# US 10,369,106 B2 · Efficient aqueous encapsulation and controlled release of bioactive agents

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- Number: US 10,369,106 B2
- Document ID: US10369106B2
- Status: Granted
- Kind: B2
- Application number: 14/537,716
- Filed: 2014-11-10
- Published: 2015-06-18
- Granted: 2019-08-06
- Earliest claimed: 2013-11-08
- Assignees: The Regents of the University of Michigan
- Applicants: The Regents of The University of Michigan
- Inventors: Steven P. Schwendeman; Ronak B. Shah; Morgan B. Giles; Rae Sung Chang; Anna A. Schwendeman
- Web page: https://patentgrep.com/patent/US10369106B2

## CPC

- A61K 9/1652: {Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin (homeopathic globules A61K9/1623)}
- A61K 9/1611: {Inorganic compounds}
- A61K 9/1623: {Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules}
- A61K 9/1647: {Polyesters, e.g. poly(lactide-co-glycolide)}
- A61K 9/1694: {resulting in granules or microspheres of the matrix type containing more than 5% of excipient}
- A61K 38/1825: {Fibroblast growth factor [FGF]}
- A61K 38/1866: {Vascular endothelial growth factor [VEGF]}
- A61K 38/2264: {Obesity-gene products, e.g. leptin}
- A61K 38/47: acting on glycosyl compounds (3.2), e.g. cellulases, lactases
- C12Y 302/01017: Lysozyme (3.2.1.17)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- C12Y: ENZYMES

## Abstract

A drug delivery system comprises a porous, self-healing biodegradable polymer matrix having a ionic, charged, biopolymer and a pH modifying species disposed within the pores. An ionic macromolecule having the opposite charge binds the biopolymer and forms a nonsoluble polyelectrolyte complex. The molecular weight of the biopolymer, the self healing polymer matrix, the concentration of pore forming agent and the concentration of the pH modifying species are selected for optimal binding and release of the macromolecule.

## Claims

### Claim 1

A porous self-healing polymer matrix suitable for encapsulation of an active macromolecules selected from net positively charged peptides and net positively charged proteins, wherein the matrix comprises a biodegradable polymer and has pores and wherein:
a biopolymer is disposed within the pores; and
a pH modifying species is disposed within the pores;
wherein the biopolymer comprises a dextran sulfate and is present at a level of greater than 0.5% and below 10% by weight based on the weight of the biodegradable polymer, and
wherein the pH modifying species comprises magnesium carbonate and is present at a level of 1% to 7% by weight based on the weight of the biodegradable polymer.

### Claim 2 (depends on 1)

The porous self-healing polymer matrix of claim 1 wherein the biodegradable polymer is selected from poly(lactides), poly(glycolides), poly(lactide-co-glycolides), poly(lactic-acid)s, poly(glycolic acid)s, poly(lactic acid-co-glycolic acid)s, poly(hydroxymethyl glycolide-co-lactide), polycaprolactone, polycarbonates, polyesteramides, polyanhydrides, poly(amino acids), polyorthoesters, polycyanoacrylates, poly(p-dioxanone), poly(alkylene oxalate)s, and polyurethanes.

### Claim 3 (depends on 2)

The porous self-healing polymer matrix of claim 2 wherein the self-healing biodegradable polymer comprises poly(lactic-co-glycolic acid).

### Claim 4 (depends on 1)

The porous self-healing polymer matrix of claim 1, wherein the porous self-healing polymer matrix is capable of sorbing at least 3.0% by weight of an active macromolecule, based on the final weight of the polymer matrix, from an active macromolecule loading solution having a concentration of 1 mg/mL.

### Claim 5 (depends on 1)

The porous self-healing polymer matrix of claim 1, further comprising the active macromolecule encapsulated within the self-healing polymer matrix.

### Claim 6 (depends on 1)

A method of using a porous self-healing polymer matrix for making a drug delivery system for an active macromolecule selected from net positively charged peptides and net positively charged proteins, the method comprising:
loading the macromolecule into the porous self-healing polymer matrix according to claim 1 by incubating the self-healing polymer matrix in an aqueous solution of the macromolecule, wherein the matrix has pores connected to an outer surface of the matrix; and
closing the pores and encapsulating the macromolecule.

### Claim 7 (depends on 6)

The method of claim 6 wherein the dextran sulfate forms a non-soluble polyelectrolyte complex with the macromolecule to be delivered.

### Claim 8 (depends on 7)

The method of claim 7 wherein the non-soluble polyelectrolyte complex stabilizes the structure of the macromolecule agent during the encapsulation process, and prevents the active macromolecule from leaching out of the porous polymer matrix.

### Claim 9 (depends on 6)

The method of claim 6 wherein the loading of the active macromolecule is at least 3.0% w/w of the delivery system.

### Claim 10 (depends on 6)

The method of claim 6 wherein the encapsulation efficiency of the active macromolecule is at least 60%.