# US 10,864,280 B2 · Nanodroplet compositions for the efficient delivery of anti-cancer agents

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- Number: US 10,864,280 B2
- Document ID: US10864280B2
- Status: Granted
- Kind: B2
- Application number: 16/308,115
- Filed: 2017-06-09
- Published: 2019-05-30
- Granted: 2020-12-15
- Earliest claimed: 2016-06-09
- Applicants: Der-Yang Tien
- Inventors: Der-Yang Tien
- Web page: https://patentgrep.com/patent/US10864280B2

## CPC

- A61K 47/6907: {the form being a microemulsion, nanoemulsion or micelle}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/1075: {Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers (A61K9/0026 takes precedence)}
- 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 31/337: having four-membered rings, e.g. taxol
- 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)
- A61P 35/00: Antineoplastic agents
- B82Y 5/00: Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
- 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)
- 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

## Abstract

Disclosed herein are nanodroplet compositions composed of a copolymer with a hydrophilic block and a hydrophobic block, a poloxamer, an oil, an anti¬cancer agent, and optionally a lyoprotectant. The nanodroplet compositions exhibit low toxicity and are biodegradable, provide for slow, sustained release of the anti-cancer agent at tumor sites, and result in a greater reduction of tumor volume when administered to subjects with cancer as compared to several commercially-available products. Furthermore, the nanodroplet compositions can be imaged and their progress through the body tracked with magnetic resonance spectroscopy or ultrasound.

## Claims

### Claim 1

One or more nanodroplets, each nanodroplet comprising
(a) a copolymer comprising a hydrophilic block and a hydrophobic block, wherein the hydrophilic block of the copolymer is monomethoxy polyethylene glycol having a molecular weight from 1,500 Da to 2,500 Da and the hydrophobic block of the copolymer is poly(D,L-lactide) having a molecular weight from 1,500 Da to 2,500 Da;
(b) a poloxamer having the formula
HO(C2H4O)b(C3H6O)a(C2H4O)bH
wherein a is from 25 to 35 and b is from 70 to 80,
(c) a hydrophobic core comprising an oil comprising a mixture of caprylic triglyceride and capric triglyceride,
(d) an anti-cancer agent, and
(e) a lyoprotectant,
wherein
the dry weight ratio of anti-cancer agent to the copolymer is from 1:5 to 1:9,
the dry weight ratio of anti-cancer agent to the poloxamer is from 1:3 to 1:5,
the weight ratio of oil to the copolymer is from 0.1 to 1,
the dry weight ratio of lyoprotectant to the copolymer is from 0.1 to 1, and
the nanodroplets have a Z-average diameter from 100 nm to 150 nm.

### Claim 2 (depends on 1)

The one or more nanodroplets of claim 1, wherein the lyoprotectant comprises a sugar.

### Claim 3 (depends on 2)

The one or more nanodroplets of claim 2, wherein the sugar comprises mannitol, sucrose, glucose, or any combination thereof.

### Claim 4 (depends on 2)

The one or more nanodroplets of claim 2, wherein the sugar is mannitol.

### Claim 5 (depends on 1)

The one or more nanodroplets of claim 1, wherein the anti-cancer agent comprises paclitaxel, doxorubicin, gemcitabine, cisplatin, methotrexate, 5-fluorouracil, betulinic acid, amphotericin B, diazepam, nystatin, propofol, testosterone, estrogen, prednisolone, prednisone, 2,3 mercaptopropanol, progesterone, docetaxel, or any combination thereof.

### Claim 6 (depends on 1)

The one or more nanodroplets of claim 1, wherein the anti-cancer agent is paclitaxel.

### Claim 7 (depends on 1)

The one or more nanodroplets of claim 1, wherein each nanodrolet further comprises an anti-body drug conjugate.

### Claim 8 (depends on 7)

The one or more nanodroplets of claim 7, wherein the anti-body drug conjugate is a maytansinoid, a dolastatin, an auristatin, a trichothecene, a calicheamicin, a duocarmycin, or any combination thereof.

### Claim 9 (depends on 1)

The one or more nanodroplets of claim 1, wherein each nanodrolet further comprises a p-glycoprotein inhibitor.

### Claim 10 (depends on 9)

The one or more nanodroplets of claim 9, wherein the p-glycoprotein inhibitor is verapamil, cyclosporin, tamoxifen, calmodulin antagonists, dexverapamil, dexniguldipine, valspodar (PSC 833), biricodar (VX-710), tariquidar (XR9576), zosuquidar (LY335979), laniquidar (R101933), elacridar (GF120918), timcodar (VX-853), taxifolin, naringenin, diosmin, quercetin, diltiazem, bepridil, nicardipine, nifedipine, felodipine, isradipine, trifluorperazine, clopenthixol, trifluopromazine, flupenthixol, emopamil, gallopamil, Ro11-2933, or any combination thereof.

### Claim 11 (depends on 9)

The one or more nanodroplets of claim 9, wherein the p-glycoprotein inhibitor is tariquidar.

### Claim 12 (depends on 1)

The one or more nanodroplets of claim 1, wherein each nanodrolet further comprises a perfluoro compound.

### Claim 13 (depends on 12)

The one or more nanodroplets of claim 12, wherein the perfluoro compound is a fluoro ether.

### Claim 14 (depends on 13)

The one or more nanodroplets of claim 13, wherein the fluoro ether is a perfluoro crown ether.

### Claim 15 (depends on 13)

The one or more nanodroplets of claim 13, wherein the fluoro ether is perfluoro 12-crown-4 ether, perfluoro 15-crown-5 ether, perfluoro 18-crown-6 ether, perfluoro 20-crown-7 ether, perfluoro dibenzo-18-crown-6 ether, perfluoro diaza-18-crown-6 ether, or any combination thereof.

### Claim 16 (depends on 13)

The one or more nanodroplets of claim 13, wherein the fluoro containing ether comprises perfluoro 15-crown-5 ether.

### Claim 17 (depends on 1)

The one or more nanodroplets of claim 1, wherein each nanodrolet further comprises a dry powder.

### Claim 18 (depends on 1)

A pharmaceutical composition comprising the one or more nanodroplets of claim 1 and a pharmaceutically acceptable carrier.

### Claim 19 (depends on 1)

A method for treating cancer in a subject comprising administering to the subject the one or more nanodroplets of claim 1.

### Claim 20 (depends on 19)

The method of claim 19, wherein the tumor or cancer is pancreatic cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer, or colon cancer.

### Claim 21 (depends on 20)

The method of claim 20, wherein the one or more nanodroplets are administered to the subject by intravenous injection.

### Claim 22 (depends on 21)

The method of claim 21, wherein the dosage of the anti-cancer agent administered to the subject is from 30 mg/kg to 50 mg/kg per single administration.

### Claim 23 (depends on 19)

The method of claim 19, wherein the one or more nanodroplets are administered to the subject at least two times per week.

### Claim 24 (depends on 1)

A method for reducing a tumor in a subject comprising administering to the subject the one or more nanodroplets of claim 1.