Process for the preparation of a controlled release system

• US 6,303,148 B1
• Filed: 08/17/1999
• Issued: 10/16/2001
• Est. Priority Date: 11/19/1996
• Status: Expired due to Term

• Current Assignee: Octoplus BV
• Original Assignee: Octoplus BV
• Inventors: Hennink, Wilhelmus Everhardus, Franssen, Okke
• Primary Examiner(s): Page, Thurman K.
• Assistant Examiner(s): TRAN, SUSAN T
• Application Number:
  US09/308,349
• Time in Patent Office: 791 Days
• Field of Search: 424/423, 424/489, 424/490, 424/496, 424/497
• US Class Current: 424/489
• CPC Class Codes: A61K 9/1652 Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin homeopathic globules A61K9/1623
• CPC Class Codes: A61K 9/1664 Compounds of unknown constitution, e.g. material from plants or animals oils, fats, waxes, shellac A61K9/1617
• CPC Class Codes: A61K 9/1694 resulting in granules or microspheres of the matrix type containing more than 5% of excipient
• CPC Class Codes: Y10S 977/906 Drug delivery

Abstract

A process for the preparation of a controlled release system, comprising forming of an aqueous two-phase system form at least two water soluble polymers which are incompatible in solution, at least one of these polymers being cross-linkable, the cross-linkable polymer phase being emulsified in the other polymer phase; adding at least one relesable compound which is soluble in the cross-linked polymer phase in the aqueous solution, allowing the releasable compound to diffuse in the cross linkable polymer phase; cross-linking the cross-linkable polymer before or after the releasable compound is added, preferably to a degree that the pores in the cross-liked structure are substantially smaller than the particle size of the releasable compound; and separating the cross-linked structures enclosing the release able compound from the other phase. Further, the invention relates to microspheres, at least 80 wt. % thereof having a particle size of between 100 nanometers and 1000 um, which microspheres are comprised of a degradable, cross-linked polymer encapsulating at least one releasable compound, the pore size of the cross-linked polymer being smaller than the particle size of the releasable compound.

Claims

1. A method to produce degradable microspheres which effect controlled release of a desired releasable therapeutic substance when in contact with an animal body which method comprises

(a) providing a ternary two phase system of

(1) a first water-soluble polymer which is crosslinkable and which, when crosslinked, can be degraded when in contact with an animal body;

(2) a second water-soluble polymer, and

(3) water,

wherein said ternary system is characterized by a phase diagram and wherein said ternary system forms one phase when composition of the ternary system is below the binodal in said phase diagram and forms two phases when the composition of the ternary system is above the binodal in said phase diagram, and wherein the composition of said ternary two phase system provided is above said binodal and is capable of forming a continuous phase and a discontinuous phase;

(b) forming a continuous and discontinuous phase, wherein said first, crosslinkable, polymer which, when crosslinked, can be degraded when in contact with an animal body is the discontinuous phase in said two-phase system and the second polymer is the continuous phase in said two-phase system, said two phase system having been obtained by adjusting the amounts of water, first polymer and second polymer so as to place the system above the binodal, and

wherein a releasable therapeutic substance is present in said two-phase system,

(c) crosslinking said first polymer to form solid degradable microspheres, wherein the degree of crosslinking and water content are adjusted so as to result in pore sizes in said microspheres which are equal to or less than the hydrodynamic diameter of the releasable therapeutic substance, said pores thus entrapping said releasable therapeutic substance, and

(d) separating the continuous phase from the discontinuous phase to recover the microspheres,

thus obtaining microspheres which exhibit controlled release of the releasable therapeutic substance when in contact with animal body by effecting expansion of the pores through degradation of said crosslinked first polymer in the animal body.

2. The method of claim 1 wherein the therapeutic substance is a proteinaceous drug, a gene, or a pharmacon.

3. The method of claim 1 wherein said first, crosslinkable polymer, when crosslinked, can be degraded when in contact with the animal body by virtue of comprising bonds that are hydrolyzable under physiological conditions, and said degradation of the crosslinked polymer occurs through hydrolyzing said bonds.

4. The method of claim 1 wherein said first, crosslinkable polymer, when crosslinked, can be degraded by virtue of including, in said microspheres, at least one enzyme which degrades said polymer, and wherein said degradation of crosslinked polymer occurs through action of said enzyme on said polymer.

5. The method of claim 1 wherein the first, crosslinkable polymer is selected from the group consisting of dextran, derivatized dextran, starch, starch derivatives, cellulose derivatives, proteins and derivatized proteins.

6. The method of claim 4 wherein said first, crosslinkable polymer is a dextran or derivatized dextran and the enzyme which degrades that polymer is dextranase.

7. The method of claim 1 wherein the second polymer is polyethylene glycol.

8. The method of claim 1 wherein said crosslinking is formed by crosslinking methacrylate or a methacrylate derivative or by using isocyanate or through poly-N-isopropyl acrylamide.

9. The method of claim 1 wherein step (d) is performed by filtration or centrifugation.

10. Microspheres, at least 80% weight percent thereof having a particle size of between 100 nm and 100 μ

m, which microspheres are free of organic solvent, and comprise a degradable, crosslinked polymer encapsulating at least one releasable therapeutic substance, the pore size of the crosslinked polymer being equal to the less than the hydrodynamic diameter of the releasable therapeutic substance, wherein said microspheres effect controlled release of said releasable therapeutic substance when in contact with an animal body.

11. The microspheres of claim 10 wherein 80% of said microspheres have a particle size between 5 and 15 μ

m.

12. The microspheres of claim 10 wherein said degradable crosslinked polymer can be degraded when in contact with the animal body by virtue of comprising bonds that are hydrolyzable under physiological conditions.

13. The microspheres of claim 10 which further include an enzyme which degrades said degradable, crosslinked polymer.

14. The microspheres of claim 10 wherein said degradable, crosslinked polymer is selected from the group consisting of dextran, derivatized dextran, starch, starch derivatives, cellulose derivatives, proteins and derivatized proteins.

15. The microspheres of claim 10 wherein said crosslinked polymer is crosslinked by crosslinking methacrylate or a methraylate derivative, or by using isocyanate, or through poly-N-isopropyl acrylamide.

16. The microspheres of claim 13 where said crosslinked polymer is dextran or derivatized dextran and said enzyme is dextranase.

17. The microspheres of claim 10 wherein the therapeutic substance is an proteinaceous drug, a gene, or a pharmacon.