# US 9,872,913 B2 · Drug loaded polymeric nanoparticles and methods of making and using same

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- Number: US 9,872,913 B2
- Document ID: US9872913B2
- Status: Granted
- Kind: B2
- Application number: 15/161,785
- Filed: 2016-05-23
- Published: 2016-11-24
- Granted: 2018-01-23
- Earliest claimed: 2008-06-16
- Assignees: Pfizer Inc.
- Applicants: Pfizer Inc.
- Inventors: Greg Troiano; Michael Figa; Abhimanyu Sabnis
- Web page: https://patentgrep.com/patent/US9872913B2

## CPC

- A61K 47/34: Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers (A61K47/10 takes precedence)
- A61J 3/00: Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
- A61K 9/10: Dispersions; Emulsions
- A61K 9/107: Emulsions {; Emulsion preconcentrates; Micelles (composition of emulsions A61K47/00)}
- 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 9/5146: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides}
- A61K 9/5153: {Polyesters, e.g. poly(lactide-co-glycolide)}
- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 31/4355: the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
- A61K 31/436: the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/439: the ring forming part of a bridged ring system, e.g. quinuclidine (8-azabicyclo [3.2.1] octanes A61K31/46)
- A61K 31/475: having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine (vincamine A61K31/4375)
- A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)}
- A61K 31/7068: having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
- A61K 47/6915: {the form being a liposome with polymerisable or polymerized bilayer-forming substances, e.g. polymersomes}
- A61K 47/6925: {the form being a microcapsule, nanocapsule, microbubble or nanobubble}
- A61K 47/6937: {the polymer being PLGA, PLA or polyglycolic acid}
- A61P 13/08: of the prostate
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- B82Y 5/00: Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
- A61K 9/1647: {Polyesters, e.g. poly(lactide-co-glycolide)}
- C07C 59/08: Lactic acid
- Y10S 977/773: Nanoparticle, i.e. structure having three dimensions of 100 nm or less
- 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)
- A61J: CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- B82Y: SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- Y10S: TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS

## Abstract

The present disclosure generally relates to methods of making nanoparticles having about 0.2 to about 35 weight percent of a therapeutic agent; and about 10 to about 99 weight percent of biocompatible polymer such as a diblock poly(lactic) acid-poly(ethylene)glycol.

## Claims

### Claim 1

A method of preparing a plurality of therapeutic nanoparticles, comprising:
combining a therapeutic agent, a first polymer bound to a ligand, and a second polymer, with an organic solvent to form a first organic phase having about 5 to about 50% solids;
combining the first organic phase with a first aqueous solution to form a second phase;
emulsifying the second phase to form an emulsion phase;
quenching the emulsion phase to form a quenched phase at least partially at a temperature of 5° C. or less;
adding a drug solubilizer to the quenched phase to form a solubilized phase of unencapsulated therapeutic agent; and
sterile filtering the solubilized phase to recover the therapeutic nanoparticles, thereby forming a slurry of therapeutic nanoparticles having a diameter of about 80 nm to about 150 nm.

### Claim 2 (depends on 1)

The method of claim 1, wherein emulsifying the second phase comprises:
emulsifying the second phase to form a coarse emulsion, and
emulsifying the coarse emulsion to form a fine emulsion phase.

### Claim 3 (depends on 2)

The method of claim 2, wherein the organic solvent comprises a solvent chosen from: ethyl acetate, benzyl alcohol, methylene chloride, chloroform, toluene, methyl ethyl ketone, dimethyl formamide, dimethyl sulfoxide, acetone, acetonitril, acetic acid, polyoxyethylene 20 sorbitan monooleate (Tween 80 )and sorbitan monooleate (Span 80), and combinations of two or more thereof.

### Claim 4 (depends on 2)

The method of claim 2, wherein the first aqueous solution comprises a reagent chosen from: sodium cholate, ethyl acetate, benzyl alcohol or combinations thereof.

### Claim 5 (depends on 2)

The method of claim 2, wherein emulsifying the second phase comprises using a rotor stator homogenizer, probe sonicator, stir bar, or high pressure homogenizer.

### Claim 6 (depends on 1)

The method of claim 1, wherein quenching is performed at least partially at about 0° C. to about 5° C.

### Claim 7 (depends on 1)

The method of claim 1, wherein the quench:emulsion ratio is about 8:1 to about 5:1.

### Claim 8 (depends on 1)

The method of claim 1, wherein filtering comprises filtering at a first temperature of about 0° C. to about 5° C., and further comprises filtering at a second temperature of about 20° C. to about 30° C.

### Claim 9 (depends on 8)

The method of claim 8, wherein filtering comprises processing about 1 to about 6 diavolumes at about 0° C. to about 5° C. and processing at least one diavolume at about 20° C. to about 30° C.

### Claim 10 (depends on 9)

The method of claim 9, wherein the second polymer is a poly (lactic) acid-block-poly(ethylene)glycol copolymer (PLA-PEG), and the first polymer is a PLA-PEG Ligand, wherein the ligand is covalently bound to the PEG, wherein the ligand is represented by the formula:
and the ligand has a molecular weight of about 100 g/mol to about 500 g/mol.

### Claim 11 (depends on 1)

The method of claim 1, wherein the therapeutic agent is a taxane.

### Claim 12 (depends on 1)

The method of claim 1, wherein filtering comprises using a tangential flow filtration system.

### Claim 13 (depends on 1)

The method of claim 1, wherein the second polymer is a PLA-PEG, and the first polymer is a PLA-PEG-Ligand, wherein the ligand is covalently bound to the PEG.

### Claim 14 (depends on 1)

The method of claim 1, wherein the ligand has a molecular weight of about 100 g/mol to about 500 g/mol.

### Claim 15 (depends on 1)

The method of claim 1, wherein the second polymer is a PLA-PEG; and the first polymer is a PLA-PEG-Ligand, wherein the ligand is covalently bound to the PEG, wherein the ligand is represented by the formula:
and the ligand has a molecular weight of about 100 g/mol to about 500 g/mol.