# US 11,439,594 B2 · Microparticles and nanoparticles having negative surface charges

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- Number: US 11,439,594 B2
- Document ID: US11439594B2
- Status: Granted
- Kind: B2
- Application number: 14/916,439
- Filed: 2013-12-04
- Published: 2016-10-27
- Granted: 2022-09-13
- Earliest claimed: 2012-12-04
- Assignees: Phosphorex, Inc.
- Applicants: Phosphorex, Inc.
- Inventors: Bin Wu
- Web page: https://patentgrep.com/patent/US11439594B2

## CPC

- A61K 9/146: {with organic macromolecular compounds}
- A61K 9/1635: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/1647: {Polyesters, e.g. poly(lactide-co-glycolide)}
- A61K 9/1652: {Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin (homeopathic globules A61K9/1623)}
- A61K 9/1682: {Processes}
- A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)}
- A61K 9/5153: {Polyesters, e.g. poly(lactide-co-glycolide)}
- A61K 9/5161: {Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin}
- A61K 9/5192: {Processes}
- A61K 47/58: obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
- A61K 47/593: {Polyesters, e.g. PLGA or polylactide-co-glycolide}
- A61K 47/61: the organic macromolecular compound being a polysaccharide or a derivative thereof
- A61K 47/6931: {the material constituting the nanoparticle being a polymer}
- A61K 47/6933: {the polymer being obtained by reactions only involving carbon to carbon, e.g. poly(meth)acrylate, polystyrene, polyvinylpyrrolidone or polyvinylalcohol}
- A61K 47/6937: {the polymer being PLGA, PLA or polyglycolic acid}
- B82Y 5/00: Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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)
- B82Y: SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

This invention provides methods for producing a polymer particle which contains unusually high negative charges on the surface of the particle. Preferably, the polymer is pharmaceutically acceptable. The negative charges can be conferred by chemical groups such as carboxyl, sulfonate, nitrate, fluorate, chloride, iodide, persulfate, and many others, with carboxyl group being preferred. The invention also provides polymer particle produced by the methods of the invention.

## Claims

### Claim 1

A method for preparing PLGA microparticles or nanoparticles having negative surface charges, said method comprising:
(1) dissolving a pharmaceutically acceptable negatively charged agent selected from a water soluble polymer in a first aqueous solvent to form a first aqueous solution having a pH that promotes ionization of the PLGA and the pharmaceutically acceptable negatively charged agent;
(2) dissolving a pharmaceutically acceptable PLGA polymer in an organic solvent to form a polymer solution, wherein the organic solvent is not miscible or is partially miscible in the first aqueous solvent;
(3) emulsifying the polymer solution in the first aqueous solution to form an emulsion; and
(4) removing the organic solvent to form said PLGA microparticles or nanoparticles having negative surface charges;
wherein the microparticles or nanoparticles have a zeta potential of from about −15 mV to about −100 mV.

### Claim 2 (depends on 1)

The method of claim 1, wherein the microparticles or nanoparticles have a zeta potential of from −35 mV to −85 mV.

### Claim 3 (depends on 1)

The method of claim 1, wherein the pharmaceutically acceptable negatively charged agent is selected from the group consisting of hyaluronic acid; gelatin; polysaccharide; polyacrylic acid; polymethacrylic acid;
poly(hydroxyethylmethacrylic acid); and copolymers or mixtures thereof.

### Claim 4 (depends on 3)

The method of claim 3, wherein the pharmaceutically acceptable negatively charged agent is polyacrylic acid.

### Claim 5 (depends on 3)

The method of claim 3, wherein the pharmaceutically acceptable negatively charged agent is hyaluronic acid.

### Claim 6 (depends on 1)

The method of claim 1, wherein the pharmaceutically acceptable negatively charged agent is incorporated onto and at least partially into the PLGA microparticles.

### Claim 7 (depends on 1)

The method of claim 1, wherein the pharmaceutically acceptable PLGA polymer has an average molecular weight of from about 1,000 to about 50,000 Da.

### Claim 8 (depends on 1)

The method of claim 1, wherein said method further comprises:
(1) dissolving an active pharmaceutical ingredient (API) in an inner aqueous solvent to form an API solution;
(2) emulsifying the API solution in the polymer solution prior to emulsifying the polymer solution in the first aqueous solution.

### Claim 9 (depends on 8)

The method of claim 8, wherein the first aqueous solvent further comprises a surfactant.

### Claim 10 (depends on 1)

The method of claim 1, wherein the first aqueous solvent further comprises a surfactant.

### Claim 11 (depends on 10)

The method of claim 10, wherein the surfactant is selected from the group consisting of polyvinyl alcohol, polyvinylpyrrolidone, or mixture thereof.

### Claim 12 (depends on 1)

The method of claim 1, wherein the organic solvent is selected from the group consisting of methylene chloride, ethyl acetate, or chloroform, and mixtures thereof.

### Claim 13 (depends on 1)

The method of claim 1, wherein the emulsifying step comprises homogenization.

### Claim 14 (depends on 1)

The method of claim 1, wherein the organic solvent is removed through evaporation.

### Claim 15 (depends on 1)

The method of claim 1, wherein the pH of the first aqueous solution is between about 6 to about 10.

### Claim 16 (depends on 1)

The method of claim 1, wherein the pH of the first aqueous solution is between about 8 to about 12.

