Preparation of homogeneous hydrogel copolymers

• US 5,266,325 A
• Filed: 12/03/1990
• Issued: 11/30/1993
• Est. Priority Date: 09/28/1990
• Status: Expired due to Term

• Current Assignee: Endo Pharmaceuticals Solutions Incorporated (Endo International PLC)
• Original Assignee: Hydro Med Science Division of National Patent Development Corporation
• Inventors: Moro, Daniel G., Kuzma, Petr, Quandt, Harry
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): Bawa, Raj
• Application Number:
  US07/621,346
• Time in Patent Office: 1,093 Days
• Field of Search: 604/57, 604/59, 604/60, 604/64, 604/59, 424/473, 424/78, 424/464, 424/422, 424/423, 523/526, 264/310, 264/311, 264/255, 264/267
• US Class Current: 424/422
• CPC Class Codes: A61K 9/0092 Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes

Abstract

A method is provided for the preparation of homogeneous copolymers having aredetermined equilibrium water content (EWC) value formed by the addition polymerization of a mixture of ethylenically unsaturated monomer A and ethylenically unsaturated monomer B, for example, 2-hydroxyethyl methacrylate and hydroxypropyl methacrylate. The method requires determining the EWC values of the hydrogel homopolymer of hydrophilic monomer A (homopolymer A) and the hydrogel homopolymer of hydrophilic monomer B (homopolymer B); determining the relationship of the EWC values of the homogeneous copolymers AB versus the chemical composition of said copolymers AB; selecting the targeted EWC value and determining the chemical composition of copolymer AB having the targeted EWC value; forming a polymerizable mixture of monomer A and monomer B in amounts sufficient to yield copolymer AB having the targeted EWC value; and effect the polymerization reaction to yield copolymer AB characterized by the targeted EWC value. A method is also provided for the preparation of a delivery device including a drug contained in the reservoir of the hydrogel of copolymer AB, said device being characterized by its capability of eluting or releasing the drug through the hydrogel membrane to a delivery environment at a predetermined rate. There is also disclosed a sterilized kit containing a trocar or hypodermic needle/syringe and the aforesaid drug delivery device having a cylindrical shape with a rounded or bullet-like extremity.

Claims

1. A method for centrifugally casting a biocompatible copolymer having predetermined equilibrium water content (EWC) value formed by the addition polymerization of a mixture containing an ethylenically unsaturated hydrophilic monomer A and an ethylenically unsaturated hydrophilic monomer B copolymerizable therewith, said copolymer being useful as a hydrogen membrane in the diffusion therethrough of a selected active compound in an aqueous medium at a predetermined rate which comprises:

a. determining the EWC values of hydrogel homopolymer of monomer A (homopolymer A) and hydrogel homopolymer of monomer B (homopolymer B);

b. determining the relationship of the EWC values of the homogeneous hydrogel copolymers of mixtures of monomer A and monomer B (copolymers AB) versus the chemical composition of said copolymers AB;

c. selecting the targeted EWC value and determining the chemical composition of homogeneous copolymer AB having this targeted EWC value;

d. forming a polymerizable liquid mixture containing said monomer A and said monomer B in amounts sufficient to yield said homogeneous copolymer AB having the targeted EWC value;

e. filling a tube comprising a core of smooth uniform cylindrical surface and closure means to prevent loss of the mixture during rotation, with a predetermined quantity of the liquid mixture;

f. rotating the tube while maintaining a longitudinal axis of the tube parallel to the ground and effecting the rotation at a speed sufficient to cause radially outward displacement of the liquid monomers to assume a cylindrically-shaped liquid cartridge shape having a predetermined configuration within said tube;

g. subjecting the tube to polymerization conditions to convert said liquid state cartridge to a predetermined solid state hollow plastic cartridge; and

h. recovering a biocompatible, non-degradable, water-swellable, water-insoluble, homogeneous copolymer AB consisting essentially of monomer A units and monomer B units in the form of a cylindrical cartridge having walls of uniform thickness between its smooth external and internal cylindrical surfaces.

2. The method of claim 1 wherein said hydrophilic monomer A is 2-hydroxyethyl methacrylate, wherein said homogeneous copolymer AB consists essentially of from about 25 to 75 weight percent of 2-hydroxyethyl methacrylate units and from about 75 to 30 weight percent of monomer B units, and wherein the predetermined EWC value of the copolymer is in the range of about 25 weight % to about 75 weight %.

3. The method of claim 2 wherein said monomer B units are hydroxypropyl methacrylate units and wherein the predetermined EWC value of the copolymer is in the range of from about 26 to 33 weight %.

4. The method of claim 1 wherein said hydrophilic monomer A is 2-hydroxyethyl methacrylate, wherein said homogenous copolymer AB consists essentially of from about 25 to 70 weight percent of 2-hydroxyethyl methacrylate units and from about 75 to 30 weight percent of monomer B units, and wherein the predetermined EWC value of the copolymer is in the range of from about 25 weight % to about 75 weight %.

5. The method of claim 4 wherein said monomer B units are hydroxypropyl methacrylate units and wherein the predetermined EWC value of the copolymer is in the range of from about 26 to 33 weight %.

