Microencapsulation and sustained release of oligonucleotides

• US 6,555,525 B2
• Filed: 03/29/2001
• Issued: 04/29/2003
• Est. Priority Date: 08/31/1995
• Status: Expired due to Fees

• Current Assignee: Alkermes Controlled Therapeutics Inc. II (Alkermes plc)
• Original Assignee: Alkermes Controlled Therapeutics Inc. II (Alkermes plc)
• Inventors: Burke, Paul A.
• Primary Examiner(s): McGarry, Sean
• Application Number:
  US09/820,587
• Publication Number:
  US 20020064557A1
• Time in Patent Office: 761 Days
• Field of Search: 514/44, 435/6, 435/91.1, 536/455, 536/24.1, 536/24.5, 424/484, 424/486, 424/487, 424/488, 424/489
• US Class Current: 514/44.00A
• CPC Class Codes: A61K 9/1647 Polyesters, e.g. poly(lactide-co-glycolide)
• CPC Class Codes: B82Y 5/00 Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery

Abstract

This invention relates to a composition, and method of forming and using the composition, for the sustained release of oligonucleotides, in particular antisense ODNs. The sustained release composition of this invention comprises a polymer matrix of a biocompatible polymer and stabilized oligonucleotide, wherein the stabilized oligonucleotide is dispersed within the biocompatible polymer.

The method of the invention, for forming a composition for the sustained release of oligonucleotide, in particular an antisense ODN, includes dissolving a polymer in a polymer solvent to form a polymer solution, dispersing stabilized oligonucleotide in the polymer solution, and then solidifying the polymer to form a polymeric matrix containing a dispersion of the stabilized oligonucleotide.

The method of using the sustained release composition of the present invention comprises providing a therapeutically effective blood level of oligonucleotide in a subject for a sustained period by administering to the subject a dose of the sustained release composition described herein.

Claims

1. A composition for the sustained release of an oligonucleotide from a polymer matrix, comprising:

a) a biocompatible polymer; and

b) a therapeutically effective amount of oligonucleotide which is complexed with a metal cation, wherein said oligonucleotide is dispersed within the biocompatible polymer.

2. The sustained release composition of claim 1 wherein the metal cation-complexed oligonucleotide is in the form of particles.

3. The sustained release composition of claim 1 wherein the biocompatible polymer is selected from the group consisting of poly(lactides), poly(glycolides), poly(lactide-co-glycolides), poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, polycaprolactone, polycarbonates, polyesteramides, polyanhydrides, poly(amino acids), polyorthoesters, polycyanoacrylates, poly(p-dioxanone), poly(alkylene oxalate)s, biodegradable polyurethanes, blends and copolymers thereof.

4. The sustained release composition of claim 3 wherein said polymer comprises poly(lactide-co-glycolide).

5. The sustained release composition of claim 1 wherein the metal cation of the metal cation-complexed oligonucleotide is multivalent.

6. The sustained release composition of claim 5 wherein the multivalent metal cation comprises a cation selected from the group consisting of:

Zn⁺², Ca<sup>−

2</sup>, Cu⁺², Mg⁺² and any combination thereof.

7. The sustained release composition of claim 6 wherein the metal cation is Zn⁺².

8. The sustained release composition of claim 1 wherein the oligonucleotide is present from about 0.01% (w/w) to about 50% (w/w) based on the dry weight of the composition and the weight of the oligonucleotide prior to stabilization.

9. A method for providing a therapeutically effective amount of an oligonucleotide in a subject for a sustained period comprising administering to the subject a dose of the sustained release composition of claim 1.

10. A method for forming a composition for the sustained release of an oligonucleotide, comprising the steps of:

a) dissolving a biocompatible polymer in a polymer solvent to form a polymer solution;

b) adding a therapeutically effective amount of oligonucleotide which is complexed with a metal cation, to the polymer solution; and

c) solidifying the polymer to form a polymer matrix containing a dispersion of said oligonucleotide.

11. The method of claim 10 wherein the biocompatible polymer is selected from the group consisting of poly(lactides), poly(glycolides), poly(lactide-co-glycolides), poly(lactic acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, polycaprolactone, polycarbonates, polyesteramides, polyanhydrides, poly(amino acids), polyorthoesters, polycyanoacrylates, poly(p-dioxanone), poly(alkylene oxalate)s, biodegradable polyurethanes, blends, and copolymers thereof.

12. The method of claim 11 wherein said polymer comprises poly(lactide-co-glycolide).

13. The method of claim 10 wherein the metal cation which is complexed to the oligonucleotide is a multivalent metal cation.

14. The method of claim 13 wherein the multivalent metal cation is selected from the group consisting of:

Zn⁺², Ca<sup>−

2</sup>, Cu⁺², Mg⁺², and any combination thereof.

15. The method of claim 14 wherein the metal cation is Zn⁺².