### Claim 17 (depends on 6)

The method of claim 6, wherein the pharmaceutically acceptable negatively charged agent is a carboxyl-containing agent and the negative surface charges are conferred by the carboxyl groups of the pharmaceutically acceptable negative charged agent.

### Claim 18

A method for preparing PLGA microparticles or nanoparticles having negative surface charges, said method comprising:
(1) dissolving an active pharmaceutical ingredient (API) in an inner aqueous solvent to form an API solution;
(2) dissolving a pharmaceutically acceptable PLGA polymer in an organic solvent to form a polymer solution, wherein the organic solvent is not miscible or is partially miscible in the inner aqueous solvent;
(3) emulsifying the API solution in the polymer solution;
(4) dissolving a pharmaceutically acceptable negatively charged agent selected from a water soluble polymer in an outer aqueous solvent to form an outer aqueous solution having a pH that promotes ionization of the PLGA and the pharmaceutically acceptable negatively charged agent;
(5) emulsifying the solution of step (3) in the outer aqueous solution to form an emulsion; and
(6) removing the organic solvent to form said PLGA microparticles or nanoparticles having negative surface charges;
wherein the microparticles or nanoparticles have a zeta potential of from about −15 mV to about −100 mV.

### Claim 19 (depends on 18)

The method of claim 18, wherein the microparticles or nanoparticles have a zeta potential of from −35 mV to -−85 mV.

### Claim 20 (depends on 18)

The method of claim 18, wherein the pharmaceutically acceptable negatively charged agent is selected from the group consisting of hyaluronic acid; gelatin; polysaccharide; polyacrylic acid; polymethacrylic acid;
poly(hydroxyethylmethacrylic acid); and copolymers or mixtures thereof.

### Claim 21 (depends on 18)

The method of claim 18, wherein the pharmaceutically acceptable negatively charged agent is polyacrylic acid.

### Claim 22 (depends on 18)

The method of claim 18, wherein the pharmaceutically acceptable negatively charged agent is hyaluronic acid.

### Claim 23 (depends on 18)

The method of claim 18, wherein the pharmaceutically acceptable negatively charged agent is incorporated onto and at least partially into the PLGA microparticles.

### Claim 24 (depends on 18)

The method of claim 18, wherein the pharmaceutically acceptable PLGA polymer has an average molecular weight of from about 1,000 to about 50,000 Da.

### Claim 25 (depends on 18)

The method of claim 18, wherein the outer aqueous solvent further comprises a surfactant.

### Claim 26 (depends on 25)

The method of claim 25, wherein the surfactant is polyvinyl alcohol.

### Claim 27 (depends on 18)

The method of claim 18, wherein the organic solvent is selected from the group consisting of methylene chloride, ethyl acetate, or chloroform, and mixtures thereof.

### Claim 28 (depends on 18)

The method of claim 18, wherein each emulsifying step comprises homogenization.

### Claim 29 (depends on 18)

The method of claim 18, wherein the organic solvent is removed through evaporation.

### Claim 30 (depends on 18)

The method of claim 18, wherein the pH of the outer aqueous solution is between about 6 to about 10.

### Claim 31 (depends on 18)

The method of claim 18, wherein the pH of the outer aqueous solution is between about 8 to about 12.

### Claim 32 (depends on 18)

The method of claim 18, wherein the pharmaceutically acceptable negatively charged agent is a carboxyl-containing agent and the negative surface charges are conferred by the carboxyl groups of the pharmaceutically acceptable negative charged agent.

### Claim 33

A method for preparing PLGA microparticles or nanoparticles having negative surface charges, said method comprising:
(1) dissolving an active pharmaceutical ingredient (API) in an inner aqueous solvent to form an API solution;
(2) dissolving a pharmaceutically acceptable PLGA polymer having an average molecular weight of from about 1,000 to about 50,000 Da, in an organic solvent to form a polymer solution, wherein the organic solvent is not miscible or is partially miscible in the inner aqueous solvent;
(3) emulsifying the API solution in the polymer solution;
(4) dissolving a pharmaceutically acceptable polyacrylic acid and a surfactant in an outer aqueous solvent to form an outer aqueous solution having a pH that promotes ionization of the PLGA and the pharmaceutically acceptable negatively charged agent;
(5) emulsifying the solution of step (3) in the outer aqueous solution to form an emulsion; and
(6) removing the organic solvent to form said PLGA microparticles or nanoparticles having negative surface charges;
wherein the microparticles or nanoparticles have a zeta potential of from about −35 mV to −85 mV.

### Claim 34 (depends on 33)

The method of claim 33, wherein the pharmaceutically acceptable polyacrylic acid is incorporated onto and at least partially into the PLGA microparticles.

### Claim 35 (depends on 33)

The method of claim 33, wherein the surfactant is polyvinyl alcohol.

### Claim 36 (depends on 33)

The method of claim 33, wherein the organic solvent is selected from the group consisting of methylene chloride, ethyl acetate, or chloroform, and mixtures thereof.

### Claim 37 (depends on 33)

The method of claim 33, wherein each emulsifying step comprises homogenization.

### Claim 38 (depends on 33)

The method of claim 33, wherein the organic solvent is removed through evaporation.

### Claim 39 (depends on 33)

The method of claim 33, wherein the pH of the outer aqueous solution is between about 6 to about 10.

### Claim 40 (depends on 33)

The method of claim 33, wherein the pH of the outer aqueous solution is between about 8 to about 12.