6. The method of claim 2 wherein said homogeneous copolymer AB is a xerogel.

7. The method of claim 2 wherein said homogeneous copolymer AB is a hydrogel.

8. The method for the preparation of a delivery device for the sustained release of an active agent therefrom which comprises:

a. introducing active agent, and optionally a pharmaceutically acceptable carrier, into a cylindrically-shaped reservoir of a biocompatible, non-biodegradable, water-swellable, water-insoluble, cylindricialy-shaped plastic cartridge formed of copolymer AB according to claim 2, in an amount sufficient to provide extended sustained release of the active agent;

b. introducing at least one polymerizable liquid monomer into the upper portion of said reservoir in an amount to completely fill the reservoir, said liquid monomer having an equilibrium water content value in its polymerized state which exceeds the equilibrium water content value of said plastic cartridge; and

c. polymerizing said monomer to effectively seal the opening of the reservoir with a plug of water-swellable, water-insoluble polymer to form a delivery device which give a predetermined release of the active agent.

9. The method of claim 8 wherein said plastic cartridge has a smooth, oval cylindrical shape.

10. The method of claim 8 wherein the outer portion of the delivery device distal to the plug of polymer is subjected to a shaping step to impart a smooth oval shape thereto.

11. The method of claim 8 wherein said active agent is a drug.

12. The method of claim 11 wherein said drug includes native and recombinant bioactive proteins.

13. The method of claim 11 wherein said drug is a hormonally active polypeptide.

14. The method of claim 11 wherein said drug is luteinizing hormone-releasing hormone polypeptide.

15. The method of claim 1 wherein said drug is a mammalian growth hormone or mammalian growth releasing hormone.

16. The method of claim 8 wherein said plastic cartridge is a xerogel.

17. The method of claim 8 wherein said plastic cartridge is a hydrogel.

18. The method of claim 2 wherein said polymerizable liquid mixture contains a water-soluble pore-forming agent.

19. As an article, a biocompatible, non-biodegradable, water-swellable, water-insoluble, hydrophilic cartridge of copolymer AB defining a reservoir or core and useful as a rate-limiting barrier in a drug delivery device capable of being implanted in an animal by perforation, said cartridge characterized by a oval cylindrical shape at its closed end, and an open end distal to the closed end, smooth unscored internal and external cylindrical surfaces, a uniform thickness between said surfaces, said copolymer AB consisting essentially of from about 25 to 70 weight % of 2-hydroxyethyl methacrylate (monomer A) units and from about 75 to 30 weight % of monomer B units, and possessing a predetermined EWC value in the range of from about 25 to about 75 weight %.

20. The article of claim 19 wherein said monomer B units are hydroxypropyl methacrylate units.

21. The article of claim 20 wherein the plastic cartridge is in the state of a xerogel.

22. The article of claim 20 wherein the plastic cartridge is in a state of hydrogel.

23. The article of claim 19 wherein the plastic cartridge is a polymer of 2-hydroxyethyl methacrylate.

24. The article of claim 23 wherein the internal cylindrical surface area proximal to the open end of the cartridge has been scored and treated with a mono- or polyhydric alcohol to enhance graft polymerization of polymerizable ethylenically unsaturated monomer thereto.

25. A delivery device for the sustained release of an active agent therefrom which comprises:

a. a biocompatible, non-biodegradable, water-swellable, water-insoluble, hydrophilic cartridge of copolymer AB defined in claim 19;

b. sealant means for closure of the open end of the cartridge comprising a plug of biocompatible, non-biodegradable, water-swellable, water-insoluble, hydrophilic polymer having an equilibrium water content value greater than that of the cartridge per se; and

c. an active agent contained in the reservoir of the cartridge in an amount sufficient to provide a predetermined sustained release thereof over an extended period of time.

26. The delivery device of claim 25 wherein said active agent is a drug.

27. The delivery device of claim 25 wherein said plastic cartridge and said sealant means are in the xerogel state.

28. The delivery device of claim 25 wherein said plastic cartridge and said sealant means are in the hydrogel state.

29. The delivery device of claim 25 wherein said active agent includes native and recombinant bioactive proteins.

30. The delivery device of claim 29 wherein said active agent is a hormonally active polypeptide.

31. The delivery device of claim 30 wherein said active agent is luteinizing hormone-releasing hormone polypeptide.

32. The delivery device of claim 25 wherein said active agent is a mammalian growth hormone or mammalian growth releasing hormone.

33. The delivery device of claim 31 wherein said delivery device contains a pharmaceutically acceptable carrier admixed with the active agent.

34. A method for the implantation of a small cylindrically-shaped delivery device into an animal for sustained release of an active agent therefrom which comprises:

a. perforating the skin of an animal at a preselected site with an instrument comprising a hollow needle and the delivery device of claim 25;

b. injecting said delivery device through said hollow needle and depositing it subcutaneously at the preselected site; and

c. withdrawing said needle from the animal.

35. The method of claim 34 wherein said active agent comprises native or recombinant bioactive proteins.

36. The method of claim 35 wherein said active agent is a luteinizing hormone-releasing hormone polypeptide.

37. The method of claim 36 wherein the delivery device comprises a cartridge in a xerogel state.

38. The method of claim 36 wherein the delivery device comprises a cartridge in a hydrated state.

39. A kit useful for the implantation by perforation of a drug delivery device in an animal for sustained release of a drug therefrom comprising:

a. the drug delivery device of claim 25;

b. delivery means to eject said drug delivery device to the delivery environment of an animal; and

c. container means to house said delivery device and said delivery means in a sterilized aqueous environment.

40. The kit of claim 39 wherein said delivery means comprises a small rigid hollow tube of uniform internal diameter having a needle-shaped opening at one end thereof, and a telescoping solid rigid rod slidably communicating with the internal surface of said tube, and wherein said drug delivery device positioned within said tube in proximity with one end of the rod for slidable ejection from said tube.