System for controlled release of biologically active compounds

• US 4,933,185 A
• Filed: 07/11/1988
• Issued: 06/12/1990
• Est. Priority Date: 09/24/1986
• Status: Expired due to Term

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Massachusetts Institute of Technology
• Inventors: Wheatley, Margaret A., Langer, Robert S., Eisen, Herman N.
• Primary Examiner(s): Lovering, Richard D.
• Application Number:
  US07/223,887
• Time in Patent Office: 701 Days
• Field of Search: 428/402.2, 428/402.21, 428/88, 428/94.3, 428/461, 428/469, 514/963
• US Class Current: 424/461
• 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 9/5031 obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
• CPC Class Codes: Y10T 428/2984 Microcapsule with fluid core [includes liposome]
• CPC Class Codes: Y10T 428/2985 Solid-walled microcapsule from synthetic polymer

Abstract

A controlled release system for delivery of a biologically-active substance. In one embodiment, there is a delayed release of a biologically-active substance. In a second embodiment, the delayed release is preceded by an initial release of biologically active substance. In other variations of the system, there are mulitple discrete releases over time or a continuous slow release combined with discrete releases. The delayed exposure is achieved through the design and construction of the system, specifically, formation of ionically-coated microcapsules around the biologically-active substance in conjunction with a microcapsule core-degrading enzyme. Release of active substance takes place in a burst at such a time as the core degrading enzyme has reduced the core to a molecular weight too low to support enough interaction with the cationic skin to maintain its integrity as a skin. In one example, microcapsules are formed of an ionically cross-linked polysaccharide, calcium alginate, which is further ionically coated with a poly-cationic skin of poly-L-lysine. The capsule coating serves a dual purpose: to control diffusion of the biologically-active substance and the core-degrading enzyme and as a substrate for the mechanism by which the biologically-active substance is released after a time delay.

Claims

1. A system for controlled release of a biologically-active substance comprising:

(a) microcapsules having an inner polysaccharide polymer core and an outer ionically interacting skin;

(b) a biologically-active substance; and

(c) an enzyme, said enzyme specifically degrading said core polysaccharide and not the ionically interacting skin;

wherein said biologically-active substance and said enzyme are encapsulated in said microcapsules, said enzyme degrading said core polysaccharide until the outer skin loses its integrity, the microcapsules completely break down and said biologically-active substance is released.

2. The system of claim 1 further comprising non-encapsulated biologically-active substance.

3. The system of claim 1 wherein said enzyme is modified to be non-immunogenic.

4. The system of claim 1 wherein the molecular weight of said enzyme is altered.

5. The system of claim 1 wherein the polysaccharide is selected from the group consisting of alginate, chitin, pectin, gums, and combinations thereof and the enzyme is selected from the group consisting of polysaccharidases, mucopolysaccharidases, lyases, hydrolases, alginase, chitinase, amylase, cellulase, pectinase, hyaluronidase, lysozyme, neuraminidase, and combinations thereof.

6. The system of claim 1 wherein the permeability of said microcapsules is increased to allow continuous passage at a controlled rate of biologically-active substance out of said microcapsules.

7. The system of claim 1 wherein the units of enzymatic activity within said microcapsule are calibrated to degrade said core polysaccharide over a specified time and said microcapsules contain different total units of enzymatic activity.

8. The system of claim 1 comprising microcapsules of different size, said capsules catastrophically breaking down at different times.

9. The system of claim 8 comprising microcapsules with increased permeability to allow continuous passage of biologically-active substance out of said microcapsule.

10. The system of claim 1 comprising more than one biologically-active substance.

11. A method for controlled release of a biologically-active substance comprising:

encapsulating the biologically-active substance and an enzyme within microcapsules, wherein said microcapsules are formed of an inner polysaccharide core and an outer ionically interacting skin, and said enzyme specifically degrades said polysaccharide core,

locating said microcapsules at the site where controlled release is to occur, and

reacting said encapsulated enzyme with said polysaccharide core to alter the integrity of said ionically interacting skin to completely break down the microcapsules and effect release of the biologically active substance from the microcapsules.

12. The method of claim 11 further comprising locating non-encapsulated biologically-active substance at the site for controlled release of said encapsulated biologically-active substance.

13. The method of claim 11 further comprising selecting the biologically-active substance from the group consisting of proteins, nucleic acids, viruses, and inorganic compounds.

14. The method of claim 11 further comprising selecting an enzyme which does not provoke an immune response.

15. The method of claim 11 further comprising selecting an enzyme modified to increase its molecular weight.

16. The method of claim 15 wherein the molecular weight of said enzyme is increased by cross linking of the enzyme itself or to other large molecular weight carriers.

17. The method of claim 11 further comprising selecting the polysaccharide from the group consisting of alginate, chitin, pectin, gums, and combinations thereof.

18. The method of claim 11 further comprising selecting the enzyme from the group consisting of polysaccharidases, mucopolysaccharidases, lyases, hydrolases, alginase, chitinase, amylase, cellulase, pectinase, hyaluronidase, lysozyme, neuraminidase, and combinations thereof.

19. The method of claim 11 wherein the biologically-active substance is encapsulated by dissolving a water-soluble polysaccharide gum in an aqueous solution containing the biologically-active substance and polysaccharide degrading enzyme to be encapsulated,

forming droplets of the dissolved gum,

cross-linking the polysaccharide gum, and

forming a semipermeable membrane about the surface of the cross-linked droplets.

20. The method of claim 19 wherein the semipermeable membrane is formed by contacting the polysaccharide gum with a solution selected from the group consisting of water-soluble polyamines, diamines, polyols, diols, glutaraldehyde, and multifunctional sulfonyl halides.

21. The method of claim 19 wherein the semipermeable membrane is formed by contacting droplets formed of a water-soluble gum containing acid groups with a solution of multivalent cations.

22. A method for immunizing an animal comprising:

encapsulating an antigen and an enzyme within microcapsules, wherein said microcapsules are formed of an inner core polysaccharide and an outer ionically interacting skin and said enzyme specifically degrades said core polysaccharide of the microcapsules to effect complete break down of the microcapsules and release of said encapsulated antigen, and injecting said microcapsules into the animal to be immunized.

23. The method of claim 22 comprising selecting an enzyme modified to be non-immunogenic.

24. The method of claim 22 further comprising selecting an enzyme that has been modified to increase its molecular weight.

25. The method of claim 22 further comprising injecting unencapsulated antigen with said microcapsule into said animal to be immunized.