Controlled release subcutaneous implant

• US 5,035,891 A
• Filed: 08/24/1989
• Issued: 07/30/1991
• Est. Priority Date: 10/05/1987
• Status: Expired due to Fees

• Current Assignee: Syntec Incorporated (Atos SE)
• Original Assignee: Syntec Incorporated (Atos SE)
• Inventors: Lee, Jung-Chung, Runkel, Richard A.
• Primary Examiner(s): Page, Thurman
• Assistant Examiner(s): Piccone, Louis A.
• Application Number:
  US07/398,106
• Time in Patent Office: 705 Days
• Field of Search: 424/473, 424/422, 424/423, 424/438
• US Class Current: 424/423
• CPC Class Codes: A61K 31/565 not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
• CPC Class Codes: A61K 9/0004 Osmotic delivery systems; Sustained release driven by osmosis, thermal energy or gas
• CPC Class Codes: A61K 9/0024 Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue compositions for intravenous administration, normal injectable solutions or dispersions for, e.g. subcutaneous administration A61K9/0019; brain implants A61K9/0085; (coated) prostheses, catheters or stents A61L
• CPC Class Codes: A61K 9/0092 Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/1641 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers

Abstract

A sustained release, reservoir-type subcutaneous implant device for the sustained administration to a subject of a biologically active compound comprises:

an effective amount of a biologically active compound;

an amount of a solid hydrophilic polymer sufficient to cause swelling of the device by osmotic pressure after implantation;

an effective amount of a solubilizing agent; and

a sufficient amount of a non-porous rate-controlling membrane which completely encapsulates said biologically active compound, wherein said rate-controlling membrane is permeable to said biologically active compound, but is impermeable to said solubilizing agent. This device is particularly advantageous for the administration of growth promoting compounds to livestock.

Claims

1. A reservoir device for the sustained administration of a steroid hormone useful for promoting weight gain in livestock, suitable for subcutaneous implantation, which device comprises:

a) a pellet or plurality of pellets, wherein each pellet comprises

1) a steroid hormone in a livestock weight gain-promoting amount,

2) a solid hydrophilic polymer in an amount sufficient to cause swelling of said device by osmotic pressure, and

3) a solubilizing agent in an amount sufficient to maintain an effective concentration of said steroid hormone in solution within said device, wherein said solubilizing agent is an ionic surfactant having an aliphatic chain of 8 to 22 carbon atoms; and

b) a sufficient amount of a non-porous, rate-controlling membrane which completely encapsulates said pellet or said plurality of pellets, wherein;

1) said membrane is prepared from a material that is selected from the group consisting of an aliphatic polyurethane, an aromatic polyurethane, a silicone rubber, a polyethylene-vinyl acetate copolymer, and a polystyrene-butadiene copolymer; and

2) said membrane is permeable to water and to said steroid hormone, but is impermeable to said solubilizing agent and said hydrophilic polymer.

2. The device of claim 1 wherein said steroid hormone comprises an estrogen derivative in combination with a progestogen, an androgen, or a combination thereof.

3. The device of claim 2 wherein said estrogen derivative is estradiol or an ester thereof.

4. The device of claim 3 wherein said steroid hormone comprises estradiol benzoate and progesterone.

5. The device of claim 3 wherein said steroid hormone comprises estradiol benzoate and testosterone or testosterone propionate.

6. The device of claim 3 wherein said steroid hormone comprises estradiol benzoate and trenbolone or trenbolone acetate.

7. The device of claim 3 wherein said steroid hormone comprises estradiol benzoate, progesterone, and trenbolone acetate.

8. The device of claim 3 wherein said steroid hormone comprises estradiol benzoate, testosterone propionate, and trenbolone acetate.

9. The device of claim 1 wherein said solubilizing agent is selected from the group consisting of cetyl pyridinium chloride, cetyl trimethylammonium bromide, cetyl trimethylammonium tosylate, and sodium lauryl sulfate.

10. The device of claim 9 wherein said solubilizing agent is sodium lauryl sulfate.

11. The device of claim 10 wherein the sodium lauryl sulfate is present at a concentration between 0.001% and 10%.

12. The device of claim 11 wherein the sodium lauryl sulfate concentration is about 0.01% to 2.5%.

13. The device of claim 1 wherein said hydrophilic polymer is selected from the group consisting of polyvinylpyrrolidone, starch, gelatin, methyl cellulose, sodium carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, and polyethylene glycol having a molecular weight between about 2000 and 20,000.

14. The device of claim 13 wherein said hydrophilic polymer is a polyethylene glycol having a molecular weight of about 8000.

