a die, an upper punch, a lower punch and a core rod;

discharging the substantially homogeneous mixture into the die;

compressing the mixture between the upper punch and the lower punch to form the flexible, compressed intravaginal ring;

separating the upper and lower punches after compressing; and

ejecting the flexible, compressed intravaginal ring from the die.

23. The process of claim 22, wherein the lower punch has a cylindrical bore and the core rod is inserted in the cylindrical bore and adjusted to a desired position.

24. The process of claim 23, wherein the cylindrical bore and the core rod have threads for adjusting the core rod to a desired position.

25. The process of claim 24, wherein the upper punch has a cavity and during the compression the core rod enters into the cavity of the upper punch.

26. The process of claim 25, wherein the die has a cavity and a diameter of the cavity controls a size of an outer diameter of the flexible, compressed intravaginal ring.

27. The process of claim 26, wherein the core rod has a diameter and the diameter of the core rod controls a size of an inner diameter of the flexible, compressed intravaginal ring.

28. A product prepared by the process of claim 14.