US4933185A
Expired / Lapsed
US
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System for controlled release of biologically active compounds
Assignee: Massachusetts Institute of Technology
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Filing: 1988-07-11
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Granted: 1990-06-12
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Expires: 2008-07-11
Abstract
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.
Inventors
- 👤 Margaret A. Wheatley
- 👤 Robert S. Langer
- 👤 Herman N. Eisen
Bibliographic Details
Application Number
—
Jurisdiction
US
Data Source
google_patents
Last Synchronized
2026-10-23 13:15
CPC Classifications
A; A61; A61K; A61K9/00; A61K9/14; A61K9/16; A61K9/1605; A61K9/1664; A61K9/1629; A61K9/1652; A61K9/48; A61K9/50; A61K9/5005; A61K9/5021; A61K9/5031; Y; Y10; Y10T; Y10T428/00; Y10T428/29; Y10T428/2982; Y10T428/2984; Y10T428/2985
Claims Analysis
Total Claims: 28
Claim 1
Independent Claim
81 words
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.
Claim 2
Independent Claim
81 words
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.
Claim 3
Dependent Claim
10 words
The system of claim 1 further comprising non-encapsulated biologically-active substance.
Claim 4
Dependent Claim
13 words
The system of claim 1 wherein said enzyme is modified to be non-immunogenic.
Claim 5
Dependent Claim
14 words
The system of claim 1 wherein the molecular weight of said enzyme is altered.
Claim 6
Dependent Claim
47 words
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.
Claim 7
Dependent Claim
28 words
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.
Claim 8
Dependent Claim
35 words
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.
Claim 9
Dependent Claim
18 words
The system of claim 1 comprising microcapsules of different size, said capsules catastrophically breaking down at different times.
Claim 10
Dependent Claim
21 words
The system of claim 8 comprising microcapsules with increased permeability to allow continuous passage of biologically-active substance out of said microcapsule.
Claim 11
Dependent Claim
11 words
The system of claim 1 comprising more than one biologically-active substance.
Claim 12
Independent Claim
90 words
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.
Claim 13
Independent Claim
90 words
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.
Claim 14
Dependent Claim
22 words
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.
Claim 15
Dependent Claim
23 words
The method of claim 11 further comprising selecting the biologically-active substance from the group consisting of proteins, nucleic acids, viruses, and inorganic compounds.
Claim 16
Dependent Claim
17 words
The method of claim 11 further comprising selecting an enzyme which does not provoke an immune response.
Claim 17
Dependent Claim
16 words
The method of claim 11 further comprising selecting an enzyme modified to increase its molecular weight.
Claim 18
Dependent Claim
28 words
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.
Claim 19
Dependent Claim
22 words
The method of claim 11 further comprising selecting the polysaccharide from the group consisting of alginate, chitin, pectin, gums, and combinations thereof.
Claim 20
Dependent Claim
30 words
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.
Claim 21
Dependent Claim
54 words
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.
Claim 22
Dependent Claim
35 words
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.
Claim 23
Dependent Claim
28 words
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.
Claim 24
Independent Claim
66 words
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.
Claim 25
Independent Claim
66 words
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.
Claim 26
Dependent Claim
13 words
The method of claim 22 comprising selecting an enzyme modified to be non-immunogenic.
Claim 27
Dependent Claim
19 words
The method of claim 22 further comprising selecting an enzyme that has been modified to increase its molecular weight.
Claim 28
Dependent Claim
19 words
The method of claim 22 further comprising injecting unencapsulated antigen with said microcapsule into said animal to be immunized.
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USPTO Annuity & Maintenance Windows
| Annuity Stage | Window Opens | Payment Deadline | Surcharge Period Until | Estimated Fee | Status |
|---|---|---|---|---|---|
| 3.5 Years (Year 4) | 1993-06-11 | 1993-12-11 | 1994-06-12 | $2000.00 | Window Closed / Lapsed |
| 7.5 Years (Year 8) | 1997-06-11 | 1997-12-11 | 1998-06-12 | $3760.00 | Window Closed / Lapsed |
| 11.5 Years (Year 12) | 2001-06-11 | 2001-12-11 | 2002-06-12 | $7700.00 | Window Closed / Lapsed |