# US 5,484,894 A · Macromolecular microparticles and method of production

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- Number: US 5,484,894 A
- Document ID: US5484894A
- Status: Granted
- Kind: A
- Application number: 08/206,456
- Filed: 1994-03-04
- Granted: 1996-01-16
- Earliest claimed: 1993-03-09
- Assignees: Middlesex Sciences, Inc.
- Inventors: James E. Woiszwillo
- Web page: https://patentgrep.com/patent/US5484894A

## Abstract

A macromolecular microparticle composition formed by dehydrating an aqueous macromolecule solution and crosslinking the dehydrated macromolecules with a crosslinking agent while in a liquid phase or with heat. Preferably, the dehydrating agent is a polymer mixture of polyvinylpyrrolidone and polyethylene glycol, the crosslinking reagent is glutaraldehyde, and the macromolecule is a protein, most preferably an immunoglobulin. Methods of use for research, diagnostics and therapeutics are also provided.

## Claims

### Claim 1

A method for making microparticles comprising the steps of:
a) combining a solution containing a macromolecule with a solution containing both polyvinylpyrrolidone and polyethylene glycol to produce a reaction solution;
b) incubating the reaction solution at a predetermined temperature greater than room temperature for a sufficient amount of time to form microparticles; and
c) separating the microparticles from the reaction solution.

### Claim 2 (depends on 1)

The method of claim 1 wherein the incubation temperature is greater than or equal to 37.degree. C. and less than or equal to 80.degree. C.

### Claim 3 (depends on 1)

The method of claim 1 wherein the reaction solution is incubated for between 5 minutes and 24 hours.

### Claim 4 (depends on 1)

The method of claim 1 wherein the incubation step is performed at a pH between approximately 5 and 8.

### Claim 5 (depends on 1)

The method of claim 1 wherein the polyvinylpyrrolidone has a molecular weight of approximately 40,000 and the polyethylene glycol has a molecular weight of approximately 3500 and wherein the concentration of each is between 1 and 40 g/100 ml.

### Claim 6 (depends on 1)

The method of claim 1 wherein the macromolecule is selected from the group consisting of a protein, carbohydrate, polysaccharide, nucleic acid molecule, virus, virus particle, pharmaceutical drug, and mixtures thereof.

### Claim 7 (depends on 1)

The method of claim 1 wherein the reaction solution of step a) further comprises a crosslinking agent.

### Claim 8 (depends on 7)

The method of claim 7 further comprising the step of washing the microparticles with a buffer, which contains a quenching reagent.

### Claim 9 (depends on 7)

The method of claim 7 wherein the crosslinking agent is selected from the group consisting of dialdehydes, amines, multivalent ions, N-substituted maleimides, bifunctional alkyl halides, aryl halides, isocyanates, aliphatic or aromatic dicarboxylic acids, aliphatic or aromatic disulphonic acids, bifunctional imidoesters, and vinylsulphones.

### Claim 10

Microparticles prepared by the method of
a) combining a solution containing a macromolecule with a solution containing both polyvinylpyrrolidone and polyethylene glycol to produce a reaction solution;
b) incubating the reaction solution at a predetermined temperature greater than room temperature for a sufficient amount of time to form microparticles; and
c) separating the microparticles from the reaction solution.

### Claim 11 (depends on 10)

The microparticles of claim 10 wherein the microparticles have a size between 1 and 10 microns.

### Claim 12 (depends on 10)

The microparticles of claim 10 wherein the incubation temperature is greater than or equal to 37.degree. C. and less than or equal to 80.degree. C.

### Claim 13 (depends on 10)

The microparticles of claim 10 wherein the reaction solution is incubated for between 5 minutes and 24 hours.

### Claim 14 (depends on 10)

The microparticles of claim 10 wherein the incubation step is performed at a pH between approximately 5 and 8.

### Claim 15 (depends on 10)

The microparticles of claim 10 wherein the polyvinylpyrrolidone has a molecular weight of approximately 40,000 and the polyethylene glycol has a molecular weight of approximately 3500 and wherein the concentration of each is between 1 and 40 g/100 ml.

### Claim 16 (depends on 10)

The microparticles of claim 10 wherein the macromolecule is selected from the group consisting of a protein, carbohydrate, polysaccharide, nucleic acid molecule, virus, virus particle, pharmaceutical drug, and mixtures thereof.

### Claim 17 (depends on 10)

The microparticles of claim 10 wherein the reaction solution of step a) further comprises a crosslinking agent.

### Claim 18 (depends on 17)

The microparticles of claim 17 wherein the crosslinking agent is selected from the group consisting of dialdehydes, amines, multivalent ions, N-substituted maleimides, bifunctional alkyl halides, aryl halides, isocyanates, aliphatic or aromatic dicarboxylic acids, aliphatic or aromatic disulphonic acids, bifunctional imidoesters, and vinylsulphones.