15. The device of claim 14 wherein said polyethylene glycol is present at a concentration of about 0.01% to 40%.

16. The device of claim 1 wherein said membrane is an aliphatic polyurethane.

17. The device of claim 16 wherein said aliphatic polyurethane is synthesized from methylene bis(cyclohexyl) diisocyanate, poly(tetramethylene ether glycol), and a 1,4-butanediol chain extender and has the following structure:

##STR2##

18. The device of claim 17 wherein said membrane is between about 0.05 and about 1 mm in thickness.

19. The device of claim 18 wherein said membrane has a surface area between about 1 and about 10 cm².

20. The device of claim 1 wherein said pellet or plurality of pellets comprises:

about 20-1,000 mg of progesterone, testosterone propionate, trenbolone, or trenbolone acetate;

about 2-100 mg of estradiol benzoate;

about 4-400 mg of a polyethylene glycol having a molecular weight of about 8000; and

about 0.2-10 mg of sodium lauryl sulfate; and

wherein said membrane has a surface area between about 1 and 10 cm², a thickness between about 0.05 and about 1 mm, and is prepared from an aliphatic polyurethane which is synthesized from methylene bis(cyclohexyl) diisocyanate, poly(tetramethylene ether glycol), and a 1,4-butanediol chain extender and has the following structure;

##STR3##

21. The device of claim 20 wherein said pellet or plurality of pellets comprises:

about 200 mg of progesterone;

about 20 mg of estradiol benzoate;

about 44 mg of a polyethylene glycol having a molecular weight of about 8000; and

about 5.2 mg of sodium lauryl sulfate.

22. The device of claim 20 wherein said pellet or plurality of pellets comprises:

about 200 mg of testosterone propionate;

about 20 mg of estradiol benzoate;

about 44 mg of a polyethylene glycol having a molecular weight of about 8000; and

about 5.2 mg of sodium lauryl sulfate.

23. The device of claim 20 wherein said pellet or plurality of pellets comprises:

about 200 mg of trenbolone acetate;

about 20 mg of estradiol benzoate;

about 44 mg of a polyethylene glycol having a molecular weight of about 8000; and

about 5.2 mg of sodium lauryl sulfate.

24. The device of claim 20 wherein said pellet or plurality of pellets comprises:

about 200 mg of trenbolone or trenbolone acetate;

about 200 mg of progesterone;

about 20 mg of estradiol benzoate;

about 64 mg of a polyethylene glycol having a molecular weight of about 8000; and

about 5.2 mg of sodium lauryl sulfate.

25. The device of claim 20 wherein said pellet or plurality of pellets comprises:

about 200 mg of trenbolone or trenbolone acetate;

about 200 mg of testosterone propionate;

about 20 mg of estradiol benzoate;

about 64 mg of a polyethylene glycol having a molecular weight of about 8000; and

about 5.2 mg of sodium lauryl sulfate.

26. The device of claim 1 which further comprises an antibiotic present in an amount sufficient to prevent infection associated with implantation of said device, wherein said antibiotic is selected from the group consisting of oxytetracycline, oxytetracycline.HCL and gentimycin.

27. The device of claim 26 wherein said antibiotic is present on the outer surface of said membrane.

28. A method for promoting weight gain and increasing feed efficiency in livestock, which method comprises:

subcutaneously administering a reservoir device which device comprises;

a) a pellet or plurality of pellets, wherein each pellet comprises;

1) a steroid hormone in a livestock weight gain-promoting amount,

2) a solid hydrophilic polymer in an amount sufficient to cause swelling of said device by osmotic pressure, and

3) a solubilizing agent in an amount sufficient to maintain an effective concentration of said steroid hormone in solution within said device, wherein said solubilizing agent is an ionic surfactant having an aliphatic chain of 8 to 22 carbon atoms; and

b) a sufficient amount of a non-porous, rate-controlling membrane which completely encapsulates said pellet or said plurality of pellets, wherein;

1) said membrane is prepared from a material that is selected from the group consisting of an aliphatic polyurethane, an aromatic polyurethane, a silicone rubber, a polyethylene-vinyl acetate copolymer, and a polystyrene-butadiene copolymer; and

2) said membrane is permeable to water and to said steroid hormone, but is impermeable to said solubilizing agent and said hydrophilic polymer.

29. The method of claim 28 wherein said pellet or plurality of pellets comprises:

20-1,000 mg of progesterone, testosterone, testosterone propionate, trenbolone, or trenbolone acetate;

2-100 mg of estradiol benzoate;

4-400 mg of a polyethylene glycol having a molecular weight of about 8000; and

0.2-10 mg of sodium lauryl sulfate; and

wherein said membrane has a surface area between about 1 and 10 cm², a thickness between about 0.05 and about 1 mm, and is prepared from an aliphatic polyurethane which is synthesized from methylene bis(cyclohexyl) diisocyanate, poly(tetramethylene ether glycol), and a 1,4-butanediol chain extender and has the following structure;

##STR4##